WO2012153225A1

WO2012153225A1 - Improved processes for obtaining high purity of dronedarone hydrochloride

Info

Publication number: WO2012153225A1
Application number: PCT/IB2012/052103
Authority: WO
Inventors: Venkat Raman JAYARAMAN; Bijukumar Gopinathan Pillai; Jitendra Kevat; Jay NIRMAL; Bhagwati DUBADIA
Original assignee: Alembic Pharmaceuticals Limited
Priority date: 2011-05-09
Filing date: 2012-04-27
Publication date: 2012-11-15

Abstract

Improved processes for obtaining high purity of Dronedarone hydrochloride (chemically known as N-(2-buty1-3-(4-(3-(dibutylamino)propoxy)benzoyl)-5-benzofuranyl)methanesulfonamide hydrochloride) are provided.

Description

IMPROVED PROCESSES FOR OBTAINING HIGH PURITY OF DRONEDARONE HYDROCHLORIDE

Field of the invention

The present invention relates to an improved process for the preparation of Dronedarone HCl having formula (I).

(I)

Background of the invention

Dronedarone HCl is chemically known as N-(2-Butyl-3-(4-(3- (dibutylamino)propoxy)benzoyl)- 5-benzofuranyl) methanesulfonamide hydrochloride salt, having molecular formula C31H44 2O5S and molecular weight 556.75.

Dronedarone HCl is a Class III anti-arrhythmic drug for the prevention of cardiac arrhythmias such as atrial fibrillation (AF). AF is a condition characterized by an irregular heart beat and occurs when the atria (the upper chambers of the heart) contract very rapidly. This causes the lower chambers of the heart, the ventricles, to contract chaotically so that blood is inefficiently pumped to the body which can lead to tissue damage and even death.

Dronedarone HCl is first disclosed in US Patent No. 5, 223, 510 which also discusses its process for preparation. The synthetic reaction scheme is as follow:

2- (n-butyl)-5- nitrobenzofuran

5-amino-3- [4-(3-di-n-butylamino- propoxy) benzoyl]2-n-butyl benzofuran

5-amino-3- [4-(3-di-n-butylamino- 2-n- butyl-3- [4-(3-di-n-butylamino- propoxy) propoxy) benzoyl]2-n-butyl benzofuran benzoyl]5- methylsulfonamido benzofuran

Anhy ethyl acetate,

HCI in ether, pH = 3,

Dronedarone HCI

A major drawback of this process is use of alcohol solvent for the hydrogenation step which gives the lower purity of the final compound & also produces unwanted impurities which is difficult to remove from the product. Further use of mesylation for 2-n-butyl-3- (4-(3-dibutylaminopropoxy) benzoyl)-5- amino benzofuran is done directly without purifying it which decrease the purity of final compound. Moreover, the use of ether solvent for HCI salt formation is not feasible as ether solvents are highly flammable, difficult to recover and hazardous to human health if inhale.

It is therefore a need to develop an improved process for the preparation of Dronedarone HCl which overcomes the disadvantages associated with prior art processes as well as applicable at an industrial scale.

Object of the invention

It is therefore an object of the present invention is to provide improved process for the preparation Dronedarone HCl.

Another object of the present invention is to provide improved purification process to obtain high purity of Dronedarone HCl which is operationally simple, easy to handle and applicable at an industrial scale.

Yet another object of the present invention is to provide an improved process for the preparation of Dronedarone HCl comprising: i) reducing 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- nitrobenzofuran in presence of Pd/C, H₂ & mixture of suitable solvent & acid as a solvent to obtain 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- aminobenzofuran

ii) treating 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- aminobenzofuran with oxalic acid & suitable solvent to obtain pure 2-n-butyl-3-(4-(3- dibutylaminopropoxy)benzoyl)-5- aminobenzofuran dioxalate salt

iii) converting 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- amino benzofuran dioxalate with Aq. ammonia solution as a base & ethylacetate as a solvent to obtain 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- amino benzofuran iv) treating 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- amino benzofuran with methane sulfonyl chloride in presence of nitrogen containing organic base & suitable solvent to obtain Dronedarone base

v) converting Dronedarone base to crude HCl salt of Dronedarone vi) optionally purifying crude HCl salt of Dronedarone with acetone to obtain pure Dronedarone HCl

Another object of the present invention is to provide a process for the preparation of Dronedarone HCl comprising a step of reducing 2-n-butyl-3-(4-(3- dibutylaminopropoxy)benzoyl)-5- nitrobenzofuran in presence of Pd/C, ¾ & mixture of suitable solvent & acid as a solvent to obtain 2-n-butyl-3-(4-(3- dibutylaminopropoxy)benzoyl)-5- aminobenzofuran.

Yet another object of the present invention is to provide a process for the preparation of Dronedarone HCl comprising a step of purifying crude HCl salt of Dronedarone with acetone to obtain pure Dronedarone HCl.

Yet another object of the present invention is to provide a process for the preparation of Dronedarone HCl comprising a step of optionally purifying crude HCl salt of Dronedarone with mix of solvent to obtain pure Dronedarone HCl.

Summary of the invention

In one aspect of the present invention, it provides an improved process for the preparation of Dronedarone HCl comprising: i) reducing 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- nitrobenzofuran in presence of Pd/C, ¾ & mixture of suitable solvent & acid as a solvent to obtain 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- aminobenzofuran

v) converting Dronedarone base to HCl salt of Dronedarone

vi) optionally purifying crude HCl salt of Dronedarone with acetone to obtain pure Dronedarone HCl

Another aspect of the present invention is to provide a process for the preparation of Dronedarone HCl comprising a step of reducing 2-n-butyl-3-(4-(3- dibutylaminopropoxy)benzoyl)-5- nitrobenzofuran in presence of Pd/C, ¾ & mixture of suitable solvent & acid as a solvent to obtain 2-n-butyl-3-(4-(3- dibutylaminopropoxy)benzoyl)-5- aminobenzofuran.

Yet another aspect of the present invention is to provide a process for the preparation of Dronedarone HCl comprising a step of purifying crude HCl salt of Dronedarone with acetone to obtain pure Dronedarone HCl.

Yet another aspect of the present invention is to provide a process for the preparation of Dronedarone HCl comprising a step of optionally purifying crude HCl salt of Dronedarone with mix of solvent to obtain pure Dronedarone HCl.

Brief description of the drawing

Fig. 1 is an X-ray powder diffraction spectrum of Dronedarone HCl crystalline form I. Fig. 2 is a DSC of Dronedarone HCl crystalline form I. Detail description of the invention

The term "Dronedarone hydrochloride" refers to the hydrochloride salt of N-(2-Butyl-3- (4-(3-(dibutylamino)propoxy)benzoyl)- 5-benzofuranyl) methane sulfonamide.

According to one general aspect of the present invention, there is provided a new, improved and industrially viable process for the preparation of Dronedarone hydrochloride with high purity yield.

In further embodiment, it provides an improved process for the preparation of Dronedarone HCl comprising: i) reducing 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- nitrobenzofuran in presence of Pd/C, H₂ & mixture of suitable solvent & acid as a solvent to obtain 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- aminobenzofuran

v) converting Dronedarone base to HCl salt of Dronedarone

In further embodiment, present invention provides an any of the above steps i) to v) for the preparation of Dronedarone HCl may be performed insitu or may be isolated for the preparation of Dronedarone HCl. In present embodiment, present invention provides a process for the preparation of Dronedarone HC1 comprising a step of reducing 2-n-butyl-3-(4-(3- dibutylaminopropoxy)benzoyl)-5- nitrobenzofuran in presence of Pd/C in mixture of suitable solvent and acid under hydrogen pressure to obtain 2-n-butyl-3-(4-(3- dibutylaminopropoxy)benzoyl)-5- aminobenzofuran.

Suitable solvent is selected from a group comprising ketones, nitriles, acetates, aromatic hydrocarbons, alcohol, ether and the like or mixtures thereof. Ketones used herein above are selected from methyl ethyl ketone, acetone, methyl isobutyl ketone, 3-heptanone. Acetates used herein above are selected from isopropyl acetate, ethyl acetate, methyl acetate, n-butyl acetate, t-butyl acetate. Nitriles used herein above are selected from acetonitrile, benzonitrile. Aromatic hydrocarbons used herein above are selected from toluene, xylene. Alcohols used herein above are selected from C1-C4 linear or nonlinear. Ethers used herein above are selected from diethyl ether, dimethyl ether, THF, dioxane.

Suitable solvent is also selected from water immiscible solvents like carbon tetrachloride, chloroform, cyclohexane, 1,2-dichloroethane, dichloromethane, diethyl ether, dimethyl formamide, ethyl acetate, heptane, hexane, methyl-tert-butyl ether, pentane, toluene and the like or mixtures thereof.

Preferred suitable solvent used for reducing 2-n-butyl-3-(4-(3-dibutylaminopropoxy) benzoyl)-5- nitrobenzofuran is ethyl acetate in presence of Pd/C under hydrogen pressure & aceticacid as acid.

In another embodiment, present invention provides a process for the preparation of Dronedarone HC1 comprising a step of treating 2-n-butyl-3-(4-(3- dibutylaminopropoxy)benzoyl)-5- aminobenzofuran with oxalic acid & suitable solvent to obtain pure 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- aminobenzofuran dioxalate. Preferred suitable solvent used for treating 2-n-butyl-3-(4-(3-dibutylaminopropoxy) benzoyl)-5- aminobenzofuran with oxalic acid is methanol.

In another embodiment, present invention provides a process for the preparation of Dronedarone HC1 comprising a step of treating 2-n-butyl-3-(4-(3- dibutylaminopropoxy)benzoyl)-5- aminobenzofuran dioxalate with Aq. Ammonia solution as a base in the presence of ethylacetate as a solvent to obtain 2-n-butyl-3-(4-(3- dibutylaminopropoxy)benzoyl)-5- amino benzofuran.

In another embodiment, present invention provides a process for the preparation of Dronedarone HC1 comprising a step of reacting 2-n-butyl-3-(4-(3- dibutylaminopropoxy)benzoyl)-5- amino benzofuran with methane sulfonyl chloride in presence of nitrogen containing organic base & suitable solvent to obtain Dronedarone base.

Base is selected from the group comprising like alkali or alkaline earth metal hydroxide, alkali or alkaline carbonate, alkali or alkaline bicarbonate, organic base and the like or mixtures thereof. Alkali or alkaline earth metal hydroxide, alkali or alkaline carbonate, alkali or alkaline bicarbonate used herein above are selected from NaOH, KOH, LiOH, NaHCOs, KHCO₃, LiHCOs, Na₂C0₃, K₂C0₃, Li₂C0₃, Mg(OH)₂, Ca(OH)₂, CaC0₃, MgC0₃, Ba(OH)₂, Be(OH)₂, BaC0₃, SrC0₃ and the like or mixtures thereof. Organic base used herein above are selected from nitrogen containing base such as pyridine, piperidine, dimethyl amino pyridine, picolines, diisopropyl ethyl amine, triethyl amine and the like or mixtures thereof.

Preferred suitable base used for reacting 2-n-butyl-3-(4-(3- dibutylaminopropoxy)benzoyl)-5- amino benzofuran with methane sulfonyl chloride is pyridine. Preferred suitable solvent used for reacting 2-n-butyl-3-(4-(3- dibutylaminopropoxy)benzoyl)-5- amino benzofuran with methane sulfonyl chloride is MDC.

In another embodiment, present invention provides a process for the preparation of Dronedarone HCl comprising a step of converting Dronedarone base in to its salt of Dronedarone HCl by reacting with suitable solvent in Aq. HCl followed by optionally purifying the crude Dronedarone HCl in to pure Dronedarone HCl in the presence of mixture of suitable solvent.

In another embodiment, the present invention is to provide a process for the preparation of Dronedarone HCl comprising a step of purifying crude HCl salt of Dronedarone with acetone to obtain pure Dronedarone HCl.

In further embodiment, the present invention is to provide a process for the preparation of Dronedarone HCl comprising a step of optionally purifying crude HCl salt of Dronedarone with mix of solvent to obtain pure Dronedarone HCl.

Preferred suitable solvent used for converting Dronedarone base in to its salt of Dronedarone HCl is ethyl acetate & the suitable solvent for the purifying crude Dronedarone HCl is selected from acetone, methanol , ethylacetate or there mixtures of.

The major advantage of this process is that the purity formation is very high in the second step of hydrogenation compare to prior art process. Using prior art process, purity is formed between 85-90%, whereas in present invention by using mixture of solvent particularly mixture of ethyl acetate & acetic acid we obtained 95-98% purity. The advantage of the present invention can be understood from the following data depicted in Table- 1. Table-1

Hydrogenation in Hydrogenation in Ethyl acetate & Acetic acid

Ethanol/Methanol

(As per prior art process)

Purity-Crude Purity -Crude Purity (after Oxalate

formation & purification)

91.28% 96.8% 99.77%

92.79% 97.5% 99.70%

Dronedarone HCl obtained according to process of present invention shows XRD pattern as depicted in Fig.l which has been characterized by an X-ray powder diffraction spectrum having peaks at about 7.68, 8.10, 8.95, 9.74, 11.25, 1 1.89, 13.02, 13.85, 14.26, 15.30, 15.72, 16.24, 16.64, 17.48, 18.04, 18.82, 20.04, 20.35, 20.78, 21.42, 21.64, 22.66, 23.25, 23.91 , 24.38, 25.09, 26.12, 26.93, 27.59, 28.45, 29.83, 30.20, 31.04, 31.61, 32.30, 32.82, 35.34, 37.14 ±0.2 degree two-theta. The XRD characteristic is obtained according to process of present invention is identical with Dronedarone HCl form I as disclosed in prior art as reported in IP.Com Journal no. IPCOM000193200D.

Dronedarone HCl obtained according to process of present invention shows DSC pattern as depicted in Fig. 2 characterized by differential scanning calorimetry (DSC) thermogram endotherm peak occurs in the temperature range from about 143°C to about 147 °C and normally occurs at 145 °C.

XRD was recorded by X-pert-PRO RDAD-1044. DSC was recorded by Mettler Toledo Star SW 7.01 Instruments.

The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims. Example-1

Preparation of 2-n-butyl-3-(4-(3-dibutylaminopropoxy) benzoyl)-5- aminobenzofuran dioxalate

In to a 5.0 lit RBF, 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (100 g), Methyl ethyl ketone (600 ml), potassium carbonate (44.69 g) & l-Chloro-3-dibutylaminopropane (66.54 g) was charged at R.T. Heat the reaction mixture to 78±3°C (Reflux temperature). Stirred the reaction mixture for 8-10 hr at 78±3°C. Cool the reaction mixture to 30±5°C. Filter it & distilled out organic layer under vacuum completely up to 50°C. Ethyl acetate and water was added to reaction mixture. The organic layer was separated and aqueous layer was discarded. Charge organic layer & add activated charcoal (2.5 g) at 30±5°C. Stir the reaction mass for 30-40 min at 30±5°C. Distil out ethyl acetate completely u/v up to 45 °C to obtain 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- nitrobenzofuran (oil). Charge Ethyl acetate (750 ml), Acetic acid (-90 ml) up to pH 4.5 -4.8 & Pd/C (15 g) into above obtained oil at R.T. Cool the reaction mixture up to 18±3°C. Apply pressure (1±2 kg) to the autoclave by Nitrogen gas. Stir the reaction mixture for 10 minutes at 18±3°C & release nitrogen gas from autoclave. Apply pressure (4±1 kg) to the autoclave by Hydrogen gas and stir for 10 minutes at 18±3°C. Release Hydrogen gas from autoclave & maintain pressure (4±1 kg) to the autoclave for 3-7 hours at 18±3°C. After the completion of the reaction, filter the reaction mass through hyflo bed. Wash the bed with ethyl acetate & charge the filtrate. Charge aq. Ammonia solution in to reaction mass (Aq.ammonia (-25%)) in to water. Stir the reaction mass for 20-30 minutes at 30±5°C. Settle the reaction mass followed by separating organic layer & discarding aqueous layer. Distil out the ethyl acetate completely under vacuum at 25- 45°C to obtain oil. Charge Methanol & Oxalic acid dehydrate in the obtained oil. Stir the reaction mixture for 1.5- 2.0 hr at 50±5°C. Cool the reaction mass up to 30±5°C. Stir the reaction mass at 30±5°C for 2.0 -2.5 hours & filter the solid. Wash the solid with methanol & dry the solid at 50±5°C to obtain the desired product. Example-2

Preparation of Crude Dronedarone hydrochloride

100 gm of 2-n-Butyl-3-(4-(3-dibutylaminopropoxy benzoyl-5-aminobenzofuran dioxalate, 500 ml Ethyl acetate & Aq. ammonia soln. (Aq. ammonia soln. (-25%) (70 ml) in water (700 ml) was charged in RBF. Stirred the reaction mass at 30±5°C for 20 to 30 minutes & settled the layers for 15-20 min. The organic layer was separated and aqueous layer was discarded. Charged organic layer followed by distil the solvent under vacuum 25- 45°C to obtained 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- amino benzofuran (oil). Charged dichloromethane (180 ml) & Pyridine (11.86 g) in to obtained oil. The reaction mixture was cooled at 0±5°C. Add Methanesulfonylchloride solution (Methanesulfonyl chloride (21.42g) in dichloromethane (36 ml) ) drop wise in 45-60 min. at 0±5°C. Stirred the reaction mixture at 0±5°C for 30 minutes. Settled the layers 10-15 min. The organic layer was separated and aqueous layer was discarded. Distiled out organic layer completely under vacuum at 25- 40°C to obtain Dronedarone base (Oil). Charged ethyl acetate in the obtained product. Add Ethyl acetate .HC1 drop wise (-93.6 ml) in 45-60 min at 25±5°C to adjust pH: 2-3. Stirred the reaction mixture for 60-90 min at 25±5°C. Filter the solid & washed the solid with ethyl acetate followed by drying the solid under vacuum at 45±5°C to obtain Crude Dronedarone HC1.

Example-3

Preparation of Dronedarone hydrochloride (API)

100 gm of Crude Dronedarone HC1 was charged in 100 ml of acetone in a clean & dry RBF at room temperature. The reaction mass was heated to 45±5°C & stirred the reaction mass for 20 to 30 minutes to get clear solution. The solid was filtered at 15 ±3°C.

Washed the solid with acetone & the product was dried under vacuum at 45±5°C to obtain pure Dronedarone HC1. Example-4

Preparation of Dronedarone hydrochloride (API)

100 gm of Crude Dronedarone HC1 was charged in methanol in a clean & dry RBF at room temperature. The reaction mass was heated to 45±5°C & stirred the reaction mass for 20 to 30 minutes to get clear solution. Charged ethyl acetate (1000 ml) for 20 to 30 minutes at 45±5°C followed by cooling the reaction mass up to 15 ±3°C. The reaction mass was stirred at 15 ±3°C for 2 hours. Filtered the solid at 15 ±3°C. Washed the solid with Ethyl acetate & the product was dried under vacuum at 45±5°C to obtain pure Dronedarone HC1.

Claims

We claim,

1. A process for the preparation of Dronedarone HCl comprising a step of reducing 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- nitrobenzofuran in presence of Pd/C in mixture of ethyl acetate and acetic acid under hydrogen pressure to obtain 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- aminobenzofuran.

2. A process for the preparation of Dronedarone HCl comprising a step of purifying crude HCl salt of Dronedarone with acetone to obtain pure Dronedarone HCl.

3. A process for the preparation of Dronedarone HCl comprising a step of purifying crude HCl salt of Dronedarone with mix of solvent to obtain pure Dronedarone HCl.

4. The process according to claim 3, wherein mix. of solvent used is selected from acetone, methanol, ethyl acetate or mixture thereof.

5. A process for the preparation of Dronedarone HCl comprising: i) reducing 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- nitrobenzofuran in presence of Pd/C in mixture of ethyl acetate and acetic acid under hydrogen pressure to obtain 2-n-butyl-3-(4-(3- dibutylaminopropoxy)benzoyl)-5- aminobenzofuran ii) treating 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- aminobenzofuran with mix. of oxalic acid & methanol to obtain pure 2-n-butyl-3- (4-(3-dibutylaminopropoxy)benzoyl)-5- aminobenzofuran dioxalate salt iii) converting 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- amino benzofuran dioxalate with mix of Aq. ammonia solution & ethylacetate to obtain 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- amino benzofuran iv) treating 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- amino benzofuran with methane sulfonyl chloride in presence of pyridine & MDC to obtain Dronedarone base v) converting Dronedarone base to HCl salt of Dronedarone vi) optionally purifying crude HCl salt of Dronedarone with mix of methanol & ethyl acetate as a solvent to obtain pure Dronedarone HCl