FORM 2
THE PATENT ACT 1970
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
A process lor the preparation of dronedarone hydrochloride
2. APPLICANTS)
(a) NAME: Emcure Pharmaceuticals Ltd
(b) NATIONALITY: an Indian Company
(b) ADDRESS: P-1,IT-BT Park
MIDC Phase-2, Hinjwadi, Pune-411057, INDIA
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention relates to an improved process for the preparation of
dronedarone hydrochloride by using specific ratio of the non-specific P2Os-
methanesulfonic acid (MSA) reagent for acylation reaction. Dronedarone
hydrochloride is chemically known as N-{2-butyl-3-[4-(3-
dibutylaminopropoxy)benzoyl]benzofuran-5-yl} methane sulfonamide,
hydrochloride and has the following structural Formula (3).

Dronedarone hydrochloride (3)
Dronedarone HCI is a white fine powder that is practically insoluble in water and freely soluble in methylene chloride and methanol. Di-onedarone hydrochloride is indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter >50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted.
An object of the present invention to provide a novel route for the preparation of dronedarone by acylation of compound of formula (1) with benzoic acid derivative of compound of formula (2) by using non-specific Eaton's reagent and to show that quality and yield of the compound vary according the ratio of Eaton's reagent (i.e. ratio of PzOs to methanesullonic acid (MSA)), temperature and quantity of the MSA. The compound of formula (1) and compound of formula (2) are obtained by the processes known in the art. Synthetic strategy for the preparation

of dronedarone of the present invention is depicted by Scheme 1.
Schemel

US patent 5223510 appears to cover dronedarone or its pharmaceutically acceptable salt generically as well as specifically. It also appears to cover its pharmaceutical composition and method of use. '51 o patent discloses process for the preparation of dronedarone, where the process includes the step of acylation of 2n-butyl-5-nitro benzoluran with anisoyi chloride by Friedel-Crafts acylation using tin tetrachloride (SnCU) as an acylating agent.
Few references like PCT publications WO2007140989, WO2003040120, WO2002048132, and WO2002048078 suggest similar kind of Friedel-Crafts

acylation by using FeCI3 as an acylating agent.
The foregoing processes do not involve use of phosphorous pentoxide in methanesulfonic acid solution for the acylation of said 2n-butyl-5-nitro benzofuran derivative or 2n-butyl-5-sulfonamide benzofuran derivative and do not describe the use of this reagent specifically for acylation.
The foregoing processes suffer from serious disadvantages such as low yields of dronedarone, use of hazardous or expensive reagents like aluminium chloride and tin tetrachloride and solvents, usage of column chromatography for purification, rendering the processes unsuitable for industrial scale manufacturing.
Consequently, it would be a significant contribution to the art to provide an improved process lor the preparation of dronedarone, which would be scalable, cost effective, and environment friendly.
Process of the present invention provides novel route for the synthesis of dronedarone in good yield and high purity by replacing Friedel-Crafts acylation with Eaton's type reagent for acylation.
Few prior art references describe the use of Eaton's reagent for the cyclization reaction. (JOC, 2007, 72, 4276-79 describes the use of Eaton's reagent for the formation of Quinolones and Quinolone heterocycles; J. Org. Chem. 1998, 63, 5736-5737 describes use of Eaton's reagent for intramoleculer cyclization (acylation on aromatic ring with carboxylic acid); Organic Process Research & Development 2006, 10, 493-499 also describes the use of Eaton's reagent for Quinolone formation; Organic Process Research & Development 2010, 14, 225-228 describes the use of Eaton's reagent for the formation of Tetrahydroisoquinoline-2-ones.) However, these references do not describe impact of different ratio of P2O5 to MSA on acylation reaction.
In an embodiment of the present invention, there is provided an improved

process for the synthesis of dronedarone with good yield and high purity by replacing Friedel-Crafts acylation with Eaton's reagent.
An improved process for the preparation of dronedarone, which includes the step
of:
a} Acylating 2n-butyl-5-sulfonamide benzofuran derivative of formula (1) with benzoic acid derivative of formula (2) by using Eaton's reagent (with 1:4 ratio of P205: MSA quantities} to produce dronedarone hydrochloride of formula (3).

MSA serves as a reagent as well as a solvent for this reaction. Volume of the MSA, temperature of the reaction and ratio of P2Os to MSA affect the quality of the final compound. Suitable volume range of MSA for this reaction is 4-6 volume; and most preferably 5 volumes.
It is the key step in the present improved process, which includes acylation of 2n-butyl-5-sulfonamide ben2ofuran derivative of formula (1) with benzoic acid derivative of formula (2) by using specific ratio of phosphorous pentoxide to MSA quantities. Suitable ratio of phosphorous pentoxide to MSA is at about 1:6-1:3 w/v; preferably at about 1:4.5-1:3.5 w/v; most preferably 1:4 w/v. Temperature for the reaction applied is about 25-45 °C; preferably at about 30-40 °C; most preferably at about 36-42 °C.
Lewis acid catalysts are already known in the literature for this acylation such as AICI3, SnCL,, and FeCI3. But, these are having certain unfortunate disadvantages. They are toxic and their use causes severe problem at scale-up and waste disposal. It may also lead to the formation of heavy metal content in final API.

Moreover, while using Friedei-Crafts acylation process, acid moiety needs to be activated to acid chloride for the reaction to move. Acid chloride derivative is corrosive and unstable. Hence, use of Eaton's reagent for condensation is more feasible and affords better purity and yield of acylated compound without column chromatography making it industrially more acceptable.
Eaton's reagent is specifically known as a 1:10 by weight solution of phosphorous pentoxide in methanesulfonic acid (P.E.Eaton, et al., J. Org. Chem., 23, 4071 (1973)). Surprisingly it is found that it is very non-specific reagent and better replacement for PPA in variety of synthetic transformations.
P2O5-MSA reagent is easy to handle, solubility of organic compounds is high in the reagent and has more convenient work up procedures. But it is found that this reagent is non-specific and reaction rate, reaction type, reactivity at different positions changes with content of phosphorous pentoxide.
Reaction is studied by using different ratio of P205: MSA and by using different volumes of MSA. It is found from the study that optimum % yield and quality of the compound is obtained with 1:4 (w/v) ratio of P2Os: MSA quantities and with 5 volumes of methanesulfonic acid. It is understood from the study that with low volume of methanesulfonic acid and deviation in ratio, reaction mass becomes sticky and impurities formation is high. Optimum temperature for the reaction to get good yield and quality is 36-42 °C. Table 1 describes the impact of different ratio of P205'.:MSA on % yield and purity of the product and Table 2 describes the impact of volume of Eaton's on % yield of product and on reaction mass.
The acylation reaction of Scheme 1 may also be peformed by using ethanesulfonic acid in place of methanesulfonic acid with same effects as described in Example 6.
In an embodiment of the present invention there is provided an improved route for the acylation of aromatic compounds by using Eaton's type reagent with specific content of phosphorous pentoxide in MSA, which leads to selective

acylation without activating acid compounds, and gives good quality and yield of the acylated compound. It is a better replacement for traditional Friedel-Crafts acylation.
The process of the present invention is simple, improved, eco-friendly, cost-effective, commercially viable, robust and reproducible on an industrial scale. Having thus described the invention with reference to particular preferred embodiments and illustrative example, those in the art may appreciate modification to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The examples are set to aid in understanding the invention but are not intended to, and should not be construed to; limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications. All references mentioned herein are incorporated in their entirety.

Table 1
Ratio of P205: MSA quantities (w/v) %Yield of the compound % Purity of the compound
1:2 37 >96
1:2.66 38 >96
1:3 49 >96
1:4 53 >99
1:4.5 49 >96
1:6 35 >96
1:8.33 20 >96

Table 2
Volume of MSA %Yield of the compound % Purity of the compound
1.0 Impurity formation observed >96
2.0 Sticky mass observed >96
3.0 31 >96
4.0 45 >96
5.0 53 >99
6.0 50 >96
An example of a HPLC method that can be used for the analysis of dronedarone includes a Symmetry C18 (4.6 mm x 150 mm) 5 µm or equivalent column. Additional method parameters are given in the Table 3 below:

Table 3
Flow rate 1.5 mL/min
Elution Retention time for about 18 minutes
Wavelength 250 nm
injection volume 20 µL
Column oven temperature 15 to 30 UC
Run time 50 min.
Diluent Methanol: water (1:1)
Sample concentration 0.5 mg/mL
Mobile phase Mobile phase A: 0.05% TFA in water Mobile phase B: Methanol:Tetrahydrofuran 1:1}
Gradient program

Time (min) Mobile phase-A % Mobile phase-B %

0.01 80 20

20 50 50

40 20 80

42 80 20

50 80 20

Example 1: preparation of dronedarone hydrochloride (3)
A mixture of 125 gm of phosphorous pentoxide and 500 mL methanesulfonic acid is heated to 36 to 42 °C for 1 h. 115.8 gm of 4-[3-(Dibutylamino)propoxy] benzoyl hydrochloride and 100 gm of 2-butyl-5-(methanesufonamido)benzofuran are added to Eaton's reagent. Reaction mixture is stirred for 4 h at 36 to 42 °C and then cooled to 5 °C, poured into the 400 mL dichloromethane and 700 mL water solution mixture at 5 °C. Organic layer is separated and washed with 4% sodium metabisuphite solution in 300 mL water followed by 200 mL water. 400 mL of ethyl acetate-HCI is added into organic layer and total reaction mass is concentrated by vacuum distillation. 900 mL of ethyl acetate and 100 mL of isopropyl alcohol are added to the concentrated reaction mass and heated to 45-50 °C to get clear solution. Reaction mass is cooled to 25 °C and maintained for 10 h at 25 °C. It is further cooled to 5 °C and stirred for 4 h, filtered and washed with 200 mL of ethyl acetate. Crude dronedarone hydrochloride is recrystallized with 600 mL of isopropyl alcohol followed by purification in acetone to afford 110 gm (yield 49.5 %) pure dronedarone hydrochloride with 99.6% purity by HPLC.
Example 2: preparation of dronedarone hydrochloride (3) by using 1:3 ratio of reagent
A mixture of 166 gm of phosphorous pentoxide and 500 mL methanesulfonic acid is heated to 36 to 42 0C for 1 h. 115.8 gm of 4-[3-(dibutylamino)propoxy] benzoyl hydrochloride and 100 gm of 2-butyl-5-(methanesufonamido)benzofuran are added to Eaton's reagent. Reaction mixture is stirred for 4 h at 36 to 42 °C and then cooled to 5 °C, poured into the 400 mL dichloromethane and 700 mL water solution mixture at 5 °C. Organic layer is separated and washed with 4% sodium metabisuphite solution in 300 mL water followed by 200 mL water. 400 mL of ethyl acetate-HCI is added into organic layer and total reaction mass is concentrated by vacuum distillation. 900 mL of ethyl acetate and 100 mL of isopropyl alcohol are added to the concentrated reaction mass and heated to 45-50 °C to get clear solution. Reaction mass is cooled to 25 0C and maintained for 10 h at 25 °C. It is further cooled to 5 °C and stirred for 4 h, filtered and washed with 200 mL of ethyl acetate. Crude dronedarone hydrochloride is obtained 110

gm (yield 49.5 %) with 96% purity by HPLC.
Example 3: preparation of dronedarone hydrochloride (3) by using 1:6 ratio of reagent
A mixture of 83.3 gm of phosphorous and 500 mL methanesulfonic acid is heated to 36 to 42 °C for 1 h. 115.8 gm of 4-[3-(dibutytamino)propoxy] benzoyl hydrochloride and 100 gm of 2-butyl-5-(methanesufonamido)benzofuran are added to Eaton's reagent. Reaction mixture is stirred for 4 h at 36 to 42 °C and then cooled to 5 °C, poured into the 400 mL dichloromethane and 700 mL water solution mixture at 5 °C. Organic layer is separated and washed with 4% sodium metabisuphite solution in 300 mL water followed by 200 mL water. 400 mL of ethyl acetate-HCI is added into organic layer and total reaction mass is concentrated by vacuum distillation. 900 mL of ethyl acetate and 100 mL of isopropyl alcohol are added to the concentrated reaction mass and heated to 45-50 °C to get clear solution. Reaction mass is cooled to 25 °C and maintained for 10 h at 25 °C. It is further cooled to 5 °C and stirred for 4 h, filtered and washed with 200 mL of ethyl acetate affords crude dronedarone hydrochloride 80 gm {yield 36.0 %) with 96.74% purity by HPLC.
Example 4: preparation of Dronedarone hydrochloride (3) by using 1:4 ratio of reagent and 6 volumes of MSA
A mixture of 150 gm of phosphorous pentoxide and 600 mL methanesulfonic acid is heated to 36 to 42 °C for 1 h. 115.8 gm of 4-[3-(dibutylamino)propoxy] benzoyl hydrochloride and 100 gm of 2-butyl-5-(methanesufonamido)benzofuran are added to Eaton's reagent. Reaction mixture is stirred for 4 h at 36 to 42 °C and then cooled to 5 °C, poured into the 400 mL dichloromethane and 700 mL water solution mixture at 5 °C. Organic layer is separated and washed with 4% sodium metabisuphite solution in 300 mL water followed by 200 mL water. 400 mL of ethyl acetate-HCI is added into organic layer and total reaction mass is concentrated by vacuum distillation. 900 mL of ethyl acetate and 100 mL of isopropyl alcohol are added to the concentrated reaction mass and heated to 45-

50 °C to get clear solution. Reaction mass is cooled to 25 ''C and maintained for 10 h at 25 0C. It is further cooled to 5 °C and stirred for 4 h, filtered and washed with 200 mL ol ethyl acetate furnishes dronedarone hydrochloride 79 gm (yield 35.6 %) with 96.74% purity by HPLC.
Example 5: preparation of dronedarone hydrochloride (3) by using 1:4 ratio of reagent and 4 volumes of MSA
A mixture of 100 gm of phosphorous pentoxide and 400 mL methanesulfonic acid is heated to 36 to 42 °C for 1 h. 115.8 gm of 4-[3-(Dibutylamino)propoxy] benzoyl hydrochloride and 100 gm of 2-butyl-5-(methanesufonamido)benzofuran are added to Eaton's reagent. Reaction mixture is stirred for 4 h at 36 to 42 0C and then cooled to 5 °C, poured into the 400 mL dichloromethane and 700 mL water solution mixture at 5 °C. Organic layer is separated and washed with 4% sodium metabisuphite solution in 300 mL water followed by 200 mL water. 400 mL of ethyl acetate-HCI is added into organic layer and total reaction mass is concentrated by vacuum distillation. 900 mL of ethyl acetate and 100 mL of isopropyl alcohol are added to the concentrated reaction mass and heated to 45-50 °C to get clear solution. Reaction mass is cooled to 25 °C and maintained for 10 h at 25 °C. It is further cooled to 5 °C and stirred for 4 h, filtered and washed with 200 mL of ethyl acetate affords dronedarone hydrochloride 99.9 gm (yield 45.0 %) with 96.74% purity by HPLC.
Example 6: preparation of dronedarone hydrochloride (3) using ethanesulfonic acid
A mixture of ethanesulfonic acid (10 mL) and phosphorous pentoxide (2.5 g) is heated to 36 to 42 °C for 1 h. 4-[3-(dibutytamino)propoxy] benzoic acid hydrochloride (2.32 g) and 2-butyl-5-(methanesulfonamido) benzofuran (2 g) are added and reaction mixture is stirred at 36 to 42 °C for 4 h and cooled to 5 °C. To this is added dichloromethane (8 mL) followed by water (14 mL) at 5 °C. Organic layer is separated washed with 4% sodium metabisulphite (6 mL) and

8% sodium bicarbonate solution (2x 6 ml) in water. Then ethyl acetate HCI (8 mL) is added and mixture distilled. Further ethyl acetate (18 ml) and isopropyl alcohol (0.5 ml) are added and mixture is heated to 45-50 0C till clear solution is obtained. Cooled to 25°C and stirred for 10 h, further cooled to 5 °C stirred for 4 h, filtered washed with ethyl acetate (2 mL). Crude dronedarone hydrochloride is recrystailized in isopropyl alcohol (12 mL) followed by purification in acetone leading to formation of dronedarone hydrochloride 1.4 g (yield 39.4 %) having purity 99.7 % by HPLC.

5. CLAIMS
We claim:
1. A process for the preparation of dronedarone hydrochloride of formula (3), comprising the steps of:
a) acylating 2-butyl-5-(methanesufanamido)benzofuran of formula (1) with 4-[3-(dibuty!amino)propoxy]-benzoyl hydrochloride of formula (2) by using phosphorus petoxide in methanesuifonic acid (Eaton's reagent) to produce dronedarone hydrochloride of formula (3)



2. A process of claim, wherein ratio of phosphorus pentoxide to methanesulfonic acid used for the acylation is 1:3 to 1:7.
3. A process of claim, wherein ratio of phosphorus pentoxide to methanesulfonic acid used for the acylation is 1:4.
4. A process of claim 1, wherein solvent used is methanesulfonic acid.
5. A process of claim 1, wherein the volume of solvent used is 4 to 6 volumes.
6. A process of claim 1, wherein temperature applied for the reaction is 30 to 50 °C.
7. A compound of formula (3) according to claim 1, having HPLC retention time of 16 to 30 min.
8. A pharmaceutical composition in a unit dosage form comprising an effective amount of a compound of formula (3) according to claim 1.
9. A pharmaceutical composition according to claim 7 comprising a compound prepared according to claims 1 in association with a pharmaceutically acceptable carrier and/or an inactive compound and/or another active compound.
10. A process for preparing a compound of formula (3) substantially as described with reference to the examples.