FORM 2
THE PATENT ACT 1970 & THE PATENTS RULES, 2003
COMPLETE SPECIFICATION (See section 10 and rule 13)
1. TITLE OF THE INVENTION
Preparation of dronedarone.
2. APPLICANT(S)
(a) NAME. Emcure Pharmaceuticals Ltd
(b) NATIONALITY: an Indian Company
(b) ADDRESS: P-l, IT-BT Park
MIDC Phased, 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 novel protection strategy and intermediates leading to the product of higher purity with good impurity profile. Dronedarone hydrochloride is chemically known as N-{2-butyl-3-[4-{3-dibutyIaminopropoxy)-benzoyl]-benzofuran-5-yl} methane sulfonamide, hydrochloride and has the following structural formula [1].

Dronedarone HC1 is fine white powder that is practically insoluble in water and freely soluble in methylene chloride and methanol. Dronedarone 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. Dronedarone is an antiarrhythmic agent for the treatment of patients with a history of atrial fibrillation or atrial flutter.

US5223510 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. This patent discloses process for the preparation of dronedarone, where the process includes the step of acylation of 2-n-butyl-5-nitro benzofuran with anisoyl chloride by Friedel-Crafts acylation using tin tetrachloride (SnCl4) as an acylating agent. Few references like PCT publications WO2007140989, WO2003040120, WO2002048132, and WO2002048078 suggest similar kind of Friedel-Crafts acylation by using FeCl3 as an acylating agent. Dronedarone HC1 is prepared in US5223510 from 2-butyl-5-nitrobenzofuran in five steps with overall yield of about 30%. However, this process uses a large amount of aluminium chloride leading to the formation of large amount of aluminium hydroxide, which is expensive to treat for disposal. Again the intermediate 2-butyl-3-(4-rnethoxybenzyol)-5-nitrobenzofuran formed has mutagenic properties. US7312345 discloses a process for the preparation of dronedarone comprising protection of 2-butyl-5-aminobenzofuran by sulphonyl chloride and reacting it with 4-(3-dibutylaminopropoxy) benzoyl chloride HC1, which results in impurities due to the use of latter reagent. Likewise, several of the methods known in the prior art have limitation in that they form impurities which are difficult to remove and degrade the quality of the final product.
The foregoing processes do not involve use of phthalic anhydride for the bis-protection of amino group in 2-butyl-5-aminobenzofuran. The disclosed method also has advantage in that with four steps dronedarone HCI of high purity and yield is obtained. Besides, the foregoing processes suffer from serious disadvantages such as low yields of dronedarone, use of hazardous or

expensive reagents like aluminium chloride, tin tetrachloride, several solvents and large chromatographic columns for the purification rendering the processes unsuitable for industrial scale manufacturing. Consequently, it would be a significant contribution to the art to provide an improved process for the preparation of dronedarone, which would be scalable, cost effective, and environment friendly.
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 Friedel-Crafts acylation using a novel primary amino group bis-protection of a starting reagent. An object of the present invention to provide a novel route for the preparation of dronedarone by protection of 2-butyl-5-aminobenzofuran moiety [2] with phthalimido group followed by Friedel-Craft acylation with 4-(3-chloropropoxy) benzoic acid leading to the formation of compound [4]. In the next step, the compound [4] is combined with n-dibutyl amine and deprotected in situ yielding a salt [6], which is converted to dronedarone HC1 in subsequent steps. Another advantage of the invention is the bis-protection of the primary amino group of the benzofuran ring, simultaneously protecting both the sides of the primary nitrogen avoiding impurity formation. This method yields at least 50% dronedarone HC1 of higher purity at the end. The synthesis plan for the preparation of dronedarone of the present invention is depicted by Scheme 1. It may be appreciated that the bis-protective group (phthalimide) disclosed can be replaced with other bis-protective agent like N-2,3-diphenylmaleimide or N-2,3 dimethylmaleimide, providing similar advantages like phthalimido group.


The reagents and catalysts used in the steps of Scheme 1 are listed for illustrative purposes and other reagents or catalysts may be substituted. In the step 1: phthalic anhydride, toluene, triethyl amine, cyclohexane, and NaHCO3 are used. In the step 2: sulfonyl chloride, aluminium chloride and methylene dichloride are used. In the step 3: di-n-butyl amine, sodium iodide, TBAB and DMF are used. In the step 4: monomethyl amine, isopropyl amine and oxalic

acid are used. And in the step 5: methane sulfonyl NaOH, aqueous HC1, triethyl amine, MDC, IPA, ethyl acetate and toluene are used.
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 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.
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 1 below:
Table 1

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 °C

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

EXAMPLES
Example 1: preparation of 2-(-2-Butyl-l-benzofuran-5-yI)-lH-isoindoIe-l, 3 (2H) dione [3]
5-Amino-2-n-dibutyl benzofuran HC1 (100 gm, 0.443 moles) is added to water (300 mL), toluene (400 mL) and sodium bicarbonate (50 gm, 0.595 moles) under controlled frothing over 30 min. The layers are separated and the organic layer is washed with water (200 mL). Then phthalic anhydride (65.6 gm, 0.443 moles) and triethyl amine (4.5 gm, 0.044 moles) are added to the organic layer followed by heating at reflux temperature for 1.5 h and then water is removed azotropically. Toluene is distilled off, cyclohexane (400 mL) is added and the mixture stirred 'at 20 °C for 1 h, product is then filtered,

washed with cyclohexane and dried at 50 °C to afford 132 gm (yield 93.4 %) of [3].
Example 2: preparation of 3-(4-(3-chloro propoxy) benzoyl]-2-n-butyl benzofuran-5-yl-lH-isoindole-l,3 (2H) dione [4]
To a mixture of [3] (100 gm, 0.313 moles) in dichloromethane (250 mL) is added anhydrous aluminium chloride (125 gm, 0.93 moles) in lots at -5 °C. To this is added 4(3-chloro propoxy) benzoyl chloride (76.5 gm, 0.328 molews) dissolved in dichloromethane (250 mL) drop wise at -5 °C. Then the reaction mixture is stirred for 30 min. at - 5 °C and quenched over ice cold water (500 mL) and layers are separated. The organic layer is washed with water (400 mL) and 5% sodium bicarbonate (250 mL). Then the organic solvent is distilled off and product [4] is isolated in methanol. This method affords 130 gm (yield 80.5%) of [4],
Example 3: preparation of 5-amino-3-[4-(3-di-n-butyl amino propoxy) benzoyl]-2-n-butyl benzofuran dioxalate [6]
A mixture of [4] (100 gm, 0.194 moles) with potassium iodide (32.17 gm, 0.194 moles), tetrabutyl ammonium bromide (10 gm, 0.031 moles) and di-n-butyl amine (50.2 gm, 0.388 moles) in dimethlyl formamide (250 mL) is heated at 85 °C for 14 h. Then the reaction mixture is cooled to 25 °C and is added water (500 mL) and dichloromethane (150 mL). Then the layers are separated and organinc layer washed with 20% hydrochloric acid (200 mL) and water (200 mL) followed by saturated sodium bicarbonate solution (200 mL). Then the organic layer is distilled completely to afford compound [5] as an oily residue. Then 20% aqueous monomethyl amine (100 mL) with isopropyl alcohol (400 mL) is added to it and mixture heated at 75 °C for 1 h. Then reaction mixture is

distilled off and oxalic acid (48.9 gm, 0.388 moles) with isopropyl alcohol (500 mL) is added and stirred at 5 °C for 1 h. The product is filtered out to afford 110 gm (yield of 86%) of [6].
Example 4: preparation of drone darone hydrochloride [1] A mixture of [6] (100 gm, 0.152 moles) with sodium hydroxide (24.3 gm, 0.6 moles) in dichloromethane (300 mL) and water (300 mL) is stirred for 30 min, filtered and residue washed with dichloromethane (300 mL). Then the filtrates are combined and layer separated and washed with water (400 mL). Dichloromethane distilled off and is triethyl amine (22.56 gm, 0.22 moles) added with toluene (300 mL). Then the reaction mixture is cooled to -5 °C, followed by drop wise addition of methane sulfonyl chloride (17.4 gm, 0.152 moles in toluene (100 mL) with stirring for 30 min. After completion of the reaction water is added and organic layer separated, washed with water (200 mL) and 5% sodium bicarbonate (200 mL). Then toluene distilled off and is added hydrochloric acid (100 mL) and dichloromethane (300 mL) and stirred for 30 min. Then layers are separated and washed with water (200 mL). Dichloromethane layer containing dronedarone HC1 distilled off and is added isopropyl alcohol (100 mL) and ethyl acetate (900 mL) and stirred at 25 °C for 12 h. Then the product is filtered and washed with ethyl acetate (100 mL) to afford 70 gm (yield of 77.7%) if dronedarone hydrochloride [1] having the melting point of 143.0 0C.

5. CLAIMS
We claim:
1. A process for the preparation of dronedarone hydrochloride of formula [1], comprising the steps of:
a. protecting the primary amino group of 5-amino-2-n-butyl-
benzofuran by a bis-protective group leading to the formation
of compound of formula [3];
b. reacting the compound [3] with 4-[3-(chloro propoxy)-benzoyl
chloride by Friedel-Crafts acylation to produce the compound
of formula [4];
c. reacting the compound [4] with di-n-butyl amine in the
presence of suitable catalysts leading to the formation of the
compound of formula [5];
d. treating the compound [5] in situ with oxalic acid leading to
the formation of its oxalate salt; and
e. reacting the oxalate salt with methane sulfonyl chloride in the
presence of suitable catalysts leading to the formation of
dronedarone hydrochloride [1].



2. A compound of formula [3].
3. A compound of formula [4].
4. A compound of formula [5].
5. A process of claim 1, wherein the bis-protective group used is

phthalimido group derived from phthalic anhydride.
6. A pharmaceutical composition in a unit dosage form comprising an effective amount of a compound of formula [1] according to claim 1.
7. A pharmaceutical composition according to claim 6 comprising a
pound prepared according to claims 1 in association with a pharmaceutically acceptable carrier and/or an inactive compound and/or another active compound.
8. A process for preparing a compound of formula [1] substantially as
described with reference to the examples.