DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
ALTERNATE PROCESSES AND INTERMEDIATES FOR THE PREPARATION OF LUMACAFTOR

INTRODUCTION
Aspects of the present application relate to processes for the preparation of Lumacaftor. Specific aspects of the present application relate to alternate processes and novel intermediates for the preparation of Lumacaftor.
The drug compound having the adopted name “Lumacaftor” has chemical name: 3-{6-{[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl] 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 (which is obtained by the N-acylation of 2-chloro-3-methyl pyridine amine with (2,2-difluorobenzo [d][1,3]dioxol-5-yl)cyclopropane carboxylic acid chloride) with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid as depicted in scheme-1.

US 8124781 B2 describes a process for the preparation of Lumacaftor by reacting t-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate with 1-(2,2-difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarbonylchloride in the presence of triethyl amine (TEA) to obtain t-butyl ester of Lumacaftor, which is either hydrolyzed directly to its free carboxylic acid form i.e., Lumacaftor or converted to its HCl salt and then neutralized to afford Lumacaftor as depicted in scheme-2.

US 8507534 B2 discloses a similar approach as in scheme-2 for the synthesis of Lumacaftor and further describes methods to obtain crystalline Form I of Lumacaftor by dispersing or dissolving a salt form, such as HCl, of Lumacaftor in an appropriate solvent for an effective amount of time (or) directly by treating t-butyl ester intermediate of Lumacaftor with an appropriate acid, such as formic acid.
Prior art processes does not disclose an amenable synthetic process for Lumacaftor and there remains a need for alternate process for its preparation in a more cost effective and industrially viable manner.

SUMMARY
In an aspect, the present application provides a process for the preparation of Lumacaftor, comprising the step of reacting the cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) to obtain 5-methylpyridin-2-amine of formula (V).

wherein R1 is selected from hydrogen, any leaving group such as halogen or a phenyl group of formula (A);

R2 is any leaving group such as halogen and R3 is hydrogen or a group selected from cyano, carboxylic acid or carboxylic ester.

In another aspect, the present application provides a process for the preparation of Lumacaftor, comprising the step of halogenating 3-methylpyridine of formula (VIII) to obtain 2-halo 5-methylpyridine of formula (IV), wherein R1, R2 and R3 are same as defined above.

In another aspect, the present application provides a process for the preparation of Lumacaftor, comprising the step of halogenating 3-methylpyridine of formula (VIII) through N-oxide formation to obtain 2-halo 5-methylpyridine of formula (IV) as depicted below, wherein R1, R2 and R3 are same as defined above.

In another aspect, the present application provides a process for the preparation of Lumacaftor, comprising the step of diazotization of 5-methylpyridin-2-amine of formula (IX) as depicted below; wherein R1, R2 and R3 are same as defined above.

In another aspect, the present application provides a process for the preparation of Lumacaftor, comprising the step of halogenating 3-methylpyridine of formula (IVc) to obtain 2-halo 3-methylpyridine of formula (IV), wherein X is any halogen

and R2 may be any halogen, amino group which is optionally protected or amide group of formula (C).

In another aspect, the present application provides a process for the preparation of Lumacaftor, comprising the step of halogenating 2-aminopyridine of formula (VI) through N-oxide formation to obtain 6-halo pyridine-2-amine of formula (VII) as depicted below, wherein R1 is a halogen.

and R4 is selected from hydrogen, a amine protecting group or a group of formula (B)

In another aspect, the present application provides a process for the preparation of Lumacaftor, comprising the step of amination of 3-methylpyridine of formula (VIII) through N-oxide formation to obtain 5-methyl pyridine-2-amine of formula (IX) as depicted below, wherein R1 is any leaving group such as halogen.

In another aspect, the present application provides an improved process for the preparation of Lumacaftor of formula or ester thereof, comprising the step of reacting N-(6-bromo pyridin-2-yl) cyclopropyl carboxamide of formula (XI) with borolanyl benzene of formula (XII) or its derivatives thereof; wherein R3 is same as defined above and R’ and R’’ may be same or different selected from hydrogen, alkyl, aryl or both together form a ring with C2 to C6 aliphatic chain.

In another aspect, the present application provides novel and alternative intermediates of formula (III), (XI) and (IVa) useful in the preparation of Lumacaftor, its esters or salts thereof, wherein R2 is leaving group such as halogen and R3 is hydrogen or a group selected from cyano, carboxylic acid or carboxylic ester.

In another aspect, the present application provides N-oxides of intermediates of formula (VI) and (VIII) useful in the preparation of Lumacaftor, its esters or salts thereof,

wherein R1 is any leaving group such as halogen and R4 is selected from hydrogen or a group of formula (B)

DETAILED DESCRIPTION
In an aspect, the present application provides a process for the preparation of Lumacaftor, comprising the step of reacting the cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) to obtain 5-methylpyridin-2-amine of formula (V).

wherein R1 is selected from hydrogen, any leaving group such as halogen or a phenyl group of formula (A);

R2 is any leaving group such as halogen and R3 is hydrogen or a group selected from cyano, carboxylic acid or carboxylic ester.
In an embodiment, the reaction of cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) may be carried out in the presence of a catalyst. Catalyst are those which can facilitate C-N bond-forming such as palladium catalysts in the presence of a ligand and palladium catalyst may include, but not limited to Palladium acetate [Pd(OAc)2] Tris(dibenzylideneacetone) dipalladium (0)-chloroform adduct [Pd2(dba)3. CHCl3] Dichloro-[1,1-bis(diphenylphosphino)ferrocene]palladium(II) (Pd(dppf)Cl2), Allylpalladium(II) chloride dimer [(allyl)PdCl]2 or the like.
In an embodiment, the reaction of cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) may be carried out in the presence of a ligand such as Xantphos (X-phos), BrettPhos, DavePhos or the like.
In an embodiment, the reaction may be carried out according to a copper-catalyzed method such as in the presence of a combination of copper iodide and N,N‘-dimethyl ethylenediamine.
In an embodiment, the reaction of cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) may be carried out under suitable coupling conditions known in the art such as Buchwald et al, (Org. Lett., 2000, 2 (8), pp 1101–1104 and Org. Lett., 2003, 5 (20), pp 3667–3669)
In an embodiment, the reaction may be carried out between cyclopropyl carboxamide of formula (III) and 3-methylpyridine of formula (IV), wherein R2 is a leaving group such as halogen like Chlorine, Bromine, Iodine; O-triflates; sulphonate or the like.
In an embodiment, the reaction of cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) may be carried out in a mole ratio of cyclopropyl carboxamide of formula (III) to 3-methylpyridine of formula (IV) of 1: 0.5 to 0.5: 1.
In an embodiment, the reaction of cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) may be carried out in the presence of a base. Base may include but not limited to an organic base such as organic amines, alkoxides or an inorganic base such as carbonates, bicarbonates, alkoxides and hydroxides. In an embodiment, the reaction may be carried out in the presence of Cesium carbonate, potassium carbonate or sodium tert butoxide.
In an embodiment, the reaction of cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) may be carried out in the presence of a suitable solvent or mixture of solvents. Suitable solvents may include but not limited to tert-butanol, dioxane, tetrahydrofuran, toluene, 2-propanol, n-butanol or the like.
In an embodiment, the reaction of cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) may be carried out at suitable temperature of about 50°C and above for atleast 10 hours and more. In an embodiment, the reaction of cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) may be carried out at 80°C to 120°C for atleast 15 hours or more.
In alternate embodiments, the reaction conditions may be altered depending on the other parameters used.
In an embodiment, when R1 is a phenyl group of formula (A), the process for the preparation of Lumacaftor or a ester thereof, comprising the step of reacting the cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IVa) to afford Lumacaftor intermediate of formula (Va), wherein R3 is selected from hydrogen or a group selected from cyano, carboxylic acid or carboxylic ester.


In an embodiment, when R1 is any leaving group such as halogen, the process for the preparation of Lumacaftor comprising the steps of:
a) reacting the cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IVb) to afford Lumacaftor intermediate of formula (Vb), wherein X is any leaving group such as halogen;

b) reacting intermediate of formula (Vb) with borolanyl benzene of formula (XII) or its derivatives thereof; wherein R3 is selected from hydrogen or a group selected from cyano, carboxylic acid or carboxylic ester and R’ and R’’ may be same or different selected from hydrogen, alkyl, aryl or both together form a ring with C2 to C6 aliphatic chain.

In an embodiment, when R1 is hydrogen, the process for the preparation of Lumacaftor comprising the steps of:
a) reacting the cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IVc) to afford Lumacaftor intermediate of formula (Vc);

b) halogenating intermediate of formula (Vc) to obtain intermediate of formula (Vb)

c) reacting intermediate of formula (Vb) with borolanyl benzene of formula (XII) or its derivative thereof to afford compound of formula (Va); wherein R3, R’ and R’’ are same as defined above.

The process of this aspect may be schematically depicted by scheme -3 as below.

In an embodiment, when R3 is other than carboxylic acid the process further comprises the step of converting intermediate of formula (Va) to Lumacaftor, its ester or salts thereof according to methods known in the art or procedures described or exemplified in the instant application.
In an embodiment, the esters of Lumacaftor may be hydrolyzed according to suitable conditions known in the art or according to methods or procedures described or exemplified in the instant applications. In an embodiment, ester of Lumacaftor may be hydrolyzed under acidic, neutral or basic conditions.
The starting materials of this aspect, compound of formula (III) and compound of formula (IV) may be prepared in different methods. However, certain alternative methods to prepare these starting materials will be explained in detail with reference to the following, 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.
In an embodiment, 3-methylpyridine of formula (IV) may be prepared employing a process comprising the step of halogenating 3-methylpyridine of formula (VIII) to obtain 2-halo 3-methylpyridine of formula (IV), wherein R1, R2 and R3 are same as defined above.

In an embodiment, 3-methylpyridine of formula (IV) may be prepared employing a process comprising the step of halogenating 3-methylpyridine of formula (VIII) through N-oxide formation as depicted below, wherein R1, R2 and R3 are same as defined above.

In an embodiment, obtain 3-methylpyridine of formula (IV) may be also prepared employing a process comprising the step of halogenating 3-methylpyridine of formula (IVc) as depicted below; wherein X is any halogen and R2 may be any leaving group such as halogen.

In an embodiment, 3-methylpyridine of formula (IV) may be also prepared employing a process comprising the step of diazotization of 5-methylpyridin-2-amine of formula (IX) as depicted below; wherein R1 and R2 are same as defined above.

Alternatively, 3-methylpyridine of formula (IV) may be prepared according to any method known in the art or procedures described in any aspect or exemplified in the present application.

In an embodiment, cyclopropyl carboxamide of formula (III) may be prepared employing a process comprising the step of hydrolysis of cyclopropyl nitrile of formula (XIII) to corresponding amide as depicted below.

Inventors of the instant application have surprisingly found that the partial hydrolysis of the cyclopropyl nitrile of formula (XIII) is advantageous over prior art methods. Prior art methods are tedious, time consuming, low yielding, multi-step synthesis as against to instant single step synthesis of this amide in a short, simple and economic approach.
In an embodiment, cyclopropyl nitrile of formula (XIII) may be hydrolyzed to corresponding amide either in the presence of an acid or a base catalyst.
Suitable acid catalyst may include, but not limited to hydrogen halides such as HCl, HBr, HI; sulphuric acid, phosphoric acid, nitric acid or the like and a suitbale base catalyst may include, but not limited to hydroxides such as NaOH, KOH, Mg(OH)2,Ca(OH)2 or the like; alkoxides such as methoxides, ethoxides, t-butoxides or the like ; carbonates such as NaCO3, KCO3 or the like.
In an embodiment, hydrolysis of cyclopropyl nitrile of formula (XIII) may be carried out in the presence of an inert solvent which include, but not limited to alcohols such as tert-butanol or the like; ketones such as methyl tert-butyl ketone or the like and hydrocarbons such as toluene or the like.
Alternatively, cyclopropyl carboxamide of formula (III) may be prepared according to any method known in the art or procedures described in any aspect or exemplified in the present application.

In another aspect, the present application provides a process for the preparation of Lumacaftor, comprising the step of halogenating 3-methylpyridine of formula (VIII) to obtain 2-halo 3-methylpyridine of formula (IV),

wherein R1 is, hydrogen, any leaving group such as halogen or a phenyl group of formula (A);

R2 is any halogen and R3 is hydrogen or a group selected from cyano, carboxylic acid or carboxylic ester.

In an embodiment, halogenating 3-methylpyridine of formula (VIII) may be carried out under suitable conditions known in the art. In an embodiment, halogenation may be carried out by reacting 3-methylpyridine of formula (VIII) with halogen source such as chlorine (Cl2), Bromine (Br2), Iodine (I2) in the presence of suitable catalyst that include, but not limited to n-Bu Li / di Isopropyl amine; n-Bu Li / dimethyl amino ethanol; PdCl2 /CCl4 or the like.
In an embodiment, halogenation may be carried out by reacting 3-methylpyridine of formula (VIII) in an inert atmosphere at suitable temperature of about 0°C or below, optionally the presence of an inert solvent such as hexane or the like.
In an embodiment, when R1 is a phenyl group of formula (A), 3-methylpyridine of formula (IVa), may be prepared following a process comprising the steps of halogenating 3-methylpyridine of formula (VIIIa) as depicted below.

In an embodiment, the process further comprises the step of converting 3-methylpyridine of formula (IVa) to Lumacaftor, salt or an ester thereof.
In an embodiment, 3-methylpyridine of formula (IVa) may be reacted with cyclopropyl carboxamide of formula (III) according to conditions or methods described at any aspect or exemplified in the instant application.
In an embodiment, when R1 is any leaving group (X) such as halogen, 3-methylpyridine of formula (IVb), may be prepared following a process comprising the steps of halogenating 3-methylpyridine of formula (VIIIb) as depicted below.

In an embodiment, the process further comprises the step of converting 2-halo 3-methylpyridine of formula (IV) to Lumacaftor. 2-halo 3-methylpyridine of formula (IV) obtained by the process of this aspect may be isolated or taken directly to the next step for the preparation of Lumacaftor.
In an embodiment, 2-halo 3-methylpyridine of formula (IV) may be converted to Lumacaftor according to any of the methods known in the art or procedures described at any aspect or exemplified in the instant application.

In another aspect, the present application provides a process for the preparation of Lumacaftor, comprising the step of halogenating 3-methylpyridine of formula (VIII) through N-oxide formation to obtain 2-halo 3-methylpyridine of formula (IV),

wherein R1 is any leaving group such as halogen or a phenyl group of formula (A);

R2 is any halogen and R3 is hydrogen or a group selected from cyano, carboxylic acid or carboxylic ester.

In an embodiment, halogenation of 3-methylpyridine of formula (VIII) may be carried out through the formation of corresponding N-oxide followed by its halogenation. In an embodiment, the N-oxide may be either isolated or continued for the halogenation directly without isolating it.
In an embodiment, formation of N-oxide of 3-methylpyridine of formula (VIII) may be carried out in the presence of an oxidation agent including, but not limited to peroxides or per acids such as hydrogen peroxide, per acetic acid perphtalic acids (magnesium- monoperphtalate (MMPP)), performic acid, pertrifuoricacetic acid, peroxymonosulfuric acid, bromate, metal oxidants such as chromic acid and permanganate, perphosphoric acid, permaleinic acid, urea-hydrogen peroxide (UHP), urea-hydrogen peroxide / phthalic anhydride , m-chloro Perbenzoic acid (m-CPBA) or the like.
In an embodiment, N-oxide formation may be carried out in a mole ratio of 3-methylpyridine of formula (VIII) to oxidation agent of 2:1 to 1:2.
In an embodiment, N-oxide formation may be carried out at suitable temperature of about 30°C and above for sufficient time of atleast 30 minutes or more.
In an embodiment, N-oxide formation may be carried out according to conditions known in the art or methods described at any aspect or exemplified in the instant application.
N-oxide obtained according to the process of this aspect may be halogenated using suitable halogen source which may include but not limited to phosphorus oxyhalide such as POCl3, POBr3; thionyl halides such as SOCl2; Oxalyl halides such as (COCl)2.
In an embodiment, halogenation of N-oxide may be carried out in a mole ratio of 3-methylpyridine of formula (VIII) to halogen source of 1:1 to 1:2.
In an embodiment, halogenation of N-oxide may be carried out in the presence of a base such as triethyl amine, diisopropyl amine, diisopropyl ethyl amine or the like.
In an embodiment, halogenation of N-oxide may be carried out in the presence of an inert solvent such as halogenated hydrocarbons such dichloromethane.
In an embodiment, halogenation of N-oxide may be carried out at suitable temperature of about 30°C and above for sufficient time of atleast 30 minutes or more.
In an embodiment, when R1 is a phenyl group of formula (A), 3-methylpyridine of formula (IVa), may be prepared following a process comprising the steps of halogenating 3-methylpyridine of formula (VIIIa) as depicted below.

In an embodiment, when R1 is any leaving group (X) such as halogen, 3-methylpyridine of formula (IVb), may be prepared following a process comprising the steps of halogenating 3-methylpyridine of formula (VIIIb) as depicted below.

In an embodiment, the process further comprises the step of converting 2-halo 3-methylpyridine of formula (IV) to Lumacaftor. 2-halo 3-methylpyridine of formula (IV) obtained by the process of this aspect may be isolated or taken directly to the next step for the preparation of Lumacaftor.
In an embodiment, 2-halo 3-methylpyridine of formula (IV) may be converted to Lumacaftor according to any of the methods known in the art or procedures described at any aspect or exemplified in the instant application.

In another aspect, the present application provides a process for the preparation of Lumacaftor, comprising the step of diazotization of 5-methylpyridin-2-amine of formula (IX) as depicted below;

wherein R1 is hydrogen, any leaving group such as halogen or a phenyl group of formula (A);

R2 is any halogen and R3 is hydrogen or a group selected from cyano, carboxylic acid or carboxylic ester.
In an embodiment, diazotization of 5-methylpyridin-2-amine of formula (IX) may be carried out using nitrites including, but not limited to sodium nitrite or other nitrites such as methyl nitrite, nitrosyl chloride or the like to obtain corresponding diazo derivative. In an embodiment, diazo derivative is prepared insitu and taken directly for the halogenation step.
Diazotization of 5-methylpyridin-2-amine of formula (IX) may be carried out under conditions known in the art or procedures described or exemplified in the instant application. Diazotization may be carried out at suitable temperature of about 0°C or below.
The diazo derivative obtain above may be treated with the halogenating agent with its isolation. In an embodiment, the diazotization may be carried out in the presence of halogenating agent. Suitable halogenating agents may include, but not limited to Hydrogen halides such as HCl, HBr, HI; Br2, I2, Cl2 or the like.
In an embodiment, halogenation of diazo derivative may be carried out in the presence of an acid such as sulphuric acid or a hydrogen halide either in concentrated or diluted form.
Diazotization and / or halogenation of 5-methylpyridin-2-amine of formula (IX) may be carried out under conditions known in the art or procedures described or exemplified in the instant application. In an embodiment, the process of this aspect may be carried out at suitable temperature of about 0°C or below, preferably at a temperature between -10°C and -30°C.
In an embodiment, 3-methylpyridine of formula (IVa) may be prepared employing a process comprising the step of diazotization of 5-methylpyridin-2-amine of formula (IXa) as depicted below.

In an embodiment, 3-methylpyridine of formula (IVb) may be prepared employing a process comprising the step of diazotization of 5-methylpyridin-2-amine of formula (IXb) as depicted below.

In an embodiment, the process further comprises the step of converting 2-halo 3-methylpyridine of formula (IV) to Lumacaftor. 2-halo 3-methylpyridine of formula (IV) obtained by the process of this aspect may be isolated or taken directly to the next step for the preparation of Lumacaftor.
In an embodiment, the processes for the preparation of 3-methylpyridine of formula (IVa) in any of the aspects further comprises the step of converting 3-methylpyridine of formula (IVa) to Lumacaftor, salt or an ester thereof. In an embodiment, 3-methylpyridine of formula (IVa) may be reacted with cyclopropyl carboxamide of formula (III) according to conditions or methods described at any aspect or exemplified in the instant application.
In an embodiment, the processes for the preparation of 3-methylpyridine of formula (IVb) in any of the aspects further comprises the step of converting 3-methylpyridine of formula (IVb) to Lumacaftor, salt or an ester thereof. In an embodiment, 3-methylpyridine of formula (IVb) may be reacted with cyclopropyl carboxamide of formula (III) or with borolanyl benzene of formula (XII) or its derivative thereof according to methods known in the art or procedures described at any aspect or exemplified in the instant application as depicted below.

In an embodiment, 2-halo 3-methylpyridine of formula (IV) may be converted to Lumacaftor according to any of the methods known in the art or procedures described at any aspect or exemplified in the instant application.

In another aspect, the present application provides a process for the preparation of Lumacaftor, comprising the step of halogenating 3-methylpyridine of formula (IVc) to obtain 2-halo 3-methylpyridine of formula (IV),

wherein X is any halogen and R2 may be any halogen, amino group which is optionally protected or amide group of formula (C).

In an embodiment, halogenating 3-methylpyridine of formula (IVc) may be carried out under suitable conditions known in the art. In an embodiment, halogenation may be carried out by reacting 3-methylpyridine of formula (IVc) with halogen source such as chlorine (Cl2), Bromine (Br2), Iodine (I2) in the presence of suitable catalyst that include, but not limited to n-Bu Li / di Isopropyl amine; n-Bu Li / dimethyl amino ethanol; PdCl2 /CCl4 or the like.
In an embodiment, halogenation may be carried out by reacting 3-methylpyridine of formula (IVc) in an inert atmosphere at suitable temperature of about 0°C or below, optionally the presence of an inert solvent such as hexane or the like.
In an embodiment, when R2 is halogen, 3-methylpyridine of formula (IVb), may be obtained following a process comprising the step of halogenating 3-methylpyridine of formula (IVc) as depicted below.

In an embodiment, when R2 is amide group of formula (C), 3-methylpyridine of formula (Vb) may be obtained following a process comprising the step of halogenating 3-methylpyridine of formula (Vc) as depicted below.

In an embodiment, when R2 is amino group which is optionally protected, 3-methylpyridine of formula (VIIb) may be obtained following a process comprising the step of halogenating 3-methylpyridine of formula (VIb) as depicted below; wherein R4 is hydrogen or amine protecting group.

In an embodiment, the process further comprises the step of converting 2-halo 3-methylpyridine of formula (IV) of this aspect to Lumacaftor. 2-halo 3-methylpyridine of formula (IV) obtained by the process of this aspect may be isolated or taken directly to the next step for the preparation of Lumacaftor.
In an embodiment, 2-halo 3-methylpyridine of formula (IV) may be converted to Lumacaftor according to any of the methods known in the art or procedures described at any aspect or exemplified in the instant application.

In another aspect, the present application provides a process for the preparation of Lumacaftor, comprising the step of halogenating 2-aminopyridine of formula (VI) to obtain 6-halo pyridine-2-amine of formula (VII),

wherein R4 is selected from hydrogen, a amine protecting group or group B and X is a halogen.

In an embodiment, halogenation of 3-methylpyridine of formula (VI) may be carried out through the formation of corresponding N-oxide followed by its halogenation. In an embodiment, the N-oxide may be either isolated or continued for the halogenation directly without isolating it.
In an embodiment, the N-oxide formation and subsequent halogenation may be carried out according to previous aspects for the preparation of 3-methylpyridine of formula (IV).
In an embodiment, when R4 is group (B), halogenation of 2-aminopyridine of formula (Vc) to obtain 6-halo pyridine-2-amine of formula (Vb), may be carried out as depicted below, wherein X is a halogen.

In an alternate embodiment, the N-oxide of 2-aminopyridine of formula (Vc) may be prepared as depicted below according any methods known in the art or procedures described in any aspect or exemplified in the instant application.

In an embodiment, when R4 is hydrogen or an amino protecting group, halogenation of 2-aminopyridine of formula (VI) to obtain 6-halo pyridine-2-amine of formula (VII), may be carried out according to any method known in the art or procedures described in any aspect or exemplified in the present application.
In an embodiment, the process for the preparation of 6-halo pyridine-2-amine of formula (VII) in any of the aspects further comprises the step of converting 6-halo pyridine-2-amine of formula (VII) to Lumacaftor, salt or ester thereof. In an embodiment, 6-halo pyridine-2-amine of formula (VII) may be reacted with borolanyl benzene of formula (XII) or its derivative, wherein R’, R’’ and R3 are same as defined in other aspects, according to any methods known in the art or procedures described at any aspect or exemplified in the instant application.
In an embodiment, 6-halo pyridine-2-amine of formula (VII) may be reacted with cyclopropyl carboxylic acid of formula (X), its derivatives or with borolanyl benzene of formula (XII) or its derivatives thereof as depicted below.

In another aspect, the present application provides a process for the preparation of Lumacaftor, comprising the step of amination of 3-methylpyridine of formula (VIII) through the formation of N-oxide to obtain 5-methyl pyridine-2-amine of formula (IX), wherein R1 is any leaving group such as halogen.

In an embodiment, amination of 3-methylpyridine of formula (VIII) may be carried out through the formation of corresponding N-oxide followed by its amination. In an embodiment, the N-oxide may be either isolated or continued for the amination directly without isolating it.
In an embodiment, the N-oxide formation may be carried out according to previous aspects for the preparation of 3-methylpyridine of formula (IV).
In an embodiment, amination of N-oxide of 3-methylpyridine of formula (VIII) may be carried out under suitable conditions for Chichibabin amination of pyridines known in the art such as in Lawin, Phillip B. et al (WO 9600216)
In an embodiment, amination of N-oxide may be carried out by reacting with a suitable amine compound which include, but not limited to ammonia; organic amines such as alkyl amines; such as methyl amine, ethyl amine, ethanol amine, propyl amine, propanol amine, butyl amine, butanol amine; aryl amines such as 4-tolyl amine; inorganic amines such as sodamide, potassamide or the like.
In an embodiment, the amination of N-oxide may be carried out in the presence of an inert solvent such as acetonitrile, toluene or the like.
In an embodiment, the amination of N-oxide may be carried out at suitable temperature of about 50°C and above for sufficient time for atleast 30 minutes.
In an embodiment, pyridine-2-amine of formula (IX) may be reacted with cyclopropyl carboxylic acid of formula (X), reactive derivatives thereof or with borolanyl benzene of formula (XII) or its derivative thereof according to methods known in the art or procedures described at any aspect or exemplified in the instant application.

In another aspect, the present application provides an improved process for the preparation of Lumacaftor or intermediate thereof, comprising the step of reacting N-(6-bromo pyridin-2-yl) cyclopropyl carboxamide of formula (XI) with borolanyl benzene of formula (XII) or its derivatives thereof; wherein R3 is same as defined above and R’ and R’’ may be same or different selected from hydrogen, alkyl, aryl or both together form a ring with C2 to C6 aliphatic chain.

N-(6-bromo 5-methyl pyridin-2-yl) cyclopropyl carboxamide of formula (XI) may be prepared according to any of the methods known in the art or procedures described in any aspect or exemplified in the instant application. In an embodiment, the N-(6-bromo 5-methyl pyridin-2-yl) cyclopropyl carboxamide of formula (XI) may be optionally purified before using by any methods known in the art such as column chromatography, fractional distillation, recrystallization or the like, before using.
In an embodiment, the N-(6-bromo pyridin-2-yl) cyclopropyl carboxamide of formula (XI) may be reacted with borolanyl benzene of formula (XII) or its derivative thereof in the presence of suitable catalyst.
Catalyst may include but not limited to palladium catalyst such as palladium acetate (Pd(OAc)2), Dichloro-[1,1-bis(diphenylphosphino) ferrocene]palladium(II) (Pd(dppf)Cl2), Tetrakis(triphenylphosphine)palladium (0) (Pd(PPh3)4) or the like.
In an embodiment, this coupling reaction may be carried out under Suzuki coupling conditions known in the art.
Inventors of the instant application have surprisingly found that this coupling step with bromo derivative of formula (XI) is furnished in a very fast and efficient manner without formation of undesired products and in good yield as compared to the coupling step using analogous chloro derivative as described in the art such as US 8993600 B2.
In an embodiment, mole ratio of N-(6-bromo 5-methyl pyridin-2-yl) cyclopropyl carboxamide of formula (XI) to borolanyl benzene of formula (XII) may vary from 0.5: 2 to 2:0.5
In an embodiment, the reaction may be carried out in the presence of an inert solvent including, but not limited to an aprotic solvent such as dimethyl formamide, dioxane, N-methyl pyrrolidone, dimethyl sulfoxide, toluene, acetonitrile, dimethyl acetamide, dichloromethane or the like.
In an embodiment, the reaction may be carried out at suitable temperature of about 0°C and above for sufficient time for atleast 15 minutes.
In an embodiment, when R3 is other than carboxylic acid, the process further comprises the step converting the obtained intermediate to Lumacaftor , its esters or salt thereof under suitable condition known in the art or procedures described at any aspect or exemplified in the present application.

In another aspect, the present application provides novel and alternative intermediates of formula (III), (XI) and (IVa) useful in the preparation of Lumacaftor, its esters or salts thereof, wherein R2 is leaving group such as halogen and R3 is hydrogen or a group selected from cyano, carboxylic acid or carboxylic ester.

In another aspect, the present application provides N-oxides of intermediates of formula (VI) and (VIII) useful in the preparation of Lumacaftor, its esters or salts thereof,

wherein R1 is any leaving group such as halogen and R4 is selected from hydrogen or a group of formula (B)

Starting materials used in any aspect of the instant application may be obtained from either commercially available sources or prepared according to the methods known in the art. Starting materials 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.
Lumacaftor obtained according to any aspects of the instant patent application may be 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 tert-butyl ester of Lumacaftor (or) tert-butyl 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamido)-3-methylpyridin-2-yl)benzoate.

To a mixture of tert-butyl 3-(6-bromo-3-methylpyridin-2-yl)benzoate (150 mg) and 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamide (124 mg) in tert-butanol (10 mL) in a 50 mL seal tube, Cesium carbonate (210 mg), 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos) (8.2 mg) and Tris(dibenzylideneacetone) dipalladium (0)-chloroform adduct [Pd2(dba)3. CHCl3] (8.9 mg) were charged at 27°C under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 30 minutes at 27°C. The reaction mixture was heated at 100°C for 16 hours. Reaction mixture monitored by TLC showed presence of starting material, the reaction mixture was cooled to 27°C and Cesium carbonate (210 mg), 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos) (8.2 mg) and Tris(dibenzylideneacetone) dipalladium(0)-chloroform adduct [Pd2(dba)3. CHCl3] (8.9 mg) were added. The reaction mixture was degassed with nitrogen for 30 minutes at 27°C. The reaction mixture was heated at 100°C for 21 hours. Cooled the reaction mixture to 27° and filtered on celite bed. The celite bed was washed with tert-butanol (10 mL). The organic filtrate was evaporated at 45°C under reduced pressure to obtain pale yellow liquid. The compound was purified by column chromatography using 60-120 silica mesh using 20% ethyl acetate / hexane as eluent to obtain title compound as brown solid.
Yield: 137 mg; Purity by HPLC: 97.40%
Example-2: Preparation of Lumacaftor.
To a mixture of 3-(6-bromo-3-methylpyridin-2-yl)benzoic acid (200 mg) and 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamide (198.1 mg) in tert-butanol (10 mL) in a 50 mL seal tube at 27°C, Cesium carbonate (669 mg), 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos) (32.6 mg) and Tris(dibenzylideneacetone) dipalladium (0)-chloroform adduct [Pd2(dba)3. CHCl3] (35.4 mg) were charged at 27°C under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 30 minutes at 27°C. The reaction mixture was heated at 100°C for 16 hours. Cooled the reaction mixture to 27°C and filtered on celite bed. The celite bed was washed with tert-butanol (10 mL). The organic filtrate was evaporated at 27°C under reduced pressure to obtain pale yellow liquid. The compound was dissolved in dichloromethane (3 mL) and added n-hexane (7 mL) to the above solution and stirred for 10 minutes at 27°C. Solid was filtered dried under vacuum to obtain title compound as pale yellow solid. Yield: 290 mg; Purity by HPLC: 89.91%
Example-3: Preparation of N-(6-bromo-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamide

To a mixture of 2, 6-dibromo-3-methylpyridine (200 mg) and 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamide (230.6 mg) in tert-butanol (10 mL) in a 50 mL seal tube at 30°C, Cesium carbonate (779 mg), 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos) (30.0 mg) and Tris(dibenzylideneacetone) dipalladium (0)-chloroform adduct [Pd2(dba)3. CHCl3] (33.0 mg) were charged at 30°C under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 30 minutes at 27°C. The reaction mixture was heated at 100°C for 22 hours. Cooled the reaction mixture to 30°C and filtered on celite bed. The celite bed was washed with tert-butanol (5 mL). The organic filtrate was evaporated at 30°C under reduced pressure to obtain title compound as pale yellow liquid.
Example-4: Preparation of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclo propane-1-carboxamide

To a mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane nitrile (6.5 g) in tert-butanol (65 mL), potassium hydroxide (9.8 g) was added at 30°C. The reaction mixture was heated to 95°C and stirred at the same temperature for 16 hours. Quenched the reaction mixture with water (150 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine (50 mL) and dried the solution over sodium sulphate. The solution was evaporated under reduced pressure at 45 °C to obtain the title compound as white solid.
Yield: 5.6 g; Purity by HPLC: 97.37%
Example-5: Preparation of Lumacaftor

To a mixture of N-(6-bromo-5-methylpyridin-2-yl)-1-(2,2-difluoro benzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamide (120 mg) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (217 mg) in dimethyl formamide - water (1.2 mL and 0.36 mL), potassium carbonate (201 mg) was added and degassed the reaction mixture with argon gas for 30 minutes at 30°C. Dichloro-[1,1-bis(diphenylphosphino) ferrocene]palladium(II) (Pd(dppf)Cl2) (3.5 mg) was added to the reaction mixture and heated to 100°C for 45 minutes under argon atmosphere. The reaction mixture was quenched with water (15 mL) and extracted the reaction mixture using ethyl acetate (3 x 20 mL). The organic layer was washed with water (2 x 15 mL) and dried over sodium sulphate. The organic layer was evaporated under reduced pressure to obtain crude product as brown semi solid. The crude product was purified by column chromatography using 60-120 silica mesh using 30-50 % ethyl acetate / hexane as eluent to obtain title compound as off-white solid. Yield: 0.04 g; Purity by HPLC: 97.24%
Example-6: Preparation of 2-bromo 3-methyl pyridine N-oxide

2-bromo 3-methyl pyridine (25 g) was dissolved in dichloromethane (250 mL) at 30°C and cooled to 0°C. m-chloroperbenzoic acid (65.58 g) was added to the above solution slowly portion wise in 20 minutes at 0°C. The reaction mixture was warmed to 30°C and stirred for 16 hours. The reaction mixture was quenched with saturated sodium sulfite (2 x 50 mL) and extracted with dichloromethane (200 mL). The organic layer was washed with saturated sodium bicarbonate solution (2 x 60 mL), then with brine solution (50 mL) and dried over sodium sulfate and concentrated the solution to obtain 18 g of 2-bromo 3-methyl pyridine N-oxide as brown color solid having 92.19% purity by HPLC.
Example-7: Preparation of 2, 6-dibromo-3-methylpyridine

2-bromo 3-methyl pyridine N-oxide (1 g) was dissolved in toluene (10 mL) at 30°C. Phosphorus oxybromide (2.38 g) was added slowly portion wise to the reaction mixture at 30°C and heated at 90°C for 4 hours. The reaction mixture was cooled to 30°C and quenched with aqueous solution of potassium carbonate (10. 2 g in 50 mL of water) to adjust the pH to 8. The reaction mixture was extracted with ethyl acetate (2 x 50 mL) and the combined organic layer was washed with saturated sodium chloride solution (30 mL). The organic solution was dried over sodium sulfate and evaporated under reduced pressure at 45°C to obtain crude product. The crude product was purified by column chromatography using 60-120 silica gel mesh and 2-3% of ethyl acetate / hexane as eluent to obtain 244 mg of title compound as white solid.
Example-8: Preparation of tert-butyl 3-(6-bromo-3-methylpyridin-2-yl)benzoate and 3-(6-bromo-3-methylpyridin-2-yl)benzoic acid

Tert-butyl 3-(6-amino-3-methylpyridin-2-yl) benzoate (3. 0 g) was added to 47% aqueous solution of hydrogen bromide (15 mL) portion wise at 27°C in 15 minutes. The reaction mixture was cooled to -20°C and bromine (1.52 mL) was added drop wise. Stirred the reaction mixture at -20°C for 90 minutes and sodium nitrite solution (1.96 g in 7.5 mL of water) was added for 20 minutes at the same temperature. Reaction mixture was warmed to 15°C and stirred for 1 hour and 45 minutes at the same temperature. Again cooled the reaction mixture to -20°C and sodium hydroxide solution (8.44 g in 30 mL of water) was added slowly. The reaction mass was extracted with ethyl acetate (3 x 50 mL) and dried over sodium sulfate. The solution was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography using (10% to 50%) ethyl acetate / hexane as eluent to obtain 185 mg of tert-butyl 3-(6-bromo-3-methylpyridin-2-yl)benzoate as a colorless liquid with 96.07% purity by HPLC and 1.0 g of 3-(6-bromo-3-methylpyridin-2-yl)benzoic acid as a white solid with 98.36% purity by HPLC.
Example-9: Preparation of 2-chloro 5-methyl pyridine

2-amino 5-methyl pyridine (5.0 g) was cooled to 5°C and Con. HCl (90 mL) was added. Sodium nitrite (5.16 g) was added portion wise slowly to the reaction mixture in 15 minutes. The reaction mixture was allowed to warm to 30°C and stirred for 1.5 hours at the same temperature. Cooled the reaction mixture to 5°C and 40% aqueous sodium hydroxide solution (150 mL) was added and pH adjusted to 13. Extracted the reaction mixture with ethyl acetate (3 x 50 mL) and washed the combined organic layer with brine solution (50 mL). The solution was dried over sodium sulfate and evaporated the solvent under reduced pressure to afford crude compound. The crude product was purified by column chromatography using 60-120 silica mesh and (10% to 20%) ethyl acetate / hexane as eluent to obtain title compound as colorless liquid. Yield: 2.62 g; Purity by HPLC: 99.97%
Example-10: Preparation of 2-bromo 3-methyl 6-chloro pyridine

A mixture of dimethyl amino ethanol (2.3 mL) in hexane (13 mL) was cooled to 0°C and n-butyl lithium (29.4 mL) was added drop wise in 15 minutes and stirred for 15 minutes at 0°C. 2-chloro 5-methyl Pyridine (1.0 g) was dissolved in hexane (10.5 mL) and added to the above solution at 0°C. Cooled the reaction mixture further to -78°C and tetrabromomethane solution (9.21 g in 47.5 mL of tetrahydrofuran) was added in 15 minutes at the same temperature. Stirred the reaction mixture at -78°C for 1 hour and allowed to warm to 30°C. Quenched the reaction mixture with water (30 mL) and extracted with ethyl acetate (2x 20 mL). The combined organic solution was washed with brine solution (10 mL) and dried over sodium sulfate. The organic solution was concentrated to obtain crude product. The crude product was purified by column chromatography using 60-120 mesh and 5% ethyl acetate / hexane as eluent to obtain 403 mg of title compound as brown solid.
Example-11: Preparation of 6-bromo 5-methyl pyridin-2-amine and 2-bromo 3-methyl pyridin-4-amine

A mixture of 6-bromo 5-methyl pyridine N-oxide (1.2 g) and Pyridine (2.06 mL) in acetonitrile (4.8 mL) was heated to 70°C and a solution of methane sulfonic anhydride (1.667 g in 2.4 mL of acetonitrile) was added to it drop wise over a period of 20 minutes. The reaction mixture was stirred for 1 hour at 70°C and allowed to cool to 30°C. Ethanol amine (3.851 mL) was added drop wise over 10 minutes under nitrogen atmosphere at 30°C and stirred the reaction mixture for 15 hours at the same temperature. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic solution was dried over sodium sulfate and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography using 60-120 mesh and 20-30% ethyl acetate / hexane as eluent to obtain 0.32 g of 6-bromo 5-methyl pyridin-2-amine with 93.41 % purity by HPLC as a brown solid and 0.34 g of 2-bromo 3-methyl pyridin-4-amine
with 97.94% purity by HPLC as a brown solid.
Example-12: Preparation of N-(6-bromo-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamide

6-bromo 5-methyl pyridin-2-amine (0.1 g) was dissolved in dichloromethane (1 mL) under nitrogen atmosphere. The solution was cooled to 0°C and triethyl amine (0.149 mL) was added. 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carbonyl chloride (0.209 g) in dichloromethane (0.5 mL) was added drop wise into the reaction mixture in 5 minutes. The reaction mixture was warmed to 30°C and stirred for 18 hours at the same temperature. Quenched the reaction mixture with saturated potassium hydroxide solution (30 mL) and extracted with dichloromethane (30 mL). The organic solution was dried over sodium sulphate and evaporated under reduced pressure to afford crude product. The crude product was purified by column chromatography using 60-120 mesh and 10-20% ethyl acetate / hexane as eluent to obtain the title compound as brown color solid. Yield: 0.150 g; Purity by HPLC: 96.90%

Example-13: Preparation of N-(5-methylpyridin-2-yl)-1-(2,2-difluorobenzo [d][1,3]dioxol-5-yl)cyclopropane-1-carboxamide

5-methyl pyridin-2-amine (2.0 g) was suspended in toluene (20 mL) under nitrogen atmosphere at 29°C. Triethyl amine (7.79 mL) and 4-dimethylaminopyridine (45 mg) were added to the reaction mixture and stirred for 10 minutes. 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carbonyl chloride (7.71 g) in toluene (4 mL) was added drop wise into the reaction mixture at 29°C in 15 minutes and stirred for 3 hours at the same temperature. Quenched the reaction mixture with saturated sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with 1N HCl (2 x 20 mL) followed by brine solution (20 mL). Dried the organic solution over sodium sulphate and evaporated under reduced pressure to afford crude product. The crude product was purified by column chromatography using 60-120 mesh and 5% ethyl acetate / hexane as eluent to obtain the title compound as pale yellow liquid. Yield: 2.5 g; Purity by HPLC: 98.62%
Example-14: Preparation of N-oxide of N-(5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamide

N-(5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamide (1 g) was dissolved in ethyl acetate (10 mL) and water (0.3 mL). To the reaction mixture urea – hydrogen peroxide (566 mg) was added and then phthalic anhydride (891 mg) was added portion wise in 20 minutes at 27°C. The reaction mixture was heated to 55°C and stirred at the same temperature for 16 hours. Cooled the reaction mixture to 27°C and diluted with ethyl acetate (10 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layer was washed with 10% sodium sulfite (10 mL), 10% sodium bicarbonate (10 mL) and brine solution (10 mL). The organic solution was dried over sodium sulfate and evaporated the solvent under reduced pressure to obtain title compound as white solid. Yield: 890 mg; Purity by HPLC: 99.80%
Example-15: Preparation of hydrochloride of 5-methyl pyridin-2-amine N-oxide

5-methyl-2-pivalamidopyridine N-oxide (500 mg) was combined with 6 N HCl (5 mL) and heated to 90°C. Stirred the reaction mixture for 6 hours at 90°C and cooled to 32°C. Evaporated HCl under reduced pressure and co-distilled the product with toluene (2 x 5 mL). The solid was dried under reduced pressure for 45 minutes to obtain title compound as white solid. Yield: 320 mg; Purity by HPLC: 99.638%
Example-16: Preparation of N-oxide of N-(5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamide

N-oxide of 5-methyl pyridin-2-amine hydrochloride (0.3 g) was dissolved in dichloromethane (6 mL) under nitrogen atmosphere. The solution was cooled to 5°C and triethyl amine (0.78 mL) was added. 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carbonyl chloride (0.486 g) in dichloromethane (3 mL) was added drop wise into the reaction mixture. The reaction mixture was warmed to 30°C and stirred for 3 hours at the same temperature. Quenched the reaction mixture with water (10 mL) and extracted with dichloromethane (2 x 5 mL). The organic solution was washed with 10% potassium hydroxide solution (10 mL), 1 N HCl (10 mL) and brine solution (5 mL). Dried the organic solution over sodium sulphate and evaporated under reduced pressure to afford crude product. The crude product was dissolved in methyl tert-butyl ether (4 mL) at 32°C and added hexane (16 mL). Stirred the mixture for 10 minutes at 32°C and the solid was filtered to obtain title compound as white solid. Yield: 0.380 g; Purity by HPLC: 99.448%
Example-17: Preparation of N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamide

N-oxide of N-(5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamide (200 mg) was dissolved in dichloromethane (5 mL) and cooled to 0°C. Triethylamine (0.12 mL) and Phosphorous oxychloride (0.079 mL) were added to the reaction mixture at 0°C. Then the reaction mixture was heated to 45°C and stirred at the same temperature for 16 hours and cooled to 29°C. Quenched the reaction mixture with water (10 mL) and extracted with dichloromethane (2 x 5 mL). The combined organic solution was washed with saturated sodium bicarbonate solution (5 mL) and brine solution (5 mL). Dried the solution on sodium sulfate and evaporated the solvent under reduced pressure to obtain crude product. The crude product was purified by column chromatography using 60-120 mesh and 20% ethyl acetate / hexane as eluent to obtain the title compound as brown solid. Yield: 53 mg; Purity by HPLC: 95.17%
,CLAIMS:We Claim:

1. A process for the preparation of Lumacaftor, comprising the step of reacting the cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) to obtain 5-methylpyridin-2-amine of formula (V).

wherein R1 is selected from hydrogen or any leaving group such as halogen; R2 is any leaving group such as halogen.
2. A process for the preparation of Lumacaftor, comprising the step of halogenating 3-methylpyridine of formula (VIII) to obtain 2-halo 5-methylpyridine of formula (IV), wherein R1 is selected from hydrogen or any leaving group such as halogen; R2 is any leaving group such as halogen.

3. A process for the preparation of Lumacaftor, comprising the step of halogenating 3-methylpyridine of formula (VIII) through N-oxide formation to obtain 2-halo 5-methylpyridine of formula (IV), wherein R1 is selected from hydrogen or any leaving group such as halogen; R2 is any leaving group such as halogen.

4. A process for the preparation of Lumacaftor, comprising the step of halogenation through diazotization of 5-methylpyridin-2-amine of formula (IX) wherein R1 is selected from hydrogen or any leaving group such as halogen; R2 is any leaving group such as halogen.

5. A process for the preparation of Lumacaftor, comprising the step of halogenating 3-methylpyridine of formula (IVc) to obtain 2-halo 3-methylpyridine of formula (IV), wherein X is any halogen and R2 may be any halogen, amino group which is optionally protected.

6. A process for the preparation of Lumacaftor, comprising the step of halogenating 2-aminopyridine of formula (VI) through N-oxide formation to obtain 6-halo pyridine-2-amine of formula (VII) as depicted below, wherein R1 is a halogen and R4 is selected from hydrogen, a amine protecting group.

7. A process for the preparation of Lumacaftor, comprising the step of amination of 3-methylpyridine of formula (VIII) through N-oxide formation to obtain 5-methyl pyridine-2-amine of formula (IX) as depicted below, wherein R1 is any leaving group such as halogen.

8. A process for the preparation of Lumacaftor of formula or ester thereof, comprising the step of reacting N-(6-bromo pyridin-2-yl) cyclopropyl carboxamide of formula (XI) with borolanyl benzene of formula (XII) or its derivatives thereof; wherein R3 is same as defined above and R’ and R’’ may be same or different selected from hydrogen, alkyl, aryl or both together form a ring with C2 to C6 aliphatic chain.