RU2698202C2 - METHOD FOR PRODUCING DIRECT FACTOR Xa INHIBITOR - Google Patents

Abstract

FIELD: chemistry.SUBSTANCE: invention relates to an industrial method of producing a compound of formula Ia,which includes steps a) reacting 5-methylanthranyl acid and 2-amino-5-chloropyridine to obtain 2-amino-N-(5-chloropyridin-2-yl)-5-methylbenzamide; b) reacting 2-amino-N-(5-chloropyridin-2-yl)-5-methylbenzamide with 4-[(tert-butoxycarbonyl)-N-methyl] aminobenzoic acid; c) removing the tert-butoxycarbonyl-protecting group from the reaction product of step (b) to obtain N-(5-chloropyridin-2-yl)-5-methyl-2-(4-(methylamino)benzamido)benzamide; d) reacting N-(5-chloropyridin-2-yl)-5-methyl-2-(4-(methylamino)benzamido)benzamide with imideacetic acid chloride to obtain a compound of formula Ia.EFFECT: obtained compounds can be used as an effective and selective inhibitor of factor Xa for controlling blood coagulation in human and other mammals, as well as for treating diseases associated with blood coagulation.6 cl

Description

FIELD OF THE INVENTION

The invention relates to the field of organic chemistry, and in particular to an industrial method for producing a compound of formula Ia, which can be used as a direct factor Xa inhibitor for controlling blood coagulation in humans and other mammals, as well as for treating diseases associated with blood coagulation.

State of the art

Blood coagulation can be controlled with anticoagulants, which are direct and indirect thrombin inhibitors. The prothrombinase complex, which includes protein (factor) Xa, converts the proenzyme of prothrombin into activated thrombin. Factor Xa belongs to the family of serine proteases and is formed from protein (factor) X. Unlike thrombin, which acts on many substrate proteins and specific receptors, protein Xa appears to act only on a single substrate, namely prothrombin. Since a single Xa protein molecule is capable of generating up to 138 thrombin molecules, direct Xa protein inhibitors, like thrombin formation inhibitors, can be used to effectively control blood coagulation. Therefore, it is obvious that substances that selectively inhibit protein Xa can be used for the diagnosis of blood coagulation in vitro, as well as drugs for diseases associated with blood coagulation.

A number of factor Xa inhibitors are known related to nitrogen-containing heterocycles containing substituted amidine groups with two functional groups that are capable of binding to factor Xa at two active sites. For example, WO 98/28269 describes pyrazole with terminal C (= NH) -NH ₂ groups; WO 97/21437 describes benzimidazole compounds substituted with groups which are attached to the naphthalene group directly or through a chain of alkyls and —C (= O) or —S (= O) ₂ groups; WO 99/10316 describes compounds having 4-phenyl-n-alkylamidinopiperidine linked to a 3-amidinophenyl group via a carboxyalkyleneamino group; and EP 798295 discloses compounds comprising a 4-phenoxy-n-alkylamidinopiperidine group coupled to an amidine group via substituted or unsubstituted sulfonamides.

Patent EA 015918 describes a compound of formula I

which is characterized by high activity and duration of action in relation to factor Xa.

Proposed in patent EA 015918 a method for producing a compound of formula I includes the following steps:

1) the interaction of 5-methyl-2-nitrobenzoic acid with SOCl ₂ and 2-amino-5-chloropyridine to obtain N- (5-chloropyridin-2-yl) -5-methyl-2-nitrobenzamide;

2) reduction of N- (5-chloropyridin-2-yl) -5-methyl-2-nitrobenzamide with tin chloride to obtain 2-amino-N- (5-chloropyridin-2-yl) -5-methylbenzamide;

3) the interaction of 2-amino-N- (5-chloropyridin-2-yl) -5-methylbenzamide with 4-methylaminobenzoic acid trifluoroacetate and an EDCI amide coupling agent to produce N- (5-chloropyridin-2-yl) -2- [ (4-methyl (trifluoroacetyl) aminophenylcarbonyl) amino] -5-methylbenzamide;

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

5) synthesis of amidine from N- (5-chloropyridin-2-yl) -2 - [(4-methylaminophenylcarbrnyl) amino] -5-methylbenzamide by reaction with acetonitrile and passing gaseous HCl to obtain N- (5-chloropyridin-2- il) -2 - [(4-ethanimidoylmethylaminophenylcarbonyl) amino] -5-methylbenzamide (compounds of formula I).

The disadvantages of the method disclosed in patent EA 015918 include a large number of stages, the need to use tin chloride and hydrochloric acid to reduce the nitro group, the introduction and removal of protective groups at the nitrogen atom in the intermediate stages, and the need to isolate and purify the products obtained at each stage.

Disclosure of invention

The objective of the invention is to develop a new, simpler, more economical and industrially used method for producing the most pharmaceutically acceptable salt of a compound of formula I — hydrochloride of formula Ia — with a purity of more than 99% and high yield. When implementing the method according to the invention, a significantly smaller amount of acidic waste is generated and there is no waste containing metals.

This invention relates to a method for producing N- (5-chloropyridin-2-yl) -5-methyl-2- (4- (N-methylacetimidamido) benzamido) benzamide hydrochloride of formula Ia

in which exercise:

a) the interaction of 5-methylanthranilic acid and 2-amino-5-chloropyridine to obtain 2-amino-N- (5-chloropyridin-2-yl) -5-methylbenzamide of the formula III;

b) the interaction of 2-amino-N- (5-chloropyridin-2-yl) -5-methylbenzamide of the formula III with 4 - [(tert-butoxycarbonyl) -N-methyl] aminobenzoic acid of the formula II;

c) removing the tert-butoxycarbonyl protecting group from the reaction product of step (b) to obtain N- (5-chloropyridin-2-yl) -5-methyl-2- (4- (methylamino) benzamido) benzamide of formula IV;

d) the interaction of N- (5-chloropyridin-2-yl) -5-methyl-2- (4- (methylamino) benzamido) benzamide of formula IV with imidoacetic acid chloride to give a compound of formula Ia.

In one embodiment of the invention, the removal of the tert-butoxycarbonyl protecting group in step (c) is carried out by reacting the reaction product of step (b) with trifluoroacetic acid.

In one embodiment of the invention, in step (c), trifluoroacetic acid is further neutralized. The neutralization can be carried out using any alkali, but preferably using potassium hydroxide or sodium hydroxide, most preferably sodium hydroxide.

In one embodiment of the invention, imidoacetic acid chloride is used in step (d) of the process, which is formed in situ from acetonitrile, thionyl chloride and water.

The proposed method for obtaining the compounds of formula 1a differs from the method disclosed in patent EA 015918 in a simpler synthetic sequence, in the absence of the need to isolate and purify intermediate products, in the absence of waste containing metals, in less acidic waste and in a higher degree of purity of the target compound, and also leads to the most pharmaceutically acceptable salt of a compound of formula I, namely a hydrochloride salt, the preparation of which is not disclosed in patent EA 015918.

As an additional advantage of the method according to the invention, the possibility of using the in situ generated hydrogen chloride required to obtain imidoacetic acid chloride in carrying out step (d) may also be considered.

The implementation of the invention

In more detail, taking into account the above-described embodiments of the invention and the following reaction examples, the proposed method can be presented as comprising the following steps:

Reaction 1 — reaction of 4- (methylamino) benzoic acid and di-tert-butyl dicarbonate to give 4 - [(tert-butoxycarbonyl) -N-methyl] aminobenzoic acid (a compound of formula II) according to WO 2004/069792;

Reaction 2 - the interaction of 5-methylanthranilic acid with SOCl ₂ to obtain an intermediate acid chloride, which, without isolation and purification, is reacted with 2-amino-5-chloropyridine to obtain 2-amino-N- (5-chloropyridin-2-yl) - 5-methylbenzamide (compounds of formula III);

Reaction 3 - the interaction of the compounds of formula II with SOCl ₂ and the compound of formula III to obtain an intermediate product, which is then reacted with trifluoroacetic acid, neutralized with alkali, to obtain N- (5-chloropyridin-2-yl) -5-methyl-2 - (4- (methylamino) benzamido) benzamide (compounds of formula IV);

Reaction 4 - the interaction of the compounds of formula IV with imidoacetic acid chloride formed in situ from acetonitrile, thionyl chloride and water, to obtain a compound of formula Ia.

The general synthesis scheme can be represented as follows:

Reaction 1. Preparation of 4 - [(tert-butoxycarbonyl) -N-methyl] aminobenzoic acid (a compound of formula II) is disclosed in WO 2004/069792:

5 kg (33 mol) of 4- (methylamino) benzoic acid was dissolved in 35 L (35 mol) of 1N NaOH (aq). To the resulting solution was added 15 L of 1,4-dioxane, 8 kg (36.7 mol) of di-tert-butyl dicarbonate and the reaction mixture was stirred at room temperature for 6 hours. An additional 2.7 kg (12.4 mol) of di-tert was added. -butyl dicarbonate, after which stirring was continued for another 18 hours. The last portion of 1.5 kg (6.8 mol) of di-tert-butyl dicarbonate was added and stirred for another 24 hours. The mixture was diluted with 100 L of water, cooled to + 5 ° C and 1N was added. HCl (aq.) To a pH of 5-6. The precipitate was filtered, washed with water and dried in air to obtain 6.8 kg of a white product.

Yield: 82%

Purity: More than 98% (NMR)

¹ H NMR (CDCl ₃ ): 1.51 (s, 9H), 3.34 (s, 3H), 7.40 (d, 2H), 8.09 (d, 2H) and 11.5 (br s , 1H).

Reaction 2. Obtaining 2-amino-N- (5-chloropyridin-2-yl) -5-methylbenzamide (compounds of formula III)

To a mixture of 30 l of toluene and 6 l of thionyl chloride, 3.0 kg (20 mol) of 5-methylanthranilic acid was added in portions and the suspension was heated to boiling with stirring. After the precipitate was completely dissolved, the light yellow solution was further heated for another 2 hours. The reaction mixture was cooled, evaporated on a rotary evaporator, 10 L of toluene was added and evaporated again to obtain an oily residue of the intermediate acid chloride. The intermediate was used further without further purification.

The resulting acid chloride was dissolved in 25 L of dry tetrahydrofuran, the solution was cooled to + 10 ° C and a mixture of 2.31 kg (18 mol) of 2-amino-5-chloropyridine and 1.42 kg (18 mol) of pyridine in 20 was added dropwise. l tetrahydrofuran. After stopping cooling, the reaction mixture was stirred for 2 hours at room temperature. Then, 70 L of cold water (+ 5 ° С) was added, stirred for 10 min, 5 kg (62.5 mol) of 50% NaOH (aq) was added, stirred vigorously for 30 min, 1.5 kg of NaHC03 was added, stirred until dissolved and tetrahydrofuran was evaporated from the reaction mixture in a rotary evaporator. The resulting aqueous suspension was filtered, the precipitate was washed successively with 20 L of water, 10 L of isopropanol and dried in vacuo to give 2.5 kg of a light yellow product.

Yield: 48%

Purity: More than 98% (NMR)

¹ H NMR (DMSO-d6): 2.19 (s, 3H); 6.24 (s, 2H); 6.70 (d, 1H); 7.05 (d, 1H); 7.59 (s, 1H); 7.91 (d, 1H); 8.15 (d, 1H); 8.40 (s, 1H); 10.52 (s, 1H).

Reaction 3. Obtaining N- (5-chloropyridin-2-yl) -5-methyl-2- (4- (methylamino) benzamido) benzamide (compounds of formula IV)

2.76 kg (11 mol) of 4 - [(tert-butoxycarbonyl) -N-methyl] aminobenzoic acid (compounds of formula II) was dissolved in 30 L of dry tetrahydrofuran, 0.91 kg (11.5 mol) of pyridine was added, and to the obtained 1.31 kg (11 mol) of thionyl chloride was added dropwise over 10 minutes at room temperature. Stirred for 30 minutes. In another vessel, 2.6 kg (10 mol) of 2-amino-N- (5-chloropyridin-2-yl) -5-methylbenzamide of the formula III and 0.91 kg (11.5 mol) of pyridine were mixed in 20 l of dry tetrahydrofuran . To this solution, the previously obtained suspension was added in portions, maintaining the temperature not higher than 25 ° C, and the reaction mixture was stirred for 3 hours at room temperature. To the mixture was added 50 L of a 13% sodium chloride solution (aq), 50 L of ethyl acetate and the aqueous layer was separated. The organic phase was washed with 40 L of a 20% sodium carbonate solution (aq.), 40 L of a 26% sodium chloride solution (aq.), Dried over anhydrous sodium sulfate and evaporated on a rotary evaporator. The oily residue was dried in vacuo to give 5.0 kg of a solid intermediate. The intermediate was used further without further purification.

5.0 kg of the obtained intermediate was dissolved in 10 L of dichloromethane, 6 L of trifluoroacetic acid was added with stirring, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into a pre-prepared solution of 6 kg of sodium hydroxide and 60 l of water with vigorous stirring and cooling (<30 ° C). To the resulting suspension was added 10 L of petroleum ether and filtered to separate the precipitate from the organic and aqueous phases. The precipitate was washed with 50 l of water, 15 l of ethanol and dried in vacuum to obtain 3.6 kg of a solid light yellow product.

Yield: 81%

Purity: More than 98% (NMR)

¹ H NMR (DMSO-d6): 2.34 (s, 3H); 2.74 (s, 3H); 6.41 (br s, 1H); 6.62 (d, 2H); 7.39 (d, 1H); 7.70 (d, 2H); 7.80 (s, 1H); 7.98 (d, 1H); 8.17 (d, 1H); 8.35 d (1H); (8.46 s, 1H); 11.05 (s, 1H); 11.20 (s, 1H).

Reaction 4. Preparation of N- (5-chloropyridin-2-yl) -5-methyl-2- (4- (N-methylacetamidamido) benzamido) benzamide hydrochloride (compounds of formula Ia)

4.160 kg (35 mol) of thionyl chloride was dissolved in 20 l of dry acetonitrile, the solution was cooled to + 10 ° C and 0.630 kg (35 mol) of distilled water was added dropwise to it. The mixture was stirred at + 10 ° C for 30 minutes and 1 kg (2.53 mol) of N- (5-chloropyridin-2-yl) -5-methyl-2- (4- (methylamino) benzamido) benzamide (compound of formula IV) was added ) After stopping cooling, the reaction mixture was stirred in a closed vessel for about 30 hours until the initial disappearance (according to thin-layer chromatography). The reaction mixture was evaporated on a rotary evaporator at 35 ° C. The dark residue (~ 3 kg) was dissolved in 5 L of isopropanol, 200 g of activated carbon was added, heated to boiling, then the carbon was filtered off and washed with 1 L of hot (+ 70 ° С) isopropanol. After cooling, the resulting precipitate was filtered off and dried in vacuo to give 1.05 kg of the crude product. The resulting product was suspended with stirring in isopropanol and heated to boiling, then cooled, filtered and dried in vacuo to give 0.91 kg of the target compound.

Yield: 78%

Purity: 99.7% (HPLC, gradient 0.1% trifluoroacetic acid - 0.1% trifluoroacetic acid / acetonitrile (95/5), column C18 (3u, 2.0 * 150))

¹ H NMR (DMSO-d6): 2.12 (br s, 3H); 2.37 (s, 3H); 3.43 (s, 3H); 7.43 (d, 1H); 7.65 (d, 2H); 7.77 (s, 1H); 7.96 (d, 1H); 8.05 (d, 1H); 8.12 (d, 2H); (8.44 s, 1H); 10.0 (br s, 1H); 11.07 (brs, 1H); 11.29 (brs, 1H).

Claims (12)

1. The method of obtaining the hydrochloride of N- (5-chloropyridin-2-yl) -5-methyl-2- (4- (N-methylacetamidamido) benzamido) benzamide of the formula Ia

, in which exercise: a) the interaction of 5-methylanthranilic acid and 2-amino-5-chloropyridine to obtain 2-amino-N- (5-chloropyridin-2-yl) -5-methylbenzamide; b) the interaction of 2-amino-N- (5-chloropyridin-2-yl) -5-methylbenzamide with 4 - [(tert-butoxycarbonyl) -N-methyl] aminobenzoic acid; c) removing the tert-butoxycarbonyl protecting group from the reaction product of step (b) to obtain N- (5-chloropyridin-2-yl) -5-methyl-2- (4- (methylamino) benzamido) benzamide; g) the interaction of N- (5-chloropyridin-2-yl) -5-methyl-2- (4- (methylamino) benzamido) benzamide with imidoacetic acid chloride to give a compound of formula Ia. 2. The method of claim 1, wherein the removal of the tert-butoxycarbonyl protecting group in step (c) is carried out by reacting the reaction product of step (b) with trifluoroacetic acid. 3. The method according to p. 2, where at the stage (C) additionally carry out the neutralization of trifluoroacetic acid. 4. The method according to p. 3, where the neutralization is carried out using potassium hydroxide or sodium hydroxide. 5. The method according to p. 4, where the neutralization is carried out using sodium hydroxide. 6. The method according to p. 1, where at the stage (d) apply imidoacetic acid chloride, which is formed in situ from acetonitrile, thionyl chloride and water.