DESC:The following specification particularly describes the invention and the manner in which it is to be performed.

SALTS OF LUMACAFTOR AND PROCESSES THEREOF
INTRODUCTION
Aspects of the present application relate to salts of Lumacaftor. Specific aspects of the present application relate to salts of Lumacaftor and processes thereof.
The drug compound having the adopted name “Lumacaftor” has chemical name: 3-{6-{[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropane carbonyl]amino}-3-methylpyridin-2-yl}benzoic acid as below.

Lumacaftor partially corrects the fundamental molecular defect caused by F508del-CFTR to increase the amount of functional F508del-CFTR at the cell surface, resulting in enhanced chloride transport. The channel gating activity of F508del-CFTR delivered to the cell surface by Lumacaftor can be potentiated by Ivacaftor to further enhance chloride transport. When added to F508del/F508del-HBE, the magnitude of chloride transport observed with the combination of Lumacaftor and either acute or chronic Ivacaftor treatment was greater than that observed with Lumacaftor alone. Orkambi is approved in US and Europe as a fixed dose combination (FDC) pink immediate-release film-coated tablet for oral administration. Orkambi contains 200 mg of Lumacaftor and 125 mg of Ivacaftor as active substances. US FDA label prescribes two tablets to be taken orally every 12 hours for the treatment of cystic fibrosis (CF) in patients age 12 years and older who are homozygous for the F508del mutation in the CFTR gene.
US 8993600 B2 discloses Lumacaftor as compound-396, its pharmaceutical use for the treatment of cystic fibrosis. Further, it discloses preparative methods for the preparation of compounds disclosed therein including Lumacaftor by reacting N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid as depicted in scheme-1.

US 8507534 B2 indicates that the process disclosed in US 8993600 B2 for the preparation of Lumacaftor results in its salt form. Further, US 8507534 B2 discloses an alternate process for the preparation of crystalline Lumacaftor Form I through the formation of t-butyl ester of Lumacaftor, which in turn is hydrolyzed to its free form i.e., Lumacaftor and alternatively, the t-butyl ester of Lumacaftor is converted to its hydrochloride salt and then neutralized to afford Lumacaftor as depicted in scheme-2.

US 8507687 B2 also discloses that, the hydrochloride salt of Lumacaftor can be used to prepare other solid forms, including Form A of hydrochloride salt and Lumacaftor solvate Form A.
US 8124781 B2 also discloses an approach similar to scheme - 2 for the conversion of hydrochloride salt of Lumacaftor to its free form.
None of these arts disclose an amenable and / or scalable solid form for salt of Lumacaftor, which are stable enough and suitable for purifying the Lumacaftor. Hence, there remains a need for alternate salt forms which can overcome said disadvantages of the prior art and their preparative processes in a more cost effective and industrially viable manner.

SUMMARY
In an aspect, the present application provides an acid addition salt of Lumacaftor, wherein the acid may be selected from the group comprising of acetic acid, formic acid, tartaric acid and hydrobromic acid.
In another aspect, the present application provides an acetic acid salt of Lumacaftor.
In another aspect, the present application provides a formic acid salt of Lumacaftor.
In another aspect, the present application provides a tartaric acid salt of Lumacaftor.
In another aspect, the present application provides a hydrobromide salt of Lumacaftor.
In another aspect, the present application provides a process for the preparation of salt of Lumacaftor comprising the step of contacting an acid with Lumacaftor, wherein acid may be selected from the group comprising of acetic acid, formic acid, tartaric acid and hydrobromic acid.
In another aspect, the present application provides a process for the preparation of Lumacaftor, comprising the step of converting a salt of Lumacaftor to its free form, wherein the salt may be selected from the group comprising of acetic acid salt, formic acid salt, tartaric acid salt and hydrobromide salt.
In another aspect, the present application provides a process for the preparation of Lumacaftor or salts thereof, comprising the step of reacting 3-boronobenzoic acid or a derivative thereof with N-(6-halo-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide in presence of an inert solvent selected from the group comprising of water, dimethylformamide, dimethoxyethane, 1,4-dioxane, 2-propanol, n-butanol, 2-butanol, tert-butanol or mixtures thereof.
In another aspect, the present application provides a pharmaceutical composition comprising salts of Lumacaftor with an acid, wherein the acid may be selected from the group comprising of acetic acid, formic acid, tartaric acid and hydrobromic acid.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative PXRD pattern of acetic acid salt of Lumacaftor prepared by the method of example No 13.
Figure 2 is an illustrative DSC thermogram of acetic acid salt of Lumacaftor prepared by the method of example No 13.
Figure 3 is an illustrative PXRD pattern of formic acid salt of Lumacaftor prepared by the method of example No 14.
Figure 4 is an illustrative DSC thermogram of formic acid salt of Lumacaftor prepared by the method of example No 14.
Figure 5 is an illustrative PXRD pattern of tartaric acid salt of Lumacaftor prepared by the method of example No 15.
Figure 6 is an illustrative DSC thermogram of tartaric acid salt of Lumacaftor prepared by the method of example No 15.
Figure 7 is an illustrative PXRD pattern of hydrobromic acid salt of Lumacaftor prepared by the method of example No 16.
Figure 8 is an illustrative DSC thermogram of hydro bromic acid salt of Lumacaftor prepared by the method of example No 16.
Figure 9 is an illustrative PXRD pattern of Lumacaftor prepared by the method of example 3.
Figure 10 is an illustrative DSC thermogram of Lumacaftor prepared by the method of example No 3.

DETAILED DESCRIPTION
In an aspect, the present application provides an acid addition salt of Lumacaftor, wherein the acid may be selected from the group comprising of acetic acid, formic acid, tartaric acid and hydrobromic acid.
In an embodiment, the acid addition salt of this aspect may contain Lumacaftor and the acid in any stoichiometric ratio.
In an embodiment, the acid addition salt may be in crystalline or an amorphous form. In preferred embodiment, the acid addition salt may be in crystalline form.

In another aspect, the present application provides an acetic acid salt of Lumacaftor. In an embodiment, the acetic acid salt is a crystalline salt, characterized by a PXRD pattern of figure 1 and / or a DSC thermogram of figure 2.

In another aspect, the present application provides a formic acid salt of Lumacaftor. In an embodiment, the formic acid salt is a crystalline salt, characterized by a PXRD pattern of figure 3 and / or a DSC thermogram of figure 4.

In another aspect, the present application provides a tartaric acid salt of Lumacaftor. In an embodiment, the tartaric acid salt is a crystalline salt, characterized by a PXRD pattern of figure 5 and / or a DSC thermogram of figure 6.

In another aspect, the present application provides a hydrobromic acid salt of Lumacaftor. In an embodiment, the hydrobromic acid salt is a crystalline salt, characterized by a PXRD pattern of figure 7 and / or a DSC thermogram of figure 8.

In another aspect, the present application provides a process for the preparation of acid addition salt of Lumacaftor comprising the step of contacting an acid with Lumacaftor, wherein acid may be selected from the group comprising of acetic acid, formic acid, tartaric acid and hydrobromic acid.
In an embodiment Lumacaftor may be contacted with acid in a mole ratio of about 1: 0.8 to 1:1.6.
In an embodiment, Lumacaftor may be contacted with an acid in a heterogeneous or homogenous phase. In an embodiment, Lumacaftor may be contacted with an acid in homogeneous phase. In an embodiment, solution comprising Lumacaftor in an inert solvent may be contacted with an acid.
In an embodiment, the acid may be used either in concentrated or diluted form before contacting with Lumacaftor.
In an embodiment, Lumacaftor may be contacted with an acid at a suitable temperature at about 0°C and above for time sufficient for salt formation. In an embodiment, the reaction mixture comprising Lumacaftor and the acid may be stirred for sufficient time and at suitable temperature for the completion of salt formation.
In an embodiment, the reaction mixture comprising Lumacaftor and the acid may be concentrated and / or cooled to suitable temperature before isolating the salt of Lumacaftor.
In an embodiment, suitable anti-solvent may be added to the reaction mixture comprising Lumacaftor and the acid before isolating the salt of Lumacaftor.
Isolation of acid addition salt of Lumacaftor may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, acid addition salt of Lumacaftor may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an embodiment, drying acid addition salt of Lumacaftor may be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
It is worth noting, that the option of purifying a low soluble drug substances among BCS class IV or class II like Lumacaftor, by conventional methods like recrystallization from a solvent or mixture of solvents may not be suitable due to the limited solvents. Therefore, purification of such drug substance through salt formation is a boon to a chemist. Lumacaftor may be purified through the formation of a suitable salt followed by its neutralization to free from.
Further, these salts may be optionally purified by any method known in the art including recrystallization, before neutralization, unlike the free forms. The salt forms are generally regarded as superior in terms of solubility compared to respective free forms and may be conveniently recrystallized from suitable solvents according to techniques known in the art such cooling crystallization, anti-solvent addition, or the like.

The present application provides a purification process for Lumacaftor, comprising the step of converting an acid addition salt of Lumacaftor obtained according any of the previous aspects into its free form.

In another aspect, the present application provides a process for the preparation of Lumacaftor, comprising the step of converting an acid addition salt of Lumacaftor to its free form, wherein the salt may be selected from the group comprising of acetic acid salt, formic acid salt, tartaric acid salt and hydrobromide salt.
In an embodiment, the acid addition salt of Lumacaftor may be converted to Lumacaftor in free form by neutralization. In an embodiment, the acid addition salt may be neutralized in the presence of a suitable base. Base may be used directly or may diluted form in water or any inert suitable solvent, before using.
Suitable base may include, but not limited to: hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide; carbonates such sodium carbonate, potassium carbonate, ammonium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate; an organic base like amines such as triethyl amine, diisopropyl amine, diisopropyl ethyl amine; alkoxides such as methoxide, ethoxide, isopropoxide, tert. Butoxide; N-heterocyclic Compounds; tetraalkylammonium and phosphonium hydroxides; Amides; metal silanoates; and the like.
In another embodiment, the acid addition salt of Lumacaftor may be converted to its free form by subjecting the acid addition salt to suitable conditions which may include, but not limited to: suspending the acid addition salt of Lumacaftor in a suitable solvent optionally at elevated temperatures.
In an embodiment, the free form of Lumcaftor obtained according to the process of this aspect may be either in crystalline form or amorphous form. In an embodiment, the free form of Lumacaftor may be in crystalline form.

The present application provides a crystalline form of Lumacaftor, characterized by a PXRD pattern of figure 9 and / or a DSC thermogram of figure 10.

In another aspect, the present application provides a pharmaceutical composition comprising salts of Lumacaftor with an acid, wherein the acid may be selected from the group comprising of acetic acid, formic acid, tartaric acid and hydrobromic acid.

Similar procedures for the preparation of any salt of Lumacaftor described here may be useful to produce other salts of Lumacaftor comprising acid addition salts with inorganic acids such as phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as oxalic acid, maleic acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like and salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts.

In another aspect, the present application provides a process for the preparation of Lumacaftor or salts thereof, comprising the step of reacting 3-boronobenzoic acid or a derivative thereof with N-(6-halo-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclo propanecarboxamide in presence of an inert solvent selected from the group comprising of water, dimethylformamide, dimethoxyethane, 1,4-dioxane, 2-propanol, n-butanol, 2-butanol, tert-butanol or mixtures thereof.
In an embodiment, the reaction between 3-boronobenzoic acid or a derivative thereof and N-(6-halo-5-methyl pyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide may be carried out in the presence of a suitable catalyst selected from the group comprising of palladium acetate; dichloro-[1,1-bis(diphenylphosphino) ferrocene]palladium(II) (Pd(dppf)Cl2); palladium acetate / triphenyl phosphine; Tetrakis(triphenylphosphine)palladium (0) (Pd(PPh3)4) or the like.
In an embodiment, the reaction between 3-boronobenzoic acid or a derivative thereof and N-(6-halo-5-methyl pyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide may be carried out in the presence of a suitable base selected from the group comprising of hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide; carbonates such sodium carbonate, potassium carbonate, ammonium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate; Potassium phosphate tribasic (K3PO4); an organic base like amines such as triethyl amine, diisopropyl amine, diisopropyl ethyl amine; alkoxides such as methoxide, ethoxide, isopropoxide, tert. Butoxide; N-heterocyclic Compounds; tetraalkylammonium and phosphonium hydroxides; Amides; metal silanoates; and the like.
In an embodiment, 3-boronobenzoic acid may reacted directly or its derivatives such as 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid or the like may be reacted with N-(6-halo-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide.
In an embodiment, the mole ratio of 3-boronobenzoic acid or a derivative thereof to N-(6-halo-5-methyl pyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide that may be used is about 1: 0.8 to 1: 1.2.
In an embodiment, the reaction between 3-boronobenzoic acid or a derivative thereof and N-(6-halo-5-methylpyridin-2-yl)-1-(2,2-difluoro benzo[d][1,3]dioxol-5yl)cyclopropane carboxamide may be carried out at a suitable temperature of about 0°C to reflux temperature of the reaction mixture.
In an embodiment, the reaction between 3-boronobenzoic acid or a derivative thereof and N-(6-halo-5-methylpyridin-2-yl)-1-(2,2-difluoro benzo[d][1,3]dioxol-5yl)cyclopropane carboxamide may be carried out for sufficient time to complete the formation of Lumacaftor or salts thereof for about 1 hour or more.
In embodiment, Lumacaftor that is obtained according to the process of this aspect may be purified through the formation of any salt described in the instant application.

Starting materials or Lumacaftor used in any aspect of the instant application may be purified according to the methods known in the art such as recrystallization, acid – base treatment, chromatography, fractional distillation, slurrying or the like, before using.
Starting materials used for the preparation of Lumacaftor may be obtained from either commercially available sources or prepared according to the methods known in the art.
Lumacaftor used as starting material for the preparation of any acid addition salt of the present application may be obtained according to the methods known in the art or according to the procedure described or exemplified in the present application.
Lumacaftor obtained according to any aspects of the instant patent application may be further purified according to any of the methods known in the art recrystallization, acid – base treatment, chromatography or the like. Further, Lumacaftor may be dried under suitable drying conditions such as air drying or vacuum drying.
In another aspect, the present application provides a pharmaceutical composition comprising Lumacaftor obtained according any of the previous aspects and atleast one additional pharmaceutically acceptable excipient.
In another aspect, the present application provides Lumacaftor or its pharmaceutical composition, wherein the chemical purity of Lumacaftor may be more than 99% by HPLC or more than 99.5% by HPLC or more than 99.9% by HPLC.
In another aspect, the present application provides Lumacaftor or its pharmaceutical composition, wherein particle size (D90) of Lumacaftor may be less than 100 microns or less than 50 microns or less than 20 microns.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

Definitions
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
The term “inert solvent” when used in the present application is a solvent that does not react with the reactants or reagent s under conditions that cause the chemical reaction indicated to take place.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, ethylene glycol, diethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called “aromatic.” Examples of “C5-C8aliphatic or aromatic hydrocarbons” include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A “nitrile” is an organic compound containing a cyano - (C=N) bonded to another carbon atom. “C2-C6Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.

EXAMPLES
Example-1: Preparation of N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo [d][1,3]dioxol-5-yl)cyclopropanecarboxamide
To a mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane carboxylic acid (50 g) in toluene (500 mL) at 26°C, Thionyl chloride (31.9 g) and dimethyl formamide (0.5 mL) was added. The reaction mixture was heated to 59.6°C and stirred for 2 hours at the same temperature. The solvent was removed from the reaction mixture through evaporation at 52°C under reduced pressure and the crude product was dissolved in toluene (300 mL). A mixture of 6-chloro-5-methylpyridin-2-amine (29.4 g) in toluene (400 mL) was added to the reaction mixture at 30°C in 35 minutes and stirred for 10 minutes at the same temperature. Triethylamine (20.89 g) was added in 10 minutes at 27.3°C and stirred for 2 hours at the same temperature. Quenched the reaction mixture with water (250 mL) and separated the organic layer. The organic layer was washed with 5% HCl (2 x 50 mL), then with 3% sodium carbonate (2 x 100 mL) and then with water (50 mL). The solvent was removed completely from the organic layer through evaporation under reduced pressure at 55°C. Hexane (2 x 100 mL) was added to the crude product and removed by evaporation at 55°C. Again hexane (130 mL) was added and stirred the mixture at 26°C for 1 hour and the solid was filtered. Washed the wet compound with hexane (50 mL) and dried under reduced pressure at 53°C for 1.5 hours to obtain the title compound. Yield: 69.4 g

Example-2: Preparation of hydrobromide salt of Lumacaftor
A solution of potassium carbonate (37.7 g) in water (125 mL) was added to a mixture of N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3] dioxol-5-yl)cyclopropanecarboxamide (25 g) and 3-boronobenzoic acid (13.57 g) in n-butanol (200 mL) at 26°C. Triphenylphosphine (2.68 g) and Palladium acetate (0.765 g) were added to the reaction mixture at 26°C and heated to 90°C. Stirred the reaction mixture at the same temperature for 1 hour and cooled to 26°C. The reaction mixture was filtered and the filtrate was concentrated by evaporating n-butanol under reduced pressure at 56°C and water (200 mL) was added. The aqueous layer was washed with toluene (200 mL) and the pH was adjusted to 2 using concentrated hydrochloric acid. The reaction mixture was extracted with ethyl acetate (500 mL) and the organic layer was washed with water (200 mL). The organic layer was washed with 5% sodium bicarbonate solution (100 mL) and then with water (200 mL). The solvent was removed from the organic layer completely by evaporation under reduced pressure at 50°C. Isopropyl alcohol (300 mL) was added to the crude product and evaporated completely at 50°C. Again Isopropyl alcohol (300 mL) was added and heated to 82.2°C to obtain clear solution and stirred for 20 minutes at the same temperature. Cooled the solution to 67.2°C and hydrobromide (6.62 g) was added slowly. Further cooled the reaction mixture to 26°C and stirred for 2 hours at the same temperature. The solid was filtered and washed with isopropyl alcohol (30 mL) to obtain the title compound. Yield: 29.5 g

Example-3: Preparation of Lumacaftor from Lumacaftor hydrobromide salt.
To a mixture of hydrobromide salt of Lumacaftor (5 g) in ethyl acetate (50 mL), a solution of sodium bicarbonate (0.788 g) in water (20 mL) at 26°C and stirred for 20 minutes at the same temperature. Separated the organic layer and removed the solvent through evaporation under reduced pressure at 26°C. The solid was dried at 45°C for 3 hours under reduced pressure to obtain the title compound. Yield: 4.1 g

Example-4: Preparation of Lumacaftor
N-(6-bromo-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamide (20 g) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (14.48 g) were added to a mixture of potassium carbonate (32.3 g) in dimethylformamide (100 mL) and water (20 mL) at 26°C. Pd(dppf)Cl2•.CH2Cl2 (1.984 g) was added to the above reaction mixture at the same temperature and heated to 70°C. The reaction mixture was stirred for 1 hour at 70°C and cooled to 26°C. The reaction mixture was quenched with water (200 mL) and ethyl acetate (200 mL) was added. Cooled the reaction mixture to 10°C and adjusted the pH of the reaction mixture to 2 using 36% hydrochloric acid. The reaction mixture was filtered and separated the organic layer. 10% aqueous hydrochloride (100 mL) was added and stirred for 15 minutes at 26°C. Separated the organic layer and again 10% aqueous hydrochloride (100 mL) was added. Stirred the reaction mixture for 15 minutes and separated the organic layer. The solvent was evaporated completely at 52°C under reduced pressure and chased with 2-propanol (50 mL). 2-propanol (50 mL) was added to the crude product at 26°C and stirred for 1.5 hours at the same temperature. 36% aqueous hydrochloride (5 mL) was added at 26°C and stirred for 15 hours at same temperature. The reaction mixture was cooled to 5°C and stirred for 1 hour at this temperature. The solid was filtered and washed with 2-propanol (5 mL). The solid was dried at 68°C for 4.5 hour under reduced pressure to obtain the title compound. Yield: 13 g; Purity by HPLC: 99.23%

Example 5: Preparation of Lumacaftor
To a mixture of N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluoro benzo[d][1,3] dioxol-5-yl)cyclopropanecarboxamide (2 g) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1.623 g) in dioxane (40 mL) under nitrogen atmosphere, Potassium carbonate (3.39 g) in water (12 mL) was added at 26°C. Pd(dppf)Cl2.CH2Cl2 (0.445 g) was added at the same temperature and heated to 87°C. Stirred the reaction mixture at 87°C for 14 hours and cooled to 26°C. Adjusted the pH of the reaction mixture to 2 with concentrated hydrochloric acid and extracted into ethyl acetate (60 mL). Solvent was evaporated under reduced pressure at 26°C to obtain the title compound. Yield: 4 g (crude)

Example 6: Preparation of Lumacaftor
To a mixture of N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluoro benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (2 g) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1.623 g) in dimethoxyethane (40 mL) under nitrogen atmosphere, Potassium carbonate (3.39 g) in water (12 mL) was added at 26°C. Pd(dppf)Cl2.CH2Cl2 (0.445 g) was added at the same temperature and heated to 77°C. Stirred the reaction mixture at 77°C for 15 hours and cooled to 26°C. Adjusted the pH of the reaction mixture to 2 with concentrated hydrochloric acid and extracted into ethyl acetate (60 mL). Solvent was evaporated under reduced pressure at 26°C to obtain the title compound. Yield: 4 g (crude).

Example 7: Preparation of Lumacaftor
To a mixture of N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluoro benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (2 g) and 3-boronobenzoic acid (1.086 g) in dimethylformamide (40 mL) under nitrogen atmosphere, sodium carbonate (3.01 g) in water (4.5 mL) was added at 26°C. Palladium acetate (0.122 g) and triphenylphosphine (0.429 g) was added at the same temperature and heated to 80°C. The reaction mixture was stirred for 3 hours at 80°C for the completion of the reaction.

Example 8: Preparation of Lumacaftor
To a mixture of N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluoro benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (2 g) and 3-boronobenzoic acid (1.086 g) in 2-propanol (15 mL) under nitrogen atmosphere, potassium carbonate (3.01 g) in water (5 mL) was added at 26°C. Palladium acetate (0.122 g) and triphenylphosphine (0.429 g) was added at the same temperature and heated to 80°C. The reaction mixture was stirred for 5.5 hours at 80°C and the solvent was removed by evaporation at 45°C and water (20 mL) was added. Washed the aqueous layer with toluene (20 mL) and adjusted the pH of the aqueous layer to 2 with concentrated hydrochloric acid. Extracted the aqueous layer with ethyl acetate (50 mL) and the organic layer was washed with water (20 mL), 5% sodium bicarbonate solution (10 mL) and then with water (20 mL). The solvent was evaporated at 45°C under reduced pressure and hexane (10 mL) was added. The mixture was stirred for 1.5 hour at 26°C and filtered to obtain the title compound. Yield: 700 mg

Example 9: Preparation of Lumacaftor
To a mixture of N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluoro benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (2 g) and 3-boronobenzoic acid (1.086 g) in dioxane (15 mL) under nitrogen atmosphere, potassium carbonate (3.01 g) in water (5 mL) was added at 26°C. Palladium acetate (0.122 g) and triphenylphosphine (0.429 g) was added at the same temperature and heated to 80°C. The reaction mixture was stirred for 14 hours at 80°C and the solvent was removed by evaporation at 45°C and water (20 mL) was added. Washed the aqueous layer with toluene (20 mL) and adjusted the pH of the aqueous layer to 2 with concentrated hydrochloric acid. Extracted the aqueous layer with ethyl acetate (50 mL) and the organic layer was washed with water (20 mL), 5% sodium bicarbonate solution (10 mL) and then with water (20 mL). The solvent was evaporated at 45°C under reduced pressure and hexane (10 mL) was added. The mixture was filtered to obtain the title compound. Yield: 1.1 g

Example 10: Preparation of Lumacaftor
To a mixture of N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluoro benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (2 g) and 3-boronobenzoic acid (1.086 g) in tert. Butanol (15 mL) under nitrogen atmosphere, potassium carbonate (3.01 g) in water (5 mL) was added at 26°C. Palladium acetate (0.122 g) and triphenylphosphine (0.429 g) was added at the same temperature and heated to 80°C. The reaction mixture was stirred for 7.5 hours at 80°C for the completion of the reaction.

Example 11: Preparation of Lumacaftor
To a mixture of N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluoro benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (2 g) and 3-boronobenzoic acid (1.086 g) in 2-butanol (15 mL) under nitrogen atmosphere, potassium carbonate (3.01 g) in water (10 mL) was added at 26°C. Palladium acetate (0.061 g) and triphenylphosphine (0.215 g) was added at the same temperature and heated to 80°C. The reaction mixture was stirred for 7 hours at 81°C for the completion of the reaction.

Example 12: Preparation of Lumacaftor
To a mixture of N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluoro benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (2 g) and 3-boronobenzoic acid (1.086 g) in n-butanol (10 mL) under nitrogen atmosphere, sodium carbonate (2.312 g) in water (10 mL) was added at 26°C. Palladium acetate (0.061 g) and triphenylphosphine (0.215 g) was added at the same temperature and heated to 80°C. The reaction mixture was stirred for 5 hours at 91°C for the completion of the reaction.

Example 13: Preparation of acetic acid salt of Lumacaftor
Lumacaftor (1 g) was dissolved in isopropyl alcohol (10 mL) at 72°C and cooled to 60°C. Acetic acid (0.199 g) was added to the above solution and cooled to 26°C. Stirred the reaction mixture for 4.5 hours at the same temperature and filtered the solid. The cake was washed with isopropyl alcohol (3 mL) and dried under vacuum at 60°C for 11.5 hours to obtain the title compound. Yield: 807 mg

Example 14: Preparation of formic acid salt of Lumacaftor
Lumacaftor (1 g) was dissolved in isopropyl alcohol (10 mL) at 72°C and cooled to 60°C. Formic acid (0.153 g) was added to the above solution and cooled to 26°C. Isopropyl alcohol (2 mL) was added to the reaction mixture 26°C and stirred for 4.5 hours at the same temperature. The solid was filtered and the cake was washed with isopropyl alcohol (2 mL). Solid was dried under vacuum at 60°C for 11.5 hours to obtain the title compound. Yield: 780 mg

Example 15: Preparation of tartaric acid salt of Lumacaftor
Lumacaftor (1 g) was dissolved in isopropyl alcohol (10 mL) at 72°C and tartaric acid (0.498 g) was added into the above solution. Stirred the reaction mixture for 30 min at 72°C and cooled to 26°C. Stirred the reaction mixture for 2 hours at 26°C and solid was filtered. The cake was washed with isopropyl alcohol (3 mL) and dried under vacuum at 60°C for 11.5 hours to obtain the title compound. Yield: 894 mg

Example 16: Preparation of hydrobromide salt of Lumacaftor
Lumacaftor (1 g) was dissolved in isopropyl alcohol (10 mL) at 72°C and cooled to 60°C. Hydrobromic acid (0.268 g) was added at 60°C into the above solution and cooled to 26°C. Stirred the reaction mixture for 3 hours at same temperature and the solid was filtered. The cake was washed with isopropyl alcohol (3 mL) and dried under vacuum at 60°C for 11.5 hours to obtain the title compound. Yield: 786 mg.
,CLAIMS:1. An acid addition salt of Lumacaftor wherein, the acid may be selected from the group comprising of acetic acid, formic acid, tartaric acid and hydrobromic acid.
2. An acid addition salt according to claim 1, wherein the acid may be selected from the group comprising of acetic acid, formic acid, and tartaric acid.
3. An acid addition salt according to claim 1, wherein the acid is hydrobromic acid.
4. A process for the preparation of acid addition salt of Lumacaftor comprising the step of contacting an acid with Lumacaftor.
5. A process according to claim 4, wherein an acid may be selected from the group comprising of acetic acid, formic acid, and tartaric acid.
6. A process according to claim 4, wherein an acid is hydrobromic acid.
7. A process for the preparation of Lumacaftor, comprising the step of converting a salt of Lumacaftor to its free form, wherein the salt may be selected from the group comprising of acetic acid salt, formic acid salt, tartaric acid salt and hydrobromide salt.
8. A process according to claim 7, wherein the salt may be selected from the group comprising of acetic acid salt, formic acid salt, and tartaric acid salt.
9. A process according to claim 7, wherein the salt is hydrobromide salt.
10. A process for the preparation of Lumacaftor or salts thereof, comprising the step of reacting 3-boronobenzoic acid or a derivative thereof with N-(6-halo-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamide in presence of an inert solvent selected from the group comprising of water, dimethylformamide, dimethoxyethane, 1,4-dioxane, 2-propanol, n-butanol, 2-butanol, tert-butanol or mixtures thereof.