EP2595976A1

EP2595976A1 - Process for preparing aminobenzoylbenzofuran derivatives

Info

Publication number: EP2595976A1
Application number: EP11754698.6A
Authority: EP
Inventors: Xavier Bon; Christine Biencourt; Corinne Leroy; Julia Mateos-Caro; Philippe Vayron
Original assignee: Sanofi SA
Current assignee: Sanofi SA
Priority date: 2010-07-19
Filing date: 2011-07-18
Publication date: 2013-05-29
Also published as: JP2013531054A; MX2013000773A; KR20130129180A; CN103108869A; SG187140A1; BR112013001335A2; FR2962731A1; US8884033B2; US20130165675A1; CA2805815A1; RU2013107023A; FR2962731B1; WO2012010788A1; AU2011281421A1

Abstract

The invention relates to a process for preparing 5-aminobenzoylbenzofuran derivatives of formula (I), in which R₁ represents hydrogen or an alkyl group and R₂ represents hydrogen, an alkyl, alkoxy or dialkylaminoalkoxy group, by reduction of a 5-nitrobenzofuran derivative of formula (II) using a hydrogen transfer agent, in the presence of palladium-on-charcoal as catalyst and in an ether or an ether mixture as solvent.

Description

PROCESS FOR THE PREPARATION OF AMINQ-BENZOYL-DERIVATIVES

BENZOFURAN

The present invention relates generally to the preparation of amino benzoyl benzofuran derivatives.

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

Wherein R 1 is hydrogen or alkyl and R ₂ is hydrogen, alkyl, alkoxy or dialkylaminoalkoxy.

In formula I above:

R 1 represents, in particular, a linear or branched C ₁ -C ₈ alkyl group, in particular a linear or branched C ₁ -C ₄ alkyl group such as methyl, ethyl, n-propyl, isopropyl or n-butyl, and butyl or tert-butyl,

R ₂ represents in particular a linear or branched C 1 -C 8 alkyl group, especially a group C ₁ -C ₄ linear or branched alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl; a linear or branched C ₁ -C ₆ alkoxy group, in particular a linear or branched C ₁ -C ₄ alkoxy group such as methoxy, ethoxy, n-propoxy, iso-hydroxy, n-butoxy, sec-butoxy or tert-butoxy; still a dialkylaminoalkoxy group in which each linear or branched alkyl group is C ₁ -C ₅ and the linear or branched alkoxy group is C ₁ -C ₅ in which each linear or branched alkyl group is C ₁ -C ₄ such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl and the linear or branched alkoxy group is C ₁ -C ₄ such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy or tert-butoxy.

Preferably, R 1 is n-butyl and R ₂ is 3- (di-n-butylamino) propoxy.

The compounds of formula I above are, for the most part, compounds described in patent EP 0 471 609 where they are presented as intermediates for the final preparation of aminoalkoxybenzoyl-benzofuran derivatives useful for their therapeutic applications in the cardiovascular field. .

Among these aminoalkoxybenzoyl-benzofuran derivatives, 2-n-butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-methanesulfonamido-benzofuran, commonly known as dronedarone, and its salts pharmaceutically acceptable, has been particularly interesting especially as antiarrhythmic agent. In the above-mentioned patent EP 0 471 609 a process for the preparation of dronedarone has been reported, in which 2-n-butyl-3- {4- [3- (di-n-butylamino) propoxy] - benzoyl} -5-nitro-benzofuran is reduced under pressure with hydrogen in the presence of platinum oxide as a catalyst to form 2-n-butyl-3- {4- [3- (di-n-butylamino)] propoxy] -benzoyl} -5-aminobenzofuran (hereinafter Compound A) which is then treated with methanesulfonyl chloride in the presence of an acid acceptor to give the desired compound. According to this method, dronedarone could be obtained with an overall yield of about 60% from the 5-nitrobenzofuran derivative.

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

On the other hand, this method requires the isolation of Compound A from its formation medium, the isolation of this compound, usually in the form of its oxalate, thus constituting an additional step in the preparation of dronedarone.

The search for an industrial preparation process able to overcome these drawbacks while offering high yields of Compound A and a facilitated implementation thereof, so as to produce significantly higher yields of dronedarone compared to the process. therefore remains of undoubted interest. Now, it has now been found that Compound A can be prepared by a process involving a selective reduction of its nitro function with respect to its ketone function. This selective reduction therefore eliminates the need to isolate this Compound A via its oxalate during the final synthesis of dronedarone which can be obtained in this way with overall yields greater than 90% from the 5-nitro derivative. benzofuran starting.

The aminoalkoxybenzoyl-benzofuran derivatives of EP 0 471 609, in particular dronedarone, may be synthesized, therefore, in the very medium for forming the appropriate compound of formula I.

According to a first subject of the invention, the 5-amino-benzofuran derivatives of formula I can be prepared by reducing a 5-nitro-benzofuran derivative of general formula:

in which R 1 and R ₂ have the same meaning as above, by means of a hydrogen transfer agent, in the presence of palladium-carbon as catalyst and in an ether or a mixture of ethers as solvent, which forms the compounds desired. In formula II above, R 1 is preferably n-butyl and R ₂ is preferably 3- (di-n-butylamino) propoxy.

In addition, according to another of its objects, the invention relates to a process for the preparation of sulphonamido-benzofuran derivatives of general formula:

as well as their pharmaceutically acceptable salts, in which R 1 and R ₂ have the same meaning as above and R 3 represents an alkyl group, the process according to which:

a) a 5-nitro-benzofuran derivative of formula II is reduced by means of a hydrogen transfer agent, in the presence of palladium-carbon as a catalyst and in an ether or a mixture of ethers as solvent, to form a reaction medium containing a 5-amino-benzoyl-benzofuran derivative of formula I, above, in free base form, b) treating the reaction medium containing the 5-amino-benzoyl-benzofuran derivative of formula I in the form of of free base obtained above, with a halide of general formula:

Hal-S0 ₂ -R ₃ IV in which Hal represents a halogen such as chlorine and R ₃ has the same meaning as above, in the presence of a basic agent, to obtain the desired compounds in free base form which is reacted, if necessary, with an acid organic or inorganic to form a pharmaceutically acceptable salt of this desired compound.

Subsequently, the pharmaceutically acceptable salt of the compound of formula III can be recovered from its forming medium, for example by crystallization.

In formula III above, R ₃ represents in particular a linear or branched C 1 -C 6 alkyl group, in particular a C 1 -C 4 linear or branched alkyl group such as methyl, ethyl, n-propyl or isopropyl, n-butyl or tert-butyl.

Preferably, R 1 is n-butyl, R ₂ is 3- (di-n-butylamino) propoxy and R ₃ is methyl in formula III above.

The reduction by hydrogen transfer according to the invention is usually carried out in an ether or a mixture of ethers as a solvent, unlike the state of the art where this type of reaction is generally carried out in an alcohol. This reduction in an ether or a mixture of ethers allows a significant chemo-selectivity of the nitro function to the detriment of the ketone function also present and which is also likely to reduce alcohol. This selective reduction of the nitro function therefore avoids the isolation of the compound of formula I in any way, in particular by transformation. of this compound, obtained in basic form, into a salt easily separable from its formation medium.

The ether used as a solvent is usually a dialkyl ether such as methyl tert-butyl ether or a cyclic ether, for example tetrahydrofuran, while the mixture of ethers generally corresponds to a mixture of dialkyl ether and cyclic ether, for example a mixture methyl tert-butyl ether and tetrahydrofuran.

Methyl tert-butyl ether represents a particularly preferred solvent in the context of the present invention, in particular for the preparation of Compound A and subsequently of dronedarone.

Usually, the hydrogen transfer agent is a formate, preferably ammonium formate or phosphinate, especially sodium phosphinate. This hydrogen transfer agent is used in excess of the compound of formula II, this excess being up to 3 to 5 equivalents of hydrogen transfer agent per equivalent of compound of formula II or more. Preferably, 5 or approximately 5 equivalents of hydrogen transfer agent per equivalent of compound of formula II, for example 5 or approximately 5 equivalents of dissolved hydrogen transfer agent, for example in a volume of water, are used. In particular, 5 equivalents of dissolved ammonium formate are used, for example, in one volume of water.

The reduction can take place at room temperature. However, this is generally undertaken by heating the reaction medium to a temperature ranging from up to, for example, 50 ° C to 60 ° C, preferably at a temperature of the order of 40 ° C, in particular at 40 ° C.

According to one of its particular aspects, the invention also relates to a process for the preparation of 2-n-butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} - 5-amino-benzofuran, in which 2-n-butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-nitro-benzofuran is reduced by means of formate d ammonium or sodium phosphinate as a hydrogen transfer agent, in the presence of palladium on carbon as catalyst and in methyl tert-butyl ether or a mixture of methyl tert-butyl ether and tetrahydrofuran as solvent, to form a reaction medium containing 2-n-butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-amino-benzofuran as free base.

On the other hand, according to another of its particular aspects, the invention relates to a process for the preparation of 2-n-butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl 5-methanesulfonamido-benzofuran or dronedarone and its pharmaceutically acceptable salts, the process according to which:

a) 2-n-butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-nitro-benzofuran is reduced by means of ammonium formate or phosphinate of sodium as a hydrogen transfer agent, in the presence of palladium-carbon as catalyst and in methyl tert-butyl ether or a mixture of methyl tert-butyl ether and tetrahydrofuran as solvent, to form a reaction medium containing 2-n- butyl 3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-aminobenzofuran in free base form,

b) treating the reaction medium containing 2-n-butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-amino-benzofuran in free base form obtained previously, with a methanesulfonyl halide in the presence of a basic agent, to obtain dronedarone in basic form which is reacted, if necessary, with an organic or inorganic acid to form a pharmaceutically acceptable salt of dronedarone.

Subsequently, the pharmaceutically acceptable salt of dronedarone can be recovered from its formation medium, for example by crystallization.

In the light of the foregoing description, the complex formed by a 5-nitro-benzofuran derivative of formula II, a hydrogen transfer agent, palladium on carbon and an ether or a mixture of ethers as a solvent, is particularly interesting as a reaction medium for the preparation of various compounds including the compounds of formula I and those of formula III above.

Accordingly, another object of the invention relates to a reaction medium, characterized in that it is formed:

a) a 5-nitro-benzofuran derivative of formula II, especially a derivative of formula II wherein R 1 is n-butyl and I is 3- (di-n-butylamino) -propoxy,

b) a hydrogen transfer agent such as ammonium formate or sodium phosphinate, (c) palladium coal,

d) an ether such as methyl tert-butyl ether or a mixture of ethers such as a mixture of methyl tert-butyl ether and tetrahydrofuran, as solvent.

The following nonlimiting example illustrates the preparation of a compound of formula I according to the process of the invention as well as its implementation in the synthesis of dronedarone.

EXAMPLE a) 2-n-Butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-amino-benzofuran (Compound A or compound of formula I: R 1 = nC ₄ H _9; R ₂ = 3- (di-n-butylamino) -propoxy)

In a 5 L reactor, 3.33 kg of a 30% solution of 2-n-butyl-3- {4- [3- (di-n-butylamino) propoxy] was charged at room temperature. benzoyl} -5-nitro-benzofuran (compound of formula II) and 0.05 kg of dry palladium-on-carbon (Pd / C). With stirring, the mixture is heated to 40 ° C. and then, in about 2 hours, a solution of 0.62 kg (5 equivalents) of ammonium formate in 0.62 kg of water is added. The temperature of the reaction medium is then maintained at 40 ° C. (+/- 2 ° C.) for 15 hours while controlling the progress of the reaction by liquid chromatography. As soon as the reduction is complete, the mixture is cooled to 23 ° C. (+/- 2 ° C.) and the palladium-based carbon is then filtered, which is then washed with methyl tert-butyl ether and water. Then decanted, at room temperature, the organic phase is washed with some water. These settling and washing operations are then repeated once more. The mixture is again decanted and the solution is concentrated at 40 ° C. under vacuum. The concentrate is then diluted with tetrahydrofuran to provide 3.47 kg of a solution of the desired compound in a mixture of methyl tert-butyl ether and tetrahydrofuran.

Estimated yield: 99% b) Dronedarone hydrochloride (hydrochloride of the compound of formula III: R 1 = nC 2 R ₂ = 3- (di-n-butylamino) propoxy; R ₃ = CH ₃ )

In a 5 L reactor, the 3.47 kg of solution of Compound A are charged at room temperature into a mixture of methyl tert-butyl ether and tetrahydrofuran obtained previously. With stirring, the methanesulfonyl chloride is then added at 1H, keeping the temperature of the reaction medium below 30 ° C. It is cooled to 25 ° C. and then a solution of ammonia is poured in, the temperature of the reaction medium being maintained at 25 ° C. The end of the reaction is checked by liquid chromatography. To the reaction medium maintained at 30 ° C., water and methyl tert-butyl ether are then added and stirring is maintained for 15 minutes. After decantation, it is washed first with a saline solution. Stirring is maintained for 10 minutes. at 28 ° C, then decanted and concentrated at 45 ° C under vacuum. Isopropanol is then added and concentrated at 50 ° C. under vacuum. Isopropanol is again added and concentrated to again at 50 ° C under vacuum. The reaction medium is adjusted by adding 2.03 kg of isopropanol so as to obtain 3.62 kg of a solution, in isopropanol, of the desired compound in base form. This solution is heated to 50 ° C., then 0.225 kg of hydrochloric acid is added to the reaction medium maintained at a temperature of 50 ° C. to 55 ° C., and crystallization of the desired hydrochloride is then initiated by adding dronedarone hydrochloride to the medium. reaction. The mixture is then filtered and the filter cake is washed with isopropanol to provide the desired hydrochloride which is dried at 45 ° C under vacuum to give 1.12 kg of dry dronedarone hydrochloride.

Overall yield (relative to compound I): 96%

The process according to the invention has undeniable advantages over the method described in patent EP 0 471 609 or patent application WO 2002/048078.

Indeed, the nitro function of the compound of formula II can be reduced in a standard reactor, which avoids the need to operate with hydrogen under pressure in a hydrogenation apparatus. On the other hand, the quality of the compound of formula I in base form is significantly improved since there is a formation of different impurities in fewer numbers and lower contents. This advantage makes it possible to avoid the preparation and isolation of the oxalate of the compound of formula I, an operation which poses numerous problems on an industrial scale.

In addition, the use of non-isolated compounds of formula I in a process for the preparation of the derivatives pharmacologically active aminoalkoxybenzoyl-benzofuran of patent EP 0 471 609 and in particular in a process for the preparation of the compounds of formula III above, makes it possible to very significantly improve the yield of this process. In the particular case of dronedarone, the overall yield of its synthesis, from its corresponding 5-nitro-benzofuran derivative, amounts to 60% according to the state of the art to 95% by implementation of the chemo process. -selective of the invention. This improvement is related in particular to the absence of isolation of the oxalate of the compound of formula I and the associated losses.

Claims

A process for the preparation of 5-amino-benzoylbenzofuran derivatives of the general formula:

in which R 1 represents hydrogen or an alkyl group and R ₂ represents hydrogen, an alkyl, alkoxy or dialkylaminoalkoxy group, characterized in that a 5-nitro-benzofuran derivative of general formula is reduced:

in which R 1 and R ₂ have the same meaning as above, by means of a hydrogen transfer agent, in the presence of palladium-carbon as catalyst and in an ether or a mixture of ethers as solvent, which forms the compounds desired.

2. Process for the preparation of sulphonamidobenzofuran derivatives of general formula:

III and their pharmaceutically acceptable salts, wherein R 1 is hydrogen or alkyl, R ₂ is hydrogen, alkyl, alkoxy or dialkylaminoalkoxy and R 3 is alkyl, characterized in that

a) a 5-nitro-benzofuran derivative of general formula is reduced:

II in which R 1 and R ₂ have the same meaning as above, by means of a hydrogen transfer agent, in the presence of palladium-carbon as catalyst and in an ether or a mixture of ethers as solvent, to form a medium reaction product containing a 5-amino-benzoylbenzofuran derivative, in free base form, of general formula:

in which R 1 and R ₂ have the same meaning as above,

b) the reaction medium containing the 5-amino-benzoyl-benzofuran derivative of formula I in free base form obtained above is treated with a halide of general formula:

Hal-S0 ₂ -R ₃ IV in which Hal represents a halogen and R 3 has the same meaning as above, in the presence of a basic agent, to obtain the desired compounds in free base form which is reacted, if necessary with an organic or inorganic acid to form a pharmaceutically acceptable salt of this desired compound.

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

R 1 represents a linear or branched C ₁ -C ₈ alkyl group,

R ₂ represents a linear or branched C ₁ -C ₈ alkyl group, a linear or branched C ₁ -C ₆ alkoxy group or a dialkylaminoalkoxy group in which each linear or branched alkyl group is C 1 -C 6 and the linear or branched alkoxy group is C 1 -C 6 • R3 represents a linear or branched C 1 -C 6 alkyl group.

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

R 1 represents a linear or branched C ₁ -C ₄ alkyl group,

• R ₂ represents an alkyl group, linear or branched C ₁ -C 4, alkoxy, linear or branched C ₁ -C 4 or a dialkylaminoalkoxy group wherein each alkyl group, linear or branched, is C ₁ - C4 and the linear or branched alkoxy group is C ₁ -C ₄ ,

• R ₃ represents a linear or branched C ₁ -C ₄ alkyl group.

5. Process according to one of Claims 1 to 4, characterized in that R 1 represents n-butyl, R ₂ represents 3- (di-n-butylamino) -propoxy and R 3 represents methyl.

6. Method according to one of claims 1 to 5, characterized in that the hydrogen transfer agent is a formate or a phosphinate.

7. Process according to claim 6, characterized in that the formate is ammonium formate and the phosphinate is sodium phosphinate.

8. Method according to one of claims 1 to 7, characterized in that the hydrogen transfer agent is used in excess relative to the compound of formula

9. Process according to claim 8, characterized in that the hydrogen transfer agent is used in a proportion of 5 equivalents per equivalent of compound of formula II.

10. Method according to one of claims 1 to 9, characterized in that the ether is a dialkyl ether, a cyclic ether or a mixture thereof.

11. The method of claim 10, characterized in that the dialkyl ether is methyl tert-butyl ether and the cyclic ether is tetrahydrofuran.

12. Method according to one of claims 1 to 11, characterized in that the reduction takes place at a temperature ranging from room temperature to 50 ° C to 60 ° C.

13. Process according to one of claims 1 and 3 to 12 for the preparation of 2-n-butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-amino- benzofuran, characterized in that 2-n-butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-nitro-benzofuran is reduced by means of formate d ammonium or sodium phosphinate as a hydrogen transfer agent, in the presence of palladium on carbon as catalyst and in methyl tert-butyl ether or a mixture of methyl tert-butyl ether and tetrahydrofuran as solvent, to form the n-Butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-amino-benzofuran in free base form.

14. Process according to one of Claims 2 and 3 to 12 for the preparation of 2-n-butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-methanesulphonamido. benzofuran or dronedarone and its pharmaceutically acceptable salts, characterized in that: a) 2-n-butyl-3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-nitro-benzofuran is reduced by means of ammonium formate or sodium phosphinate as a hydrogen transfer agent, in the presence of palladium-carbon as catalyst and in methyl tert-butyl ether or a mixture of methyl tert-butyl ether and tetrahydrofuran as solvent, to form 2-n-butyl- 3- {4- [3- (di-n-butylamino) -propoxy] -benzoyl} -5-amino-benzofuran in free base form,

15. Reaction medium, characterized in that it is formed:

a) a 5-nitro-benzofuran derivative of general formula:

wherein R 1 is hydrogen or alkyl and R ₂ is hydrogen, alkyl, alkoxy or dialkylaminoalkoxy,

c) a hydrogen transfer agent, (d) palladium coal,

e) an ether or a mixture of ethers, as solvent 16. Reaction medium according to claim 1 characterized in that R 1 represents n-butyl and represents 3- (di-n-butylamino) -propoxy.