WO2013014478A1

WO2013014478A1 - Reductive amination process for preparation of dronedarone using carboxyl intermediary compound

Info

Publication number: WO2013014478A1
Application number: PCT/HU2012/000063
Authority: WO
Inventors: Antal Friesz; Zsolt DOMBRÁDY
Original assignee: Sanofi
Priority date: 2011-07-26
Filing date: 2012-07-23
Publication date: 2013-01-31

Abstract

The invention relates to a novel process for preparation of dronedarone of formula (I) and pharmaceutically acceptable salts thereof : Formula (I) characterized in that a compound of formula (II) : Formula (II) is aminated with compound of formula (III) among reductive conditions, : Formula (III) and the obtained product is isolated and, if desired, converted into a pharmaceutically acceptable salt thereof. The invention also relates to some novel intermediary compounds and the preparation thereof.

Description

Reductive amination process for preparation of dronedarone using carboxyl

intermediary compound

FIELD OF THE INVENTION

This invention relates to a novel process for the preparation of dronedarone and pharmaceutically acceptable salts thereof, to novel intermediary compounds used in this process and their preparation.

TECHNICAL BACKGROUND

Dronedarone is a known drug for the treatment of arrhythmia and has the chemical name of N-[2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]benzofuran-5- yljmethanesulfon-amide [see also formula (I) below]. There are some known processes for the preparation of dronedarone as follows:

In EP 0471609 the following scheme is disclosed for the preparation of dronedarone [Process A]

esulfonylation

The above mentioned patent description discloses some new intermediary compounds, too.

In WO 02/48078 the following scheme is disclosed for the preparation of dronedarone [Process B]:

The novelty of the process is based on the adaptation of the Friedel-Crafts reaction in the first step. The process and the intermediary compounds used for the preparation of the benzoylchloride compound of the first step are also disclosed in this document. The further steps of the process are identical with the final steps of the synthetic route disclosed in EP 0471609 [Process A], but in the claims the whole synthetic route is claimed, up to

dronedarone.

In WO 02/48132 (Sanofi) the following reaction route is disclosed [Process C]. This method is the so called superconvergent route. In the first step of it 5-amino-2-butyl- benzofuran

is mesylated and the obtained 2-butyl-5-methanesulfonamido-benzofuran (in HC1 salt form) is further reacted in the next ste as follows:

In this process the order of reaction steps are altered, the reduction and the

methansulfonylation steps are performed at the beginning of the procedure. Besides the reaction route for preparation of dronedarone, the starting material 2-butyl-5- methansulfonamido-benzofuran and its preparation is also claimed.

From among the mentioned procedures the first one [Process A] is the so called linear synthesis. In this way of procedure the different parts of the dronedarone are stepwise built up on the starting compound. This method is the least economical because the step by step building of the chemical groups is performed where more and more complicated and expensive molecules are applied which rises the costs of preparation. Furthermore, it comprises complicated and dangerous reaction step because aluminium chloride is used in the cleaving reaction of the methoxy group which makes the industrial feasibility more complicated.

In WO 02/48078 (Process B) a shorter synthetic route is disclosed which makes this process more economical, but its last reaction step remained the methansulfonylation reaction of the amino group. This reaction step (see the method described in example 6 of of WO 02/48078) is complicated and give a low yield, only 61.6%. Pure product can be obtained after purification using chromatographic column purification, which method is necessary because of the separation difficulties of the bis-methanesulfonylated product.

The process disclosed in WO 02/48132 (process C) is simpler and more economical taken into consideration the number of the reaction steps. Unfortunately, in the last reaction step rather impure dronedarone. HC1 (hydrochloride salt) is formed which is the obvious consequence of the presence of dibutylamino group in the Friedel-Crafts reaction. According to Examples 3 and 4, the crude dronedarone hydrochloride salt is prepared with a yield of 90% which was further purified and finally the crude dronedarone base was produced with a yield of 86%. This base is reacted with hydrogen chloride gas dissolved in isopropanol which results in pure dronedarone hydrochloride salt. No yield was given for this reaction step. According to example 5 crude dronedarone hydrochloride salt was prepared with a yield of 90%, which was washed with water and reacted with hydrogen chloride gas dissolved in isopropanol, resulting dronedarone hydrochloride salt again. The quality of this product is not known. However, neither the components used in the Friedel-Crafts reaction nor the resulted products and by-products are soluble in water, the washing step with water cannot result any purification apart from the removal of inorganic salts.

It is an object of present invention to provide a novel process for the preparation of dronedarone of formula (I). Starting with known and commercially available materials, using, simple and environmentally compatible reagents and solvents to afford high overall yields and good purity of the product.

SUMMARY OF THE INVENTION

The main aspect of the invention is a process for preparation of dronedarone (I) and pharmaceutically acceptable salts thereof

^"nButyl

(Π)

is aminated with compound of formula (III) among reductive conditions,

^nButyl

HNL

nButyl

(III)

and the obtained product is isolated and, if desired, converted into a pharmaceutically acceptable salt thereof.

Present invention avoids the drawbacks of the procedures mentioned before, because formation of dronedarone in the final step is completed using a special form of reductive animation performed between carboxylic acid and secondary amine. We have found surprisingly that the reductive amination step can be performed with success using carboxylic acid of formula (II) and dibutylamine, when the reaction with alkali (e.g. sodium) borohydride is performed under acidic conditions. As acids for this reaction the excess of compound (II) or inorganic acids as sulfuric acid, methanesulfonic acid, boric acid or p-toluenesulfonic acid can be used. As a result of this reaction dronedaron can be produced in good yield and quality.

Compounds of formula (VII) can be prepared according to known procedures (see EP 0471609). The other intermediary compounds used in synthesis of dronedarone are new. Further aspects of the invention are the novel intermediary compounds and the methods for the preparation thereof (see below in the "Detailed description of the invention" part).

DETAILED DESCRIPTION OF THE INVENTION

Therefore the present invention relates to a process for the preparation of dronedarone and pharmaceutically acceptable salts thereof. The whole process - starting from compounds available commercial sources - reads as follows:

A) For the preparation of compound of (VI)

(VI)

the compound of formula (VII)

(VII)

is reacted with acrylonitrile of formula CH₂=CH-CN.

The reaction can be carried out in presence or absence of solvent. Typically the reaction can be carried out in presence of solvent, which can be e.g. a C alcohol, typically methanol or ethanol. Moreover, the reaction is carried out in the presence of a strong basic catalyst which can be selected from the group of alkyl alcoholates and quaternary ammonium hydroxides, and it can be e.g. benzyltrimethylammonium hydroxide.

Typically the reaction is carried out in the excess of acrylonitrile as solvent at the boiling point of the solvent, e.g. about 70 to 90 °C . Typically strong water free ammonium quaternary hydroxides or alkali alkoxydes can be applied as catalyst.

B) For the preparation of compound of formula (V)

(V)

the above compound of formula (VI) is hydrogenated.

Typically the hydrogenation is carried out in the presence of catalyst, e.g. palladium catalyst. The hydrogenation process is carried out in a solvent typically, e.g. the solvent is selected from the group of Ci_-4 alcohols, ethyl acetate and cyclohexane, e.g. the solvent is methanol or ethanol.

C) For the preparation of compound of formula (IV)

(IV)

the above compound of formula (V) is mesylated.

Typically the reaction is carried out in an indifferent solvent, typically in the presence of an acid binding agent. In another embodiment the solvent is selected from the group of dichloromethane, dichloroethane and chlorobenzene. Typically the acid binding agent is a tertiary nitrogen base, for example pyridine or triethylamine.

In the process a mesylating reagent should be applied. It can be any reagent which can be used for inserting a CH3SO2- group into the free amino group of compound of general formula (V). It is practical to use methanesulfonic anhydride or methanesulfonyl halogenide, e.g. methanesulfonyl chloride.

D) For the preparation of compound of formula (II)

(II)

the above compound of formula (IV) is hydrolysed.

Typically the hydrolysis is carried out in the presence of acid. The acid can be a strong inorganic acid, e.g. hydrochloric acid. Typically the hydrolysis is carried out in water in presence of a phase transfer catalyst, e.g. triethyl-benzyl-ammonium chloride.

E) Finally, for the preparation of dronedarone (I) and pharmaceutically acceptable salts thereof

nButyl

(I)

the above compound of formula (II) is aminated with compound of formula (III) ^nButyl

HNL

nButyl

(III)

among reductive conditions.

The reaction can be carried out in the presence of acid and alkali borohydride, typically sodium borohydride. The reaction should be carried out among acidic conditions. Such acids can be applied which are not reduced among the applied conditions. Typically methansulfonic acid, boric acid, sulfuric acid, benzenesulfonic acid, toluenesulfonic acid etc. can be applied. However, the excess of compound (II) can be applied to ensure the acidic conditions.

The reaction can be carried out in indifferent solvent or solvent mixture. Typically the solvent is selected from the group of THF, diethyleneglycol, dimethyl ether,

dichloroethane, dichloromethane, e.g. it can be THF or dichloroethane.

The reaction is performed at temperature between 0 to 70 °C. Typically reaction is carried out between 50 to 55 °C.

The applicable acid for the preparation of pharmaceutically acceptable salts can be any inorganic or organic acid which forms an acid addition salt with the compound of general formula (I). Exemplary acids which can form an acid addition salt are as follows: acetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, methansulfonic acid, ethansulfonic acid, boric acid, butyric acid, citric acid, ethanesulfonic acid, fumaric acid, hydrogen chloride, hydrogen bromide, hydrogen iodide, 2- hydroxyethanesulfonic acid, maleic acid, oxalic acid, methanesulfonic acid, nitric acid, salicylic acid, tartaric acid, sulfuric acid (forming sulfate or bisulfate anion), sulfonic acid (such as those mentioned herein), succinic acid, toluenesulfonic acid and the like. The hydrogen halogenide salts are typical, especially the hydrogen chloride salt.

Here it is mentioned that on the mesylate group of compound of general formula (I)

(see the "left side" of the molecules) a salt formation can be carried out (on the amide part of it) by a strong base, e.g. an alkaline hydroxide, typically by sodium hydroxide. However, these salts have less practical importance, but they are within the scope of salts which can be prepared by the claimed process. It means that the phrase "salts" embraces both the acid addition salts and the salts formed by bases (basic salts) in case of compounds of general formula (I). The further starting materials are commercially available or can be prepared by applying known synthetic ways.

Other objects of the invention are the novel intermediary compounds applied in the processes, namely the following compounds:

- Compound of formula (II) and salts thereof

- Com ound of formula (IV) and salts thereof

(IV)

- Compound of formula (V) and salts thereof

(V)

Compound of formula (VI)

(VI)

Other objects of the invention are the processes for the preparation of the novel intermediary compounds, namely the following ones:

- Process for preparation of compound of formula (II) and salts thereof, CH₃SO₂NK O— (CH₂)₂— COOH

O nButyl

(II)

wheren the com ound of formula (IV)

(IV)

is hydrolysed.

The typical reaction conditions are disclosed above in point D).

- Process for preparation of compound of formula (IV) and salts thereof, wherein the compound of formula (V)

(V)

is mesylated.

The typical reaction conditions are disclosed above in point C).

- Process for preparation of compound of formula (V) and salts thereof, wherein the compound of formula (VI)

(VI)

is hydrogenated.

The typical reaction conditions are disclosed above in point B). - Process for preparation of compound of formula (VI), wherein the compound of formula VII)

(VII)

is reacted with acrylonitrile of formula CH₂=CH-CN.

The typical reaction conditions are disclosed above in point A).

As used herein, the term alkyl includes straight or branched aliphatic hydrocarbon chains of 1 to 6 carbon atoms, e.g., methyl, ethyl, isopropyl and t-butyl.

In the processes for the preparation of the intermediary compounds the product is isolated as a base typically (if the compound has a free amino or an alkylated amino group). If desired, the isolated base can be converted into a salt (acid adition salt) thereof, which is typically a pharmaceutically acceptable salt [the possible acids are mentioned under point I)]. Theoretically the acid addition salt can be prepared directly if the relating acid is in the final reaction mixture from which the solid product is made (however, this way is not applied in case of these compounds where the base type form has practical importance).

Here it is mentioned that some of the above intermediary compounds have a mesylate group (see the "left side" of the molecules) where a salt formation can be carried out (on the amide part of it) by a strong base, e.g. an alkaline hydroxide, typically by sodium hydroxide. However, these salts have less practical importance, but they are within the scope of salts which can be prepared by the claimed process, i.e. the phrase "salts" embraces the salts formed by bases (basic salts) in such cases (where the molecule has a mesylate group).

In case of compound of general formula (II) the salt formation can be made on the free COOH group, too. This reaction can be carried among usual basic reaction conditions, typically applying a base, e.g. an alkaline hydroxide (e.g. sodium hydroxide).

In the above reactions the temperature is chosen according to the general practice of a person skilled in organic chemistry. Typically the temperature is between 10 °C and the boiling point of the applied solvent (which can be the mixture of the mentioned solvents in a specific embodiment). Applicable temperature values can be found in the examples. All the above reactions are carried out under atmospheric pressure with the exception of the hydrogenation steps where higher pressure also can be applied, typically up to 20 bar, e.g. 5 to 10 bar.

Examples

Example 1

N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl } - 1 -benzofuran-5- yl]methanesulfonamide (I)

1 g of 3-[4-(-{2-butyl-5-[(methanesulfonyl)-amino]-l-benzofuran-3- yl}carbonyl)phenoxy] -propanoic acid (II) was dissolved in 20 ml of THF and 0.30 g of dibutylamine was added. After stirring of 1 minute 0.64 g of methanesulfonic acid was added to the mixture and it was warmed to 50 °C. 0.34 g of sodium borohydride was added at 50- 55 °C in 15 minutes and the mixture was stirred at this temperature for 9 hours. The reaction mixture was cooled down, and it was made alkaline (pH= 10) with 2N sodium hydroxide. The solvent was evaporated, 15 ml of dichloromethane and 15 ml of water were added. The phases were separated. The dichloromethane phase was washed with 2 x 15 ml of water and the solvent was evaporated. Yield: 1.05 g. The product was purified by column

chromatography on silica gel (ethyl acetate/heptanes = 1 :3)

Yield: 82%.

Purity : 99.9% (HPLC).

lH NMR(DMSO): 0.8-0.9 ppm (m, 9H); 1.2-1.5 ppm (m, 10H); 1.67 ppm (5\ 2H);

1.87 ppm (5', 2H); 2.38 ppm (t, J=7.2 Hz, 4H); 2.57 ppm (m, 2H); 2.88 ppm (t, J=7.5Hz, 2H); 2.91 ppm (s, 3H); 9.51 ppm (t, J=6.2Hz, 2H); 7.09 ppm (d, J=8.8Hz, 2H); 7.24 ppm (dd, J=8.9, 2.2Hz, 1H); 7.38 ppm (d, J=2.1Hz, 1H); 7.65 ppm (d, J=8.8Hz, 1H); 7.81 ppm (d, J=8.8Hz, 2H)

Example 2

N- [2-butyl-3 - {4- [(3 -dibutylamino)propoxy] benzoyl } - 1 -benzofuran-5 - yl]methanesulfonamide (I)

The process was performed according to example 1 with the difference that instead of methanesulfonic acid 0,40 g of boric acid was added.

Yield of purified product: 83%. Purity: 99.9% (HPLC).

The product was identical with the compound prepared in example 1. Example 3

N-[2-butyl-3-{4-[(3-dibutyIamino)propoxy]benzoyl}-l-benzofuran-5- yl]methanesulfonamide (I)

The process was performed according to example 1 with the difference that instead of THF dichloroethane was added.

Yield of purified product: 80.4%. Purity: 99.8% (HPLC).

The product was identical with the compound prepared in example 1.

Example 4

3 - [4-(- { 2-butyl-5 - [(methanesulfonyl)-amino] - 1 -benzofuran-3 -yl } carbonyl)phenoxy] - propanoic acid (II)

1.1 g of N-[2-butyl-3 - {4- [(2-cyanoethoxy)-benzoyl } - 1 -benzofuran-5 - yl]methanesulfon-amide (IV) and 0.2 g of triethyl-benzyl-ammonium chloride were added to 15 ml of concentrated hydrochloric acid and it was warmed at 80-90°C for 6 hours. The mixture was cooled down and the precipitated solid material was filtered and washed with 2 x 10 ml of water. The solid was dried in vacuum at 60°C.

Yield 1.09 g (94.7%). Mp.: 128.7-131.8°C.

1H NMR(DMSO): 0.81 ppm (t, J=7.32 Hz, 3H); 1.24 (sxt, J=7.60 Hz, 2H); 1.66 (quin., J-7.50 Hz, 2H) ; 2.75 (t, J=5.95Hz, 2H); 2.81 (t, J=7.44Hz, 2H); 2.89 (s, 3H); 4.28 (t,

J=5.95Hz, 2H); 7.09 (d, J=8.93 Hz, 2H); 7.21(dd, J=8.81 , 2.17 Hz, 1H); 7.27 (d, J=2.06 Hz, 1H); 7.62 (d, J=8.70 Hz, 1H); 7.78 (d, J= 8.93 Hz, 2H)

Purity: 98% (HPLC).

Example 5

N-[2-butyl-3-{4-[2-cyanoethoxy]benzoyl}-l-benzofuran-5-yl]methanesulfonamide (IV)

4.0 g (5-amino-2-butyl-benzofur-3-yl)-[4-(2-cyanoethoxy)phenyl]methanon (V) was dissolved in 40 ml of dichloromethane. The mixture was warmed to 30-35°C and 1.05 g of pyridine was added at this temperature in 5 mins. At this temperature 1.5 g of

methanesulfochloride was added in 5 mins and the mixture was stirred at 30-35°C for 3 hours. The mixture was cooled to 20°C and washed with 2 x 15 ml of water, 2 x 15 ml of NaHC0₃ of 5% and lx 15 ml of water. The phases were separated and the dichloromethane evaporated.

Yield: 4.81 g (100%). Purity: 94.8% (HPLC). Mp.: 120.9-121.7°C. 1H NMR(DMSO): 9.6 ppm (s, 1H) 7.79 ppm (d, J=8.93 Hz, 2 H) 7.62 ppm (d, J=8.93 Hz, 1H) 7.27 ppm (d, J=2.06 Hz, 1 H) 7.21 ppm (dd, J=8.70, 2.06 Hz, 1 H) 7.13 ppm (d, J=8.93 Hz, 2 H) 4.31 ppm (t, J=5.84 Hz, 2 H) 3.07 ppm (t, J=5.84 Hz, 2 H) 2.88 ppm (s, 3 H) 2.80 ppm (t, J=7.44 Hz, 2 H) 1.65 ppm (quin., J=7.44 Hz, 2 H) 1.24 ppm (sxt, J=7.37 Hz, 2 H) 0.80 ppm (t, J=7.44 Hz 3 H)

Example 6

(5-amino-2-butyl-benzofur-3-yl)-[4-(2-cyanoethoxy)phenyl]methanon (V)

1 g of (2-butyl-5-nitro-benzofur-3-yl)-[4-(2-cyanoethoxy)phenyl]methanon (VI) was dissolved in 15 ml of methanol and 0.1 g of 10% wet Pd/C catalyst was added and the reaction mixture was heated to 50°C at 800 rpm. Hydrogen pressure of 5 bar was set to the reactor and the mixture was stirred at this temperature for 2 hours. After cooling down the catalyst was filtered out and the solvent was evaporated.

Yield: 0.92 g (100%). Purity (HPLC): 97.3%.

1H NMR(DMSO): 7.76 ppm (d, J=8,93Hz, 2H); 7.26 ppm (d, J=8.70Hz, 1H); 7.12 ppm (d, J=8.70Hz, 2H); 6.57 ppm (dd, J=8.70, 2.29Hz, 1H); 6.49 ppm (d, J=2.29Hz, 1H); 4.30 ppm (t, J=5.84Hz, 2H); 3.06 ppm (t, J=5.84Hz, 2H); 2.73 ppm (t, J=7.55Hz, 2H); 1.62 ppm (quin., J=7.50Hz, 2H); 1.23 ppm (sxt, J=7.28Hz, 3H); 0.80 ppm (t, J=7.32Hz, 4H)

[M+H]⁺ _measured = 363.1711Da, [M+H]⁺ _counted = 363.1709Da

Example 7

(2-butyl-5-nitro-benzofur-3-yl)-[4-(2-cyanoethoxy)phenyl]methanon (VI)

27.8 g of (2-butyl-5-nitro-l-benzofur-3-yl)-(4-hydroxyphenyl)methanon (VII) 43.5 g of acrylonitrile and 3.8 g Triton B (benzyltrimethylammonium hydroxide) were added and heated to 80-85°C under stirring and the mixture was stirred at this temperature for 48 hours. After cooling the reaction mixture to room temperature it was evaporated and the

acrylonitrile was recovered for the next trial. To the residue 150 ml of dichloromethane was added and the mixture was washed with 3 x 80 ml of sodium hydroxide of 5%. From the sodium hydroxide solution 16.2 g of starting (2-butyl-5-nitro-l-benzofur-3-yl)-(4- hydroxyphenyl)methanon was recovered. The dichloromethane solution was evaporated.

Yield: 12.07 g (94.2% for the consumed starting material).

Purity: 97.6% (HPLC). Mp.: 108.6-108.,9°C. IH NMR(DMSO): 0.80 ppm (t, J=7.44Hz, 3H); 1.24 ppm (sxt, J=7.37Hz, 2H); 1.68 ppm (quin., J=7.50Hz, 2H); 2.84 ppm (t, J=7.55Hz, 2H); 3.07 ppm (t, J=5.95Hz, 2H); 4.33 ppm (t, J=5.95Hz, 2H); 7.15 ppm (d, J=8,70Hz, 2H); 7.84 ppm (d, J=8.70Hz, 2H); 7.92 ppm (d, 9.84Hz, IH); 8.22-8.28 ppm (m,2H)

Claims

1. Process for preparation of dronedarone (I) and pharmaceutically acceptable salts thereof

O. n Butyl

CH₃SO₂NH. ^■O— (CH 2-)'3 N

n Butyl

0 nButyl

(I) characterized in that a compound of formula (II)

0 nButyl

(II)

is aminated with compound of formula (III) among reductive conditions,

^nButyl

HNL

nButyl

(III)

2. Process according to claim 1 characterized in that the reaction is carried out in the presence of an acid and an alkali borohydride.

3. The com ound of formula (II) and salts thereof

4. Process for preparation of compound of formula (II) and salts thereof,

O nButyl

(II)

characterized in that the compound of formula (IV)

(IV)

is hydrolysed,

5. Process according to claim 4, characterized in that the hydrolysis is carried out in the presence of acid and phase transfer catalyst.

6. The compound of formula (IV) and salts thereof

Ό nButyl

(IV)

7. Process for preparation of compound of formula (IV) and salts thereof

Ό nButyl

(IV)

characterized in that the compound of formula (V)

(V)

is mesylated,

8. The com ound of formula (V) and salts thereof

(V)

9. Process for reparation of compound of formula (V) and salts thereof

(V)

characterized in that the com ound of formula (VI)

(VI)

is hydrogenated,

10. The compound of formula (VI)

(VI)

1 1. Process for preparation of compound of formula (VI)

(VI)

characterized in that the com ound of formula (VII)

(VII)

is reacted with acrylonitrile of formula CH₂ ⁼CH-CN.

12. Process for the preparation of dronedarone (I)

nButyl

(I)

and pharmaceutically acceptable salts thereof, characterized in that the compound of the formula (VII) is reacted with acrylonitrile of formula CH₂=CH-CN, according to claim 11

the obtained compound of formula (VI) is hydrogenated, according to claim 9 the obtained compound of formula (V) is mesylated, according to claim 7

the obtained compound of formula (IV) is hydrolysed, according to claims 4 and 5 the obtained compound of formula (II) is aminatedjwh¾cp^

(III)

and the obtained dronedarone of the formula (I) is isolated andj if desired, cohyerted intd a pharmaceutically acceptable salt thereof.