HK1136559B - Process for the preparation of a benzimidazole derivative - Google Patents

Description

Process for preparing benzimidazole derivatives

The present invention relates to a process for preparing a compound of formula 1

This compound is a valuable intermediate in the synthesis of the pharmaceutically active substance dabigatran etexilate.

Prior Art

Dabigatran etexilate is known in the prior art and was originally disclosed in international patent application WO 98/37075. Methods for preparing dabigatran etexilate are also known from WO 2006/000353 or Hauel et al (j.med. chem, 2002, 45, 1757 ff).

From WO 2006/000353, compounds of formula1The compound is very important as an intermediate product in the synthesis of dabigatran etexilate.

The object of the present invention is to provide a suitable formula1A method for the improved large-scale industrial synthesis of compounds.

Detailed Description

The present invention relates to a large-scale industrial process for the preparation of a compound of the formula:

optionally in the form of an acid addition salt thereof, preferably in the form of its p-toluenesulphonate salt,

characterized in that in the first step, the formula2With carboxylic acids3In the presence of a suitable coupling reagent,

form type4Compound (I)

Without isolation, converting it to formula4-BrHydrobromide salt

Finally converting it into the formula1Amidines of (1).

To make it in2Reacting the compound to form the formula4The following procedure is preferably employed according to the invention.

First of all, the formula2The compound is dissolved in a suitable solvent. Suitable solvents of the present invention are preferably selected from the group consisting of: dichloromethane, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, dioxane and mixtures thereof, of which dimethylformamide and tetrahydrofuran are preferred. According to the invention, tetrahydrofuran is particularly important as a solvent in this regard.

Each 1mol of the formula2Compound (I)It is preferable to use from 0.5 to 1 liter, particularly preferably from 0.65 to 0.85 liter, more preferably from 0.7 to 0.8 liter, of the above-mentioned solvent.

In addition to the above solutions, also prepared are solutions containing3Carboxylic acid and another solution of the above coupling reagent. For this purpose, according to the invention, the coupling reagent is preferably first dissolved in its entirety in a solvent, which is preferably selected from the solvents mentioned above. Preferably, the use and dissolution forms2The same solvent as used for the compound. The coupling reagent is preferably selected from the group consisting of N, N ' -dicyclohexylcarbodiimide, N ' -carbonyldiimidazole and carbonyl-bis- (1, 2, 4-triazole), whereas according to the invention N, N ' -carbonyldiimidazole and carbonyl-bis- (1, 2, 4-triazole) are preferred, carbonyl-bis- (1, 2, 4-triazole) being particularly important.

Each 1mol of the formula2As the compound, it is preferable to use 1 to 2mol, particularly preferably 1 to 1.5mol, more preferably 1.05 to 1.25mol of the above-mentioned coupling agent. Preferably, 1mol of a compound of the formula2The compound is preferably used in an amount of 1 to 3 liters, particularly preferably 1.5 to 2.5 liters, and more preferably 1.8 to 2.2 liters, of the above-mentioned solvent to dissolve the coupling agent in the above-mentioned solvent.

The coupling reagent solution thus obtained is heated at ambient temperature, with stirring or with stirring, to about 25 to 50 ℃, preferably 30 to 40 ℃, particularly preferably 32 to 38 ℃ and subsequently reacted with a compound of formula3Mixing the above compounds. Formula (II)3The compound is preferably added in portions over a period of 0.25 to 4 hours, preferably 0.5 to 3 hours, particularly preferably 1 to 2 hours. Compound (I)3The addition of (b) is preferably carried out with the existing solution at constant temperature.

Each 1mol of the formula2The compounds, preferably from 1 to 2mol, particularly preferably from 1 to 1.5mol, in particular from 1.05 to 1.15mol, of the abovementioned formula3A compound is provided.

In the additive mode3After compounding, the coupling reagent thus obtained is reacted with3Optionally, the solution of (a) is stirred for a further 0.25 to 4 hours, preferably 0.5 to 3 hours, particularly preferably 0.5 to 1 hour. During this time, the temperature of the solution is preferably kept in one of the above-mentioned temperature ranges, and the temperature is particularly preferably kept constant.

The solution thus obtained is then added to the already prepared formula2Solution of the compound. The above-mentioned compounds are preferably used2Is preheated with stirring to a temperature in the range of about 30 to 65 ℃, preferably 40 to 60 ℃ and particularly preferably 47 to 53 ℃.

The coupling reagent prepared is reacted with the compound in 0.5 to 5 hours, preferably 1 to 4 hours, particularly preferably 2 to 3 hours3Is preferably metered into the compound2In the solution of (1). During this period, the compound is preferably reacted2The temperature of the existing solution is kept constant.

After the addition of the active ingredients3And the solution prepared by the coupling reagent, the reaction solution is optionally further diluted by addition of a solvent. If more solvent is added, it is preferred to use one of the abovementioned solvents, and particular preference is given to using the solvents which have already been used for preparing the compounds2A solvent for the solution of (1).

If the solution is further diluted, 1mol of the formula is used per mole2As the compound, it is preferable to use 0.1 to 0.5 liter, particularly preferably 0.2 to 0.3 liter of the above-mentioned solvent.

After the addition of the active ingredients3And the solution prepared with the coupling agent and after addition of any further solution, the solution obtained is stirred for a further period of at least 1 to 8 hours, preferably at least 2 to 7 hours, particularly preferably at least 3 to 6 hours. The solution is preferably kept in one of the above temperature ranges, and the temperature is particularly preferably kept constant.

Subsequently, the bulk of the solvent is optionally distilled off under reduced pressure, 1mol of compound being used per mole2It is particularly preferred to remove 1 to 1.8 liters, particularly preferably 1.2 to 1.7 liters, more preferably 1.4 to 1.5 liters of the above solvent by distillation.

The distillation of the solvent is preferably carried out at a temperature in the range from about 40 to 65 ℃ and particularly preferably in the range from 50 to 60 ℃. If, due to the choice of solvent, it is not possible to remove the solvent by distillation at atmospheric pressure in this temperature range, the pressure is reduced until distillation successfully takes place in the specified temperature range.

Optionally by adding a further solvent to advantageously carry away any residual amounts of the initially used solvent present in the distillation residue. If, for example, tetrahydrofuran is used as solvent for the above-described reaction, it has proven advantageous to use n-butyl acetate. If n-butyl acetate is used here, it is distilled off together with tetrahydrofuran at a temperature of about 50 to 85 ℃ under reduced pressure. The distillation is carried out so that the tetrahydrofuran used previously is almost completely removed and only n-butyl acetate remains as solvent, after completion of the distillation the remaining solution is mixed with acetic acid, preferably here concentrated acetic acid, in particular glacial acetic acid (about 99% acetic acid).

Each 1mol of the formula2As the compound, 100-200g (g), particularly preferably 120-170g, more preferably 130-145g of the above-mentioned concentrated acetic acid is preferably used.

The mixture is then heated with stirring to about 65-100 ℃, preferably 75-95 ℃, particularly preferably 85-90 ℃ and stirred at constant temperature for at least 0.5-5 hours, preferably 1.4 hours, particularly preferably 2.3 hours.

The mixture is then preferably warmed to about 45-85 ℃, preferably 55-80 ℃, particularly preferably 65-75 ℃ and mixed with water for further processing. Each 1mol of the formula2The compound is particularly preferably added with 0.5 to 2 liters, particularly preferably 0.75 to 1.5 liters, more preferably 0.9 to 1.1 liters of water.

Optionally, in addition to water, an aqueous NaCl solution is also added. If NaCl is also added, 1mol of the formula is used2The compound is preferably used in an amount of 20 to 80g (g), particularly preferably 30 to 60g, more preferably 40 to 50g, of NaCl.

The phase mixture thus obtained is mixed thoroughly and the aqueous phase is separated off using conventional methods. Optionally, the separated phase is re-extracted with the previously used organic solvent. The solvent was removed from the organic phase by distillation under reduced pressure.

The distillation of the solvent is preferably carried out at less than 80 ℃, preferably at about 60 to 80 ℃, particularly preferably at 70 to 80 ℃. If, due to the choice of solvent, it is not possible to remove the solvent by distillation at atmospheric pressure in this temperature range, the pressure is reduced until distillation takes place successfully in the specified temperature range.

The remaining distillation residue contains the formula4The compounds, according to the invention, are directly further reacted without isolation using the procedure described below to give the formula4-BrA compound is provided.

The distillation residue is mixed with an alcohol, preferably with ethanol or isopropanol, particularly preferably with isopropanol, and optionally heated slightly. Each 1mol of the formula2As the compound, the above-mentioned alcohol is preferably added in an amount of 0.5 to 3 liters, particularly preferably 1 to 2.5 liters, and more preferably 1.5 to 2 liters.

If the mixture obtained is heated, a temperature of preferably about 25 to 50 ℃, preferably 30 to 40 ℃, particularly preferably 32 to 38 ℃ is selected.

Aqueous hydrobromic acid is added. Particularly preferably, concentrated aqueous hydrobromic acid is used. For example, a 48% aqueous hydrobromic acid solution may be used. Sufficient hydrobromic acid is added with stirring at constant temperature until the pH of the mixture obtained is less than 3, preferably less than 2, and particularly preferably in the range of 0.6 to 1.3. In the case of using the above-mentioned 48% hydrobromic acid, for example, per 1mol of the formula2To the compound, 0.1 to 0.3kg, preferably 0.15 to 0.25kg, particularly preferably 0.17 to 0.21kg of hydrobromic acid (48%) are added.

After the addition of hydrobromic acid is complete, the mixture obtained is stirred for a further at least 5 to 60 minutes, preferably at least 10 to 45 minutes, particularly preferably at least 20 to 30 minutes. During this time, the temperature of the solution is preferably kept in one of the above-mentioned temperature ranges, and the temperature is particularly preferably kept constant. The resulting mixture is then preferably cooled to 0 to 20 ℃, preferably 5 to 15 ℃, particularly preferably 7 to 13 ℃, and stirred at this temperature for a further at least 0.5 to 2 hours, preferably at least 0.75 to 1.5 hours, particularly preferably at least 1 hour.

Then, the resultant was centrifuged4-BrThe suspension in alcohol is freed of the solvent and the residue remaining is optionally washed with one of the alcohols mentioned above. Followed by mixing the obtained4-BrAt a temperature of not more than 30-65 ℃, preferably not more thanDrying under vacuum at a temperature of over 50-60 deg.C.

The invention further relates to the formula so obtained4-BrHydrobromide salt

It has been surprisingly found that this formula4The salts of the compounds are particularly easy to isolate, which makes it quite simple to isolate this intermediate product during a reaction on an industrial scale. Easy separation within the scope of the present invention refers to the ability to liberate the resulting crystalline product from the solvent by filtration, suction filtration, centrifugation or similar separation methods. The improvement of the quality of the separation has a direct effect on the throughput of the process and is therefore of great importance, especially when the reaction is carried out on an industrial scale. Products with better separation quality can be separated faster, washed faster and better, and thus dried faster.

The following procedure can be used from the compounds4-BrIs of the formula1A compound is provided.

Firstly, preferably will4-BrAdded to an organic solvent mixed with a suitable acid. According to the invention, the acid is preferably hydrochloric acid and the solvent is preferably an alcohol. Particular preference is given to using isopropanol or ethanol, particular preference to using ethanol. It has proven particularly preferred according to the invention to use 5 to 12 molar, particularly preferably 9 to 11 molar, solutions of hydrochloric acid in ethanol (ethanolic acid). Particularly preferably, according to the invention, a 10 molar solution of hydrochloric acid in ethanol is used, per 1mol of compound4-BrPreference is given to using from 0.4 to 1.5kg, preferably from 0.6 to 1.0kg, particularly preferably from 0.75 to 0.85kg, of a 10 molar solution of hydrochloric acid in ethanol.

Preferably, it will be stirred at a temperature in the range of about 20-25 deg.C, preferably at ambient temperature (23 deg.C)4-BrTo the acid-containing alcohols of the invention, preferably, according to the invention, a compound of formula (II b)1The compounds are prepared in the form of acid addition salts. Is particularly preferredGround, general formula1The compound was prepared in the form of its p-toluenesulfonate salt. Is of type1The compound was obtained as the p-toluenesulfonic acid addition salt, confirming that the addition of p-toluenesulfonic acid at this stage is advantageous. Therefore, the acid (preferably hydrochloric acid) is added to the above-mentioned alcohol4-BrP-toluenesulfonic acid was also added after the solution of (2). The p-toluenesulfonic acid is preferably added in the form of its hydrate.

An alternative to the above procedure, first all p-toluenesulfonic acid may be added, followed by the compound4-BrTo an acid containing alcohol. Each 1mol of the formula4-BrThe compound is preferably added with 180-300g (g), particularly preferably 200-300g, more preferably 245-255g of the above-mentioned aqueous p-toluenesulfonic acid solution.

After the end of the addition, the mixture is preferably brought to about 23 to 40 ℃, preferably 25 to 35 ℃, particularly preferably 28 to 29 ℃ with stirring and is stirred at constant temperature for a further time of up to 12 to 36 hours, preferably up to 20 to 28 hours, particularly preferably up to 23 to 25 hours.

The reaction solution is then optionally further diluted by the addition of a solvent. If more solvent is added, it is preferable to use one of the abovementioned alcohols, and particular preference is given to using those which have already been used for preparing the compounds4-BrThe particular alcohol of the solution. Therefore, ethanol is preferably used here as well.

If the solution is further diluted, 1mol of the compound of the formula4-BrThe compound is preferably used in an amount of from 0.5 to 1.5 l, particularly preferably from 0.8 to 1.0 l, of the abovementioned solvent, preferably an alcohol, particularly preferably ethanol.

The mixture is then cooled to about-10 to 15 ℃, preferably-5 to +5 ℃, particularly preferably 1 to 3 ℃ with stirring and mixed with an aqueous ammonia solution. Particular preference is given to using from 20 to 30%, preferably from 20 to 25%, aqueous ammonia solution, whereas according to the invention preference is given to using 25% aqueous ammonia solution. When a 25% aqueous ammonia solution is used, 1mol of the compound of formula (II) is used4-BrAs the compound, 0.5 to 1.5kg, particularly preferably 0.6 to 1.0kg, more preferably 0.7 to 0.8kg of the above-mentioned 25% aqueous ammonia solution is preferably used.

The aqueous ammonia solution is preferably added so that the temperature is maintained in the range of about 0-15 c, preferably 0-10 c. It is particularly preferred to control the addition to keep the temperature constant. The pH of the solution is preferably raised to a pH of 9 to 10.5, preferably to a pH of 9.3 to 10.

After the end of the addition, the mixture is preferably heated with stirring to about 20 to 30 ℃, preferably 22 to 27 ℃, particularly preferably about 25 ℃ and stirred at constant temperature for a further at least 2 to 8 hours, preferably at least 2.4 to 6 hours, particularly preferably at least 3 to 5 hours.

Subsequently, the bulk of the solvent is optionally distilled off under reduced pressure. Each 1mol of the compound is used4-BrIt is particularly preferred to remove from 0.2 to 0.8 liter, particularly preferably from 0.3 to 0.7 liter, more preferably from 0.4 to 0.5 liter, of the above-mentioned solvent by distillation.

The distillation of the solvent is preferably carried out at a temperature in the range from about 40 to 65 ℃ and particularly preferably in the range from 50 to 60 ℃. If, due to the choice of solvent, it is not possible to remove the solvent by distillation at atmospheric pressure in this temperature range, the pressure is reduced until distillation successfully takes place in the specified temperature range.

The mixture is then mixed with water at a constant temperature (about 50-60 ℃) for further processing. Each 1mol of the compound is used4-BrIt is particularly preferred to add from 2 to 8 liters, particularly preferably from 4 to 7 liters, more preferably from 5 to 6 liters of water. In addition to the addition of water, aqueous NaOH solutions, preferably 30 to 60%, particularly preferably 40 to 50%, NaOH solutions, can also be added. According to the invention, the addition of a 50% aqueous NaOH solution is particularly preferred.

When a 50% NaOH solution is added, 1mol of the compound is used4-BrPreferably 50 to 200ml, particularly preferably 70 to 150ml, more preferably 90 to 110ml of a 50% NaOH solution are added.

After the end of the addition, the mixture is preferably brought to about 40 to 70 ℃, preferably 50 to 60 ℃, particularly preferably about 55 ℃ with stirring and stirred at constant temperature for a further at least 0.5 to 1.5 hours, preferably at least 0.6 to 1.25 hours, particularly preferably at least 0.75 to l hours.

The mixture is then optionally cooled to about 0 to 30 ℃, preferably 5 to 20 ℃, particularly preferably 10 to 15 ℃, and stirred at constant temperature for a further at least 0.5 to 2 hours, preferably at least 0.75 to 1.5 hours, particularly preferably at least 1 hour.

The crystals obtained are isolated, washed with water and optionally organic solvents and then dried under vacuum at a temperature of at most 50-90 ℃, preferably at most 60-70 ℃.

The following examples serve to illustrate the synthesis method carried out by way of example. Which are intended only as examples of possible steps and not to limit the invention to its content.

Example 1 formula4-BrLarge-scale industrial synthesis of compounds

88kg of carbonyl-bis- (1, 2, 4-triazole) are taken and mixed with 920 l of tetrahydrofuran. The contents of the apparatus were heated to 35 ℃ with stirring. Subsequently, 90kg of the compound are added portionwise over a period of 1 to 2 hours at 35 ℃3。

160kg of compound2Placed in a second reaction vessel, 350 liters of tetrahydrofuran were then added and the mixture was heated to 50 ℃ with stirring.

Within 2 to 3 hours at 47 ℃ -53 DEG C3Metering in of the solution of2And the obtained solution was diluted with 115 liters of tetrahydrofuran.

Next, the mixture is stirred at 47 ℃ to 53 ℃ (preferably 50 ℃) for an additional 4 hours. 670 to 695 l of tetrahydrofuran are subsequently distilled off in vacuo at 50 to 60 ℃. 235 l of n-butyl acetate were subsequently passed into the residue. Thereafter, 600 l to 630 l of the butyl acetate/THF mixture are distilled off in vacuo at 50 ℃ to 85 ℃. During the distillation, 700 l of butyl acetate are metered in.

65kg of acetic acid were passed into the residue, the contents were heated to 85 ℃ to 90 ℃ and stirred at this temperature for at least a further 2.5 hours. The mixture was then cooled to 65-75 ℃. To the contents was added a solution of 165 l water and 20kg common salt, and the mixture was rinsed with 300 l water. The temperature is then adjusted to 60 ℃ to 70 ℃ and the mixture is stirred at this temperature for a minimum of 15 minutes. To phase separate, the stirrer was stopped and the mixture was allowed to stand for at least 15 minutes. The aqueous phase was discharged into a further reaction vessel containing 120 l of n-butyl acetate. The mixture was heated to 60-70 ℃ with stirring and stirred for at least 10 minutes. After phase separation, the aqueous phase was drained into a chemical waste drain. The butyl acetate phase was mixed with 20 liters of butyl acetate for rinsing. 590 liters to 620 liters of n-butyl acetate were distilled off from this content under vacuum at a maximum internal temperature of 80 ℃.

880 l of isopropanol were passed into the distillation residue and the content was adjusted to 32-38 ℃. Approximately 90kg of 48% hydrobromic acid are subsequently metered in at 32 ℃ to 38 ℃ until a pH of 0.6 to 1.3 is reached. The mixture is stirred at 32-38 ℃ for a minimum of 20 minutes, then cooled to 7-13 ℃ and stirred at this temperature for at least 1 hour. The resulting suspension was centrifuged, washed with a total of 840 l isopropanol and dried under vacuum at maximum 55 ℃.

Yield: 211kg-250 kg. M.p.: 200 ℃ and 215 ℃ (decomposition).

Compound (I)4-HBrAny standard commercially available centrifuge can be used for separation.

Example 2 Large Scale Industrial Synthesis of a Compound of formula 1 (in the form of the p-toluenesulfonic acid addition salt)

330kg of the compound are mixed at 23 ℃ with stirring4-BrAnd 147kg of p-toluenesulfonic acid (as an aqueous solution) were added to 470kg of a 10 molar solution of hydrochloric acid in ethanol. The mixture was then heated to 28-29 ℃ and stirred at this temperature for 23 hours. The reaction mixture was diluted with 693 liters of ethanol and transferred to a second reaction vessel. The contents of this reaction vessel were diluted with another 536 liters of ethanol and cooled to 2 ℃. While maintaining the temperature at about 10 ℃ with further cooling and stirring, 440kg of a 25% aqueous ammonia solution are metered inUntil a pH value of 9.3 to 10 is obtained. The contents of the apparatus were heated to 25 ℃ and stirred at this temperature for 4 hours. The contents were then heated to 50 to 60 ℃ and 248-261 liters of ethanol were removed in vacuo. 1220 litres of water are then added at an internal temperature of 50-60 ℃. The contents of the apparatus were distributed in equal amounts (about 1450 litres) in two reaction vessels of the same size. Processing continues in parallel (simultaneously) in both devices. In each case, a solution of 950 l of water and 31 l of sodium hydroxide solution (50%) was added. The contents of both devices are adjusted to a temperature of 50 to 60 c (preferably 55 c) and stirred for 45 minutes. The mixture was then cooled to 10-15 ℃ over 3 hours and stirred at this temperature for a further 60 minutes.

The crystal suspension was separated by two centrifuges. The product was washed first with water, then with acetone and subsequently dried under vacuum at a temperature of up to 70 ℃.

Yield: 314kg-371 kg; melting point: 209 ℃ and 211 ℃.

Claims (30)

1. A process for preparing a compound of the formula:

optionally in the form of an acid addition salt thereof,

characterized in that in the first step, the formula2With carboxylic acids3In the presence of a suitable coupling reagent,

form type4Compound (I)

Without isolation, converting it to formula4-BrA salt of a hydrogen bromide with a hydrogen bromide,

finally converting it into the formula1Amidines of (1).

2. The process as claimed in claim 1, characterized in that2And3the reaction of (a) is carried out in a solvent selected from: dichloromethane, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, and dioxaneAlkanes and mixtures thereof.

3. The method of claim 2, characterized in that2And3the reaction of (a) is carried out in a solvent selected from: dimethylformamide and tetrahydrofuran.

4. The method of claim 2, characterized in that2And3the reaction of (a) is carried out in the following solvents: dimethylformamide (DMF).

5. The process of claim 2, wherein 1mol of the compound of the formula2Compound, using 0.5-1 liter of said solvent.

6. The method of claim 2Process in which 1mol of a compound of the formula2Compound, using 0.65-0.85 liter of said solvent.

7. The process of claim 2, wherein 1mol of the compound of the formula2Compound, using 0.7-0.8 l of said solvent.

8. The process of claim 1, characterized in that the coupling reagent is selected from the group consisting of N, N '-dicyclohexylcarbodiimide, N' -carbonyldiimidazole and carbonyl-bis- (1, 2, 4-triazole).

9. The process according to claim 1, characterized in that the coupling reagent is selected from the group consisting of N, N' -carbonyldiimidazole and carbonyl-bis- (1, 2, 4-triazole).

10. The process of claim 1, characterized in that the coupling reagent is carbonyl-bis- (1, 2, 4-triazole).

11. The process of claim 8, wherein 1mol of the compound of the formula2Compound, using 1-2mol of coupling reagent.

12. The process of claim 8, wherein 1mol of the compound of the formula2Compound, using 1-1.5mol of coupling reagent.

13. The process of claim 8, wherein 1mol of the compound of the formula2Compound, using 1.05-1.25mol of coupling reagent.

14. Process according to one of claims 1 to 13, characterized in that acetic acid is added for the preparation of formula (la)4A compound is provided.

15. Process according to one of claims 1 to 13, characterized in that formula (la)4-BrThe compound is prepared from the formula4The compound is obtained.

16. The process of claim 14, characterized by formula (la)4-BrCompounds of formula (I) by addition of aqueous hydrobromic acid4The compound is obtained.

17. A process according to any one of claims 1 to 13 for the preparation of formula (la)1The compound in the form of an acid addition salt with p-toluenesulfonic acid, characterized in that it is of formula4-BrConversion of the compound to the formula1The amidine of (a) in the form of an acid addition salt with p-toluenesulfonic acid is prepared by the following process: the 4-Br compound and p-toluenesulfonic acid were added to the acid-containing alcohol, followed by the addition of an aqueous ammonia solution.

18. The process of claim 14 for the preparation of formula (la)1The compound in the form of an acid addition salt with p-toluenesulfonic acid, characterized in that it is of formula4-BrConversion of the compound to the formula1The amidine of (a) in the form of an acid addition salt with p-toluenesulfonic acid is prepared by the following process: the 4-Br compound and p-toluenesulfonic acid were added to the acid-containing alcohol, followed by the addition of an aqueous ammonia solution.

19. The process of claim 15 for the preparation of formula (la)1The compound in the form of an acid addition salt with p-toluenesulfonic acid, characterized in that it is of formula4-BrConversion of the compound to the formula1The amidine of (a) in the form of an acid addition salt with p-toluenesulfonic acid is prepared by the following process: the 4-Br compound and p-toluenesulfonic acid were added to the acid-containing alcohol, followed by the addition of an aqueous ammonia solution.

20. The process of claim 16 for the preparation of formula (la)1The compound is in the form of an acid addition salt with p-toluenesulfonic acid, characterized in thatIn the formula4-BrConversion of the compound to the formula1The amidine of (a) in the form of an acid addition salt with p-toluenesulfonic acid is prepared by the following process: the 4-Br compound and p-toluenesulfonic acid were added to the acid-containing alcohol, followed by the addition of an aqueous ammonia solution.

21. The process of claim 17, characterized by formula (la)4-BrThe reaction of the compounds with the acid-containing alcohol is started with the addition of the entire amount of p-toluenesulfonic acid.

22. The process of claim 18, characterized by formula (la)4-BrThe reaction of the compounds with the acid-containing alcohol is started with the addition of the entire amount of p-toluenesulfonic acid.

23. The process of claim 19, characterized by formula (la)4-BrThe reaction of the compounds with the acid-containing alcohol is started with the addition of the entire amount of p-toluenesulfonic acid.

24. The process of claim 20, characterized by formula (la)4-BrThe reaction of the compounds with the acid-containing alcohol is started with the addition of the entire amount of p-toluenesulfonic acid.

25. The method according to claim 17, characterized in that the acid-containing alcohol is ethanol containing hydrochloric acid.

26. The method according to claim 18, characterized in that the acid-containing alcohol is ethanol containing hydrochloric acid.

27. The method of claim 19, characterized in that the acid-containing alcohol is ethanol containing hydrochloric acid.

28. The method of claim 20, characterized in that the acid-containing alcohol is ethanol containing hydrochloric acid.

29. The method of claim 21, characterized in that the acid-containing alcohol is ethanol containing hydrochloric acid.

30. Formula (II)4-BrCompound (I)