MX2008007170A - Improved process for the preparation of the salts of 4-(benzimidazolylmethylamino)-benzamides - Google Patents

Abstract

The invention relates to a process for preparing a salt of an optionally substituted 4-benzimidazol-2-ylmethylamino)-benzamidine, characterised in that (a) an optionally correspondingly substituted diaminobenzene is condensed with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid, b) i) the product thus obtained is hydrogenated, ii) optionally the amidino group is carbonylated, without isolating the intermediate product of the hydrogenation beforehand and iii) without prior isolation of the intermediate product of the carbonylation the desired salt is isolated.

Description

IMPROVED PROCEDURE FOR THE PREPARATION OF SALTS OF 4- (BENZYMIDAZOLYL-METHYLAMIN) -BENZAMIDINES BACKGROUND OF THE INVENTION 1. TECHNICAL FIELD The invention relates to a process for the preparation of a salt of a 4- (benzimidazol-2-ylmethylamino) -benzamidine optionally substituted, wherein (a) a diaminobenzene is optionally substituted correspondingly with 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid and (b) ) i) the product is hydrogenated, thus obtained, ii) optionally the amidino group is carbonylated, without previously isolating the intermediate product from the hydrogenation. 2. PREVIOUS TECHNIQUE 4- (benzimidazol-2-ylmethylamino) -benzamidines substituted, in particular? / - (2-pyridyl) -? / - (2-ethoxycarbonylethyl) -amide of 1-methyl-2- [? / - [4 - (? / - n-hexyloxycarbonylamino-dino) phenyl] -amino-methyl] -benzimidazol-5-yl-carboxylic acid are already known from international patent application WO 98/37075 as active substances with a thrombin inhibiting effect and thrombin time extension. Main sectors for the indication of the compound of chemical formula I are the postoperative prophylaxis of deep venous thrombosis and the prophylaxis of stroke (prevention of stroke due to atrial fibrillation, abbreviated SPAF - stroke prevention due to atrial fibrillation). In WO 98/37075 it is proposed to prepare the (4- benzimidazol-2-ylmethylamino) -benzamidines substituted by reaction of the corresponding (4-benzimidazol-2-ylmethylamino) -benzonitriles substituted with ammonia. This process is very complex from a production technique point of view and leads to a high load of acids to be discarded. The aim of the present invention was to indicate a process variant for the preparation of the substituted (4-benzimidazol-2-ylmethylamino) -benzamidines, in which this step of the complex process can be avoided from a production technique point of view. . THE INVENTION Surprisingly, it has been found that the salts of the substituted 4- (benzimidazol-2-methylamino) -benzamidines can be prepared in high yields and with the use of inexpensive adjuvants, if (a) an optionally substituted diaminobenzene is condensed in a manner corresponding with 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid and (b) i) the product is hydrogenated, thus obtained, ii) optionally carbonyl is amidino group, without previously isolating the intermediate product of the hydrogenation, and iii) without previous isolation of the carbonylation intermediate product the desired salt is isolated. DETAILED DESCRIPTION OF THE INVENTION A process for the preparation of a salt of an optionally substituted 4- (benzimidazol-2-ylmethylamino) -benzamidine of the formula (I) with an inorganic or organic acid is preferred, wherein R1 represents a Ci-βO cycloalkyl C3-7 alkyl group, R2 (i) represents a C6-6 alkyl group, a C3-7 cycloalkyl group optionally substituted by a C3 -3 alkyl group, wherein the group C 1-3 alkyl may be further substituted with a carboxyl group or with an in-vivo transformable group in a carboxy group, or (ii) represents a group R 21 NR 22, wherein R 21 means a C 6 alkyl group, which may be substituted with a carboxy group, C 1-6 alkoxycarbonyl, benzyloxycarbonyl, alkyl C3-sulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, trifluorosulfonyl-amino, trifluorosulfonylaminocarbonyl or 1H-tetrazolyl, a C2- alkyl group substituted with a hydroxy group, phenyl-C3-3alkoxy, carboxy-C3-aminoalkyl, alkoxy C ? -3-carbonyl-alkyl C? -3-amino, N- (C? -3 alkyl) -carboxy-C1-3-alkylamino or N- (C? -3 alkyl) -alkoxy C? -3-carbonyl -alkyl C? -3-amino, wherein in the groups mentioned above the carbon atom a located adjacent to the nitrogen atom can not be substituted, or a piperidinyl group optionally substituted with an alkyl group R22 means a hydrogen atom, a C? -6 alkyl group, a C3-7 cycloalkyl group, optionally substituted with a C? -3 alkyl group, or a C3-6 alkenyl group or C3-6 alkynyl, wherein the unsaturated part can not be directly linked with the nitrogen atom of the group R21NR22, a phenyl group optionally substituted with a fluorine, chlorine or bromine atom, with a C---3 alkyl or C1-3 alkoxy group, a benzyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl group , pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl or imidazolyl optionally substituted with a C? -3 alkyl group, or R21 and R22, together with the nitrogen atom situated therebetween, represent a cycloalkyleneimino group of 5-7 members , optionally substituted with a carboxy or C 1-4 alkoxycarbonyl group, to which a phenyl ring may additionally be condensed, and R 3 represents a hydrogen atom, a C 1-9 -alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-alkoxy C group ? -3-carbonyl, benzoin lo, p-alkyl d-3-benzoyl or pyridinoyl, wherein the portion of ethoxy at the 2-position of the aforementioned d-carbonyl alkoxy group can be further substituted with a C1-3-sulfonyl or 2- (C-alkoxy C ^ -ethyl, wherein in step (a) a phenyldiamine of the formula (II) where R1 and R2 have the meaning indicated for the formula (0, reacted with 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid, the product obtained from the formula (III) where R1 and R2 have the meaning indicated for the formula (I), hydrogenated in step (b) i), then, without previous isolation of the hydrogenation product, optionally the compound of the formula (I), thus obtained, wherein R3 means hydrogen, is reacted in the step (b) ii) with a compound of the formula (IV) R3-X (IV) wherein R3 has the meaning indicated for the formula (I), and X represents a suitable leaving group and then, without previous isolation of the product of carbonylation, in a step (b) iii), the compound of the formula (I), thus obtained, wherein R1, R2 and R3 are defined as mentioned above, is transformed into the desired salt, in particular in a pharmaceutically acceptable salt. Particularly preferred are the processes according to the invention for the preparation of the salts of the compounds of the formula (I), in which R1 represents a C---3 alkyl group, R2 represents a group R21NR22, in which R21 means a C? -3 alkyl group, which may be substituted with a carboxy group, C? -3-carbonyl alkoxy, and R22 signifies a hydrogen atom, a C-? -3 alkyl group, a pyridinyl group optionally substituted with an alkyl group d-3, and R 3 represents a hydrogen atom, a C 1 -8-carbonyl alkoxy group. Most preferred are the processes according to the invention for the preparation of the salts of the compounds of the formula (I), in which R1 represents a methyl group, R2 represents a group R21NR22, in which R21 means an ethyl group , which is substituted with an ethoxycarbonyl group, and R22 means a pyridin-2-yl group, and R3 represents an n-hexyloxycarbonyl group. Preferred salts are the methanesulfonate, chloride, maleinate, tartrate, salicylate, citrate and malonate of the compound of the formula (I). A particularly preferred salt is methanesulfonate. The following embodiments (A) to (F) of the process according to the invention are preferred: (A) The condensation of step (a) is carried out in the presence of an inert diluent and a water-binding agent . The correspondingly substituted diaminobenzenes of formula (II) are known, eg. eg, of the international patent application WO 98/37075, for example from Example 25 (steps a and b), or can be prepared in analogy to those described therein. For the hydrogenation of the nitro precursor compound for the preparation of the diaminobenzene of the formula (II), there can be used as solvents, for example, toluene, isopropanol, triethylamine, ethanol, butyl acetate, ethyl acetate, methanol or mixtures of these solvents. Preferably, it is hydrogenated at a hydrogen pressure of 1 to 20 bar, but higher pressures are also possible. The concentration of the nitroaromatic compound (precursor) is suitably 10 to 40% by weight; preferably, it is present in a concentration of 20 to 30% by weight. The catalyst used can be, for example, 5-10% palladium on carbon, preferably using palladium catalyst at 2-20% by weight-wet carbon based on the nitroaromatic compound, which corresponds to approximately 0.05-1% by weight based on to the nitroaromatic compound. Particular preference is given to using 3-amino-4-methylaminobenzoic acid amides, in particular? / - (2-pyridyl) -? / - (2-ethoxycarbonylethyl) -amide of 3-amino-4-methylaminobenzoic acid. The inert diluents employed can be both apolar aprotic solvents - such as, for example. ex. aliphatic or aromatic hydrocarbons, optionally halogenated - or polar aprotic solvents such as, e.g. ethers and / or amides or lactams and / or mixtures thereof. The apolar aprotic solvents used are preferably aliphatic C5-C8 alkanes, C4-Cio cycloalkanes, aliphatic Ci-Ce haloalkanes, branched or unbranched C6-C-io aromatic alkanes, or mixtures thereof. Particular preference is given to alkanes such as pentane, hexane or heptane, cycloalkanes such as cyclohexane or methylcyclohexane, halogenoalkanes such as dichloromethane, aromatic alkanes such as benzene, toluene or xylene or mixtures thereof. Suitable aprotic solvents are polar ethers such as, for example, tetrahydrofuran (THF), methyltetrahydrofuran, dioxane, rerc-butyl methyl ether or dimethoxyethyl ether, or amides such as, for example, dimethylformamide, or lactams such as, for example, N- methylpyrrolidone. Water-binding agents which may be employed are hygroscopic salts, inorganic or organic acids or their acid chlorides, anhydrides of inorganic or organic acids, anhydrides of alkanephosphonic acids, molecular sieves or urea derivatives. 1,1 '-carbonyldiimidazole and alkanephosphonic anhydrides are preferred, alkanephosphonic acid anhydrides are particularly preferred. In a preferred embodiment, 1,1 '-carbonyldiimidazole is suspended in THF and heated. 2- [4- (1, 2,4-Oxadiazol-5-on-3-yl) -phenylaminoj-acetic acid is added. The correspondingly substituted diaminobenzene is added in THF. The reaction mixture is stirred at about 50 ° C and then concentrated after the addition of acetic acid, mixed with water and the solid substance is filtered off, washed and dried. In a particularly preferred second embodiment, anhydrides of alkanephosphonic acid are added, in the presence of an organic base, preferably a tertiary amine amine such as, for example, ex. DIPEA is added to a solution of 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid and diaminobenzene correspondingly substituted in THF. The reaction mixture is stirred, preferably at temperatures between -10 and 50 ° C, and then concentrated after the addition of acetic acid. It mixes with ethanol / water and, optionally, a filtration aid, for example diatomaceous earth (eg Clarcel®), and filtered hot. Subsequently, the precipitated substance is filtered off from the cooled solution, washed and dried. (B) The hydrogenation of step (b) i) is carried out in the presence of an inert diluent and a hydrogenation catalyst. Particularly preferred is a process, in which the hydrogenation is carried out in a temperature range from 0 ° C to 100 ° C, preferably from 0 ° C to 70 ° C, in particular from 25 ° C to 60 ° C. Furthermore, a process is preferred, in which the hydrogenation is carried out at a pressure of more than 0.5 bar at 100 bar, preferably at a pressure of 1 bar to 10 bar, in particular to about 1-5 bar. Inert diluents can be both protic solvents - such as, e.g. ex. alcohols, carboxylic acids and / or water - or polar aprotic solvents such as, e.g. ethers and / or amides or lactams and / or mixtures thereof. Water may optionally be added to all solvents. Preferred protic solvents are preferably branched or unbranched Ci-Ce alkanols, Ci-C3 carboxylic acids or mixtures thereof. Particularly preferred are lower alcohols such as methanol, ethanol, n-propanol and isopropanol, carboxylic acids such as formic acid, acetic acid and propionic acid or mixtures thereof. It is particularly preferred to use ethanol and / or acetic acid as the reaction medium, wherein these may optionally contain water. Suitable aprotic solvents are polar ethers such as, for example, tetrahydrofuran, dioxane or dimethoxyethyl ether, or amides such as, for example, dimethylformamide, or lactams such as, for example, N-methylpyrrolidone. From THF and / or acetic acid are particularly preferred, wherein these may optionally contain water in any ratio. Preferably solvents are used that tend little to combustion. Aprotic solvents are preferred over protic solvents in hydrogenation. Suitable hydrogenation catalysts are, in general, transition metals such as, for example, nickel, platinum or palladium or its salts or oxides. Raney nickel, platinum oxide and palladium are preferred over an inert support material, in particular palladium on active carbon (Pd / C). Processes are preferred in which the product of step (a) to give the hydrogenation catalyst is used in a weight ratio of 1: 1 to 1000: 1, preferably 5: 1 to 100: 1. In a preferred embodiment of step (b) i), the product of step (a) is taken up in THF / water (7: 3 based on volume) and hydrogenated at 4 bar of hydrogen with 10% Pd / C wet to approx. 40 ° C. The catalyst is filtered, the filter is further washed with THF / water (7: 3) and the filtrate is rinsed with activated charcoal. The carbon is separated by filtration and the filter is washed with THF and water. The filtrate thus obtained is further reacted directly in step (b) ii). (C) The optional optional carbonylation in step (b) ii), in order to obtain, from a compound of the formula (I), wherein R3 means hydrogen, a compound of the formula (I), wherein R3 has another meaning than hydrogen, is carried out without prior isolation of the hydrogenation product by direct reaction of the compound of the formula (I), obtained in step (b) i), wherein R3 means hydrogen, with a carbonylation agent R3-X, where R3 has the meanings indicated above, except hydrogen and X means a labile group. Preferably, X can mean a halogen such as, for example, chlorine or bromine, or a p-toluenesulfonyl, methanesulfonyl or trifluoromethanesulfonyl group. N-hexyl chloroformate is very particularly preferred for the preparation of a compound of the formula (I), in which R3 signifies n-hexyl. The reaction is preferably carried out at a temperature of 0 to 50 ° C, in particular at 10 to 20 ° C, in the presence of a base. As the base, alkali metal carbonates such as, for example, potassium carbonate or sodium carbonate, alkali metal hydrogen carbonates such as, for example, sodium hydrogen carbonate or potassium hydrogen carbonate or tertiary amines may conveniently be used. , such as, for example, triethylamine. Preferably, potassium carbonate is used. The reaction can be carried out, for example, in mixtures based on water and acetone, water and dioxane or water and THF; a THF water mixture is preferred. After the reaction is complete, by heating the suspension, p. ex. up to about 50 ° C, the formation of a transparent two-phase mixture can be achieved, so that the aqueous phase containing a large part of the inorganic components can be separated. Then, a solvent change can be made. Suitable solvents are, for example, ketones or esters such as MIBK, butyl acetate, ethyl acetate, propyl acetate, isopropyl acetate or isobutyl acetate. Preferably MIBK or butyl acetate is used, butyl acetate is particularly preferred. In a preferred embodiment of step (b) ii), the product of step (b) i) (= the filtration of the hydrogenation) is mixed, at room temperature, with an aqueous solution of potassium carbonate. Then it is added at a temperature of 10-20 ° C, the carbonylating agent, for example, n-hexyl chloroformate. The suspension is heated to 50 ° C, forming a transparent two-phase mixture. Depending on the result of the control of the conversion carried out then, until the complete reaction of the precursor is added, optionally, more carbonylation agent to approx. 50 ° C. The THF is then distilled off and replaced with butyl acetate. The organic phase, under heating to 50-70 ° C, is repeatedly washed with water in order to remove polar impurities. The remnants of moisture remaining are then removed by azeotropic distillation. (D) Subsequently, before the precipitation of salts in step (b) iii) a solvent exchange can be effected. For this purpose, the previously used organic solvent, for example butyl acetate, is distilled off and replaced by the solvent for the precipitation of salts. Suitable solvents for partial stage (b) iii) are, for example, ketones, such as, for example, acetone or MIBK, ethers such as, for example, THF, esters such as, for example, ethyl acetate, acetate of isopropyl or butyl acetate, or alcohols such as, for example, methanol, ethanol or isopropanol. Preferably acetone and / or ethanol are used, particularly preferably it is a mixture of the two solvents. Then, by adding the corresponding acid, for example methanesulfonic acid for the preparation of the methanesulfonate, conveniently 1 equivalent, the desired salt is directly precipitated and isolated. In a preferred embodiment of step (b) iii), the product of step (b) ii) (= carbonylation solution), after the change of solvent to a mixture based on acetone and ethanol at a temperature of approx. 30-36 ° C in the presence of inoculation crystals, mix slowly with a solution of the corresponding acid, e.g. ex. methanesulfonic acid, in acetone. The suspension is continued stirring, and the precipitated product is isolated by filtration, washed with acetone and dried under suitable conditions. (E) For the preparation of 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylaminoj-acetic acid is reacted 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -aniline with an ester of 2-halogenoacetic acid, preferably bromoacetic acid ethyl ester, in the presence of a weak base, preferably a tertiary amine such as, for example, triethylamine or an alkali metal carbonate such as, for example, sodium carbonate in an inert solvent, and the obtained 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid ester is saponified. The inert diluents employed can be both protic solvents - such as, for example. ex. alcohols and / or water - or polar aprotic solvents such as, e.g. ethers and / or amides or lactams and / or mixtures thereof. Water may optionally be added to all solvents. Preferred protic solvents are preferably branched or unbranched Ci-Ce water or alkanols, or mixtures thereof. Particularly preferred are water or lower alcohols such as methanol, ethanol, n-propanol and isopropanol or their mixtures. Very particularly preferably, ethanol is used as reaction medium, wherein it may optionally contain water. Also, isopropanol, optionally together with water, may be used. However, the most suitable solvent is water. Suitable aprotic solvents are polar ethers such as, for example, tetrahydrofuran or dimethoxyethyl ether, or amides such as, for example, example, dimethylformamide, or lactams such as, for example, N-methylpyrrolidone. In a particularly preferred embodiment, bromoacetic acid ethyl ester is metered into a suspension of 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -aniline and sodium carbonate in water. isopropanol or, preferably, in water / ethanol and stirred at 35-45 ° C. The cooled suspension is filtered with suction, washing in several portions with water and ethanol is continued and dried. The saponification is preferably carried out in a protic solvent with an alkali metal or alkaline earth metal hydroxide, in particular with lithium, sodium or potassium hydroxide. In a particularly preferred embodiment, 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid ester is suspended in water or, preferably, in water / ethanol and it is mixed at room temperature, slowly, with an aqueous solution of NaOH. The suspension is transformed into a solution and heated to 45 to 75 ° C. The solution, thus obtained, is mixed with HCl until approximately pH 5 or, preferably, pH 3 has been reached. The solid is isolated and washed with cold water, as well as cold ethanol and MtBE. (F) For the preparation of 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -aniline, 4-aminophenyl-amidoxime is reacted with a dialkyl carbonate, preferably dimethyl carbonate or diethyl carbonate in the presence of a base, preferably an alkali metal alcoholate, in particular sodium methylate, sodium ethylate or potassium tert-butanolate. 4-aminophenyl-amidoxime can also be prepared, e.g. eg, by reaction of 4-aminobenzonitrile with hydroxylamine hydrochloride.

In a particularly preferred embodiment, sodium methylate or, preferably, sodium ethylate is added at 65-75 ° C, preferably at 70-75 ° C, to a suspension of 4-aminophenyl-amidoxime in ethanol and further clarification with ethanol After stirring for 15 min, diethyl carbonate or, preferably, dimethyl carbonate is added dropwise. After a reaction time of 2-4 hours, it is cooled and ethanol is distilled off at 120 mbar and 40 ° C. The residue is taken up in water and, after heating, it is adjusted to pH 10-12 by means of semi-concentrated sodium hydroxide, then, by acidification with concentrated hydrochloric acid, it is adjusted to pH < 6, preferably at pH < 4, particularly preferably at pH 2-3 and cooled slowly. The solution is transformed into a suspension, which is filtered and continued to be washed several times with cold water and ethanol. The preparation of 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid, required as an intermediate product, from 4-aminobenzonitrile is shown in the following scheme Reactions: Diagram I (Intermediate non-isolated stages, indicated by brackets, may optionally vary among the various variants of the procedure.) A preferred embodiment is indicated.) (2B) The preparation of a 4- (benzimidazol-2-ylmethylamino) -benzamidine is represented by way of example in the following reaction scheme: Diagram II The elaboration of the different reactions can be carried out in a customary manner, for example by separating the reaction coadjuvant, separating the solvent and isolating the pure final product by crystallization, distillation, extraction or chromatography. In the last step of the above process, the compound of formula (I), thus obtained, is transformed into a physiologically compatible salt. In the case of the physiologically compatible salts, it may be salts with inorganic or organic acids or, if the compound contains a carboxy group, with inorganic or organic bases. Suitable acids are, for example, methanesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid., citric acid, tartaric acid or maleic acid. Suitable bases are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine. The compound of the formula. { 6.} it is preferably transformed into its mesylate. The procedure according to the invention must now be explained by the following examples. The person skilled in the art is aware that the examples are only for illustration and are not to be considered as limiting. EXAMPLES The following abbreviations are used above and in the following: AcOH acetic acid AMBPA? / - (2-pyridyl) -? / - (2-ethoxycarbonylethyl) -amide of 3-amino-4-methylaminobenzoic acid CDI 1 , r-carbonyldiimidazole DIPEA diisopropylethylamine EE ethyl ester of acetic acid EtOH ethanol HCl hydrochloric acid MIBK methyl isobutyl ketone (4-methyl-2-pentanone) MtBE methyl tert-butyl ether NaOH sodium hydroxide NMP N-methylpyrrolidone PPA propanophosphonic acid anhydride PTSA p-toluenesulfonic acid TA room temperature THF tetrahydrofuran desc. decomposition Example 1 Preparation of 2- [4- (1,2,4-oxadiazol-5-on-3-yl) -aniline (IB): LIA) 41.3 g (0.35 mol) of 4 are placed in the reaction vessel. -aminobenzonitrile and 36.5 g (0.53 mol) of hydroxylamine hydrochloride in 175 ml of ethanol and the mixture is heated to 60 ° C. 170.1 g (0.53 mol) of sodium ethylate solution (~ 21% in ethanol) are added slowly, dropwise, to this suspension. The mixture is then stirred overnight at 60 ° C. Upon cooling to 0-5 ° C, the substance precipitates, it is separated by filtration and it is continued to wash several times with a total of 70 ml of cold ethanol. Approx. 86 g of wet product. This continues to be elaborated directly. (1B) To a suspension of 86 g of (1A) in 270 ml of ethanol is added 32 g (0.35 mol) of dimethyl carbonate. At 65-75 ° C, 125 g (0.38 mol) of sodium ethylate solution (~ 21% in ethanol) are added and the mixture is further rinsed with 20 ml of ethanol. After 3 hours of reaction, it is cooled to 40 ° C and the ethanol is distilled off at 120 mbar and 40 ° C. A dark residue is obtained. It dissolves at 40-45 ° C in 280 ml of water and, after heating to 70 ° C, it is adjusted to pH 11 first by slow addition of semi-concentrated soda lye; then, by acidification with concentrated hydrochloric acid, it is adjusted to pH 3-4 or, preferably, to pH 2-3 and cooled slowly. The solution is transformed into a suspension, which is filtered and continued to be washed several times with a total of 50 ml of cold water and 20 ml of ethanol. Approx. 88 g of wet substance that is dried under vacuum at max. 50 ° C. Yield: 48 g of beige substance (77.5% of theory); melting point: from 178 ° C (dec); purity: > 98% peak surface by HPLC Example 2 Preparation of 2- [4- (1,2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid 2B): (2A) At 45 ° C 60.2 g (0.36 mol) of bromoacetic acid ethyl ester are metered in to a suspension of 53.2 g (0.3 mol) of (1B) and 19.1 g (0.18 mol) of sodium carbonate in 500 ml of water / ethanol (90: 10 to 95: 5) and, optionally, is stirred overnight. The reaction mixture becomes brown-reddish orange The suspension cooled to 0 ° C is suctioned, washed in several portions with 100 ml of ethanol and dried at max. 50 ° C in vacuum. Yield: 69.5 g of beige-brown substance (87.7% of theoretical) melting point: from 186.1 ° C (dec); purity: > 98% peak surface area by HPLC Í2B) The ester (2A) (86.9 g, 0.33 mol), thus obtained, is suspended in 400 ml of water or, preferably, ethanol / water (1: 1) and at RT slowly, dropwise, 120 g of water are added dropwise. 45% NaOH. The suspension becomes a solution and turns reddish (pH 12.5). Heat to ~ 60 ° C and saponify for 1 h.

The solution obtained is mixed in portions with HCl (37% or, preferably, with concentrated HCl), until a pH of 3 is reached. It is cooled to 0 ° C. The solid is filtered with suction and washed in several portions with a total of 400 ml of cold water, as well as in each case 40 ml of cold ethanol. 81.4 g of wet substance are obtained. This is dried at 35 ° C under vacuum. Yield: 76.7 g of substance (98% of theory) Melting point: from 193 ° C (dec.) Purity: > 99% peak area by HPLC Example 3 Preparation of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide of 3-amino-4-methylaminobenzoic acid (AMBPA) (3) Variant A: 5% Pd / C In a hydrogenation autoclave 150 g (0.4 mol) of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide of 4-methylamino-3-nitrobenzoic acid are placed, 12 g of 5% palladium on carbon catalyst and 627 ml of ethyl acetate. The mixture is hydrogenated under a hydrogen atmosphere of 3-4 bar at 35-55 ° C until constancy of hydrogen uptake (1-2 h). After cooling to 20 ° C, the hydrogenation solution is filtered off from the catalyst and concentrated in vacuo in the rotary evaporator. The residue is taken up in 650 ml of isopropanol, distilled to half the initial volume and cooled to 5-10 ° C. After 4 h the resulting suspension is filtered, and the precipitate, thus isolated, is further washed in portions with a total of 100 ml of isopropanol.

The solid obtained is dried in the vacuum drying oven at 50 ° C. Yield: 114.2 g (corresponding to 83% of theory) Variant B: 10% Pd / C 25 g (0.07 mol) of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) are placed in a hydrogenation autoclave 4-methylamino-3-nitrobenzoic acid amide, 2. 5 g of 10% palladium on carbon catalyst and 83 ml of ethyl acetate.

The batch is hydrogenated under a hydrogen atmosphere of 3-4 bar at 50 ° C until constancy of hydrogen uptake (4-5 h). After cooling to 20 ° C, the hydrogenation solution is filtered off from the catalyst and concentrated in vacuo on the rotary evaporator. The residue dissolves hot in a little ethyl acetate and mixed with 68 ml of toluene. After cooling to 5 ° C, stirring is continued for 1 h, then the precipitate is filtered off and washed with toluene. The product obtained is dried in the vacuum drying oven at 40 ° C. Yield: 20.9 g (corresponding to 91% of theory) Example 4 Preparation of? - (2-pyridyl) -? / - (2-ethoxycarbonylethyl) -amide of 1-methyl-2 - [? / - [4- (1,2,4-oxadiazol-5-on-3-yl) phenyl) ] -amino-methyl] -benzimidazol-5-yl-carboxylic acid (4): Variant A: CDI as coupling reagent 11.35 g (70 mmol) of 1,1 '-carbonyldiimidazole are suspended in 100 ml of THF and heated to 50 ° C. 14.23 g (60.5 mmol) of (2B) 17.1 g (50 mmol) of AMPBA 3 are added in portions and dissolved in 37 ml of THF under heating to 50 ° C. After approx. 90 min, the suspension is added to the AMPBA solution metered and it is further clarified with 20 ml of THF. The reaction mixture is stirred for approx. 18 h and then, after the addition of 100 ml of acetic acid, it is heated to reflux, so that THF is distilled off. After approx. 1 h is mixed with 400 ml of water and stirred. The solution is cooled, the precipitated pink solid is separated by filtration and it is further washed with 20 ml of water in 2 portions and dried at maximum 50 ° C in vacuum. Yield: 24.8 g of substance (75% of theoretical) melting point: from 167 ° C with dec. (DSC); purity: > 95% peak surface area by HPLC Variant B: PPA as coupling reagent 34.2 g (0.1 mol) of AMBPA 3, 27.5 g (0.12 mol) of (2B) and 30.3 g (0.23 mol) of DIPEA are placed in 170 ml of THF and cooled to slightly below room temperature. Thereto is now added 85 g (0.13 mol) of PPA (in the form of a -50% solution in ethyl acetate). The mixture is stirred for 90 min. And then the solvent is distilled off. Towards the end, 73.5 g of acetic acid are added and heated to an internal temperature of 90 ° C. It is then mixed with 400 ml of ethanol or, preferably, with 400 ml of ethanol / water (approx 85: 15) and diatomaceous earth filtering aid (eg Clarcel®) and filtered hot. The solution is cooled, the precipitated solid is filtered off and the mixture is washed with 50 ml of ethanol in 2 portions and dried at max. 50 ° C in vacuum. Yield: 56 g of substance (85% of theory); melting point: from 167 ° C with dec. (DSC); purity: > 95% peak surface by HPLC Variant C: Pivaloyl chloride as coupling reagent 96 g (0.41 mol) of (£ B) are suspended at 0 ° C in 250 ml of NMP and 550 ml of THF. The liquid suspension is successively mixed with 48 g (0.4 mol) of pivaloyl chloride and 52 g (0.4 mol) of DIPEA and stirring is continued for 30 minutes. Then, 125 g (0.36 mol) of AMBPA 3 are added, dissolved in 800 ml of acetic acid and the reaction mixture is refluxed for 3 h. THF is removed by distillation under a slight vacuum and, in hot, 1600 ml of water are metered in. The solid is isolated at 5 ° C, washed with 550 ml of water and dried overnight in the air drying oven. circulating to max. 50 ° C. Yield: 183 g (76%) Purity: > 95% peak surface by HPLC Example 5 Preparation of? / - (2-pyridyl) -? - (2-ethoxycarbonyl-ethyl) -amide of 1-methyl-2 - [? / - [4 - (? / - n-hexyloxycarbonylamine) phenyl] -amino-methyl] -benzimidazol-5-yl acid -carboxylic (6) from / V- (2-pyridyl) -? - (2-ethoxycarbonylethyl) -amide of 1-methyl-2- [? - [4- (1,2,4-Oxadiazol-5-on-3-yl) phenyl] -amino-methyl] -benzimidazol-5-yl-carboxylic acid (4) 60 g (91 mmol) of? / - ( 2-pyridyl) -? / - (2-ethoxycarbonylethyl) -amide of acid 1-methyl-2 - [? / - [4- (1, 2,4-oxadiazol-5-on-3-yl) phenyl] -amino-methyl] -benzimidazol-5-yl-carboxylic acid (4) are hydrogenated with 3.0 g of 10% palladium on carbon (wet) in 126 ml of THF and 54 ml of water at 40 ° C and a hydrogen pressure of 4 bar for 25 min. The hydrogenation solution is filtered and the filter is washed with 75 g of THF / water (7: 3). The filtrate is mixed successively with 56 ml of THF, 260 ml of water and in portions with 75.2 g (544 mmol) of potassium carbonate at room temperature. Next, 14.2 g (86 mmol) of n-hexyl chloroformate are metered in over 40 min. After control of the conversion, another 1.2 g (7.3 mmol) of n-hexyl chloroformate is metered in, so that all the starting material has been reacted. The suspension is heated to approx. 45 ° C. A transparent two-phase mixture is formed. The aqueous phase is discarded and THF is widely separated by distillation. To the suspension, 150 ml of acetone are added, the mixture is heated to 50 ° C. and filtered to clarity. The filter is further clarified with 100 ml of acetone. The filtrate is cooled to room temperature and the Product is precipitated by slow addition of 100 ml of water. The wet product is washed with 150 ml of acetone / water (1: 1) and 150 ml of water and dried in vacuo. Yield: 56.9 g (94%) Purity by HPLC: > 98.8% Example 6 Preparation of 1 - methyl - 2- [2 -] - (2-pyridyl) -? - (2-ethoxycarbonylethyl) -amide acid mesylate. - [4- (? -n-hexyloxycarbonylamino) phenyl] -amino-methyl] -benzyl-imidazol-5-yl-carboxylic acid (7) 100 g (0.16 mol) of the compound (6) are dissolved in 890 ml of low acetone heating and mixing with a solution of 15 g (0.16 mol) of methanesulfonic acid in 200 ml of acetone. The solution is filtered and, after the addition of 77 ml of acetone, it is cooled to approx. 20 ° C. The precipitated product is isolated and continued to be washed with acetone. It is then dried in the drying oven at max. 50 ° C. Yield: 90-98 g (103-113 g) Example 7 Preparation of β / - (2-pyridyl) -? / - (2-ethoxycarbonylethyl) -amide 1-methyl-2 - [? / - [4 - (? / - n-hexyloxycarbonylamino) phenyl] -amino-methyl] -benzimidazole-5-carboxylic acid (7) from? / - (2-pyridyl) -? / - (2-ethoxycarbonylethyl) -amide of 1-methyl-2 - [? / - [4- (1,2,4-oxadiazol-5-on-3-yl) phenyl] -amino-methyl] -benzimidazol-5-yl-carboxylic acid (4) 60 g (91 mmol) of 4 (optionally with acetate content) are hydrogenated with 3.0 g of 10% palladium on carbon (wet) in 126 ml of THF and 54 ml of water at 40 ° C and at a hydrogen overpressure of 4 bar for 30 min. The hydrogenation solution is filtered, the filter is washed with 51 g of THF / water (7: 3) and the filtrate is carbonated. The activated carbon is separated by filtration and the filter is washed with 102 ml of THF and 80 ml of water. The filtrate is mixed at room temperature with a solution of 75.2 g (544 mmol) of potassium carbonate in 80 ml of water and, at 10-20 ° C, 14.6 g (88.9 mmol) of n-chloroformate are metered in. hexyl for 1 h. The suspension is heated to approx. 50 ° C. A transparent biphasic mixture is formed in which 0.452 g (2.7 mmol) of n-hexyl chloroformate are metered in after a conversion control, so that all the starting material has reacted. After separation of the aqueous phase, 180 ml of THF are then distilled off and replaced with 350 ml of butyl acetate. The organic phase is extracted at 50-70 ° C twice with 30 ml of water, 210 ml of butyl acetate are distilled off and replaced by 300 ml of acetone and 60 ml of ethanol. The reaction solution is cooled to 30-36 ° C, mixed with inoculation crystals of 7 (which were obtained, for example, from a reaction previously carried out according to Example 5 or according to the procedure described in Example 3 of the document) and a previously prepared solution of 7.84 g (82 mmol) of methanesulfonic acid in 50 ml of acetone is added dropwise. The suspension is continued stirring, the product is isolated by filtration and washed with acetone. The isolated substance is dried at 45 ° C in vacuo. Yield: 56.2 g (86%) Purity: > 99% peak surface area by HPLC The other compounds of the formula (I) and their salts can be prepared analogously to the previous examples.

Claims (11)

1. CLAIMS 1. Prs for the preparation of a salt of an optionally substituted 4- (benzimidazol-2-ylmethylamino) -benzamidine, characterized in that (a) an optionally substituted diaminobenzene is condensed correspondingly with 2- [4- (1 , 2,4-oxadiazol-5-on-3-yl) -phenylaminoj-acetic acid and (b) i) the product is hydrogenated, thus obtained, i) optionally the amidino group is carbonylated, without previously isolating the intermediate from the hydrogenation, and iii) without prior isolation of the carbonylation intermediate, the desired salt is isolated. 2. Prs according to claim 1 for the preparation of a salt of an optionally substituted 4- (benzimidazol-2-ylmethylamino) -benzamidine of the formula (I) with organic or inorganic acids, wherein R1 represents a C6-6 alkyl or C3-7 cycloalkyl group, R2 (i) represents a C6-6 alkyl group, a C3-7 cycloalkyl group optionally substituted by a C-? -3 alkyl group, wherein the alkyl group d-3 may be further substituted with a carboxyl group or with an in-vivo transformable group in a carboxy group, or (ii) represents a group R21NR22, wherein R2 means a C1-6 alkyl group, which may be substituted with a carboxy group, C6-C6-alkoxy, benzyloxycarbonyl, C3-alkyl-sulfonyl-carbonyl, phenylsulfonylaminocarbonyl, trifluorosulfonyl-amino, trifluorosulfonylaminocarbonyl group or 1 H-tetrazolyl, a C 2-4 alkyl group, substituted with a hydroxy group, phenyl-C 1 -3 alkoxy, carboxy-C 1 -3-amino alkyl, C 1 -3-carbonyl-C 1 alkyloxy 3-amino, N- (C C-alkyl) -carboxy-C C-3-amino alkyl or N- (C C-3 alkyl) -alkoxy C - ω -3-carbonyl-Cil-3-amino alkyl , wherein in the above-mentioned groups the carbon atom adjacent to the nitrogen atom can not be substituted, or a piperidinyl group optionally substituted with a C? -3 alkyl group, and R22 signifies a hydrogen atom, an alkyl group C -? - 6, a C3- cycloalkyl group, optionally substituted by a C -? - 3 alkyl group, a C3-6 alkenyl group or a C3-6 alkynyl group, wherein the unsaturated part can not be directly linked to the nitrogen atom of the group R21NR22, a phenyl group optionally substituted with a fluorine, chlorine or bromine atom, with a C-? - 3 alkyl or C -? - 3 alkoxy group, or a benzyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl group , pyridinyl, pyrimidini it, pyrazinyl, pyridazinyl, pyrrolyl, thienyl or imidazolyl optionally substituted with a C? -3 alkyl group, or R21 and R22, together with the nitrogen atom located therebetween, represent a 5- to 7-membered cycloalkyleneimino group, optionally substituted with a carboxy or C-- 4 -carbonyl group, to which a phenyl ring may additionally be condensed, and R 3 represents a hydrogen atom, a C 1 -9-carbonyl, cyclohexyloxycarbonyl, phenyl-C 1 -C 3 alkoxy group -carbonyl, benzoyl, p-alkyl C? -benzoyl or pyridinoyl, wherein the portion of ethoxy in the 2-position of the aforementioned d-carbonyl alkoxy group can be further substituted with an alkyl d-sulphonyl or 2- (alkoxy) group d ^ -ethyl, wherein in step (a) a phenyldiamine of the formula (II)
2. R ' wherein R1 and R2 have the indicated meaning for formula (I), is reacted with 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid, the product obtained from the formula (III) wherein R1 and R2 have the indicated meaning for formula (I), hydrogenated in step (b) i) and then, without previous isolation of the hydrogenation product, optionally the compound of formula (I), as well obtained, wherein R3 means hydrogen, is reacted in step (b) ii) with a compound of the formula (IV) R3-X (IV) wherein R3 has the meaning indicated for the formula (I), and
3. X represents a suitable leaving group. 3. Prs according to claim 1 or 2, for the preparation of a salt of a compound of the formula (I), in which R1 represents a C3_3 alkyl group, R2 represents a group R21NR22, in which R21 means an alkyl group d-3, which may be substituted with a carboxy group, d -3-alkoxy carbonyl, and R22 means a hydrogen atom, an alkyl group d-3, a pyridinyl group optionally substituted with an alkyl group d-3, and R3 represents a hydrogen atom, an alkoxy d-s-carbonyl group.
4. 4. Process according to claim 3, for the preparation of a salt of the compound of the formula (I), in which R1 represents a methyl group, R2 represents a group R21NR22, in which R21 means an ethyl group, which is substituted with an ethoxycarbonyl group, and R22 means a pyridin-2-yl group, and R3 represents an n-hexyloxycarbonyl group.
5. 5. Process according to one of the preceding claims, characterized in that the compound of formula (I), thus obtained, is then transformed into a physiologically compatible salt.
6. 6. Process according to claim 5, characterized in that the physiologically compatible salt is methanesulfonate, hydrochloride, maleinate, tartrate, salicylate, citrate or malonate.
7. 7. Process according to claim 6, characterized in that the physiologically compatible salt is methanesulfonate.
8. 8. Method according to one of the preceding claims, characterized in that the condensation of stage (a) is carried out in the presence of an inert diluent and a water binding agent.
9. 9. Method according to one of the preceding claims, characterized in that the hydrogenation of step (b) i) is carried out in the presence of an inert diluent and a hydrogenation catalyst.
10. 10. Process according to one of the preceding claims, characterized in that for the preparation of 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylaminoj-acetic acid, 2- [4-] (1, 2,4-oxadiazol-5-on-3-yl) -aniline is reacted with a 2-halogenoacetic ester in the presence of a weak base, and the obtained 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid ester is saponified.
11. 11. Method according to one of the preceding claims, characterized in that 4-aminophenyl-amidoxime is reacted with the preparation of 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -aniline. a dialkyl carbonate in the presence of a base.