EP2552900A1

EP2552900A1 - Process for preparing aminobenzofuran derivatives

Info

Publication number: EP2552900A1
Application number: EP11718443A
Authority: EP
Inventors: Xavier Bon; Corinne Leroy
Original assignee: Sanofi SA
Current assignee: Sanofi SA
Priority date: 2010-04-01
Filing date: 2011-03-31
Publication date: 2013-02-06
Also published as: KR20130021359A; SG184370A1; CA2794648A1; US20130023677A1; WO2011121245A1; AU2011234294A1; IL222290A0; FR2958291A1; JP2013523700A; RU2012146522A; US8686180B2; CN102906081A; FR2958291B1; MX2012011413A; BR112012024403A2

Abstract

The invention relates to a process for preparing 5-aminobenzofuran derivatives of general formula: Formula (I), in which R₁is hydrogen or an alkyl group and R₂ is an alkyl or dialkylaminoalkyl group. According to the invention, the compounds of formula (I) are prepared by treating a 5‑N‑alkylamidobenzofuran derivative of general formula: in which R₁ and R₂ have the same meaning as above and R₃ is an alkyl group, with a strong acid, so as to form an acid addition salt of the compound of formula (I), which salt is itself treated, if necessary, with a basic agent so as to form this compound of formula (I) in free base form.

Description

PROCESS FOR PREPARING AMINO-BENZOFURAN DERIVATIVES

The present invention relates, in general, to the preparation of amino benzofuran derivatives.

More specifically, the invention relates to a process for the preparation of 5-amino-benzofuran derivatives of general formula:

as well as its acid addition salts, wherein R 1 is hydrogen or alkyl and R ₂ is alkyl or dialkylaminoalkyl.

In formula I above:

• R represents in particular an alkyl group, linear or branched dC ₈ include an alkyl group, linear or branched C ₁ -C 4 such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl or tert-butyl,

• R ₂ represents in particular an alkyl group, linear or branched dC ₈ include an alkyl group, linear or branched C ₁ -C 4 such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec butyl or tert-butyl or a dialkylaminoalkyl group in which each linear or branched alkyl group is in CC ₈ in which each linear or branched alkyl group is in CC ₄ such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

In particular, represents n-butyl and R ₂ represents 3- (di-n-butylamino) -propyl. Among the compounds of formula I above, 2-n-butyl- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-amino-benzofuran described in EP 0471609. is particularly useful as an intermediate for the final preparation of aminoalkoxybenzoyl-benzofuran derivatives, particularly for the preparation of 2-n-butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} - 5-methanesulfonamido-benzofuran commonly known as dronedarone and its pharmaceutically acceptable salts. This Methanesulphonamido-benzofuran derivative has been described in the aforementioned patent as well as its therapeutic applications especially in the cardiovascular field where it has proved particularly interesting for example as antiarrhythmic.

In addition, EP 0471609 discloses a process for the synthesis of 2-n-butyl-3- {4- [3- (di-n-butylamino) propoxy] benzoyl} -5-amino benzofuran using 2-n-butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-nitrobenzofuran which is reduced under pressure with the hydrogen in the presence of platinum oxide as a catalyst, which produces the desired compound.

However, this method is not devoid of inherent drawbacks including the type of reaction used namely a hydrogenation under pressure which involves an industrial risk.

The search for a process for the preparation of 2-n-butyl-3- {4- [3- (di-n-butylamino) propoxy] -benzoyl} -5-amino-benzofuran capable of overcoming this disadvantage and disadvantage therefore of prime interest.

U.S. Patent Application 4,666,931 and Chemistry of Heterocyclic Compounds (1975), Vol. 1 1, p. 1361 -1364, Journal of Organometallic Chemistry (1998), vol. 560, p. 163-167, Bulletin of the Chemical Society of Japan (1967), vol. 40, p. 1724-1726, describe derivatives N-phenyl-alkylamide and 5-N-alkylamido-benzofuran but do not suggest their use in the preparation of compounds of formula (I) according to the invention.

In addition, WO 03/040120 describes a process for the preparation of Dronedarone, in 6 steps, using a Friedel-Crafts reaction. However, this document does not describe the preparation of Dronedarone comprising a simple step of treating a 5-N-alkylamido-benzofuran derivative of formula (IIa) according to the invention with a strong acid.

According to the invention, the 5-amino-benzofuran derivatives of formula I can be prepared by treating, with a strong acid such as a hydracid, for example hydrochloric acid, a 5-N-alkylamido-benzofuran derivative of general formula:

in which R 1 and R ₂ have the same meaning as above and R ₃ represents a linear or branched C ₁ -C ₄ alkyl group, for example methyl, to form an acid addition salt of the compound of formula I, which salt is itself treated, if necessary, with a basic agent such as an alkali metal hydroxide, to produce this compound of formula I in free base form.

In what precedes and what follows, and except specific mention:

By "strong acid" is meant any chemical compound which has a very high affinity for providing protons in the reaction medium and which is characterized, in aqueous solution, by a pKa less than or equal to 1. By "strong acid" is meant in particular any hydracid such as selected from hydrochloric acid, hydrobromic acid or hydrofluoric acid.

By "basic agent" is meant any chemical compound which has a strong affinity for H ⁺ protons and which is characterized, in aqueous solution, by a pKa greater than 7. By "basic agent" is meant in particular all types of bases as chosen from organic bases, weak bases and strong bases, especially chosen from tertiary amines, alkali metal carbonates and alkali metal hydroxides.

By "strong base" is meant any chemical compound which has a very high affinity for H ⁺ protons and which is characterized, in aqueous solution, by a pKa greater than 14. By "strong base" is meant in particular any hydroxide of alkali metal, as selected from sodium or potassium hydroxide.

The acid treatment can be carried out in a polar solvent such as an alcohol, for example ethanol, by means of an acid generally in excess, for example from 1 to 6 equivalents of this acid per equivalent of compound of formula II.

On the other hand, the acid addition salt of the compound of formula I can be treated with a basic agent, after isolation of the reaction medium in which it is formed or, conversely, in situ, that is to say within this same reaction medium.

The starting compounds of formula II may be prepared according to the following reaction scheme: 

that is to say starting from a compound of formula III, in which R ₃ has the same meaning as above, which compound is heated in the presence of trifluoroacetic acid in a suitable solvent, usually an amine, for example hexamethylenetetramine to form an N-phenylalkylamide derivative of formula IV wherein R ₃ has the same meaning as above.

This amide of formula IV is then reacted with an ester of formula V in which R 1 has the same meaning as above, R ₄ represents a linear or branched alkyl group at dC ₄ and Hal represents a halogen, for example bromine, in the presence of a basic agent generally a weak base such as an alkali metal carbonate and by heating in a polar solvent so as to form an ester of formula VI in which R 1, R ₃ and R ₄ have the same meaning as above.

The ester of formula VI is then saponified in the presence of a strong base generally an alkali metal hydroxide, the reaction usually taking place at room temperature. and a suitable solvent, for example an ether, to give a carboxylic acid derivative salt which is treated with a strong acid, such as a hydric acid, for example hydrochloric acid, which provides a derivative of carboxylic acid of formula VII wherein R 1 and R ₃ have the same meaning as above.

The compound of formula VII thus produced is then cyclized to a benzofuran derivative of formula VIII in which R 1 and R ₃ have the same meaning as above and this, in the presence of an organic base, generally a tertiary amine and a halide of benzenesulfonyl. The reaction is usually conducted by heating in a suitable solvent, generally an aprotic solvent such as an aromatic hydrocarbon or an ether.

The benzofuran derivative of formula VIII thus obtained is then coupled with an acyl halogen of formula IX in which R ₅ represents an alkyl group, linear or branched, in CC ₄ for example methyl and Hal has the same meaning as previously for example chlorine and this, in the presence of a Lewis acid for example ferric chloride and in a non-polar solvent for example a halogenated compound. The reaction medium thus obtained is then hydrolysed in the presence of a strong acid, for example a hydric acid, to produce a ketone of formula X in which R 1, R ₃ and R ₅ have the same meaning as above.

This ketone of formula X is then dealkylated by heating in the presence of aluminum chloride and in a non-polar solvent usually a halogenated solvent such as chlorobenzene to form a 4-hydroxyphenyl derivative of formula XI in which R 1 and R ₃ have the same meaning as before.

Subsequently, the compound of formula XI is reacted with an alkyl halide of formula XII in which R ₂ has the same meaning as above and Hal has the same meaning as above, for example chlorine, the reaction taking place in the presence of a basic agent such as an alkali metal carbonate and by heating usually in a polar solvent such as a ketone to produce the desired compound of formula II.

Another subject of the present invention relates to N-phenylalkylamide derivatives of general formula:

in which R ₃ has the same meaning as above and Y represents hydrogen or a group of general formula:

in which R / and R ₆ each represent, independently of one another, hydrogen or a linear or branched alkyl group, in CC ₄

excluding compounds for which R ₃ = Me, Et, isopropyl and Y = H.

Among the N-phenyl-alkylamide derivatives of general formula XIII, mention may be made of those in which R ₃ represents a linear or branched alkyl group at CC ₄ and Y represents a group of general formula XIV:

in which R / and R ₆ each independently represent hydrogen or a linear or branched alkyl group at CC ₄ .

Among the compounds of formula XIII, there may be mentioned the following subgroup wherein Y represents hydrogen or group XIV in which R 1 represents n-butyl, as well as compounds of formula XIII in which R ₃ represents methyl.

On the other hand, among the compounds of formula XIII, mention may also be made of the subgroups in which R ₃ represents methyl, Y represents hydrogen or group XIV in which R 1 represents n-butyl and R ₆ represents hydrogen. or methyl.

Accordingly, the subgroups of N-phenylalkylamide derivatives of formula XIII may be those in which: a) R ₃ represents methyl and Y represents group XIV in which R represents n-butyl and R ₆ represents methyl,

b) R ₃ represents methyl and Y represents group XIV in which R represents n-butyl and R ₆ represents hydrogen.

In addition, another object of the present invention relates to 5-N-alkylamido-benzofuran derivatives of the general formula.

in which R and R ₃ have the same meaning as above and Z represents hydrogen or a group of general formula:

in which R ₂ 'is hydrogen, a linear or branched alkyl group of CC ₄ or a dialkylaminoalkyl group in which each linear or branched alkyl group is C ₁ -C ₄

excluding compounds for which R3 = Me, Z = H and R'1 = H, Me, Et, n-Bu.

Among the 5-N-alkylamido-benzofuran derivatives of general formula XV, mention may be made of those in which R represents hydrogen or a linear or branched C ₁ -C ₄ alkyl group and R ₃ represents a linear alkyl group or branched to CC ₄ and Z a group of general formula XVI:

wherein R ₂ 'is hydrogen, a linear or branched alkyl group of CC ₄ or a dialkylaminoalkyl group in which each linear or branched alkyl group is C ₁ -C ₄ .

Among the compounds of formula XV above, mention may be made of those in which R 1 represents n-butyl, as well as the compounds of formula XV in which R ₃ represents methyl.

On the other hand, among the compounds of formula XV, there may be mentioned the following subgroups, wherein Z is hydrogen or a group XVI in which R ₂ 'is hydrogen, methyl or 3- (di-n-butylamino) ) propyl.

In addition, among the compounds of formula XV, there may also be mentioned those in which R / is n-butyl, R ₃ is methyl and R ₂ 'is hydrogen, methyl or 3- (di-n-butylamino) propyl.

Accordingly, subgroups of the 5-N-alkylamido-benzofuran derivatives of formula XV may be those wherein: a) R / is n-butyl, R ₃ is methyl, and Z is the group XVI wherein R ₂ ' represents hydrogen,

b) R / represents n-butyl, R ₃ represents methyl and Z represents group XVI in which R ₂ 'represents methyl,

c) R / represents n-butyl, R ₃ represents methyl and Z represents group XVI in which R ₂ 'represents 3- (di-n-butylamino) -propyl.

A further object of the present invention is the use of compounds of formula II for the preparation of dronedarone and its pharmaceutically acceptable salts.

Thus, according to another characteristic of the present invention, the dronedarone of formula:

and its pharmaceutically acceptable salts, can be obtained a) treating a 5-N-alkylamido-benzofuran derivative of general formula:

in which R ₃ has the same meaning as above, for example methyl, with a strong acid such as a hydro acid for example hydrochloric acid, to form an addition salt (also called "acid addition salt") ) 2-n-butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-amino-benzofuran of the formula:

salt which is itself treated with a basic agent such as an alkali metal hydroxide, to produce this compound of formula I _a in free base form,

b) by coupling the derivative of 5-amino-benzofuran of formula _a with methanesulfonyl chloride to form the compound dronedarone form of the free base can be reacted, if necessary, with an acid to produce a pharmaceutically acceptable salt of this compound.

The derivatives of 5-N-alkylamido-benzofuran of formula II can be obtained _has, in turn, by implementing a sequence of steps of:

a) reacting an N-phenyl-alkylamide derivative of general formula:

in which R ₃ has the same meaning as above, with an ester of general formula:

in which R ₄ and Hal have the same meaning as above and in the presence of a basic agent and by heating in a polar solvent to form an ester of general formula:

in which R ₃ and R ₄ have the same meaning as above,

hydrolyzing the ester of formula _Vl in the presence of a strong base, the reaction proceeding at room temperature and in a suitable solvent to give a carboxylic acid derivative salt which is treated with a strong acid to form the carboxylic acid derivative of general formula:

in which R ₃ has the same meaning as before, c) cyclizing the carboxylic acid derivative of the formula VI _is by heating in an aprotic solvent and in the presence of an organic base and a benzene sulfonyl halide to form a benzofuran derivative of general formula:

in which R ₃ has the same meaning as before,

d) coupling the benzofuran of formula VIII _has with an acyl halide of general formula:

in which R ₅ and Hal have the same meaning as above and in the presence of a Lewis acid and in a non-polar solvent, the reaction medium thus formed then being hydrolysed in the presence of a strong acid to form a ketone of general formula:

in which R ₃ and R ₅ have the same meaning as above, e) dealkylated the ketone of formula _X in the presence of aluminum chloride and a nonpolar solvent to form a 4-hydroxy-phenyl derivative of general formula:

in which R ₃ has the same meaning as before,

f) reacting the 4-hydroxyphenyl derivative of formula Xl _a with an alkyl halide of the general formula: wherein Hal has the same meaning as above, the reaction taking place in the presence of a basic agent and by heating in a polar solvent to form the desired compound of formula II _a.

The following non-limiting example illustrates the invention.

PREPARATIONS

A. N- (3-Formyl-4-hydroxyphenyl) -acetamide (compound IV: R ₃ = CH ₃ ) 25 g of N- (4-hydroxyphenyl) acetamide are charged to a 500 ml reactor (0.165 mole, 1 equivalent) and 92.7 g of trifluoroacetic acid (0.661 mole, 4 equivalents). 92.7 g of hexamethylenetetramine (0.661 mol, 4 equivalents) are then added in small portions. The reaction is exothermic. A temperature of 70 Ό is then maintained for 18 hours while monitoring the evolution of the reaction by thin layer chromatography (eluent: toluene / ethanol 8/2). The reaction medium is allowed to return to ambient temperature, which thickens and is diluted by addition of 200 ml of water to facilitate stirring. 100 ml of ethyl acetate are then added. Stir and leave to settle. 300 ml of water and 200 ml of ethyl acetate are added, the mixture is stirred and then decanted. The aqueous phase is then withdrawn first and then the organic phase. The organic phase is then washed twice with 150 ml of water in total to recover, after decantation, a new organic phase and a new aqueous phase. This new organic phase is then concentrated on a rotary evaporator (t ° = 45 ° C., 50 mmHg). 14 g of the desired compound are thus obtained in the form of crystals recovered from an orange-red solution.

1 H NMR (DMSO-d ₆ )

¹³ C NMR (DMSO-d ₆ )

In an Erlenmeyer flask, 5.1 g of N- (3-formyl-4-hydroxy-phenyl) -acetamide is charged.

(compound IV) (0.028 mmol, 1 equivalent) and 10 ml of N, N-dimethylformamide (2 volumes). The reaction mixture is stirred at 50 ° C to provide a first dark orange solution.

In a 50 ml reactor, potassium carbonate (0.6 equivalent) and 8 ml of N, N-dimethylformamide (1.5 volume) are introduced. Stir at δΟ 'Ό and then add the first solution. Stirring is continued for 1 hour at 50 ° C. which provides a second solution. Next, a solution of 6.5 g of methyl 2-bromo-hexanoate (compound V) (1.05 equivalents) in 5 ml of Ν, Ν-dimethylformamide is added and the second solution is added. The mixture is stirred at 75 ° for 5 h. The reaction mixture is taken up in 15 ml of dichloromethane and 15 ml of water, the two phases are stirred, decanted and withdrawn. The dichloromethane layer is washed with water (3 x 10 ml) and then this phase is concentrated on a rotary evaporator to give 9 g of brown crystals. These crystals are re-empted with 20 ml of water and then crushed with a spatula to recover finely divided crystals suspended in water. It is then filtered, which gives 8.9 g of wet crystals which are taken up in 25 ml of methyl tert-butyl ether. 5 ml of methanol are added and the mixture is then refluxed for 1 hour in the presence of black (0.1 g). The hot reaction mixture is filtered through Celite and then concentrated to 50%. 4 g of a precipitate of 98% organic purity are thus recovered. The filtrate is concentrated again and then stirred at room temperature which causes the appearance of a new precipitate which is filtered and dried. In this way 1.6 g of the desired compound is recovered.

H-NMR (CDCI ₃ )

C. 2- (2-Formyl-4-N-acetamido-phenoxy) -hexanoic acid

(compound VII: R _{1 =} nC ₄ H ₉ ; R ₃ = CH ₃ )

3.5 g of methyl 2- (2-formyl-4-N-acetamido-phenoxy) -hexanoate (compound VI) (0.01 mol / 1 equivalent) and then approximately 15 ml of methyl are introduced into a flask. tert-butyl ether (about 3 volumes). It is stirred at room temperature so as to form a suspension of this ester. A solution of sodium hydroxide (0.57 g / 5 ml of water) is then added and the mixture is stirred for 1 hour. 5 ml of water are then added and the stirring is continued until a total solution of the ester compound. Two phases are thus recovered, one of methyl tert-butyl ether and the other of aqueous phase containing a carboxylic acid. These two phases are decanted and then, in the aqueous phase (pH = 14), 5 ml of 36% hydrochloric acid / 5 ml of water are added. The aqueous phase is brought to pH = 1, which causes the appearance of a yellow precipitate and then stirred for 30 min at room temperature. The precipitate is filtered on sintered glass, which gives a mass of 3.1 g of 99.7% organic purity and yellow-orange color. This mass is taken up in 20 ml of acetone, brought to reflux and then filtered while hot. 1.7 g of wet white compound are thus recovered and dried to give 1.5 g of the desired compound in the form of white crystals with an organic purity of 99.7%.

1 H NMR (DMSO-d ₆ )

D. 2-n-Butyl-5-N-acetamido-benzofuran (Compound VIII: R _{1 =} nC ₄ H ₉ ; R ₃ = CH ₃ )

In a flask, 1 g of benzenesulphonyl chloride and 1 ml of toluene are charged. After stirring, 1.3 g of triethylamine (3.6 equivalents) are added and the mixture is stirred again at 80 ° C. for 20 minutes, which darkens the reaction medium more and more. A solution of 1 g of 2- (2-formyl-4-N-acetamido-phenoxy) -hexanoic acid (compound VII) (0.00355 mol, 1 equivalent) in 3 ml of toluene and 2 ml of methyl tert-butyl ether. It is heated at δΟ'Ό for 2H while controlling the kinetics of the reaction by gas chromatography. The reaction mixture is cooled to about 50 ° C and hydrolyzed by adding 4 ml of water. The toluene phase and the aqueous phase are decanted and drawn off. To this organic phase, 2 ml of water and 0.2 of 36% hydrochloric acid are added. Stirring is carried out for 5 min, decanting and withdrawing the two phases. The toluene phase is washed with 2 ml of water, decanted and withdrawn the two phases. The organic phase is washed with a solution of 0.9 g of 23% sodium hydroxide in 1.5 ml of water. The toluene phase is stirred, decanted and washed with a solution of 2 g of 10% sodium chloride. The two phases are decanted, the two phases are withdrawn and the toluene phase is concentrated on a rotary evaporator to recover 1.1 g of the desired compound in the form of a brown oil.

H-NMR (CDC | ₃ )

¹³ C NMR (CISC ₃ )

E. 2-n-butyl-3- (4-methoxy-benzoyl) -5-N-acetamido-benzofuran (compound X: R 1 = nC ₄ H ₉ ; R 3 = CH ₃ ; R 5 = CH ₃ ) In a reactor of 250 ml, 10 g of 2-n-butyl-5-N-acetamido-benzofuran (compound VIII) (0.04 mole, 1 equivalent) and then a solution of 29.4 g of 4-methoxy-benzoyl chloride are charged. (Compound IX) (0.054 mole, 1.25 g equivalent) in dichloroethane. The mixture is stirred at 40 ° C. until complete dissolution and then 8.8 g of ferric chloride (0.054 mol, 1.25 equivalents) are added in small portions. The temperature is maintained at 40 ° C. for 1 hour while controlling the evolution of the reaction. The reaction medium is hydrolyzed by adding 100 ml of water and heated to 50 ° C. The two phases are then decanted and the organic phase is recovered and concentrated under vacuum on a rotary evaporator. There is thus obtained 21 g of an orange oil which forms crystals. This oil is taken up in 40 ml of ethyl acetate (2 volumes) and refluxed in a flask, which causes the solubilization of the crystals. While stirring, the reaction medium is allowed to return to ambient temperature, which causes the appearance of a precipitate which is kept in contact with an ice bath (5 ° C.) for 10 min. The reaction medium is filtered and pale yellow crystals are recovered. It is dried in an oven under vacuum and δΟ'Ό which provides 10.1 g of crystals. These crystals are taken up in ethyl acetate (4 volumes) and the mixture is then brought to reflux until dissolution takes place. The reaction medium is allowed to return to ambient temperature and then the crystals formed are filtered on sintered glass. Rinsed with 10 ml of ethyl acetate and dried in an oven at 50 ° C and under vacuum the crystals obtained which provides 8.2 g of the desired compound in the form of a first jet of crystals (organic purity 99.7%) and 1.3 g of the same compound as a second crystal stream (organic purity: 99.1%).

H-NMR (CDCI ₃ )

¹³ C NMR (CISC ₃ )

F. 2-n-Butyl-3- (4-hydroxy-benzoyl) -5-N-acetamido-benzofuran (compound XI: R 1 = nC ₄ H ₉ ; R ₃ = CH ₃ )

In a 250 ml reactor, 5 g of 2-n-butyl-3- (4-methoxy-benzoyl) -5-N-acetamido-benzofuran (compound X) (0.0137 mole, 1 equivalent) were charged and ml of chlorobenzene (3 volumes). The mixture is stirred at 60 ° C. until the methoxy derivative is partially dissolved and then 5.5 g of aluminum chloride (0.041 l mole, 3 equivalents) are added in one go, which causes a change in the reaction medium. The methoxy derivative is dissolved and a temperature of 60 ° C. is maintained for 4 hours. Then hydrolyzed by adding 15 ml of water (3 volumes) while stirring at about 45 ° C +/- 5 ° C. The reaction medium is then extracted with n-butanol and at a temperature of approximately 45.degree. It is decanted hot and the two phases are withdrawn. A phase of butanol is thus recovered in which a precipitate is observed which appears when the temperature is lowered. The organic phase is filtered and thus 2 g of a white product are recovered. The filtrate is concentrated under vacuum on a rotary evaporator and then the 4 g of oil thus obtained and the precipitate are taken up in ethyl acetate (2 volumes). The mixture is heated to reflux to dissolve particles while allowing the medium to return to room temperature. The crystals obtained are filtered and thus 1.3 g of slightly yellow product (organic purity: 97.9%) is recovered. A new recrystallization is carried out in ethyl acetate from the filtrate obtained, which makes it possible to recover 0.8 g of the desired compound with an organic purity of 96.6%.

¹ H NMR (DMSO-d ₆ )

³ C NMR (DMSO-d ₆ )

G. 2-n-Butyl-3- [4- [3- (di-n-butylamino) -propoxy-benzoyl) -5-N-acetamido-benzofuran (Compound II: R 1 = nC ₄ H ₉ ; R ₂ = 3- (di-n-butylamino) -propyl; R ₃ = CH ₃ ) 4 g of 2-n-butyl-3- (4-hydroxy-benzoyl) -5-N-acetamido are charged into a three-necked flask. benzofuran (compound XI) (0.01 mol: 1 equivalent), 2.1 g of potassium carbonate (1.3 equivalents) and 15 ml of methyl ethyl ketone. The reaction medium is stirred, 2.8 g of 1-chloro-3- (di-n-butylamino) -propane (compound XII) (0.0137 mol, 1.2 g) are added at the temperature of δΟ'Ό. equivalent) and the whole is heated to the reflux temperature of the methyl ethyl ketone for at least 8 hours. The white deposit formed around the flask is taken up and stirred again, adding 0.1 equivalent of additional chloramine. The heating is continued for approximately 5 hours and then the reaction medium is concentrated under vacuum on a rotary evaporator. We take the oil thus obtained in 15 ml of water and 15 ml of methyl tert-butyl ether are decanted and the two phases are withdrawn. The organic phase is washed with 0.5 equivalents of acetic acid in 15 ml of water. The organic phase is stirred, decanted and washed with 15 ml of water. This organic phase is concentrated and 5.2 g of the desired compound are thus recovered in the form of a whitish oil.

H-NMR (CDCI ₃ )

EXAMPLE

2-n-butyl-3- [4- (3- (di-n-butylamino) -propoxy-1-benzoyl) -5-aminobenzofuran hydrochloride (compound I: R 1 = nC ₄ H ₉ ; R ₂ = 3- (di-n-butylamino) propyl)

In a reactor, 1 equivalent of 2-n-butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-N-acetamido-benzofuran (compound II) is introduced and 4 volumes of ethanol. 6 equivalents of 36% hydrochloric acid are then added and the reaction mixture is heated under reflux, which forms the desired hydrochloride. The reaction medium is then washed at ambient temperature with an aqueous solution of sodium carbonate so as to release this hydrochloride which passes into the aqueous phase in which it is extracted.

In this way, the desired compound is obtained with an organic purity of 93%. Conversion rate of compound II: 100%

The conversion of 2-n-butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-amino-benzofuran hydrochloride to dronedarone hydrochloride is then carried out as described in US Pat. EP 0471609.

Claims

1. Process for the preparation of 5-amino-benzofuran derivatives of general formula:

as well as its acid addition salts, in which R 1 is hydrogen or an alkyl group and R ₂ is an alkyl or dialkylaminoalkyl group, characterized by treating with a strong acid a 5-N-alkylamido-benzofuran of general formula:

in which R 1 and R ₂ have the same meaning as above and R ₃ represents a linear or branched alkyl group, in CC _4, to form an acid addition salt of the compound of formula I, which salt is itself treated if necessary, with a basic agent to form this compound of formula I as a free base.

2. Method according to claim 1, characterized in that:

R 1 represents a linear or branched alkyl group, in dC ₈ ,

R ₂ represents a linear or branched alkyl group, in CC ₈ or a dialkylaminoalkyl group in which each linear or branched alkyl group is C 1 -C 6,

3. Method according to claim 1 or 2, characterized in that:

R 1 represents a linear or branched alkyl group, in CC ₄ , • R ₂ represents a linear or branched alkyl group in CC ₄ or a dialkylaminoalkyl group in which each linear or branched alkyl group is in CC ₄ .

4. Method according to one of claims 1 to 3, characterized in that the derivative of 5-N-acetamido-benzofuran of formula II is obtained by reaction between a 4-hydroxy-phenyl derivative of general formula:

in which R 1 represents hydrogen or an alkyl group and R ₃ represents a linear or branched C ₄ alkyl group with an alkyl halide of the general formula: wherein R ₂ represents an alkyl or dialkylaminoalkyl group and Hal represents a halogen, the reaction taking place in the presence of a basic agent and by heating in a polar solvent to form the desired compound.

5. Process according to claim 4, characterized in that the 4-hydroxy-phenyl derivative of formula XI is obtained by dealkylation of a ketone of general formula:

wherein R 1 is hydrogen or alkyl and R ₃ and R ₅ are each a linear or branched alkyl group, dC ₄ , in the presence of aluminum chloride and in a non-polar solvent to form the compound longed for.

6. Process according to claim 5, characterized in that the ketone of formula X is obtained by coupling between, on the one hand, a benzofuran derivative of general formula:

in which R 1 represents hydrogen or an alkyl group and R ₃ represents a linear or branched alkyl group at CC ₄ and, on the other hand, an acyl halide of general formula:

in which R ₅ represents a linear or branched alkyl group at CC ₄ and Hal represents a halogen and this, in the presence of a Lewis acid and in a non-polar solvent, the reaction medium thus formed being then hydrolysed in the presence of a strong acid to form the desired compound.

7. Process according to claim 6, characterized in that the benzofuran derivative of formula VIII is obtained by cyclization of a carboxylic acid derivative of general formula:

in which R 1 represents hydrogen or an alkyl group and R ₃ represents a linear or branched alkyl group, at CC ₄ , by heating in an aprotic solvent and in the presence of an organic base and a benzenesulphonyl halide to form the desired compound.

8. Process according to claim 7, characterized in that the carboxylic acid derivative of formula VII is obtained by saponification of an ester of general formula: in which R 1 represents hydrogen or an alkyl group and R ₃ and R ₄ each represent a linear or branched C ₁ -C ₄ alkyl group and this, in the presence of a strong base, the reaction taking place at room temperature and a suitable solvent to give a carboxylic acid derivative salt which is then treated with a strong acid to form the desired compound.

9. Process according to claim 8, characterized in that the ester of formula VI is obtained by reacting an N-phenyl-alkylamide derivative of general formula:

in which R ₃ represents a linear or branched alkyl group, in CC _4, with an ester of general formula:

in which R 1 represents hydrogen or an alkyl group, R ₄ represents a linear or branched C ₁ -C ₄ alkyl group and Hal represents a halogen in the presence of a basic agent and by heating in a solvent polar to form the desired compound.

A process for the preparation of 2-n-butyl-3- {4- [3- (di-n-butylamino) propoxy] benzoyl} -5-methanesulfonamido-benzofuran or dronedarone of the formula: as well as its pharmaceutically acceptable salts, characterized in that:

a) treating a 5-N-alkylamido-benzofuran derivative of general formula:

wherein R ₃ represents a linear or branched C ₁ -C ₄ alkyl group with a strong acid to form an acid addition salt of 2-n-butyl-3- {4- [3- (di- n-butylamino) -propoxy] -benzoyl} -5-amino-benzofuran of formula:

salt which itself is treated with a basic agent to produce the compound of formula I _is free base form,

b) 2-n-butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-aminobenzofuran thus obtained is coupled with methanesulfonyl chloride to form the dronedarone compound in free base form which can be reacted, if necessary, with an acid to produce a pharmaceutically acceptable salt thereof.

1 1. Process according to claim 10, characterized in that the 5-N-alkylamido-benzofuran derivative of formula IIa is obtained by carrying out a sequence of steps according to which:

a) reacting an N-phenyl-alkylamide derivative of general formula: in which R ₃ represents a linear or branched alkyl group, in CC _4, with an ester of general formula:

in which R ₄ represents a linear or branched alkyl group at CC ₄ and Hal represents a halogen and this, in the presence of a basic agent and by heating in a polar solvent to form an ester of general formula:

in which R ₃ and R ₄ have the same meaning as above,

b) the ester of formula VI is saponified in the presence of a strong base, the reaction being carried out at room temperature and in a suitable solvent to give a carboxylic acid derivative salt which is treated with a strong acid for forming the carboxylic acid derivative of the general formula:

in which R ₃ has the same meaning as before,

c) cyclizing the carboxylic acid derivative of the formula VI by heating in _a aprotic solvent in the presence of an organic base and a benzenesulfonyl halide to form a benzofuran derivative of general formula:

in which R ₃ has the same meaning as before,

d) the benzofuran derivative of formula Villa is coupled with an acyl halide of general formula:

in which R ₅ represents a CC ₄ alkyl group and Hal represents a halogen and this, in the presence of a Lewis acid and in a nonpolar solvent, the reaction medium thus formed being then hydrolysed in the presence of a strong acid to forming a ketone of the general formula:

in which R ₃ and R ₅ have the same meaning as above,

e) dealkylated the ketone of formula _X in the presence of aluminum chloride and a nonpolar solvent to form a 4-hydroxy-phenyl derivative of general formula:

in which R ₃ has the same meaning as before,

12. The method of claim 10 or 1 1, characterized in that R ₃ , R ₄ and R ₅ are each methyl and Hal is chlorine or bromine.

13. N-phenyl-alkylamide derivatives of the general formula:

in which R ₃ represents a linear or branched alkyl group at CC ₄ and Y represents hydrogen or a group of general formula:

in which R and R ₆ each represent, independently of one another, hydrogen or a linear or branched alkyl group, in CC ₄

excluding compounds for which R ₃ = Me, Et, isopropyl and Y = H.

14. N-phenyl-alkylamide derivative according to claim 13, characterized in that R ₃ represents methyl and Y represents group XIV in which R / represents n-butyl and R ₆ represents methyl.

15. N-phenyl-alkylamide derivative according to claim 13, characterized in that R ₃ represents methyl and Y represents group XIV in which R / represents n-butyl and R ₆ represents hydrogen.

16. Derivatives of 5-N-alkylamido-benzofuran of the general formula:

in which R represents hydrogen or a linear or branched alkyl group at CC ₄ and R ₃ represents a linear or branched alkyl group at CC ₄ and Z represents hydrogen or a group of general formula: in which R ₂ 'is hydrogen, a linear or branched alkyl group, in CC ₄ or a dialkylaminoalkyl group in which each linear or branched alkyl group is in CC ₄

excluding compounds for which R ₃ = Me, Z = H and R'1 = H, Me, Et, n-Bu.

17. A 5-N-alkylamido-benzofuran derivative according to claim 16, characterized in that R represents n-butyl, R ₃ represents methyl and Z represents group XVI in which R ₂ 'represents hydrogen.

18. The 5-N-alkylamido-benzofuran derivative according to claim 16, characterized in that R represents n-butyl, R ₃ represents methyl and Z represents the group XVI in which R ₂ 'represents methyl.

19. A 5-N-alkylamido-benzofuran derivative according to claim 16, characterized in that R / represents n-butyl, R ₃ represents methyl and Z represents the group XVI in which R ₂ 'represents 3- (di-n- butylamino) -propyl.