KR20120094090A - New process for the preparation of dronedarone - Google Patents

Abstract

The present invention provides for the preparation of N- [2- n -butyl-3- {4-[(3-dibutylamino) propoxy] benzoyl} -1-benzofuran-5-yl] methanesulfonamide of formula I Novel methods and novel intermediates in the above process.
Formula I

Description

New method for manufacturing dronedarone {NEW PROCESS FOR THE PREPARATION OF DRONEDARONE}

The present invention provides N- [2- n -butyl-3- {4-[(3-dibutylamino) -propoxy] benzoyl} -1-benzofuran-5-yl] methanesulfonamide Nedarone) and pharmaceutically acceptable salts thereof, and novel intermediates in the process.

(I)

The dronedarone of formula (I) is used for the treatment of certain pathological changes in the cardiovascular system, in particular for the treatment of angina, hypertension, arrhythmia and insufficient cerebral blood circulation (see European Patent No. 0471609 B1).

There are several known methods for preparing dronedarone of formula (I). In one conventional method (European Patent No. 0471609 B1), 2-hydroxy-5-nitro-benzylbromide of formula (VII) is reacted with triphenylphosphine and thus obtained 2-hydroxy-5- of formula (VIII) Nitro-benzyl-triphenyl-phosphonium bromide is reacted with pentanoyl chloride to give 2- n -butyl-5-nitro-benzofuran of formula (IX).

(VII)

(VIII)

(IX)

Treatment of a compound of formula IX with anisoyl chloride under Friedel-Crafts conditions to yield 2- n -butyl-3- (4-methoxy-benzoyl) -5-nitro-benzofuran of formula X And it is heated in the presence of aluminum chloride to give 2- n -butyl-3- (4-hydroxy-benzoyl) -5-nitro-benzofuran of formula (XI).

(X)

(XI)

Industrial application of this last reaction step is difficult, as 2- n -butyl-3- (4-methoxybenzoyl) -5-nitro-benzofuran of formula X is mutagenic and aluminum chloride is harmful to health Because it is. The resulting 2- n -butyl-3- (4-hydroxybenzoyl) -5-nitro-benzofuran of formula XI was reacted with dibutylamino-propylchloride to yield 2- n -butyl-3- [4 -(3-dibutylamino-propoxy) benzoyl] -5-nitro-benzofuran, which in the presence of a platinum oxide catalyst is 5-amino-2- n -butyl-3- [4- ( 3-dibutylamino-propoxy) benzoyl] benzofuran.

(XII)

(XIII)

Finally, the compound of formula (XIII) is mesylated to form dronedarone of formula (I).

It is a linear synthesis, which uses the more and more complex molecules in the next step to form the desired molecule step by step.

Another conventional method for the preparation of dronedarone of formula (I) is described in the patent application of WO 02/48078. In this process, 2- n -butyl-5-nitro-benzofuran of formula IX reacts with 4- [3- (dibutylamino) -propoxy] benzoyl chloride of formula XIV under Friedel-Crafts conditions, and so The obtained 2- n -butyl-3- [4- (3-dibutylamino-propoxy) benzoyl] -5-nitro-benzofuran of formula (XII) is 5-amino-2 of formula (XIII) in the presence of a platinum oxide catalyst. n -butyl-3- [4- (3-dibutylamino-propoxy) benzoyl] benzofuran.

(XIV)

The latter compound (formula XIII) is mesylated to form dronedarone of formula (I). However, in the final process, ie the mesylation step, double mesylated derivatives are also formed, the yield is low, and the purification of dronedarone by column chromatography is complicated. Therefore, the industrial application of this method is not economical.

A third known method for the preparation of dronedarone of formula (I) is described in the patent application of WO 02/48132. This superconvergence method contains the following steps:

Mesylating 5-amino-2- n -butyl-benzofuran of formula XV, and the resulting 2- n -butyl-5-mesylamino-benzofuran of formula III under 4-Delta Crafts conditions Reacting with [3- (dibutylamino) propoxy] benzoyl chloride hydrochloride salt to obtain the hydrochloride salt of dronedarone of formula Ia.

(XV)

[Formula III]

Formula XIVa

(Ia)

In this method, the order of the reaction steps can be varied and the reduction and mesylation steps take place at the beginning of the synthesis.

This method is very simple and economical in terms of the number of reaction steps. However, there is a drawback that in the last step the hydrochloride salt of dronedarone is obtained in a highly contaminated form. This can be explained by the presence of dibutylamino-propyl groups in the Friedel-Crafts reaction. In the published example, the yield is 90% and purified dronedarone hydrochloride is obtained (90%) after treatment with the raw material dronedarone hydrochloride followed by a solution of hydrogen chloride in isopropanol during the purification step.

Another drawback of this process is that the reactants used in the Friedel-Crafts reaction and the by-products obtained are not soluble in water and therefore they cannot be removed from the reaction system by aqueous washing.

The aim of the present inventors is to find a novel method for producing economically and industrially applicable dronedarone and its pharmaceutically acceptable salts, avoiding the above mentioned disadvantages.

The inventors have found that if the benzofuran derivative of formula (II) is reacted with dibutylamine and optionally converted to its salt form, this method avoids the disadvantages of the process described above and is suitable for economic and industrial application.

≪ RTI ID = 0.0 &

In Chemical Formula II,

X is a chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group.

One reactant is a dibutylamine which is volatile and can be removed from the reaction system and regenerated after workup, and the other reactant is a compound of formula II which can be treated well under the applied reaction conditions, wherein the meaning of X Equals). By selecting suitable reaction conditions, the dronedarone of formula (I) is obtained in suitable purity and yield, no by-products are formed, and only a few percent of unreacted starting material can be present in the reaction mixture, which can be regenerated have.

According to the invention, the reaction of a compound of formula II, wherein X is a chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group, with dibutylamine is equivalent or excess of dibutylamine Is done using The reaction is carried out in an organic solvent or a mixture of organic solvents. As the organic solvent, a mixture of ketones (acetone, methyl ethyl ketone) and organic solvents as a mixture of ketones and aromatic hydrocarbons (xylene, toluene) is used. Optionally, other organic solvents and mixtures thereof may also be used.

According to the invention, the compound of formula II, wherein X means as described above, is optionally reacted with dibutylamine in the presence of a catalyst. If X in formula (II) is a chloro- or bromo atom, iodide (eg sodium iodide or potassium iodide) is used as catalyst. If X in formula (II) is a hydroxyl group, then [Ru ( p -cymene) Cl ₂ ] ₂ and 1,1'-bis- (diphenylphosphino) ferrocene or [Ru ( p -cymene) Cl _{2 2} and bis- (2-diphenylphosphinophenyl) ester compounds are used. If X in formula (II) is an iodo atom or an activated hydroxyl group, no catalyst is used.

The reaction of the compound of formula II, wherein X is a chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group, with dibutylamine is carried out at the boiling point of the solvent used or at 60-120 ° C. do.

In the compound of formula II, the hydroxyl group can be activated with methylsulfonyl or substituted benzenesulfonyl group. Substituents of the benzenesulfonyl group is C _{1 -4} - can be an alkyl group, a halogen atom or a nitro group.

In one embodiment of the invention, 2- n -butyl-5-mesylamino-benzofuran of formula III is reacted with an acid halide of formula IV and the compound of formula II thus obtained, wherein X means Is reacted with dibutylamine in the manner described above to afford dronedarone of formula (I):

(III)

(IV)

In the above formula (IV)

Y is a chloro- or bromo atom,

X is a halogen atom or a protected hydroxyl group.

According to the invention, the reaction of the benzofuran derivative of formula III with the acid halide of formula IV, wherein X and Y are as described above, is carried out in the presence of a Friedel-Crafts catalyst in a halogenated organic solvent or nitrobenzene do.

The reaction of the compound of formula III with the compound of formula IV is carried out in a temperature range of 10 to 80 ° C.

In another embodiment of the invention, the compound of formula VI is treated with a hydrogenation reaction, the compound of formula V thus obtained is mesylated, and the resulting compound of formula II is reacted with dibutylamine in the manner described above Form I dronedarone.

(VI)

(V)

In Formulas VI and V,

X is a chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group.

The hydrogenation reaction of the compound of formula VI is carried out in the presence of a catalyst. In one version of the method, a palladium catalyst is used. In another version of the method, a platinum catalyst is used. The hydrogenation reaction of the compound of formula VI is carried out in an organic solvent and in a temperature range of 10 to 80 ° C.

Mesylation of the compound of formula V is carried out using methanesulfonyl chloride or methanesulfonic anhydride. Mesylation of the compound of formula V is carried out in an inert solvent. In one preferred embodiment of the reaction, ether or halogenated solvents are used. Mesylation of the compound of formula V is carried out in a temperature range of 5 to 80 ° C. Mesylation of the compound of formula V is carried out in the presence of a base. In one preferred embodiment of the reaction, amines (pyridine, triethylamine) are used as the base.

Benzofuran derivatives of formula (II), benzofuran derivatives of formula (V) and benzofuran derivatives of formula (VI) are novel compounds that are not known in the literature.

(II)

Formula V

VI

In Chemical Formulas II, V, and VI,

X is a chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxy group.

In one embodiment of the invention, the compound of formula II, wherein X is as defined above, comprises a compound of formula III, wherein Y is a chloro- or bromo atom, A halogen atom or a protected hydroxyl group). Compounds of formula III are known and their preparation by mesylation of 5-amino-2- n -butyl-benzofuran is described in the patent application of WO 02/048132. Compounds of formula IV, wherein the meanings of X and Y are as described above, are also known in the literature and their preparation is described in patent EP 0471609 B1.

In another embodiment of the invention, the compound of formula II wherein X is as defined above is a compound of formula V wherein X is a chloro-, bromo- or iodo atom, hydroxyl- or activation Refers to hydroxyl groups). Compounds of formula (V), wherein X is as described above, are prepared by catalytic hydrogenation of benzofuran derivatives of formula (VI), wherein X is as described above. Compounds of formula VI wherein X is a bromo atom are known in the literature. The compound itself and its preparation are described in patent EP 0471609 B1. Preparation of compounds of formula VI, wherein X represents a chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group, from a benzofuran derivative of formula XI is described in EP 0471609 B1. It is performed similarly to the method.

Further details of the invention are illustrated by the following examples, which are not intended to limit the scope of the claims.

Example  One

(2- n -Butyl-5-nitro-1- Benzofuran -3-yl)-[4- (3- Chloropropoxy ) Phenyl ] Methanone That is X Chloro  Chemical formula VI Compound of

40 g (2- n -butyl-3- (4-hydroxybenzoyl) -5-nitro-benzofuran (XI)) are dissolved in 320 ml methyl ethyl ketone and added to 48.9 g potassium carbonate solution. 37.2 g 1-bromo-3-chloropropane are added and the mixture is heated under reflux (81-82 ° C.) and stirred at this temperature for 4 hours After cooling, the solid salt is filtered off and 3 × 20 Washed with ml methyl ethyl ketone The filtrate was evaporated The removed methyl ethyl ketone containing excess 1-bromo-3-chloropropane was used in the next reaction.

Product mass: 44.93 g (99.1%)

Purity (HPLC): 98.9%

Molecular weight: (calculated): 416.1265 Da;

(Measured): 416.1274 Da

Example   2

(5-amino-2- n Butyl Benzofuran -3-yl)-[4- (3- Chloropropoxy ) Phenyl ] Methanone That is X Chloro  A compound of formula V that is an atom

93.8 g (2- n -butyl-5-nitro-1-benzofuran-3-yl)-[4- (3-chloro-propoxy) phenyl] -methanone in a 500 ml hydrogenation reactor equipped with a turbo stirrer Compound of formula VI, wherein X is a chloro atom) and 470 ml anhydrous ethanol were added followed by 4.9 g of 10% palladium on carbon catalyst. The reaction mixture was heated to 50 ° C. at a speed of 800 revolutions / minute under stirring. After cooling, 5 bar pressure of hydrogen was set in the reactor and the mixture was stirred at this pressure and temperature for 2 hours. After cooling, the catalyst was filtered off and the solvent was removed.

Product mass: 85.46 g (98%).

Purity (HPLC): 93.8%

Molecular weight: (calculated): 386.1523 Da

(Measured): 386.1524 Da

Example  3

(5-amino-2- n Butyl Benzofuran -3-yl)-[4- (3- Bromo - Propoxy ) Phenyl ] Methanone , In other words X Bromo  A compound of formula V that is an atom

Starting from (2- n -butyl-5-nitro-1-benzofuran-3-yl)-[4- (3-bromopropoxy) phenyl] methanone (compound of formula VI wherein X is bromo atom) The method described in Example 2 was carried out.

Yield of product: 97.6%

Purity (HPLC): 92.4%

Molecular weight: (calculated): 430.1018 Da

(Measured): 430.1032 Da

Example  4

N -(2- n -Butyl-3- [4- (3- Chloropropoxy ) Benzoyl ] Benzofuran -5 days) Methanesulfonamide That is X Chloro  Chemical formula II Compound of

8.7 g (5-amino-2- n -butyl-benzofuran-3-yl)-[4- (3-chloropropoxy) phenyl] methanone (compound of formula (V), wherein X is a chloro atom) is completely dissolved. Stir in 90 ml dichloromethane until. The solution was cooled to 15 ° C., 1.8 g pyridine was added while maintaining this temperature, and then 2.6 g methanesulfonyl chloride was added dropwise at 15 ° C. in 15 minutes. The reaction mixture was examined by HPLC and further 0.19 g pyridine and 0.26 g methanesulfonyl chloride were added and stirring continued for 30 minutes. The reaction mixture was washed with 2 x 20 ml water, 2 x 20 ml 5% hydrochloric acid and 2 x 20 ml 5% NaHCO ₃ solution, which was then evaporated.

Product mass: 10.1 g (96.6%)

Purity: 87.5%

Purity of the product after crystallization with anhydrous ethanol (yield 72%) (by HPLC): 100%

Melting point: 109.7 to 110.3 ° C

Example  5

N -(2- n -Butyl-3- [4- (3- Bromopropoxy ) - Benzoyl ] Benzofuran -5 days) Methanesulfonamide That is X Bromo  Chemical formula II Compound of

(5-amino-2- n -butyl-benzofuran-3-yl)-[4- (3-bromopropoxy) phenyl] methanone (compound of formula (V) wherein X is a bromo atom) The method described in Example 4 was performed.

Yield of product: 95.8%

Purity: 86.8% (HPLC)

Molecular weight: (calculated): 508.0793 Da

(Measured value): 508.0780 Da

Example  6

N -(2- n -Butyl-3- [4- (3- Chloropropoxy ) Benzoyl ] Benzofuran -5 days) Methanesulfonamide That is X Chloro  Chemical formula II Compound of

5.2 g 2- n -butyl-5-mesylamino-benzofuran (compound of formula III) is mixed with 30 ml dichloromethane and in the resulting suspension 5.55 g 4- (3-chloropropoxy) benzoic acid chloride (X and Compound of formula IV wherein Y is a chloro atom) was added slowly. The reaction mixture was cooled to 5 ° C. and within 15 minutes 3.89 g iron (III) chloride was added in 4 portions and maintained at a temperature of 5-10 ° C. The mixture was stirred at 20 ° C. for 1 hour, then heated to 40-45 ° C. and 54 ml water was added within 30 minutes. The mixture was stirred at this temperature for 30 minutes. The phases were separated when still warm. The dichloromethane phase was washed by stirring with 2 x 16 ml 5% NaHCO ₃ solution followed by 2 x 16 ml water. The solvent was removed by evaporation.

Product mass: 9.13 g (98.4%)

Purity (HPLC) 89.6%.

Purity of the product after crystallization with anhydrous ethanol (88%) (by HPLC): 100%

Melting point: 109.8 ~ 110.2 ° C

The product is the same as the product prepared in Example 4.

Example  7

N -(2- n -Butyl-3- [4- (3- Chloropropoxy ) Benzoyl ] Benzofuran -5 days) Methanesulfonamide That is X Chloro  Chemical formula II Compound of

The reaction was carried out as described in Example 6, but chlorobenzene was used as solvent instead of dichloromethane.

Product mass: 97.6%

Purity (HPLC): 88.6%

Example  8

N -(2- n -Butyl-3- [4- (3- Chloropropoxy ) Benzoyl ] Benzofuran -5 days) Methanesulfonamide That is X Chloro  Chemical formula II Compound of

The reaction was carried out as described in Example 7, but aluminum chloride was used instead of iron (III) chloride.

Yield of product: 96.8%

Purity (HPLC): 86.5%

Example  9

N -(2- n -Butyl-3- [4- (3- Bromopropoxy ) Benzoyl ] Benzofuran -5 days) Methanesulfonamide That is X Bromo  Chemical formula II Compound of

In a suspension of 5 g 2- n -butyl-5-mesylamino-benzofuran (compound of formula III) in 35 ml dichloromethane, 5.19 g 4- (3-bromopropoxy) benzoyl chloride (X is a bromo atom , Compound of formula IV wherein Y is a chloro atom) was added slowly. The reaction mixture was cooled to 5 ° C., 9 g iron (III) chloride was added in 5 fractions within 20 minutes, and the temperature was maintained at 5-10 ° C. The mixture was stirred at 20 ° C. for 1 hour, then heated to 40-45 ° C. and 55 ml water was added within 30 minutes. The mixture was stirred at this temperature for 40 minutes. The phases were separated when still warm. The dichloromethane phase was washed by stirring with 2 x 16 ml 5% NaHCO ₃ solution followed by 2 x 16 ml water. The solvent was removed by evaporation.

Product mass: 8.1 g (93.4%)

Purity (HPLC): 88.2%.

The product is the same as the product prepared in Example 5.

Example  10

N -(2- n -Butyl-3- [4- (3- Bromopropoxy ) Benzoyl ] Benzofuran -5 days) Methanesulfonamide That is X Bromo  Chemical formula II Compound of

The reaction was carried out as described in Example 9, but chlorobenzene was used instead of dichloromethane as solvent.

Product mass: 7.9 g

Purity (HPLC): 86.7%

Example  11

N -(2- n -Butyl-3- [4- (3- Bromopropoxy ) Benzoyl ] Benzofuran -5 days) Methanesulfonamide That is X Bromo  Chemical formula II Compound of

The reaction was carried out as described in Example 9, but an aluminum chloride catalyst was used instead of iron (III) chloride.

Product mass: 8.0 g

Purity (HPLC): 85.6%

Example  12

N -[2- n -Butyl-3- {4-[(3- Dibutylamino ) Propoxy ] Benzoyl }-One- Benzofuran -5 days]- Methanesulfonamide That is, a compound of formula (I)

90 ml of 5 g N- (2- n -butyl-3- [4- (3-chloropropoxy) benzoyl] benzofuran-5-yl) -methanesulfonamide (compound of formula II wherein X is a chloro atom) Dissolved in methyl ethyl ketone, then 16.7 g dibutylamine and 6.46 g sodium iodide were added and the mixture was stirred for 16 hours. The reaction mixture was evaporated and 100 ml dichloromethane and 100 ml water were added. The phases were separated. The organic phase was washed by stirring with 50 ml 5% hydrochloric acid and then 50 ml water. The solvent was distilled off. Dibutylamine recovered from the solvent was used in the next reaction.

Product mass: 5.9 g (100.0%)

Purity (HPLC): 98.7%

The product is purified through its oxalate salt (90%).

Purity of oxalate salt (HPLC): 100%

Example  13

N -[2- n -Butyl-3- {4-[(3- Dibutylamino ) Propoxy ] Benzoyl }-One- Benzofuran -5 days]- Methanesulfonamide That is, a compound of formula (I)

The reaction was carried out as described in Example 12, but potassium iodide was used instead of sodium iodide.

Product mass: 100.0%

Purity (HPLC): 97.8%

Example  14

N -[2- n -Butyl-3- {4-[(3- Dibutylamino ) Propoxy ] Benzoyl }-One- Benzofuran -5 days]- Methanesulfonamide That is, a compound of formula (I)

The reaction was carried out as described in Example 12, but acetone was used instead of methyl ethyl ketone.

Product mass: 98.7%

Purity (HPLC): 97.1%

Example  15

N -[2- n -Butyl-3- {4-[(3- Dibutylamino ) Propoxy ] Benzoyl }-One- Benzofuran -5 days]- Methanesulfonamide That is, a compound of formula (I)

The reaction was carried out as described in Example 12, but a 9: 1 mixture of methyl ethyl ketone and toluene was used as the solvent.

Yield of product: 98.8%

Purity (HPLC): 98.7%

Example  16

N -[2- n -Butyl-3- {4-[(3- Dibutylamino ) Propoxy ] Benzoyl }-One- Benzofuran -5 days]- Methanesulfonamide That is, a compound of formula (I)

N- (2- n -butyl-3- [4- (3-bromopropoxy) benzoyl] benzofuran-5-yl) methanesulfonamide (compound of formula II wherein X is bromo atom) as starting material The reaction was carried out as described in Example 12.

Yield of product: 98.7%

Purity (HPLC): 97.7%

The product is the same as the product prepared in Example 12.

Example  17

N -[2- n -Butyl-3- {4-[(3- Dibutylamino ) Propoxy ] Benzoyl }-One- Benzofuran -5 days]- Methanesulfonamide That is, a compound of formula (I)

The reaction is carried out as described in Example 12, but the starting material is N- (2- n -butyl-3- [4- (3-methanesulfonyloxy-propoxy) benzoyl] benzofuran-5-yl) Methanesulfonamide (compound of formula II, wherein X is a methanesulfonyloxy group), with the difference that no sodium iodide was used.

Yield of product: 89.1%

Purity (HPLC): 98.1%

Example  18

N -[2- n -Butyl-3- {4-[(3- Dibutylamino ) Propoxy ] Benzoyl }-One- Benzofuran -5 days]- Methanesulfonamide That is, a compound of formula (I)

The reaction is carried out as described in Example 12, but the starting material is N- (2- n -butyl-3- [4- (3-tosyloxy-propoxy) benzoyl] benzofuran-5-yl) -methane The difference was that they were sulfonamides (compounds of formula II wherein X is a tosyloxy group) and no sodium iodide was used.

Yield of product: 97.81%

Purity (HPLC): 97.6%

Example  19

N -[2- n -Butyl-3- {4-[(3- Dibutylamino ) Propoxy ] Benzoyl }-One- Benzofuran -5 days]- Methanesulfonamide That is, a compound of formula (I)

0.5 g N- (2- n -butyl-3- [4- (3-hydroxy-propoxy) -benzoyl] -benzofuran-5-yl) -methanesulfonamide (of Formula II wherein X is a hydroxyl group) Compound) was dissolved in 8 ml toluene. To the solution was added 1.5 g dibutylamine and 1.2 mol% [Ru ( p -cymene) Cl ₂ ] ₂ and 2.5 mol% 1,1′-bis- (diphenylphosphino) -ferrocene catalyst and the reaction mixture was It was kept under reflux for 24 hours. The solvent was removed by evaporation and the residue was dissolved in 10 ml dichloromethane and washed by stirring with 5 ml 1% hydrochloric acid and then 10 ml water. The solvent was removed by evaporation.

Product mass: 0.51 g (82.5%)

Purity (HPLC): 92.4%

The product is the same as the product prepared according to Example 12.

Example  20

N -[2- n -Butyl-3- {4-[(3- Dibutylamino ) Propoxy ] Benzoyl }-One- Benzofuran -5 days]- Methanesulfonamide Hydrogen  Chloride salts, i.e. Ia Compound of

5 g dronedarone base material was dissolved in 24 ml isopropanol, and 0.98 g 37% hydrochloric acid was added thereto. The mixture was cooled to 0 ° C. and maintained at this temperature for 5 hours. The precipitated white crystals were collected and washed with 3.5 ml isopropanol. The product was dried at 50 ° C. under vacuum.

Product mass: 5.2 g (97.6%)

Purity (HPLC): 100%

Claims (37)

The benzofuran derivative of formula (II) is reacted with dibutylamine and, if necessary, forms a salt of the product, N- [2- n -butyl-3- {4-[(3- Dibutylamino) propoxy] benzoyl} -1-benzofuran-5-yl] methanesulfonamide and a method for preparing a pharmaceutically acceptable salt thereof.
Formula I

(II)

In Chemical Formula II,
X is a chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group. The process according to claim 1, wherein the reaction is carried out using excess dibutylamine. The process according to claim 1 or 2, characterized in that the reaction is carried out in an organic solvent or a mixture of organic solvents. The method of claim 3, wherein the organic solvent is selected from ketones. The method of claim 4, wherein the ketone is acetone or methyl ethyl ketone. 4. The process according to claim 3, wherein a mixture of ketones and aromatic hydrocarbons is used as the mixture of organic solvents. The method according to claim 6, wherein toluene or xylene is used as the aromatic hydrocarbon. The process according to claim 1, wherein when X in formula II means chloro- or bromo atom or hydroxyl group, the reaction is carried out in the presence of a catalyst. The process according to claim 8, wherein when X means in formula (II) is a chloro- or bromo atom, the catalyst is sodium iodide or potassium iodide. 9. The catalyst of claim 8 wherein X in formula II is a hydroxyl group, wherein the catalyst is [Ru ( p -cymene) Cl ₂ ] ₂ and 1,1′-bis- (diphenylphosphino) ferrocene or [Ru ( p -cymene) Cl ₂ ] ₂ and bis- (2-diphenylphosphinophenyl) ester compound. The process according to any one of the preceding claims, characterized in that the reaction is carried out at the boiling point of the solvents or at a temperature of 60 to 120 ° C. The process according to claim 1, wherein when the meaning of X in formula (II) is an activated hydroxyl group, the activation group is a mesyloxy- or substituted benzenesulfonyloxy group. . The method of claim 12, wherein the substituent of the substituted benzenesulfonyloxy group is selected from methyl group, nitro group or halogen atom. The process according to claim 1, wherein the benzofuran derivative of formula III is reacted with the benzoyl halogenide of formula IV and the resulting benzofuran derivative of formula II is reacted with dibutylamine and Accordingly, forming a salt of the product.
Formula III

Formula IV

(II)

In Chemical Formulas IV and II,
Y is a chloro- or bromo atom,
X is a halogen atom or a protected hydroxyl group. The method of claim 14, wherein the reaction of the compound of formula III with the compound of formula IV is carried out in the presence of a Friedel-Crafts catalyst. The process according to claim 15, characterized in that aluminum chloride or iron (III) chloride is used as Friedel-Crafts catalyst. The method of claim 14, wherein the reaction of the compound of formula III with the compound of formula IV is carried out in a halogenated solvent. 18. The process of claim 17, wherein dichloromethane, dichloroethane or chlorobenzene is used as the halogenation solvent. The method of claim 14, wherein the reaction of the compound of formula III with the compound of formula IV is carried out in nitrobenzene. The method of claim 14, wherein the reaction of the compound of formula III with the compound of formula IV is carried out at a temperature of 10 to 80 ° C. 16. 14. The benzofuran of any one of claims 1 to 13, wherein a) the compound of formula VI is subjected to a hydrogenation reaction, b) mesylated compound c is produced, and c) the resulting benzofuran of formula II The derivative is reacted with dibutylamine and, if necessary, is characterized in that the compound of formula (I) thus obtained is converted to its salt.
Formula VI

Formula V

(II)

In Formulas VI, V and II,
X is a chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group. The process according to claim 21, wherein in the reaction step a) the hydrogenation reaction is carried out in the presence of a catalyst. 23. The method of claim 22, wherein palladium or platinum is used as a catalyst. The process according to claim 21, wherein in the reaction step a) the reaction is carried out in an organic solvent at a temperature of from 10 to 80 ° C. 23. The process according to claim 21, wherein in reaction step b) methanesulfonyl chloride or methanesulfonic anhydride is used as mesylating agent. The process according to claim 21, wherein in the reaction step b) the reaction is carried out in an inert solvent. 27. The method of claim 26, wherein an ether or halogenated hydrocarbon is used as the inert solvent. The process according to claim 21, wherein in the reaction step b) the reaction is carried out at a temperature of 5 to 80 ° C. 23. The process of claim 21, wherein in reaction step b) the reaction is carried out in the presence of a base. The method according to claim 29, wherein an amine compound is used as the base. 31. The method of claim 30, wherein pyridine or triethylamine is used as the amine. Compound of formula II.
(II)

In Chemical Formula II,
X is a chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group. The compound of claim 32, wherein X is a mesyloxy group or a substituted benzenesulfonyloxy group. Compound of Formula V.
Formula V

In Formula V,
X is a chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group. The compound of claim 34, wherein X is a mesyloxy group or a substituted benzenesulfonyloxy group. Compound of Formula VI.
Formula VI

In the formula (VI)
X is a chloro or iodo atom, hydroxyl- or activated hydroxyl group. The compound of claim 36, wherein X is a mesyloxy group or a substituted benzenesulfonyloxy group.