FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
le of the invention
"A NOVEL PROCESS FOR THE PREPARING DRONEDARONE HYDROCHLORIDE"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17lhFioor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

A NOVEL PROCESSES FOR PREPARING DRONEDARONE HYDROCHLORIDE
FIELD OF THE INVENTION:
The invention relates to a novel processes for preparing dronedarone hydrochloride and to novel intermediates and processes for their preparation. The process comprises acylating a compound of structural formula II with a compound of structural formula IV to get a compound of structural formula V and then converting a compound of formula V into dronedarone hydrochloride compound of structural formula I.

Wherein X is a halogen atom, hydroxy group, halogen substituted alkoxy group, amino substituted alkoxy group or alkyl amino substituted alkoxy group, Y is a halogen atom and R is nitro group, amino group or alkyl sulfonyl amino group.

BACKGROUND OF THE INVENTION:
Dronedarone hydrochloride is a benzofuran derivative having chemical name N-{2-butyl-3-[4-(3-dibutylaminopropoxy) benzoyl] benzofuran-5-yl} methanesulfonamide, hydrochloride is known from US Patent No. 5,223,510 and is represented by compound of structural formula I.

Dronedarone hydrochloride is sold in USA under the proprietary name of "MULTAQ". It is an antiarrhythmic agent and is indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial filrillation (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 > 50mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted.
U.S. Patent No. 5,223,510 describes a process of preparing dronedarone hydrochloride via a stepwise procedure which involves acylation of 2-n-butyl 5-nitro benzofuran with anisoyl chloride in the presence of tin tetrachloride in dichloroethane solvent, followed by the dealkylation with aluminium chloride in dichloromethane; condensation with 1-chloro 3-di-n-butylamino propane in the presence of potassium carbonate in methyl ethyl ketone solvent; reduction of nitro group by hydrogenation in ethanol solvent in the presence of platinum oxide ;methyl sulphonation with methanesulfonyl chloride in dichloromethane in the presence of triethyl amine and hydrochloride salt formation wit hydrogen chloride in ether solvent.
U.S. Patent No.7, 544, 817 describes a process for preparing 2-(n-butyl)-3-(4-methoxybenzoyl)-5-nitrobenzofuran, an intermediate for the antiarrhythmic dronedarone, by reacting 2-(n-butyl)-3-chlorocarbonyl-5-nitrobenzofuran with anisole in the presence of aluminium chloride.

U.S. Patent Nos. 6,828,448; 6,846,936 and 7,312,345 describe several processes for preparing dronedarone hydrochloride, which are incorporated herein by reference only.
The aim of the present invention is to provide new efficient methods of synthesising dronedarone hydrochloride and to provide new intermediate compounds
SUMMARY OF THE INVENTION:
The first aspect of the present invention is to provide a process for preparing dronedarone hydrochloride compound of structural formula I comprising the steps of:
a. converting a compound of formula III into a compound of formula IV,

wherein Y is a halogen atom and R is nitro group, amino group or alkyl sulfonyl amino group
b. acylating a compound of structural formula II with a compound of structural formula IV to get a compound of structural formula V and


wherein X is a halogen atom, hydroxy group, halogen substituted alkoxy group, amino substituted alkoxy group or alkyl amino substituted alkoxy group
c. converting a compound of formula V into dronedarone hydrochloride compound of structural formula I.

Wherein R' is -NH2 or CH3S02NH-.
A second aspect of the present invention is to provide an intermediate compound of structural formula VI, which is being used for the preparation of dronedarone hydrochloride compound of structural formula I.


DETAIL DESCRIPTION OF THE INVENTION:


The compound of structural formula III includes followings compounds:
The compound of structural formula IV includes followings compounds:



A compound of formula III is converted into a compound of formula IV by reacting compound of formula III with halogenating reagents like phosphorus trichloride, phosphorous pentachloride, oxalyl chloride, phosgene or thionyl chloride in an organic solvent.
The examples of organic solvents include toluene, xylene, chlorobenzene, dichloromethane, dichloroethane or carbon tetrachloride.
The reaction of a compound of formula III with halogenating reagents like phosphorus trichloride, phosphorous pentachloride, oxalyl chloride, phosgene or thionyl chloride is carried out at a temperature in the range of 20°C to 50°C for a period of 30 minutes to 4 hours.
The amount of halogenating agent employed is such that the molar ratio of halogenating agent / compound of structural formula III has a value from 0.9 to 3.

The amount of organic solvent employed is 5 to 20 volume / weight of a compound of structural formula III.
The compound of formula IV may be isolated from the reaction mixture or may be used as such for carry out the reaction of next step.


The compound of structural formula II includes followings compounds:

The acylation of a compound of structural formula II with a compound of structural formula IV to get a compound of structural formula V is carried out in the presence of Lewis acid in an organic solvent.
Examples of Lewis acid employed include aluminium halide, boron halide, tin halide, bismuth halide, iron halide or titanium halide preferably aluminium chloride or stannic chloride
Examples of organic solvent include toluene, xylene, chlorobenzene, dichloromethane, dichloroethane or carbon tetrachloride.
The amount of lewis acid employed is such that the molar ratio of Lewis acid / compound of structural formula IV has a value from 1 to 6.
The acylation of a compound of structural formula II with a compound of structural formula IV is carried out at a temperature in the range of-5°C to 50°C.
The compound of structural formula V includes followings compounds:

The compound of structural formula V is isolated from the reaction mixture by quenching the reaction mixture with water, followed by the extraction with dichloromethane or ethyl acetate solvent, washing with saturated sodium bicarbonate solution and drying over anhydrous sodium sulfate.
The compound of structural formula Va, wherein R is -NHSO2CH3 and X is -O(CH2)3N (Butyl)2 may be converted into dronedarone hydrochloride compound of structural formula I by reacting compound of structural formula Va with hydrogen chloride in an organic solvent at a temperature in the range of 0°C to 30°C for a period of 30 minutes to 8 hours.
The hydrogen chloride used for preparing dronedarone hydrochloride compound of structural formula I may be dissolved in water or in an organic solvent such as toluene, methanol, ethanol or isopropanol.
The compound of structural formula Vb, wherein R is -NH2 and X is -O(CH2)3N (Butyl)2 may be converted into dronedarone hydrochloride compound of structural formula I by reacting the compound of structural formula Vb with methane sulfonyl chloride or methane sulfonic anhydride in the presence of organic base such as ammonia or triethyl amine in organic solvents such as dichloromethane, dichloroethane, carbon tetrachloride, tetrahydrofuran or methyl tert-butyl ether followed by the reaction with hydrogen chloride in an organic solvent.
The compound of structural formula Vc, wherein R is -NO2 and X is -O(CH2)3N (Butyl)2 may be converted into dronedarone hydrochloride compound of structural formula I by first converting it into a compound of formula Vb by reducing nitro group by hydrogenation in the presence of catalyst such as platinum oxide, or an ammonium formate / palladized charcoal at a temperature in the range of 25°C to 50°C under pressure of the order of 20 to 50 bar and then the converting compound of formula Vb into dronedarone hydrochloride compound of structural formula I by aforementioned process.
The compound of structural formula Vd, wherein R = CH3SO2NH- and X = O (CH2)3NH2 may be converted into dronedarone hydrochloride compound of structural formula I by reacting a

compound of formula Vd with butyl halide such as butyl bromide in the presence of organic and inorganic base such as sodium hydroxide, potassium carbonate, triethyl amine, sodium carbonate, sodium bicarbonate, potassium tertiary butoxide or sodium methoxide in an organic solvent at a temperature in the range of 25°C to 80°C for a period of 1 hour to 12 hours followed by the reaction with hydrogen chloride in an organic solvent.
The compound of structural formula Ve, wherein R = NO2 and X = O(CH2)3NH2 may be converted into dronedarone hydrochloride compound of structural formula I by reacting a compound of formula Ve with butyl halide such as butyl bromide in the presence of organic and inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, triethyl amine, sodium carbonate, sodium bicarbonate, potassium tertiary butoxide or sodium methoxide in an organic solvent at a temperature in the range of 25°C to 60°C for a period of 2 hour to 6 hours followed by the reducing nitro group into amino group and alkyl sulfonation of amino group by aforementioned processes followed by the reaction with hydrogen chloride in an organic solvent.
The compound of structural formula Vf, wherein R = CH3SO2NH- and X = O (CH2)3CI may be converted into dronedarone hydrochloride compound of structural formula I by reacting a compound of formula Vf with dibutyl amine in the presence of inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate in an organic solvent at a temperature in the range of 25°C to 60°C for a period of 2 hour to 6 hours followed by the reaction with hydrogen chloride in an organic solvent.
The compound of structural formula Vg, wherein R = NH2 and X = O (CH2)3C1 may be converted into dronedarone hydrochloride compound of structural formula I via the formation of a compound of formula Vf by the alkyl sulfonation of a compound of formula Vg by above mentioned process.
The compound of structural formula Vf may be converted into dronedarone hydrochloride compound of structural formula I by aforementioned process.

The compound of structural formula Vh, wherein R = NO2 and X = O (CH2)3C1 may be converted into dronedarone hydrochloride compound of structural formula I by converting it into a compound of formula Vg by the reduction of a nitro group of a compound of formula Vh followed by the same process as described above for converting a compound of structural formula Vg into dronedarone hydrochloride compound of structural formula I.
The compound of structural formula Vi, wherein R = CH3SO2NH- and X = O (CH2)3Br may be converted into dronedarone hydrochloride compound of structural formula I by the same procedure as described above for converting a compound of structural formula Vf into dronedarone hydrochloride compound of structural formula I.
The compound of structural formula Vj, wherein R = NH2 and X = O (CH2)3Br may be converted into dronedarone hydrochloride compound of structural formula I by the same procedure as described above for converting a compound of structural formula Vg into dronedarone hydrochloride compound of structural formula I.
The compound of structural formula Vk, wherein R = NO2 and X = O (CH2)3Br may be converted into dronedarone hydrochloride compound of structural formula I by the same procedure as described above for converting a compound of structural formula Vh into dronedarone hydrochloride compound of structural formula I.
The compound of structural formula VI, wherein R = CH3SO2NH- and X = OH may be converted into dronedarone hydrochloride compound of structural formula I by reacting a compound of structural formula VI with 1-chloro 3-di-n-butylamino propane or 1-bromo 3-di-n-butylamino propane in the presence of inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate in an organic solvent such as ketones, ethers and alcohols.
Examples of ketone solvents include acetone, methyl ethyl ketone, methyl propyl ketone, methyl isobutyl ketone or mixture(s) thereof.

Examples of ether solvents include dioxane, diethyl ether, tetrahydrofuran, methyl tertiary butyl ether, dipropyl ether, dibutyl ether, methyl ethyl ether or mixture(s) thereof.
Examples of alcohols solvent include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or mixture(s) thereof.
The present inventions are further illustrated by the following examples which are provided merely to be exemplary of the inventions and are not intended to limit the scope of the invention.
The compound of structural formula VI, wherein R = CH3SO2NH- and X = OH may be converted into dronedarone hydrochloride compound of structural formula I by first converting into a compounds of structural formula Vi or Vf by reacting it with dichloro propane or dibromo butane respectively and then by the above mentioned processes for converting a compounds of structural formula Vi or Vf into dronedarone hydrochloride compound of structural formula I.
The compound of structural formula Vm, wherein R = NH2 and X = OH may be converted into dronedarone hydrochloride compound of structural formula I by reacting a compound of formula Vm with halogenating agents in an organic solvent to get a compounds of structural formula Vp, Vs or Vv followed by the alkyl sulfonation of a compounds of structural formula Vp, Vs or Vv by above mentioned processes to get a compounds of structural formula Vo, Vr or Vu and then reacting a compounds of structural formula Vo, Vr or Vu with 3-(dibutylamino)propan-l-ol to get a dronedarone compound of structural formula VII, which may be converted into dronedarone hydrochloride compound of structural formula I by reacting with hydrochloride in an organic solvent.


The compound of structural formula Vn, wherein R = NO2 and X = OH may be converted into dronedarone hydrochloride compound of structural formula I via the formation of a compound of formula Vm by reducing nitro group of a compound of structural formula Vn and then by following the same process as mentioned above for preparing dronedarone hydrochloride compound of structural formula I starting from a compound of structural formula Vm.
The compound of structural formula Vn, wherein R = NO2 and X = OH may be converted into dronedarone hydrochloride compound of structural formula I by reacting it first with 1-chloro 3-di-n-butylamino propane or 1-bromo 3-di-n-butylamino propane to get a compound of structural formula Vc and then by the similar process as described above for the preparation of dronedarone hydrochloride compound of structural formula I starting from a compound of structural formula Vc.

The compound of structural formula Vn, wherein R = NO2 and X = OH may be converted into dronedarone hydrochloride compound of structural formula I by converting first into a compound of structural formula Vh and Vk by the reaction of dichloro propane and dibromo propane respectively in the presence of base in an organic solvent followed by the same procedure as mentioned above for converting a compounds of structural formula Vh and Vk into a dronedarone hydrochloride compound of structural formula I.
The compound of structural formula Vo, wherein R = CH3SO2NH- and X = Br may be converted into dronedarone hydrochloride compound of structural formula I by reacting it with 3-(dibutylamino) propan-1 -ol in the presence of inorganic base in an organic solvent.
The compound of structural formula Vp, wherein R = NH2 and X = Br may be converted into dronedarone hydrochloride compound of structural formula I by converting it into a compound of formula Vo by reacting it with methane sulfonyl chloride in the presence of base in an organic solvent and then by the similar process as described above for preparing dronedarone hydrochloride compound of structural formula I starting from a compound of structural formula Vo.
The compound of structural formula Vq, wherein R = NO2 and X = Br may be converted into dronedarone hydrochloride compound of structural formula I by first converting it into a compound of formula Vp by reducing nitro group of a compound of structural formula Vq and then by the similar process as described above for preparing dronedarone hydrochloride compound of structural formula I starting from a compound of formula Vp.
The compounds of structural formula Vr, wherein R = CH3SO2NH- and X = C1; and Vu wherein R = CH3SO2NH- and X = I may be converted into dronedarone hydrochloride compound of structural formula I by reacting them with 3-(dibutylamino) propan-l-ol in the presence of inorganic base or organic base in an organic solvent.
The compound of structural formula Vs, wherein R = NH2 and X = CI and Vv wherein R = NH2 and X=I may be converted into dronedarone hydrochloride compound of structural formula I by

first converting them into a compound of structural formula Vr and Vu respectively by the reaction of methane sulfonyl chloride in the presence of inorganic or organic base in an organic solvent and then by the similar process as described above for converting a compound of structural formula Vr and Vu respectively into a dronedarone hydrochloride compound of structural formula I.
The compound of structural formula Vt, wherein R = NO2 and X = C1 and Vw whererin R = NO2 and X = I may be converted into dronedarone hydrochloride compound of structural formula I first by converting them into a compound of structural formula Vs and Vv respectively by reducing nitro group of a compound of structural formula Vt and Vw respectively then by a similar process as described above for converting a compound of structural formula Vs and Vv respectively into a dronedarone hydrochloride compound of structural formula I.
The dronedarone hydrochloride compound of structural formula I obtained by the present invention may be isolated by the steps of cooling, filtration, centrifugation, washing, drying and combination thereof.
The dronedarone hydrochloride compound of structural formula I obtained by the present invention may be dried at a temperature in the range of 40°C to 70°C under reduced pressure.
The dronedarone hydrochloride compound of structural formula I obtained by the present invention is crystalline in nature.

EXAMPLE:
In the following example, the preferred embodiment of the present invention is described only by way of illustrating the processes of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of dronedarone hydrochloride
Step A: Preparation of 2-butyl-5-(methylsulfonamido) benzofuran-3-carbonyl chloride.
A solution of 2-butyl-5-(methylsulfonamido) benzofuran-3-carboxylic acid (20gm) in dichloromethane (200ml) was added thionyl chloride (15ml) and then resulting reaction mixture was stirred for 3 hours at 40-45°C. The resulting reaction mixture was concentrated under reduced pressure to get title compound. Yield:21.1gm
Step B: Preparation of dronedarone
A solution of 2-butyl-5-(methylsulfonamido) benzofuran-3-carbonyl chloride (20gm) in toluene (300ml) was added N-butyl-N-(3-phenoxypropyl) butan-1-amine (15gm) and aluminum chloride (lOgm) and resulting reaction mixture was refluxed for 12 hours. The resulting reaction mixture was cooled to 20-25°C and quenched with water (500ml) followed by extract with dichloromethane (400ml), washed with sodium bicarbonate (40ml) and dry over anhydrous sodium sulfate (20gm). The resulting organic layer was then concentrated under reduced pressure to get title compound. Yield: 33.8gm
Step C: Preparation of dronedarone hydrochloride
A solution of dronedarone (10gm) in isopropanol (110ml) was added isopropanolic hydrochloric acid (9.4ml, 7% weight / weight) and then it was stirred for 1 hour at 20-25°C. The resulting

solution was cooled to 10°C and then it was stirred for 2 hours at 10-15°C. The resulting solids
were filtered, washed with chilled isopropanol (10ml) and dried at 45-50oC for 4 hours to get
title compound.
Yield: 10.6gm
Purity: 99.8% (By HPLC)

WE CLAIM:
1. A process for preparing dronedarone hydrochloride compound of structural formula I comprising the steps of:
a. converting a compound of formula III into a compound of formula IV,

wherein Y is a halogen atom and R is nitro group, amino group or alkyl sulfonyl amino group
b. acylating a compound of structural formula II with a compound of structural formula IV to get a compound of structural formula V and

Formula II Formula IV Formula V
wherein X is a halogen atom, hydroxy group, halogen substituted alkoxy group, amino substituted alkoxy group or alkyl amino substituted alkoxy group
c. converting a compound of formula V into dronedarone hydrochloride compound of structural formula I.


2. A compound of structural formula VI.

Wherein R' is -NH2 or CH3SO2NH-.
3. A compound of structural formula VI, which is being used for the preparation of dronedarone hydrochloride compound of structural formula I.

Formula VI
Wherein R' is -NH2 or CH3SO2NH-.
4. The process according to claim no. 1, wherein compound of formula III is reacted with halogenating reagents like phosphorus trichloride, phosphorous pentachloride, oxalyl chloride, phosgene or thionyl chloride to get a compound of formula IV.

5. The process according to claim no. 4, wherein reaction of compound of formula III with halogenating reagents is carried out at a temperature in the range of 20°C to 50°C for a period of 30 minutes to 4 hours to get a compound of formula IV.
6. The process according to claim no. 1, wherein acylation of a compound of structural formula II with a compound of structural formula IV is carried out in the presence of lewis acid in an organic solvent
7. The process according to claim no. 6 wherein lewis acid is selected from the group comprising of aluminium halide, boron halide, tin halide, bismuth halide, iron halide or titanium halide and an organic solvent is selected from the group comprising of toluene, xylene, chlorobenzene, dichloromethane, dichloroethane or carbon tetrachloride.
8. The process according to claim no. 1, wherein acylation of a compound of structural formula II with a compound of structural formula IV is carried out at a temperature in the range of -5°C to 50°C.
9. An intermediates compound of structural formula IVc, IVd, IVe, and IVf.


10. Use of an intermediates compound of structural formula IIe, IIf, IIg and IIh for preparation of dronedarone hydrochloride.