KR20140020981A - Process for preparation of dronedarone by mesylation - Google Patents

Abstract

화학식 II

상기 화학식 II에서,
A는 화학식 II의 화합물과 산 부가염을 형성하는 일염기성 또는 이염기성 산이고,
n은 A가 이염기성 산인 경우 1이고,
n은 A가 일염기성 산인 경우 1 또는 2이다.The present invention is a heterogeneous salt of (5-amino-2-butyl-l-benzofuran-3-yl) {4- [3- (di-n-butylamino) propoxy] phenyl} methanone of formula II. Reactions, optionally with N- [2-n-butyl-3- [4- [3- (di-n-butylamino) -pro, of formula I, reacted with mesylation reagents in the presence of a phase transfer catalyst. Foxy] -benzoyl] -benzofuran-5-yl] methanesulfonamide and pharmaceutically acceptable salts thereof. The invention also relates to novel salts of the compounds of the formula (II), their preparation and their use in the preparation of dronedarone.
Formula I

(II)

In the above formula (II)
A is a monobasic or dibasic acid forming an acid addition salt with a compound of formula II,
n is 1 when A is a dibasic acid,
n is 1 or 2 when A is a monobasic acid.

Description

Production method of dronedarone by mesylation {PROCESS FOR PREPARATION OF DRONEDARONE BY MESYLATION}

The present invention relates to a novel process for the preparation of dronedarone and pharmaceutically acceptable salts thereof, to novel intermediate compounds used in the process and to the preparation thereof.

Dronedarone is a drug known for the treatment of arrhythmia, which is N- [2-n-butyl-3- [4- [3- (di-n-butylamino) propoxy] benzoyl] benzofuran-5-yl] methane Has the chemical name of sulfone-amide [see Formula I below]. There are several known methods for the preparation of dronedarone:

In EP 0471609, the following scheme for the preparation of dronedarone is disclosed.

[Method A]

The above mentioned patent specification also discloses several novel intermediate compounds.

International Publication No. WO 02/48078 discloses the following scheme for the preparation of dronedarone:

[Method B]:

The novelty of the method is based on the application of the Friedel-Crafts reaction in the first step. Processes and intermediate compounds used in the preparation of the benzoylchloride compounds of the first step are also disclosed in this document. Further steps of the method are the same as the final steps of the synthetic route disclosed in EP 0471609 [Method A], but the claims claim the entire synthetic route up to dronedarone.

International Publication WO 02/48132 (Sanofi) discloses the following reaction route [method C]. This method is also called a superconvergent route. In its first step, 5-amino-2-butyl-benzofuran

Mesylate and the resulting 2-butyl-5-methanesulfonamido-benzofuran (in HC1 salt form) is further reacted in the following step as follows:

In this method, the order of the reaction steps is changed and the reduction and methanesulfonylation steps are carried out at the beginning of the process. In addition to the reaction route for the preparation of dronedarone, the starting material 2-butyl-5-methanesulfonamido-benzofuran and its preparation are also claimed.

Among the processes specified, the first method [Method A] is the so-called linear synthesis. In this manner, different parts of dronedarone accumulate stepwise on the starting compound. This method is minimally economical because stepwise accumulation of chemical groups is performed when more complex and expensive molecules are used which increase the manufacturing cost. In addition, this involves a complex and dangerous reaction step, since aluminum chloride is used in the cleavage reaction of the methoxy group, which further complicates the industrial feasibility.

International Publication No. WO 02/48078 (Method B) discloses a simpler synthetic route to make this process more economical, but its final reaction step still contains the methanesulfonylation of amino groups. This reaction step (see the method described in Example 6 of WO 02/48078) is complex and gives a low yield of only 61.6%. Pure product can be obtained after purification using chromatography column purification, which purification method is essential because of the difficulty of separation of bis-methanesulfonylated products.

The method disclosed in WO 02/48132 (Method C) is simpler and more economical given the number of reaction steps. Unfortunately, somewhat impure dronedarone.HCl (hydrochloride) is formed in the last reaction step, which is a clear result of the presence of dibutylamino groups in the Friedel-Crafts reaction. According to Examples 3 and 4, crude dronedarone hydrochloride is prepared in 90% yield, which is further purified to finally produce crude dronedarone base in 86% yield. This base is reacted with hydrogen chloride gas dissolved in isopropanol to give the pure dronedarone hydrochloride salt. No yield is provided for this reaction step. According to Example 5, the crude dronedarone hydrochloride salt is prepared in 90% yield, which is washed with water and reacted with hydrogen chloride gas dissolved in isopropanol to yield the dronedarone hydrochloride salt. The quality of this product is unknown. However, none of the components used in the Friedel-Crafts reaction and the resulting products and by-products are soluble in water, and the washing step with water can kill the inorganic salts and cause no purification.

There is another drawback with the process, namely that the mesylation reaction of 5-amino-2-butyl-benzofuran results in the formation of dimesylated byproducts. Purification is carried out by crystallization, which has a yield of 78.5%.

The methanesulfonylation reaction of amino groups in the preparation of dronedarone is carried out using methanesulfonyl chloride as methanesulfonyl chloride in the presence of triethylamine as an acid binder in a dichloromethane solvent (see EP 0 471 609). Known from example 3 of method A). Perhaps the reaction is carried out at room temperature since the temperature used is not provided. The reaction time is 20 hours. The yield of crude dronedarone is 100%, but pure dronedarone can be prepared from crude material in a yield of only 61.6%. In another example, purification of crude dronedarone is by hexane. The yield of this purification step is 56.5%. The purity of pure dronedarone obtained is 96.1% (HPLC).

In Example 35 of EP 0 471 609 (Method A), methanesulfonylation of 2-n-butyl-5-amino-benzofuran is disclosed. The solvent is carbon tetrachloride, triethylamine is used as the base, and methanesulfonyl chloride is used as the methanesulfonylation reagent in an amount of 3 equivalents. After 6 hours of reaction time, 2- (bis-methanesulfonamido) -2-n-butyl-benzofuran [3] is isolated.

Selective mono-methanesulfonylation of amino groups is difficult, and it is very clear from these two experiments that, according to Example 3 mentioned previously, in addition to unreacted amino compounds, bis-methanesulfonylated compounds (2) are also present. . This is the reason for the moderate yield of the purification of crude dronedarone and the relatively low purity level of 96.1% (HPLC) (the resultant material cannot be used directly for pharmaceutical purposes).

It is an object of the present invention to provide a novel process for the preparation of dronedarone of formula (I) for starting with known commercial materials to obtain products of high overall yield and good purity using simple and environmentally friendly reagents and solvents. will be.

The main aspect of the present invention is a salt of (5-amino-2-butyl-l-benzofuran-3-yl) {4- [3- (di-n-butylamino) propoxy] phenyl} methanone of formula (II). Is a heterogeneous reaction, optionally with N- [2-n-butyl-3- [4- [3- (di-,), which is reacted with a mesylation reagent in the presence of a phase transfer catalyst. n-butylamino) -propoxy] -benzoyl] -benzofuran-5-yl] methanesulfonamide (dronedarone) and a pharmaceutically acceptable salt thereof.

(I)

≪ RTI ID = 0.0 &

In the above formula (II)

A is a monobasic or dibasic acid forming an acid addition salt with a compound of formula II,

n is 1 when A is a dibasic acid,

n is 1 or 2 when A is a monobasic acid.

The obtained salt is separated and, if desired, the free base form is liberated therefrom and optionally the free compound obtained is converted to another salt.

The acids usable for the preparation of pharmaceutically acceptable salts can be any inorganic or organic acid which forms an acid addition salt with the compound of formula (I). Exemplary acids that can form acid addition salts are: acetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, boric acid, butyric acid, citric acid, fumaric acid , Hydrogen chloride, hydrogen bromide, hydrogen iodide, 2-hydroxyethanesulfonic acid, maleic acid, nitric acid, salicylic acid, tartaric acid, sulfuric acid (forms sulfate or nonsulfate anions), sulfonic acids (e.g., those mentioned herein) ), Succinic acid, toluenesulfonic acid, etc. Hydrogen halide salts are common, especially hydrogen chloride salts.

Herein it is stated that on the amide portion of the mesylate group of the compound of formula (I) (see "left" of the molecule), salt formation can be carried out by strong bases, for example alkali hydroxides, usually by sodium hydroxide. It is. However, such salts are less important in practice, but are within the scope of salts that can be prepared by the claimed method, that is, the phrase "salt" includes both acid addition salts and salts formed by bases (basic salts).

Another aspect of the present invention is a novel of (5-amino-2-butyl-l-benzofuran-3-yl) {4- [3- (di-n-butylamino) propoxy] phenyl} methanone of formula II. It relates to one intermediate salt.

(II)

In the above formula (II)

A is a monobasic or dibasic acid forming an acid addition salt with a compound of formula II,

n is 1 when A is a dibasic acid,

n is 1 or 2 when A is a monobasic acid,

Provided that A is other than oxalic acid.

A further aspect is a process for the preparation of a novel salt of a compound of formula II, wherein the nitro group of the compound of formula III is hydrogenated in the presence of acid A in a solvent.

(II)

[Formula III]

In the above formula (II)

A is a monobasic or dibasic acid forming an acid addition salt with a compound of formula II,

n is 1 when A is a dibasic acid,

n is 1 or 2 when A is a monobasic acid,

Provided that A is other than oxalic acid.

A further aspect is N- [2-n-butyl-3- [4- [3- (di-n-butylamino) -propoxy] -benzoyl] -benzofuran-5-yl] methanesulfonamide of formula I And (5-amino-2-butyl-l-benzofuran-3-yl) {4- [3- (di-n-butylamino) propoxy of formula II for the preparation of pharmaceutically acceptable salts thereof. ] Phenyl} methanone salt. In this use, the compound of formula (II) is subjected to a heterogeneous reaction, optionally in the presence of a phase transfer catalyst, with the mesylation reagent to mesylate it.

Formula I

(II)

In the above formula (II)

A is a monobasic or dibasic acid forming an acid addition salt with a compound of formula II,

n is 1 when A is a dibasic acid,

n is 1 or 2 when A is a monobasic acid.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel process for carrying out the mesylation reaction starting from the novel salts of the compounds of formula II. The method is simple and practical; There is no need to use other amines to bind the acid prepared in the mesylation reaction, and furthermore, the use of novel salts of the compounds of formula (II) results in negligible formation of bis-mesylation products (<0.1%). This makes unnecessary material consuming purification for the removal of bis-mesylated products. Salts of the compounds of formula II can be prepared in a simple manner by mixing the base of formula II with one or two equivalents of the desired acid.

Starting amine bases of formula II are known from EP 0471609. Oxalate salts of compounds of formula II are also known from example 2 of EP 0471609, which can be used for the purification of compounds of formula II. Other salts are not known from the prior art. However, moderate yields and purity can be achieved by the use of oxalate salts in the process of the invention (ie this is not an advantageous aspect).

While not wishing to be bound by itself to the following theory, the inventors assume that the heterogeneous nature of the reaction plays an important role in the selectivity of the mesylation reaction (selectivity for the preparation of mono-mesylated products). In this process, the salt form of the compound of formula (II) is not soluble in the inert solvent used (which may also be a solvent mixture), but the base form and dissociated acid (acid A) are not used in the solvent used Is soluble). We note that after the formation of the mono-mesylated compound, salt formation takes place in the di-N-alkylated amino group (see "right side" of the molecule) and the formed salt remains in an inert solvent, which prevents formation of the di-mesylated product. Assume that it interferes. This theory provides an explanation for the surprising selectivity observed for mono-mesylation.

The phrase "insoluble" or "not soluble" has the general meaning used in the chemical arts, i.e. shows very poor solubility because the minimum solubility cannot be explicitly theoretically excluded (solution less than 0.1 or 0.01 or 0.001% by weight). From this component). The phrases "soluble" and "soluble" indicate much better solubility (at least 0.1% by weight, for example at least 1% by weight solution can be prepared from the components).

The acid that can be used may be any inorganic or organic acid which forms an acid addition salt with the compound of formula II. Exemplary meanings of acid A are: acetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, boric acid, butyric acid, citric acid, ethanesulfonic acid, fumaric acid , Hydrogen chloride, hydrogen bromide, hydrogen iodide, 2-hydroxyethanesulfonic acid, maleic acid, methanesulfonic acid, nitric acid, salicylic acid, tartaric acid, sulfuric acid (forms sulfate or nonsulfate anion), sulfonic acid (e.g. Mentioned), succinic acid, toluenesulfonic acid, and the like. Hydrogen halide salts are common, especially hydrogen chloride salts. In addition, methanesulfonic acid and p-toluenesulfonic acid salts are also practical.

The reaction is usually carried out at a temperature of 50 to 140 ° C., for example 65 to 100 ° C., usually under atmospheric pressure.

The heterogeneous nature of the reaction can be ensured by the appropriate choice of solvent used in the reaction. The salt of (5-amino-2-butyl-1-benzofuran-3-yl) {4- [3- (di-n-butylamino) propoxy] phenyl} -methanone of formula (II) is insoluble but not a base thereof Form and acid A must be used as the solvent in which it is dissolved. Alternatively, the solvent must be inert, ie it must not react with any reagents used in the process.

In one embodiment, the solvent is selected from the group of aromatic compounds, halogenated aromatic compounds, halogenated alkenes or cycloalkanes, ethers and ketones and any mixtures thereof. Typically the solvent is selected from the group of toluene, xylene, chlorobenzene, anisole, dichloroethane, heptane, 2-methyl cyclohexane, dibutyl ether, methylethyl ketone and any mixtures thereof.

In this process, mesylation reagents must be used. This can be any reagent that can be used to insert the CH ₃ SO ₂ -group into the free amino group of the compound of formula II (see “left” of formula II). It is advantageous to use methanesulfonic anhydride or methanesulfonyl halides such as methanesulfonyl chloride.

With regard to the heterogeneous nature of the process of the invention, it is advantageous to use phase transfer catalysts. This phrase is evident to the skilled person and includes ingredients which allow the base form compound of formula II to be dissolved in the inert solvent used. Phase transfer catalysts are typically quaternary ammonium salts, for example quaternary ammonium chloride.

Salts of compounds of formula II can be prepared by known procedures. Typically, one or two equivalents of acid A (5-amino-2-butyl-l-benzofuran-3-yl) {4- [3- (dibutylamino) propoxy] phenyl} methanone of formula (II) It is typically reacted with hydrogen chloride, hydrogen bromide, methanesulfonic acid, p-toluenesulfonic acid, for example hydrogen chloride. The reaction is carried out in a conventional inert solvent (or solvent mixture) and the salts obtained are separated (if desired, this can be further purified by known purification methods).

In another embodiment of the present invention, salts of compounds of formula II can be prepared by reducing (hydrogenating) the nitro groups of compounds of formula III in the presence of one or two equivalents of acid A (see above). The product obtained can be used in the mesylation step without further purification.

(III)

The reduction is usually the solvent to be used in hydrogenation (typically C _{1 -4} alcohol (e.g., methanol and ethanol), ethyl acetate, cyclohexane) in such a conventional catalyst (for example commonly used for hydrogenation, Pd or Pt catalyst, in particular a hydrogenation process carried out in the presence of a catalyst for the hydrogenation of nitro groups, for example Pd / C).

Thus, the dronedarone of formula (I) and pharmaceutically acceptable salts thereof are prepared by the reaction of the compound of formula (III) in acid (see above, which is typically hydrochloric acid, hydrobromic acid or methanesulfonic acid) After hydrogenation in the presence and completion of the reaction, the catalyst is filtered off, the solvent is removed, the residual salt of formula II is reacted with a mesylation reagent (as discussed above) in another solvent and the The salts of dronedarone can be separated and optionally prepared by the process of releasing the base form of dronedarone of formula (I) and optionally forming another salt thereof.

Example

Example 1

N- [2-n-butyl-3- [4- [3- (di-n-butylamino) propoxy] benzoyl] benzofuran-5-yl] methanesulfonamide (I)

(5-amino-2-butyl) -1-benzofuran-3-yl) [4- [3- (di-n-butylamino) propoxy] -phenyl] -methanone dihydrochloride salt and tetrabutyl 0,12 g of ammonium chloride is added to 10 ml of toluene. It is heated to 80-90 ° C. under stirring, at which temperature 0.41 g of methanesulfonyl chloride is added within 30 minutes. The mixture is stirred at 80-90 ° C. for 5 hours. The mixture is cooled to room temperature and 10 ml of ethyl acetate and 10 ml of water are added. The organic layer is separated and the aqueous layer is extracted with 5 ml of ethyl acetate. The combined organic layers are dried over Na ₂ S0 ₄ and evaporated.

Yield: 1.07 g (99.5%).

This product is purified by forming its oxalate salt as follows: 4 ml of methylethyl ketone is added to the residue and the mixture is heated to 70 ° C. To this solution, 0.22 g of oxalic acid dissolved in 2.5 ml of methyl ethyl ketone was added at 70 ° C. After cooling to 20 ° C. in 6 hours, the mixture is stirred at 10 ° C. for 1 hour and filtered. To the obtained oxalate salt, 3.5 ml of water, 5 ml of dichloromethane and 0.59 g of potassium carbonate were added. After stirring for 30 minutes, the separated potassium oxalate is filtered off, washed with 3 ml of dichloromethane and the solvent is evaporated.

0.98 g (92%) mass of purified product.

Purity of the title product obtained: 99.8% (HPLC).

Example 2

The process according to example 1 is carried out except that chlorobenzene is used instead of toluene.

Yield of the product after purification through its oxalate salt according to example 1: 94.6%. Purity (HPLC): 99.7%.

Example 3

The process according to example 1 is carried out except that 0.04 g of tetramethyl ammonium chloride is used instead of tetrabutyl ammonium chloride.

Yield of the product after purification through its oxalate salt according to example 1: 95.1%. Purity (HPLC): 99.6%.

Example 4

N- [2-n-butyl-3- [4- [3- (di-n-butylamino) propoxy] benzoyl] benzofuran-5-yl] methanesulfonamide (I)

0.9 g of (5-amino-2-butyl) -1-benzofuran-3-yl) [4- [3- (di-n-butylamino) propoxy] -phenyl] methanone is dissolved in 10 ml of dichloromethane. . 0.37 g methanesulfonic acid is added within 5 minutes and the mixture is stirred for 5 minutes. Evaporate the solvent. 10 ml of heptane and 0.11 g of triethylbenzyl ammonium chloride are added to the residual salt, and the mixture is heated to 80 to 90 ° C. At this temperature 0.62 g of methanesulfonic anhydride are added within 5 minutes and the mixture is stirred for an additional 5 hours at this temperature. After cooling to room temperature, 15 ml of ethyl acetate and 1 ml of sodium bicarbonate (5%) are added. The organic layer is washed with 5 ml of water and evaporated.

Yield: 0.98 g (94.8%). This product is purified via its oxalate salt according to Example 1 (yield: 90.6%). Purity of the title product obtained (HPLC): 99.8%.

Example 5

N- [2-n-butyl-3- [4- [3- (di-n-butylamino) propoxy] benzoyl] benzofuran-5-yl] methanesulfonamide (I)

4.8 g of (5-amino-2-butyl) -1-benzofuran-3-yl) [4- [3- (di-n-butylamino) propoxy] -phenyl] methanone was dissolved in 15 ml of anhydrous ethanol and 0.9 ml of 37% hydrochloric acid is added within 10 minutes. The solution is stirred at 50 ° C. for 30 minutes and evaporated completely under reduced pressure. Residue: 5.1 g (99%) (5-amino-2-butyl) -1-benzofuran-3-yl) [4- [3- (di-n-butylamino) propoxy] phenyl] -methanone Monohydrochloride salt.

0.5 g of tetrabutylammonium chloride and 50 ml of toluene are added to this salt, and it is heated to 80-90 degreeC. At this temperature 1.9 g of methanesulfonyl chloride are added within 30 minutes. The mixture is stirred at 80-90 ° C. for 5 hours and cooled to room temperature. 50 ml of ethyl acetate and 50 ml of water are added and the phases are separated. The aqueous layer is washed with 25 ml of ethyl acetate. The combined organic layers are dried over Na ₂ S0 ₄ and evaporated.

Yield: 5.4 g (99%). This product is purified via its oxalate salt according to Example 1 (yield: 87%). Purity of the title product obtained (HPLC): 99.7%.

The product is the same as the compound prepared in Example 1.

Example 6

(5-amino-2-butyl-1-benzofuran-3-yl) [4- [3- (di-n-butylamino) propoxy] phenyl] -methanone dihydrochloride (II)

4.8 g of (5-amino-2-butyl) -1-benzofuran-3-yl) [4- [3- (di-n-butylamino) propoxy] -phenyl] methanone was dissolved in 15 ml of anhydrous ethanol and 1.8 ml of 37% hydrochloric acid is added within 10 minutes. The solution is stirred at 50 ° C. for 30 minutes and evaporated completely under reduced pressure. The residual foam solidified upon cooling.

Mp .: 81.5-82.1 ℃

Yield: 5.5 g (99%). Purity (HPLC): 99.8%.

Molecular weight: [M + 2H] ²⁺ _measured = 240.1657 Da; [M + 2H] ²⁺ _calcd = 240.1676 Da.

Example 7

(5-amino-2-butyl) -1-benzofuran-3-yl) [4- [3- (di-n-butylamino) propoxy] phenyl] methanone dihydrochloride (II)

5.08 g of (2-n-butyl-5-nitro-1-benzofuran-3-yl) [4- (di-n-butylamino) propoxy] -phenyl] methanone (III) was dissolved in 50 ml of ethanol and Add 0.3 g of Pd / C (10%). Under stirring, 1.8 ml of hydrochloric acid (37%) are added to the mixture, heated to 50 ° C. and placed under H ₂ pressure of 10 bar. After 4 hours of reaction time, the mixture is cooled to room temperature, the catalyst is filtered off and the solvent is evaporated under reduced pressure.

Yield: 5.5 g (99%). Purity of the product (HPLC): 97.6%.

The product is the same as the compound prepared in Example 6.

Example 8

N- [2-n-butyl-3- [4- [3- (di-n-butylamino) propoxy] benzoyl] benzofuran-5-yl] methanesulfonamide (I)

5.08 g of (2-n-butyl-5-nitro-1-benzofuran-3-yl) [4- (di-n-butylamino) propoxy] -phenyl] methanone (III) was dissolved in 50 ml of ethanol and 0.3 g Pd / C (10%) and 1.8 ml hydrochloric acid (37%) are added. Under stirring the mixture is heated to 50 ° C. and placed under H ₂ pressure of 10 bar. After 4 hours reaction time at 50 ° C., the mixture is cooled to room temperature, the catalyst is filtered off and the solvent is evaporated under reduced pressure. To the residual salt 50 ml of toluene and 4.8 g of tetramethylammonium chloride are added and the mixture is heated to 80-90 ° C. At this temperature 2.25 g of methanesulfonyl chloride are added within 30 minutes and the mixture is stirred at this temperature for 6 hours. After cooling to 25 ° C., 60 ml of isopropyl acetate and 25 ml of 5% aqueous sodium hydrogen carbonate are added and stirred for 10 minutes. Separate the phases. The organic layer is washed with 10 ml of water. After drying over Na ₂ SO ₄ , the solvent is evaporated.

Yield: 5.5 g (99.1%). The product is purified by its oxalate salt according to Example 1 (yield 94%). Purity of the title product obtained: 99.7% (HPLC).

The product is the same as the compound prepared in Example 1.

Claims (15)

Heterogen reaction of salts of (5-amino-2-butyl-l-benzofuran-3-yl) {4- [3- (di-n-butylamino) propoxy] phenyl} methanone of formula II ) Optionally N- [2-n-butyl-3- [4- [3- (di-n-butyl) of formula I, characterized in that it reacts with mesylation reagents in the presence of a phase transfer catalyst. Amino) -propoxy] -benzoyl] -benzofuran-5-yl] methanesulfonamide and a method for the preparation of pharmaceutically acceptable salts thereof.
Formula I

(II)

In the above formula (II)
A is a monobasic or dibasic acid forming an acid addition salt with a compound of formula II,
n is 1 when A is a dibasic acid,
n is 1 or 2 when A is a monobasic acid. The process of claim 1, wherein the acid A is selected from the group of hydrogen chloride, hydrogen bromide, methanesulfonic acid, p-toluenesulfonic acid and sulfuric acid. A salt of (5-amino-2-butyl-1-benzofuran-3-yl) {4- [3- (di-n-butylamino) propoxy] phenyl} -methanone according to claim 2 Wherein the base form and acid A are insoluble and do not dissolve. The method of claim 3, wherein the solvent is selected from the group of aromatic compounds, halogenated aromatic compounds, halogenated alkenes or cycloalkanes, ethers and ketones and any mixtures thereof. 5. The process of claim 4 wherein the solvent is selected from the group of toluene, xylene, chlorobenzene, anisole, dichloroethane, heptane, 2-methyl cyclohexane, dibutylether, methylethyl ketone and any mixtures thereof. How to. The method according to any one of claims 1 to 5, characterized in that the mesylation reagent is methanesulfonic anhydride or methanesulfonyl halide. The process according to any one of claims 1 to 6, characterized in that the reaction is carried out in the presence of a phase transfer catalyst. Salt of (5-amino-2-butyl-l-benzofuran-3-yl) {4- [3- (di-n-butylamino) propoxy] phenyl} methanone of formula II.
(II)

In the above formula (II)
A is a monobasic or dibasic acid forming an acid addition salt with a compound of formula II,
n is 1 when A is a dibasic acid,
n is 1 or 2 when A is a monobasic acid,
Provided that A is other than oxalic acid. The salt of claim 8, wherein A is selected from the group of hydrogen chloride, hydrogen bromide, methanesulfonic acid, p-toluenesulfonic acid and sulfuric acid. The salt of claim 8, wherein A is hydrogen chloride and n is 2. 10. A process for preparing a salt of a compound of formula II, characterized in that the nitro group of the compound of formula III is hydrogenated in the presence of acid A in a solvent.
(II)

(III)

In the above formula (II)
A is a monobasic or dibasic acid forming an acid addition salt with a compound of formula II,
n is 1 when A is a dibasic acid,
n is 1 or 2 when A is a monobasic acid,
Provided that A is other than oxalic acid. 12. The method of claim 11, wherein the acid A is selected from the group of hydrogen chloride, hydrogen bromide, methanesulfonic acid, p-toluenesulfonic acid and sulfuric acid. The process according to claim 11 or 12, characterized in that the hydrogenation process is carried out in the presence of a Pd or Pt catalyst in a solvent. 14. The method of claim 13, wherein said solvent is characterized in that C _{1 -4} alcohol, ethyl acetate, and selected from the group of cyclohexane. N- [2-n-butyl-3- [4- [3- (di-n-butylamino) -propoxy] -benzoyl] -benzofuran-5-yl] methanesulfonamide of formula I and pharmaceutical (5-amino-2-butyl-l-benzofuran-3-yl) {4- [3- (di-n-butylamino) propoxy] phenyl} meta of formula II to prepare acceptable salts thereof Use of salts.
Formula I

(II)

In the above formula (II)
A is a monobasic or dibasic acid forming an acid addition salt with a compound of formula II,
n is 1 when A is a dibasic acid,
n is 1 or 2 when A is a monobasic acid.