WO2017056031A1 - Process for preparation of lumacaftor - Google Patents

Abstract

The present invention relates to a process for the preparation of amorphous lumacaftor. The present invention relates to a process for the preparation of intermediate 6-amino-2- halo-3-methylpyridine compounds used in the preparation of lumacaftor. The present invention relates to lumacaftor hydrobromide, process for its preparation and conversion thereof to lumacaftor.

Description

PROCESS FOR PREPARATION OF LUMACAFTOR

PRIORITY

[0001] This application claims the benefit of Indian Provisional Application 3746/MUM/2015 filed on October 1, 2015, entitled "PROCESS FOR PREPARATION OF LUMACAFTOR", the contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Technical Field

[0002] The present invention relates to a process for the preparation of amorphous lumacaftor. The present invention relates to a process for the preparation of intermediate 6-amino-2-halo-3 -methyl pyridine compounds used in the preparation of lumacaftor. The present invention relates to lumacaftor hydrobromide, process for its preparation and conversion thereof to lumacaftor.

Description of the Related Art

[0003] Lumacaftor, also known as 3-[6-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, is represented by the structure of formula I.

[0004] Lumacaftor, in combination with ivacaftor, is indicated for the treatment of cystic fibrosis in patients age 12 years and older who are homozygous for the F508del mutation in the CFTR gene.

[0005] The preparation of lumacaftor involves use of 6-amino-2-halo-3-methylpyridine compounds of formula V,

V

wherein, X is selected from the group consisting of CI, Br, I. [0006] J. Org. Chem., 1962, 27, 2473-2478 discloses preparation of the compound of formula V, wherein X is Br, from rarely available chemical 3-hydroxy-2- methylglutaronitrile with very poor yield. Highly corrosive hydrogen bromide gas was bubbled within the process. Product was isolated via multiple purification steps.

[0007] The preparation of the compound of formula V, wherein X is Br, was also disclosed in Tetrahedron, 2011, 67(47), 9063-9066. Pyridine- 1 -oxides were treated with benzoxazines to give benzoxazinones as 1 : 1 mixture which on purification with HPLC and subsequent treatment with acid afforded 6-amino-2-halo-3-methylpyridine compounds of formula V. Over all yields were about 10% from pyridine- 1 -oxide.

[0008] The object of the present invention is to provide a more convenient and more efficient method, involving less number of steps and avoiding inherently dangerous transformations, than the previously known methods for the synthesis of 6-amino-2-halo- 3-methylpyridine compounds of formula V.

[0009] Further, the object of the present invention is to provide lumacaftor via lumacaftor hydrobromide.

SUMMARY OF THE INVENTION

[0010] The present invention provides a process for the preparation of lumacaftor, a compound of formula I

the process comprising:

(a) obtaining lumacaftor;

(b) reacting lumacaftor obtained in step (a) with hydrobromic acid to form lumacaftor hydrobromide; and

(c) converting lumacaftor hydrobromide to lumacaftor.

[0011] In another embodiment, the present invention provides lumacaftor hydrobromide.

[0012] In another embodiment, the present invention provides a process for the preparation of lumacaftor hydrobromide, the process comprising: (i) providing a solution of lumacaftor in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;

(ii) adding hydrobromic acid to the solution of step (i);

(iii) obtaining lumacaftor hydrobromide from the mixture of step (ii); and

(iv) isolating lumacaftor hydrobromide.

[0013] In another embodiment, the present invention provides an amorphous form of lumacaftor.

[0014] In another embodiment, the present invention provides a process for the preparation of amorphous form of lumacaftor, the process comprising:

(a) providing a mixture of lumacaftor, or salt or solvate thereof, in a suitable solvent;

(b) obtaining amorphous lumacaftor from the mixture of step (a); and

(c) isolating the amorphous lumacaftor.

[0015] In another embodiment, the present invention provides a stable amorphous form of lumacaftor.

[0016] In another embodiment, the present invention provides a process for the preparation of amorphous form of lumacaftor, the process comprising:

(a) providing a mixture of lumacaftor hydrobromide in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;

(b) stirring the mixture obtained in step (a);

(c) optionally, separating the aqueous and organic layers from the mixture of step (b);

(d) isolating the amorphous lumacaftor from the mixture of step (b) or the organic layer of step (c).

[0017] In another embodiment, the present invention provides use of lumacaftor hydrobromide in the preparation of amorphous form of lumacaftor.

[0018] In another embodiment, the present invention provides a process for the preparation of lumacaftor a compound of formula I,

the process comprising:

(a) reacting a compound of formula VIII with an oxidising agent to give a compound of formula VII,

wherein, X is selected from the group consisting of CI, Br, I;

(b) aminating the compound of form a compound of formula V;

(c) reacting the compound of formula V with a compound of formula IV to give a compound of formula II and

(d) reacting the compound of formula II with a com ound of formula III,

wherein, R represents boronic acid, boronic acid ester,

in the presence of a metal catalyst to give lumacaftor, the compound of formula I.

[0019] In another embodiment, the present invention provides a compound of formula

Ila,

BRIEF DESCRIPTION OF THE DRAWINGS [0020] Figure 1 is the proton NMR spectrum of compound of formula Ila.

[0021] Figure 2 is a characteristic XRPD of amorphous lumacaftor as obtained in example 24.

[0022] Figure 3 is the proton NMR spectrum of lumacaftor hydrobromide.

[0023] Figure 4 is a characteristic XRPD of lumacaftor hydrobromide as obtained in example 20.

[0024] Figure 5 is a TGA thermogram of lumacaftor hydrobromide as obtained in example 20.

DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention provides a process for the preparation of lumacaftor, a compound of formula I

I

the process comprising:

(a) obtaining lumacaftor;

(b) reacting lumacaftor obtained in step (a) with hydrobromic acid to form lumacaftor hydrobromide; and

(c) converting lumacaftor hydrobromide to lumacaftor.

[0026] In the present application, the term "room temperature" means a temperature of about 25°C to about 30°C.

[0027] In (a) of the above process, lumacaftor is obtained by a process comprising:

(i) reacting a compound of formula VIII with an oxidising agent to give a compound of formula VII,

VI I I VI I

wherein, X is selected from the group consisting of CI, Br, I; (ii) aminating the compound of form a compound of formula V;

(iii) reacting the compound of formula V with a compound of formula TV to give a compound of formula II and

(iv) reacting the compound of formula II with a com ound of formula III,

I II

wherein, R represents boronic acid, boronic acid ester,

in the presence of a metal catalyst to give lumacaftor, the compound of formula I.

[0028] In (i) of the process for the preparation of lumacaftor, the compound of formula Vni is reacted with an oxidising agent to give the compound of formula VII.

[0029] A suitable oxidising agent includes but is not limited to peroxides such as hydrogen peroxide, sodium peroxide, potassium peroxide, lithium peroxide, barium peroxide, magnesium peroxide, calcium peroxide, zinc peroxide and the like; peracids such as peracetic acid, perbenzoic acid, 3-chloroperbenzoic acid and the like; per carbamide. Preferably, the oxidising agent selected is 3-chloroperbenzoic acid.

[0030] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, 1 -pentanol, 1 -octanol and the like; acetonitrile; dimethyl formamide; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof. Preferably, the solvent selected is dichloromethane. [0031] In one embodiment, the compound of formula VIII, wherein X is Br, is reacted with an oxidising agent to give the compound of formula VII.

[0032] In (ii) of the process for the preparation of lumacaftor, the compound of formula VII is aminated to give the compound of formula V.

[0033] The reaction may be carried out in the presence of an activating reagent selected from the group consisting of methanesulfonic anhydride, methanesulfonyl chloride, p- toluenesulfonic anhydride, /7-toluenesulfonyl chloride, trifluoromethansulfonic anhydride, benzenesulfonic anhydride, benzenesulfonyl chloride, trifluoroacetic anhydride. Preferably, the activating reagent selected is trifluoromethansulfonic anhydride, methanesulfonic anhydride.

[0034] The reaction may be carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, dimethylaminopyridine, 2,4,6- trimethylpyridine. Preferably, the base selected is pyridine, triethylamine.

[0035] The reaction may be carried out in the presence of an aminating reagent selected from the group consisting of methanolamine, ethanolamine, propanolamine, butanolamine, pentanolamine, hexanolamine, ieri-butylamine, ammonia, sodamide. Preferably, the aminating reagent selected is ethanolamine.

[0036] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; acetonitrile; dimethyl formamide; dimethyl sulfoxide; dimethyl acetamide; or mixtures thereof. Preferably, the solvent selected is acetonitrile.

[0037] In one embodiment, the compound of formula VII, wherein X is Br, is aminated to give the compound of formula V.

[0038] In one embodiment, the compound of formula V is purified by a process comprising: (x) reacting the compound of formula V with an acid to form an acid addition salt of the compound of formula V; and

(y) treating the acid addition salt of the compound of formula V with a base to give the compound of formula V.

[0039] A suitable acid includes but is not limited to /7-toluenesulphonic acid and the like.

[0040] A suitable base includes but is not limited to an alkali or an alkaline earth metal hydroxide, an alkali or an alkaline earth metal carbonate and the like, an alkali or an alkaline earth metal bicarbonate for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.

[0041] In one embodiment, the compound of formula V is purified by a process comprising:

(x) reacting the compound of formula V with /7-toluenesulphonic acid to form p- toluenesulphonic acid salt of the compound of formula V; and

(y) treating the /7-toluenesulphonic acid salt of the compound of formula V with a base to give the compound of formula V.

[0042] In one embodiment, the compound of formula V is obtained in a purity of >99%.

[0043] In (iii) of the process for the preparation of lumacaftor, the compound of formula V is reacted with the compound of formula IV to give the compound of formula II.

[0044] The reaction may be carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, di-isopropyl ethylamine, dimethylaminopyridine, N-methyl morpholine. Preferably, the base selected is triethylamine, pyridine.

[0045] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; acetonitrile; dimethyl formamide; dimethyl sulfoxide; dimethyl acetamide; N-methyl-2-pyrrolidone; or mixtures thereof. Preferably, the solvent selected is dichloromethane.

[0046] In one embodiment, the compound of formula V, wherein X is Br, is reacted with the compound of formula IV to ive the compound of formula Ila,

I la

[0047] In (iv) of the process for the preparation of lumacaftor, the compound of formula II is reacted with the compound of formula III in the presence of a metal catalyst to give lumacaftor.

[0048] A suitable metal catalyst includes but is not limited to Pd(PPh₃)₄, PdCl₂(PPh₃)₂, PdCl₂(dppf), Pd(OAc)₂, NiCl₂(PPh₃)₂, PdCl₂(dppb), PdCl₂(PhCN)₂, Pd(dba)₂. Preferably, the metal catalyst selected is PdCl₂(dppf), PdCl₂(PPh₃)₂.

[0049] The reaction may be carried out in the presence of a base which includes organic base such as triethylamine, N-methylmorpholine, DBU; inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate. Preferably, the base is selected from inorganic base and more preferably the base is potassium carbonate.

[0050] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; acetonitrile; dimethyl formamide; dimethyl sulfoxide; dimethyl acetamide; water or mixtures thereof. Preferably, the solvent selected is toluene, dioxane.

[0051] In one embodiment, the compound of formula II, wherein X is Br, is reacted with the compound of formula III, wherein R is boronic acid, to give lumacaftor. [0052] In (b) of the above process, lumacaftor obtained in step (a) is reacted with hydrobromic acid to form lumacaftor hydrobromide.

[0053] The reaction may be carried out in a solvent selected from esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; water; or mixtures thereof.

[0054] The reaction may be carried out at a temperature in the range of about 10°C to 100°C. The stirring time may range from about 2 hours to about 12 hours, or longer.

[0055] In one embodiment, the level of any single impurity in the lumacaftor hydrobromide obtained in step (b) is less than 0.15% w/w of lumacaftor hydrobromide.

[0056] The single impurity is re resented by a compound of formula II,

I I

[0057] In one embodiment, the compound of formula II is less than 0.15% w/w of lumacaftor hydrobromide.

[0058] In (c) of the above process, lumacaftor hydrobromide is converted to lumacaftor by a process comprising:

(i) providing a mixture of lumacaftor hydrobromide in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;

(ii) stirring the mixture obtained in step (i);

(iii) optionally, separating the aqueous and organic layers from the mixture of step (ii); (iv) isolating lumacaftor from the mixture of step (ii) or the organic layer of step (iii).

[0059] The reaction may be carried out in a solvent selected from esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; water; or mixtures thereof.

[0060] The mixture of lumacaftor hydrobromide in the solvent may be stirred for a period of about 10 hours to about 24 hours, or longer. The temperature may range from about 20°C to about 40°C.

[0061] The mixture may be stirred in the presence or absence of a base. A suitable base includes but is not limited to an alkali or an alkaline earth metal hydroxide, an alkali or an alkaline earth metal carbonate and the like, an alkali or an alkaline earth metal bicarbonate for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.

[0062] In step (iii) of the above process, the aqueous and organic layers from the mixture of step (ii) are separated to give organic layer which contains lumacaftor.

[0063] In step (iv) of the above process, lumacaftor is isolated by a process comprising: (p) removing the solvent from the mixture of step (ii) or the organic layer of step (iii); or (q) treating the mixture of step (ii) or the organic layer of step (iii) with an anti-solvent; or

(r) partially or completely evaporating the mixture of step (ii) or the organic layer of step (iii) and adding an organic solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, or mixtures thereof to the obtained reaction mass followed by removal of the solvent; or

(s) filtering the mixture of step (ii).

[0064] The anti-solvent is selected such that lumacaftor is precipitated out from the solution.

[0065] The organic solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; or mixtures thereof.

[0066] Removal of solvent may be accomplished by filtering the obtained solid, substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.

[0067] In one embodiment, lumacaftor hydrobromide is converted to lumacaftor by a process comprising:

(i) providing a mixture of lumacaftor hydrobromide in a solvent selected from ester-water mixture;

(ii) stirring the mixture obtained in step (i);

(iii) separating the aqueous and organic layers from the mixture of step (ii);

(iv) isolating lumacaftor from the organic layer of step (iii) by completely evaporating the organic layer of step (iii) and adding an organic solvent selected from hydrocarbons to the obtained reaction mass followed by removal of the solvent by filtering the obtained solid.

[0068] In one embodiment, the lumacaftor obtained by above process is in polymorphic form I.

[0069] In one embodiment, lumacaftor hydrobromide is converted to lumacaftor by a process comprising:

(i) providing a mixture of lumacaftor hydrobromide in a solvent selected from ester-water mixture;

(ii) stirring the mixture obtained in step (i);

(iii) separating the aqueous and organic layers from the mixture of step (ii);

(iv) isolating lumacaftor from the organic layer of step (iii) by a process comprising: (r) completely evaporating the organic layer of step (iii) and adding an organic solvent selected from alcohols to the obtained reaction mass followed by removal of the solvent.

[0070] In one embodiment, the lumacaftor isolated in step (iv) is in amorphous form.

[0071] In one embodiment, the lumacaftor obtained in step (c) has a purity of >99.8% and wherein the level of any single impurity is less than 0.1% w/w of lumacaftor.

[0072] The present invention provides lumacaftor obtained by above process, as analyzed by chemical purity using high performance liquid chromatography (HPLC) with the conditions described below:

Column: Zorbax SB, C8, (75 x 4.6mm, 3.5μ)

Mobile Phase A: 0.05% TFA in Water

Mobile Phase B: Acetonitrile containing 0.05% TFA

Sample concentration of 500 ppm was prepared in diluent containing Mobile phase A and Mobile phase B (20:80 v/v).

Gradient elution was performed with a flow rate of 1 mL/min.

The retention time of lumacaftor is about 17.5 minutes under these conditions.

Relative retention time for compound of formula II is about 1.3 with respect to lumacaftor.

[0073] The present invention provides lumacaftor hydrobromide.

[0074] In one embodiment, the present invention provides lumacaftor hydrobromide characterized by a proton NMR spectrum having peak positions at 9.13 (s,lH), 7.98-7.92 (m,3H), 7.84-7.82 (m,lH), 7.73-7.70 (m,lH), 7.59-7.52 (m,2H), 7.38-7.30 (m,2H), 2.21 (s,3H), 1.51 (m,2H), 1.17 (m,2H) ppm.

[0075] In one embodiment, the present invention provides lumacaftor hydrobromide characterized by an X-ray powder diffraction (XRPD) spectrum as depicted in Figure 4.

[0076] In one embodiment, the present invention provides lumacaftor hydrobromide characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 9.08, 10.18, 10.56, 14.34, 17.36, 18.63, 18.8, 25.61 and 25.87 ±0.2 degrees 2 theta.

[0077] In one embodiment, the present invention provides lumacaftor hydrobromide characterized by TGA thermogram as depicted in Figure 5.

[0078] The present invention provides process for the preparation of lumacaftor hydrobromide, the process comprising:

(i) providing a solution of lumacaftor in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;

(ii) adding hydrobromic acid to the solution of step (i);

(iii) obtaining lumacaftor hydrobromide from the mixture of step (ii); and

(iv) isolating lumacaftor hydrobromide.

[0079] The solvent used for dissolution includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1- propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; water; or mixtures thereof.

[0080] Suitable temperature for dissolution may range from about 25°C to about the reflux temperature of the solvent. Stirring may be continued for any desired time period to achieve a complete dissolution of the compound. The stirring time may range from about 30 minutes to about 1 hour, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.

[0081] In step (iii) of the above process, lumacaftor hydrobromide is obtained by stirring the mixture of step (ii).

[0082] Stirring may be carried out for a period of about 10 hours to about 24 hours, or longer till lumacaftor hydrobromide is precipitated out from the mixture. [0083] Lumacaftor hydrobromide is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.

[0084] The present invention provides a process for the preparation of lumacaftor, a compound of formula I

the process comprising:

(a) reacting a compound of formula VIII with an oxidising agent to give a compound of formula VII,

VI I I VI I

wherein, X is selected from the group consisting of CI, Br, I;

(b) aminating the compound of form a compound of formula V;

V

(c) reacting the compound of formula V with a compound of formula IV to give a compound of formula II and

IV I I

(d) reacting the compound of formula II with a com ound of formula III,

wherein, R represents boronic acid, boronic acid ester,

in the presence of a metal catalyst to give lumacaftor, the compound of formula I.

[0085] In (a), (b), (c) and (d) of the process for the preparation of lumacaftor, the reaction conditions are as discussed supra.

[0086] In one embodiment, the present invention further provides a process comprising:

(i) reacting lumacaftor obtained in step (d) with an acid selected from the group of hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid in a solvent to form salt of lumacaftor; and

(ii) converting the salt of lumacaftor to lumacaftor.

[0087] In one embodiment, lumacaftor is reacted with hydrobromic acid to form lumacaftor hydrobromide which is converted to lumacaftor.

[0088] The process of reacting lumacaftor with hydrobromic acid to form lumacaftor hydrobromide is as discussed supra.

[0089] In one embodiment, the level of any single impurity in the lumacaftor hydrobromide, obtained by a process as described herein, is less than 0.15% w/w of lumacaftor hydrobromide.

[0090] The process of converting lumacaftor hydrobromide to lumacaftor is as discussed supra.

[0091] In one embodiment, the lumacaftor has a purity of >99.8% and wherein the level of any single impurity is less than 0.1% w/w of lumacaftor.

[0092] The present invention provides a process for the preparation of salts of lumacaftor, the process comprising:

(a) dissolving lumacaftor in a suitable solvent to form a solution;

(b) obtaining salt of lumacaftor from the solution of step (a); and

(c) isolating the salt of lumacaftor.

[0093] The salt of lumacaftor includes salt with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid. [0094] The reaction may be carried out in a solvent selected from esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; water; or mixtures thereof.

[0095] The present invention rovides a compound of formula Ila,

Ma

[0096] The present invention provides use of compound of formula Ila in preparation of lumacaftor.

[0097] The present invention provides a process for the preparation of a compound of formula V,

V

wherein, X is selected from the group consisting of CI, Br, I,

the process comprising:

(a) reacting a compound of formula VIII with an oxidising agent to give a compound of formula VII; and

VI I I VI I

(b) aminating the compound of formula VII to give the compound of formula V.

[0098] In (a) and (b) of the process for the preparation of the compound of formula V, the reaction conditions are as discussed supra. [0099] In one embodiment, the compound of formula V is purified by a process comprising:

(x) reacting the compound of formula V with an acid to form an acid addition salt of the compound of formula V; and

(y) treating the acid addition salt of the compound of formula V with a base to give the compound of formula V.

[0100] The suitable acids used for the preparation of the acid addition salts of the compound of formula V are as discussed supra.

[0101] The suitable bases used for converting the acid addition salts of the compound of formula V to the compound of formula V are as discussed supra.

[0102] In one embodiment, the compound of formula V is purified by a process comprising:

(x) reacting the compound of formula V with /7-toluenesulphonic acid to form p- toluenesulphonic acid salt of the compound of formula V; and

(y) treating the /7-toluenesulphonic acid salt of the compound of formula V with a base to give the compound of formula V.

[0103] In one embodiment, the compound of formula V is obtained in a purity of >99%.

[0104] In one embodiment, the compound of formula V is further converted to lumacaftor by the process as described herein.

[0105] The present invention provides an amorphous form of lumacaftor.

[0106] The present invention provides a process for the preparation of amorphous form of lumacaftor, the process comprising:

(a) providing a mixture of lumacaftor, or salt or solvate thereof, in a suitable solvent;

(b) obtaining amorphous lumacaftor from the mixture of step (a); and

(c) isolating the amorphous lumacaftor.

[0107] In (a) of the process for the preparation of amorphous lumacaftor, lumacaftor or salt or solvate thereof, is dissolved in a suitable solvent to form a solution.

[0108] In one embodiment, lumacaftor is dissolved in a suitable solvent to form a solution.

[0109] In one embodiment, salt of lumacaftor is dissolved in a suitable solvent to form a solution. [0110] In one embodiment, solvate of lumacaftor is dissolved in a suitable solvent to form a solution.

[0111] The salt of lumacaftor includes salt with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid.

[0112] The solvate of lumacaftor includes solvate with water, methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, acetonitrile, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, chloroform, dichloromethane, hexane, n-heptane, toluene, N-methyl pyrrolidone, dimethyl formamide or dimethyl sulfoxide.

[0113] The solvent used for dissolution but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water; or mixtures thereof.

[0114] Suitable temperature for dissolution may range from about 25°C to about the reflux temperature of the solvent. Stirring may be continued for any desired time period to achieve a complete dissolution of the compound. The stirring time may range from about 30 minutes to about 1 hour, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.

[0115] In (b) of the process for the preparation of amorphous lumacaftor, amorphous lumacaftor is obtained from the solution of step (a).

[0116] In one embodiment, the amorphous lumacaftor is obtained by removing the solvent from the solution obtained in (a). Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.

[0117] In one embodiment, the amorphous lumacaftor is obtained by adding an anti- solvent to the solution obtained in (a) to form a mixture and optionally, cooling and stirring the obtained mixture. The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 90°C.

[0118] The anti-solvent is selected such that amorphous lumacaftor is precipitated out from the solution.

[0119] The anti-solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1- pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.

[0120] In (c) of the process for the preparation of amorphous lumacaftor, the amorphous lumacaftor is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.

[0121] The present invention provides a stable amorphous form of lumacaftor.

[0122] As used herein, the term "stable" includes the amorphous form of lumacaftor, after storage for a period of at least three months at about 2°C to about 8°C, shows no change in polymorphic form by X-ray powder diffraction.

[0123] In one embodiment, the present invention provides stable amorphous lumacaftor, wherein the lumacaftor has no change in the XRPD pattern after storage for three months at about 2°C to about 8°C. [0124] In one embodiment, the present invention provides stable amorphous lumacaftor, wherein the lumacaftor has no change in the XRPD pattern as determined by absence of any crystalline peaks.

[0125] In one embodiment, the present invention provides stable amorphous lumacaftor, having no or little tendency to convert to any of the other polymorphic forms or solvates including hydrates.

[0126] The present invention provides amorphous lumacaftor, obtained by processes as described herein, characterized and analyzed by X-ray powder diffraction with the conditions described below:

X-ray powder diffraction profiles were obtained using an X-ray Diffractometer (Philips X'Pert Pro, PANalytical). The measurements were carried out with a Pre FIX module programmable divergence slit and anti-scatter Slit (Offset 0.00°) ; target, Cu; filter, Ni; detector, X'Celerator; Scanning Mode; Active length (2Theta) = 2.122°; generator 45KV; tube current 40mAmp. The samples were scanned in the full 2Θ range of 2-50° with a "time-per-step" optimized to 50 sec.

[0127] The stable amorphous form of lumacaftor is stored under nitrogen atmosphere and packed in a LDPE (low density polyethylene) bag followed by black LDPE bag optionally containing oxygen busters and sealing it, which is kept in triple laminated aluminium pouch optionally containing oxygen busters and sealing it, which is placed in HDPE (high density polyethylene) drum and stored in controlled environment chamber, at a temperature of about below 8°C. Preferably, the stable amorphous form of lumacaftor is stored under nitrogen atmosphere and packed in a LDPE bag followed by black LDPE bag and is kept in triple laminated aluminium pouch placed in HDPE drum at about 2°C to about 8°C.

[0128] The present invention provides a process for the preparation of amorphous form of lumacaftor, the process comprising:

(a) providing a mixture of lumacaftor hydrobromide in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;

(b) stirring the mixture obtained in step (a);

(c) optionally, separating the aqueous and organic layers from the mixture of step (b); (d) isolating the amorphous lumacaftor from the mixture of step (b) or the organic layer of step (c).

[0129] The reaction may be carried out in a solvent selected from esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; water; or mixtures thereof.

[0130] The mixture of lumacaftor hydrobromide in the solvent may be stirred for a period of about 10 hours to about 24 hours, or longer. The temperature may range from about 20°C to about 40°C.

[0131] The mixture may be stirred in the presence or absence of a base. A suitable base includes but is not limited to an alkali or an alkaline earth metal hydroxide, an alkali or an alkaline earth metal carbonate and the like, an alkali or an alkaline earth metal bicarbonate for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.

[0132] In step (c) of the above process, the aqueous and organic layers from the mixture of step (b) are separated to give organic layer which contains lumacaftor.

[0133] In step (d) of the above process, amorphous lumacaftor is isolated by a process comprising:

(i) removing the solvent from the mixture of step (b) or the organic layer of step (c); or

(ii) treating the mixture of step (b) or the organic layer of step (c) with an anti-solvent; or (iii) partially or completely evaporating the mixture of step (b) or the organic layer of step (c) and adding an organic solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, or mixtures thereof to the obtained reaction mass followed by removal of the solvent; or

(iv) filtering the mixture of step (b).

[0134] The anti-solvent is selected such that lumacaftor is precipitated out from the solution. [0135] The organic solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; or mixtures thereof.

[0136] Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.

[0137] In one embodiment, the present invention provides a process for the preparation of amorphous lumacaftor, the process comprising:

(a) providing a mixture of lumacaftor hydrobromide in a solvent selected from ester- water mixture;

(b) stirring the mixture obtained in step (a);

(c) separating the aqueous and organic layers from the mixture of step (b);

(d) isolating lumacaftor from the organic layer of step (c) by completely evaporating the organic layer of step (c) and adding an organic solvent selected from alcohols to the obtained reaction mass followed by removal of the solvent by spray drying or by complete evaporation on rotavapor under reduced pressure.

[0138] In one embodiment, the lumacaftor hydrobromide is prepared by a process comprising:

(i) reacting a compound of formula VIII with an oxidising agent to give a compound of formula VII,

VIII VI I

wherein, X is selected from the group consisting of CI, Br, I;

(ii) aminating the compound of form a compound of formula V;

V

(iii) reacting the compound of formula V with a compound of formula TV to compound of formula II and

(iv) reacting the compound of formula II with a com ound of formula III,

I I I

wherein, R represents boronic acid, boronic acid ester,

in the presence of a metal catalyst to give lumacaftor, the compound of formula I.

(v) providing a solution of lumacaftor in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;

(vi) adding hydrobromic acid to the solution of step (v);

(vii) obtaining lumacaftor hydrobromide from the mixture of step (vi); and

(viii) isolating lumacaftor hydrobromide.

[0139] In (i), (ii), (iii), (iv), (v), (vi), (vii) and (viii) of the process for the preparation of lumacaftor hydrobromide, the reaction conditions are as discussed supra.

[0140] The present invention provides use of lumacaftor hydrobromide in the preparation of amorphous form of lumacaftor. [0141] The present invention provides a process for the preparation of lumacaftor, a compound of formula I

I

the process comprising:

(a) reacting a compound of formula VIII with an oxidising agent to give a compound of formula VII,

VI I I VI I

wherein, X is selected from the group consisting of CI, Br, I;

(b) aminating the compound of form a compound of formula V;

(c) reacting the compound of formula V with a compound of formula VI in the presence of an activatin agent to give a compound of formula II; and

(d) reacting the compound of formula II with a com ound of formula III,

I II

wherein, R represents boronic acid, boronic acid ester,

in the presence of a metal catalyst to give lumacaftor, the compound of formula I. [0142] In (a), (b) and (d) of the process for the preparation of lumacaftor, the reaction conditions are as discussed supra.

[0143] In (c) of the process for the preparation of lumacaftor, the compound of formula V is reacted with a compound of formula VI in the presence of an activating agent to give a compound of formula II.

[0144] A suitable activating agent includes but is not limited to thionyl chloride, carbonyldiimidazole (CDI), 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HC1), 1 -Hhydroxybenzotriazole (HOBt), 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 3-[bis(dimethylamino)methyliumyl]-3H-benzotriazol-l- oxide hexafluorophosphate (HBTU), 0-(benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU), propylphosphonic anhydride (T3P), dicyclohexylcarbodiimide (DCC), 3-hydroxytriazolo[4,5-b]pyridine (HO AT).

[0145] The reaction may be optionally carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, di-isopropyl ethylamine, dimethylaminopyridine, N-methyl morpholine.

[0146] The present invention provides a process for the preparation of lumacaftor re resented schematically in Scheme I.

Scheme I [0147] The present invention provides use of compounds of formula ΓΧ and X in preparation of lumacaftor.

[0148] The present invention provides a process for the preparation of solvates of lumacaftor, the process comprising:

(a) dissolving lumacaftor in a suitable solvent, optionally in presence of additional solvent, to form a solution;

(b) obtaining solvate of lumacaftor from the solution of step (a); and

(c) isolating the solvate of lumacaftor.

[0149] The solvate of lumacaftor includes solvate with water, n-propanol, isopropanol, n- butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, methyl isobutyl ketone, dioxane, chloroform, dichloromethane, hexane, n- heptane, toluene, N-methyl pyrrolidone, dimethyl formamide or dimethyl sulfoxide.

[0150] The suitable solvent includes water, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, methyl isobutyl ketone, dioxane, chloroform, dichloromethane, hexane, n-heptane, toluene, N-methyl pyrrolidone, dimethyl formamide or dimethyl sulfoxide.

[0151] The additional solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1 -propanol, 2-propanol, 1- butanol, 2-butanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.

[0152] In (b) of the process for the preparation of solvate of lumacaftor, the solvate of lumacaftor is obtained from the solution of step (a), the process comprising:

(i) cooling and stirring the solution obtained in step (a); or

(ii) removing the solvent from the solution obtained in step (a); or

(iii) treating the solution of step (a) with an anti-solvent to form a mixture and optionally, cooling and stirring the obtained mixture. [0153] The anti-solvent is selected such that the solvate of lumacaftor is precipitated out from the solution.

[0154] The anti-solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1- pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.

[0155] The present invention provides a premix comprising lumacaftor and a pharmaceutically acceptable carrier.

[0156] The pharmaceutically acceptable carrier may be selected from the group consisting of cellulose derivatives such as croscarmellose sodium, microcrystalline cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethyl cellulose (EC), methylcellulose (MC), cellulose esters, cellulose glycolate, hydroxypropyl methylcellulose phthalate (HPMCP), polymethylacrylate, hypromellose; vinylpyrrolidone polymers such as polyvinylpyrrolidone; polyols such as mannitol, sorbitol and the like; sugars such as lactose.

[0157] The present invention provides a premix comprising salt of lumacaftor and a pharmaceutically acceptable carrier.

[0158] In one embodiment, the present invention provides a process for the preparation of a premix comprising lumacaftor and a pharmaceutically acceptable carrier, the process comprising:

(a) dissolving lumacaftor in a solvent;

(b) adding a pharmaceutically acceptable carrier to the solution prepared in step (a); and

(c) removing the solvent from the mixture obtained in step (b).

[0159] The solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1- pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.

[0160] In one embodiment, the present invention provides a premix comprising lumacaftor and a pharmaceutically acceptable carrier, wherein the lumacaftor is in amorphous form.

[0161] In one embodiment, the present invention provides a premix comprising lumacaftor and a pharmaceutically acceptable carrier, wherein the premix contains amorphous lumacaftor in stable form.

[0162] In one embodiment, the present invention provides pharmaceutical compositions comprising lumacaftor or salt or solvate thereof obtained by the processes herein described, having a D₅₀ and D₉₀ particle size of less than about 150 microns, preferably less than about 100 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns. The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state lumacaftor or salt or solvate thereof into any of the foregoing desired particle size range.

[0163] The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES

[0164] EXAMPLE 1 Preparation of 2-bromo-3-methylpyridine-l-oxide

To a stirred solution of 2-bromo-3-methylpyridine (50g) in dichloromethane (500mL) was added 3-chloroperbenzoic acid (100g) at about room temperature. The reaction mixture was stirred for about 12h at about room temperature and was filtered. The filtrate was quenched in to saturated sodium thiosulfate solution. The reaction mixture was stirred for about lh at about room temperature. The two layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layer was washed with water and saturated brine solution, dried and concentrated under reduced pressure at about 40°C. The solid was purified by column chromatography (5- 7% methanol in ethyl acetate). Yield: 33g (60%)

1H NMR (300MHz, CDC1₃): δ 8.30-8.29 (m,lH), 7.14-7.12 (m,2H), 2.47 (s,3H)

JR. 3382, 3051, 1670, 1436, 1410, 1275, 1240, 1067, 958, 786, 695, 599 cm^"1

Mass [M+H] ⁺: 188.09

[0165] EXAMPLE 2 Preparation of 6-amino-2-bromo-3-methylpyridine

To a stirred solution of 2-bromo-3-methylpyridine-l -oxide (2g) and pyridine (3.3g) in acetonitrile (20mL) at about 70°C, was added a solution of trifluoromethanesulfonic anhydride (4.2g) in acetonitrile (4mL) over about 20min. The reaction mixture was stirred for about lh at about the same temperature. The reaction mixture was allowed to cool to about 10°C to about 15°C and ethanolamine (6. lg) was added to it. The reaction mixture was stirred for about 3h at about room temperature and water and ethyl acetate were added to it. The two layers were separated and the organic layer was washed with water and saturated brine solution, dried and concentrated under reduced pressure at about 40°C. The residue was purified by column chromatography (10-15% ethyl acetate in hexane). Yield: 600mg (30%)

1H NMR (300MHz, CDCI₃): δ 7.31-7.28 (d,J=7.8Hz,lH), 6.46-6.44 (d,J=7.8Hz,lH), 4.02 (brs,2H), 2.26 (s,3H)

JR. 3364, 3200, 2914, 1634, 1601, 1475, 1373, 1057, 820 cm^"1

DSC: 94.73°C

A polar compound was obtained (200mg) which was eluted at 20-25% ethyl acetate in hexane. 1H NMR (300MHz, CDC1₃): δ 7.80-7.79 (d,J =4.8 Ηζ,ΙΗ), 6.46-6.45 (d,J=4.8Hz,lH), 4.38(brs,2H), 2.20 (s,3H)

JR. 3319, 3194, 2925, 1638, 1590, 1480, 1394, 1273, 1199, 1010, 819 cm^"1

DSC: 121.47°C

Mass [M+H]⁺: 187.11

[0166] EXAMPLE 3 Preparation of 6-amino-2-bromo-3-methylpyridine

To a stirred solution of 2-bromo-3 -methyl pyridine- 1 -oxide (25g) and pyridine (42g) in acetonitrile (250mL) at about 70°C, was added a solution of trifluoromethanesulfonic anhydride (55g) in acetonitrile (50mL). The reaction mixture was stirred for about lh at about the same temperature. The mixture was cooled to about 10°C to about 15°C and ethanolamine (80.52g) was added to it. The reaction mixture was stirred for about 3h at about room temperature and water and ethyl acetate were added to it. The two layers were separated and the organic layer was washed with saturated brine solution, dried and concentrated under reduced pressure at about 40°C. The residue was purified by column chromatography (15-20% ethyl acetate in hexane). Yield: 4g (16%)

1H NMR (300MHz, CDC1₃): δ 7.26-7.24 (d,J=8.10Hz,lH), 6.42-6.39 (d,J=8.4Hz,lH), 4.28 (brs,2H), 2.22 (s,3H)

¹³C NMR (400MHz, CDCI₃): 156.52, 141.56, 140.50, 122.99, 107.26, 20.58

IR: 3364, 3199, 2913, 1635, 1601, 1373, 1058, 819 cm^"1

4-Amino-2-bromo-3 -methyl pyridine (3g) was obtained which was eluted at 25-30% ethyl acetate in hexane.

1H NMR (300MHz, CDCI₃): δ 7.82-7.80 (d,J=5.4Hz,lH), 6.48-6.46 (d,J =5.4Hz,lH), 4.35 (brs,2H), 2.21 (s,3H)

¹³C NMR (400MHz, CDC1₃): 152.70, 146.94, 145.05, 116.88, 109.25, 15.73

[0167] EXAMPLE 4 Preparation of 6-amino-2-bromo-3-methylpyridine

To a stirred solution of 2-bromo-3-methylpyridine-l -oxide (18g) and pyridine (30mL) in acetonitrile (180mL) at about 71 °C, was added a solution of methanesulfonic anhydride (33.31g) in acetonitrile (40mL). The reaction mixture was stirred for about 90min at about the same temperature and acetonitrile (30mL) was added to it. The reaction mixture was cooled to about 10°C to about 15°C and ethanolamine (58.59g) was added to it. The reaction mixture was stirred for about 13h at about room temperature and water and ethyl acetate were added to it. The two layers were separated and the organic layer was washed with water and saturated brine solution, dried and concentrated under reduced pressure at about 45°C. The residue was purified by column chromatography (25-30 % ethyl acetate in hexane). Yield: lO. lg (56%)

1H NMR (300MHz, CDC1₃): δ 7.24-7.22 (d,J=8.1 Ηζ,ΙΗ), 6.39-6.36 (d,J=8.4 Ηζ,ΙΗ), 4.27 (brs,2H), 2.21 (s,3H)

JR. 3365, 3200, 2915, 1636, 1601, 1475, 1374, 1058, 820 cm^"1

Mass [M+H]⁺: 187.05

[0168] EXAMPLE 5 Preparation of 6-amino-2-bromo-3-methylpyridine

To a stirred solution of 2-bromo-3-methylpyridine-l -oxide (2g) and triethylamine (3.22g) in acetonitrile (20mL) at about 0°C to about 5°C, was added a solution of trifluoromethanesulfonic anhydride (8.9g) in acetonitrile (4mL) over about lOmin. The reaction mixture was stirred for about 2h at about the same temperature. The temperature of the reaction mixture was raised to about 10°C to about 15°C. Ethanolamine (6.1g) was added to the reaction mixture which was maintained for about 12h at about room temperature. Water and ethyl acetate were added to the reaction mixture. The two layers were separated and the organic layer was washed with water and saturated brine solution, dried and concentrated under reduced pressure at about 40°C. The residue was purified by column chromatography (25-30% ethyl acetate in hexane). Yield: 400mg (20%) 1H NMR (300MHz, CDCI₃): δ 7.27-7.24 (d,J=8.4Hz,lH), 6.40-6.37 (d,J =7.8Hz,lH), 4.44 (brs,2H), 2.24 (s,3H)

[0169] EXAMPLE 6 Preparation of l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarbonyl chloride

To a mixture of l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxylic acid (50mg) in thionyl chloride (lmL) was added dimethyl formamide (0.125mL). The reaction mixture was stirred at about room temperature for about 2h. Excess of thionyl chloride and dimethyl formamide were removed in vacuum after co-distilling with toluene and the resulting product was used directly without further purification.

[0170] EXAMPLE 7 Preparation of iV-(2-bromo-3-methylpyridin-2-yl)-l-(2,2- difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxamide To a solution of 6-amino-2-bromo-3-methylpyridine (46.7mg) and triethylamine (38.84mg) in dichloromethane (2.5mL) was added a solution of l -(2,2-difluoro-l,3- benzodioxol-5-yl)cyclopropanecarbonyl chloride in dichloromethane (2.5mL). The reaction mixture was stirred at about room temperature for about 15h and water was added to it. The two layers were separated and the organic layer was washed with water, dried and concentrated. The crude product was purified by preparative TLC. Yield: 2mg ESI-MS m/z: 410.97 (M)⁺

1H NMR (300MHz, DMSO-d6): δ 9.36 (s,lH), 7.90-7.87 (d,lH), 7.74 (d,lH), 7.53 (s,lH), 7.38-7.32 (m,2H), 2.25 (s,3H), 1.49 (m,2H), 1.16 (m,2H)

[0171] EXAMPLE 8 Preparation of iV-(2-bromo-3-methylpyridin-2-yl)-l-(2,2- difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxamide

To the solution of (2,2-difluoro-l,3-benzodioxol-5-yl)-cyclopropane carboxylic acid (250mg) in dichloromethane (5mL) wad added CDI (335mg) and stirred for about 4h at about room temperature. The solvent was evaporated under reduced pressure. The residue was taken into toluene (5mL) and 6-bromo-5-methylpyridin-2-amine (212.4mg) was added to it. The reaction mixture was maintained at about 110°C to about 115°C for about 18h. The reaction mixture was concentrated under vacuum at about 45°C. The residue was purified by column chromatography. Yield: lOOmg

1H NMR (300MHz, DMSO-d6): δ 9.35 (brs,lH), 7.9-7.87 (d,lH,J=8.4Hz), 7.73-7.71 (d,lH,J=8.1Hz ), 7.52 (s,lH), 7.40-7.37 (d,lH,J=8.4Hz), 7.32-7.29(d,lH,J=8.4Hz), 2.25 (s,3H), 1.48(brs,2H), 1.16(brs,2H)

ESI-MS m/z: 411.17 (M)⁺

[0172] EXAMPLE 9 Preparation of Lumacaftor

To the solution of N-(2-bromo-3-methylpyridin-2-yl)-l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide (50mg) in toluene (lmL) were added potassium carbonate solution (80.66mg in 0.5mL of water) and bis(diphenylphosphino)ferrocenedichloropalladium(II) (1.98mg) catalyst. The reaction mixture was stirred for about lh at about room temperature and 3-carboxyphenylboronic acid (22.12mg) was added to it. The reaction mixture was stirred at about 80°C for about 16h and then filtered to remove the catalyst. The filtrate was concentrated under vacuum and the obtained residue purified by column chromatography or preparative TLC. [0173] EXAMPLE 10 Preparation of 2-chloro-3-methylpyridine-l-oxide

To a stirred solution of 2-chloro-3 -methyl pyridine (lOg) in dichloromethane (150mL) was added 3-chloroperbenzoic acid (26.9g) at about room temperature. The reaction mixture was stirred for about 12h and was filtered. The filtrate was quenched in to saturated sodium thiosulfate solution. The reaction mixture was stirred for about lh. The two layers were separated and the aqueous layer was extracted with dichloromethane. The organic layer was concentrated under reduced pressure at about 45 °C. The solid was purified by column chromatography (50% methanol in ethyl acetate). Yield: 9.1g (98%). 1H NMR (300 MHz, CDC1₃): δ 8.19 (m,lH), 7.09-7.07 (m,2H), 2.39 (s,3H)

Mass [M+H]⁺: 143.57

[0174] EXAMPLE 11 Preparation of 6-amino-2-chloro-3-methylpyridine

To a stirred solution of 2-chloro-3 -methyl pyridine- 1 -oxide (9g) and pyridine (19.9mL) in acetonitrile (90mL) at about 65 °C, was added a solution of trifluoroacetic anhydride (19.53g) in acetonitriie (1 8mL). The reaction mixture was stirred for about l h at about 70°C. The reaction mixture was allowed to cool to about 10°C to about 15°C and ethanolamme (37.82g) was added to it. The reaction mixture was maintained for about 12b at about room temperature and water and ethyl acetate were added to it. The two layers were separated and the organic layer was washed with water and saturated brine solution, dried and concentrated under reduced pressure at about 45°C. The residue was purified by column chromatography (20-25% ethyl acetate in hexane). Yield: 4. lg (44%). 1H NMR (300MHz, CDC1₃): δ 7.29-7.26 (d,J=7.8Hz,lH), 6.37-6.34 (d,J=8.1Hz,lH), 4.22 (brs,2H), 2.22 (s,3H)

Mass [M+H] ⁺: 142.58

[0175] EXAMPLE 12 Preparation of 6-amino-2-bromo-3-methylpyridine

To a stirred solution of 2-bromo-3-methylpyridine-l -oxide (20g) and pyridine (34.2mL) in acetonitrile (160mL) at about 70°C, was added a solution of trifluoroacetic anhydride (33.39g) in acetonitrile (20mL). The reaction mixture was stirred for about lh at about the same temperature. The reaction mixture was allowed to cool to about 10°C to about 15°C and ethanolamine (64.6g) was added to it. The reaction mixture was maintained for about 15h at about room temperature and water and ethyl acetate were added to it. The two layers were separated and the organic layer was washed with water and saturated brine solution, dried and concentrated under reduced pressure at about 50°C to give a residue. HPLC purity of residue: 80.1%, other isomer 9.89%. The residue was dissolved in ethyl acetate and /7-toluenesulphonic acid (3g) was added to it. The precipitated solid was stirred for about 15h at about room temperature and was filtered and washed with ethyl acetate. HPLC purity of salt: 95.51%, other isomer 3.71%. To a stirred slurry of the obtained solid in water was added a solution of sodium carbonate. The precipitated solid was stirred for about 3h at about room temperature, filtered, washed with water and dried at about 45°C for about 15h. Yield: 9.8g (49%); HPLC purity: 99.56%

[0176] EXAMPLE 13 Preparation of l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarbonyl chloride

To a mixture of l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxylic acid (20g) in toluene (200mL) and dimethyl formamide (5mL) was added thionyl chloride (14.9mL). The reaction mixture was stirred at about 80°C for about 3h. Excess thionyl chloride and solvents were removed under reduced pressure after co-distilling with dichloromethane and the resulting product was used directly without further purification.

[0177] EXAMPLE 14 Preparation of iV-(2-chloro-3-methylpyridin-2-yl)-l-(2,2- difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxamide

To a solution of 6-amino-2-chloro-3-methylpyridine (H.8g) and pyridine (19.4g) in dichloromethane (200mL) was added a solution of l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarbonyl chloride in dichloromethane (40mL). The reaction mixture was stirred at about room temperature for about 3h and water was added to it. The two layers were separated and the organic layer was treated with hydrochloric acid solution and then with sodium bicarbonate solution. The organic layer was washed with water, saturated brine solution, then treated with charcoal, filtered through hyflo bed, concentrated under reduced pressure at about 45 °C and was co-distilled with hexane. A mixture of the obtained residue in hexane was stirred for about 5h. The solid obtained was filtered and dried at about 60°C for about 8h. Yield: 23. lg (76%)

1H NMR (300MHz, DMSO-d6): δ 9.27 (s,lH), 7.88-7.85 (m,lH), 7.76-7.73 (m,lH), 7.51 (m,lH), 7.39-7.29 (m,2H), 2.24 (s,3H), 1.50 (m,2H), 1.15 (m,2H).

Mass [M+H] ⁺: 366.74

HPLC purity: 99.89% [0178] EXAMPLE 15 Preparation of iV-(2-bromo-3-methylpyridin-2-yl)-l-(2,2- difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxamide

To a solution of 6-amino-2-bromo-3-methylpyridine (7.72g) and pyridine (9.7g) in dichloromethane (500mL) was added a solution of l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarbonyl chloride in dichloromethane (20mL). The reaction mixture was stirred at about room temperature for about 3h and water was added to it. The two layers were separated and the organic layer was treated with hydrochloric acid solution and then with sodium bicarbonate solution. The organic layer was washed with water, saturated brine solution, then treated with charcoal, filtered through hyflo bed, concentrated under reduced pressure at about 35°C to about 45 °C and was co-distilled with hexane. A mixture of the obtained residue in hexane was stirred for about 5h. The solid obtained was filtered and dried at about 60°C for about 8h. Yield: 12.4g (73%).

[0179] EXAMPLE 16 Preparation of iV-(2-bromo-3-methylpyridin-2-yl)-l-(2,2- difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxamide

To a solution of l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxylic acid (20g) in dichloromethane (120mL) was slowly added Ι,Γ-carbonyldiimidazole (CDI) (14.72g) and the reaction mixture was stirred for about lh at about room temperature. The reaction mixture was concentrated under reduced pressure and was co-distilled with toluene at about 50°C. To the obtained residue in toluene (120mL), was added 6-amino-2-bromo-3- methylpyridine (16g). The reaction mixture was maintained at about reflux temperature for about 40h to about 44h. The reaction mixture was cooled to about room temperature and was stirred for about lh. The solid obtained was filtered and toluene was added to the clear filtrate. The organic layer was washed aqueous sodium hydroxide followed by brine solution and concentrated under reduced pressure at about 50°C. A mixture of the obtained residue in hexane was stirred for about 2h. The solid obtained was filtered and dried at about 60°C for about 8h. Yield: 22g (65%)

[0180] EXAMPLE 17 Preparation of iV-(2-bromo-3-methylpyridin-2-yl)-l-(2,2- difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxamide

To a solution of l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxylic acid (25g) in toluene (250mL) and dimethylformamide (6.25mL) was slowly added thionyl chloride (14.3mL) and the reaction mixture was stirred for about 3h at about 110°C. The reaction mixture was concentrated under reduced pressure and was co-distilled with toluene at about 50°C. To the obtained residue in toluene (50mL) were added 6-amino-2-bromo-3- methylpyridine (21.25g) in toluene (250mL) and di-isopropyl ethylamine (52.29mL) at about room temperature. The reaction mixture was maintained for about 3h at about room temperature and water and ethyl acetate were added to it. The two layers were separated and the organic layer was treated with 10% hydrochloric acid solution. The organic layer was washed with water and brine solution, concentrated under reduced pressure at about 45°C and was co-distilled with hexane. Hexane was added to the obtained residue and the mixture was stirred for about 8h. The solid obtained was filtered and dried at about 50°C for about 2h. Yield: 28. lg (66%)

[0181] EXAMPLE 18 Preparation of iV-(2-bromo-3-methylpyridin-2-yl)-l-(2,2- difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxamide

To a solution of l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxylic acid (5g) in toluene (50mL) and dimethylformamide (1.25mL) was slowly added thionyl chloride (3.63mL) and the reaction mixture was stirred for about 3h at about 80°C. The reaction mixture was concentrated under reduced pressure at about 50°C. To the obtained residue in dichloromethane (lOmL) were added 6-amino-2-bromo-3-methylpyridine (3.86g) in dichloromethane (50mL) and pyridine (5mL) at about room temperature. The reaction mixture was maintained for about 3h at about room temperature and water was added to it. The two layers were separated and the organic layer was treated with 10% hydrochloric acid solution and then with sodium bicarbonate solution. The organic layer was washed with water and brine solution, treated with charcoal, filtered, concentrated under reduced pressure at about 50°C and was co-distilled with hexane. Hexane was added to the obtained residue and the mixture was stirred for about 6h. The solid obtained was filtered and dried at about 60°C for about 8h. Yield: 65.3g (76%)

[0182] EXAMPLE 19 Preparation of lumacaftor hydrobromide

To the solution of N-(2-chloro-3-methylpyridin-2-yl)-l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide (12g) in 1,4-dioxane (120mL) were added solution of potassium carbonate (18.57g) in water (120mL) and bis(triphenylphosphine)dichloropalladium (1.99g) catalyst. The reaction mixture was stirred for about lh at about room temperature and 3-carboxyphenylboronic acid (6.1 lg) was added to it. The reaction mixture was stirred at about 85°C to about 90°C for about 4h, then cooled to about 50°C to about 55°C and filtered to remove the catalyst. The filtrate was concentrated under reduced pressure at about 50°C to about 55°C. To the obtained residue, ethyl acetate and water were added. The mixture was stirred for about 15min and the two layers were separated. The organic layer was concentrated under reduced pressure at about 50°C to about 55°C. The residue obtained was dissolved in ethyl acetate and treated with 47% aqueous of hydrobromic acid solution. The mixture was stirred for about 12h at about room temperature. The solid was filtered, washed with ethyl acetate and dried at about 55°C to about 60°C for about 12h. Yield: 14.3g

1H NMR (300MHz, DMSO-d6): δ 9.13 (s,lH), 7.98-7.92(m,3H), 7.84-7.82(m,lH), 7.73- 7.70 (m,lH), 7.59-7.52 (m,2H), 7.38-7.30(m,2H), 2.21 (s,3H), 1.51 (m,2H), 1.17 (m,2H) HPLC: 99.88%

Compound of formula II: 0.04%

HBr Content: 15.3%

[0183] EXAMPLE 20 Preparation of lumacaftor hydrobromide

To the solution of N-(2-bromo-3-methylpyridin-2-yl)-l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide (12g) in 1,4-dioxane (120mL) was added solution of potassium carbonate (16.5g) in water (120mL). The mixture was stirred for about lh at about room temperature and 3-carboxyphenylboronic acid (5.53g) and bis(triphenylphosphine)dichloropalladium (1.8g) were added to it. The mixture was stirred at about 90°C to about 95°C for about 3h, then was cooled to about 50°C to about 55°C and filtered through hyflo bed. The filtrate was concentrated under reduced pressure at about 50°C to about 55°C. To the obtained residue, ethyl acetate and water were added. The mixture was stirred for about 15min and the two layers were separated. The organic layer was treated with charcoal, filtered through hyflo bed and concentrated under reduced pressure at about 45°C to about 50°C. The residue obtained was dissolved in ethyl acetate and treated with 48% aqueous of hydrobromic acid solution. The mixture was stirred for about 16h at about room temperature. The solid was filtered, washed with ethyl acetate and dried at about 60°C to about 65°C for about lOh. Yield: 12.5g

HPLC purity: 100%

Compound of formula II: Not detected DSC: Endotherm (70.84°C, 215.53°C), Exotherm (219.31°C)

1H NMR (300MHz, DMSO-d6): δ 9.13 (s,lH), 8.003-7.85(m,3H), 7.74 (m,lH), 7.72 (m,lH), 7.61-7.54 (m,2H), 7.34-7.31(m,2H), 2.23 (s,3H), 1.52 (m,2H), 1.19 (m,2H)

[0184] EXAMPLE 21 Preparation of lumacaftor hydrochloride

To the solution of N-(2-bromo-3-methylpyridin-2-yl)-l -(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide (lOg) in 1,4-dioxane (70mL) and ethanol (25mL) were added solution of potassium carbonate (12g) in water (70mL) and bis(triphenylphosphine)dichloropalladium (0.852g) catalyst. The reaction mixture was stirred for about lh at about room temperature and 3-carboxyphenylboronic acid (4.14g) was added to it. The reaction mixture was stirred at about 85°C to about 90°C for about 4h, then cooled to about 65 °C and filtered to remove the catalyst. The filtrate was concentrated under reduced pressure at about 55°C. To the obtained residue, ethyl acetate and water were added. The two layers were separated and the organic layer was washed with brine solution and concentrated under reduced pressure at about 50°C and co- distilled with acetone. To the obtained residue, acetone and concentrated hydrochloric acid were added and the mixture was stirred for about 12h at about room temperature. The solid was filtered, washed with acetone and dried at about 60°C for about 4h.

HPLC: 99.53%

Compound of formula II: 0.27%

[0185] EXAMPLE 22 Preparation of crystalline lumacaftor

A slurry of lumacaftor hydrobromide in ethyl acetate (18QmL) and water (1 8QmL) was stirred for about 5h at about room temperature. The two layers were separated and the organic layer was washed with water and concentrated under reduced pressure at about 45°C to about 50°C. Hexane (120mL) was added to the obtained residue and the mixture was stirred for about 2h at about room temperature. The solid obtained was filtered, washed with hexane and dried at about 55°C to about 60°C for about 5h. Yield: 5.2g HPLC purity: 99.8%

Compound of formula II: 0.08%

[0186] EXAMPLE 23 Preparation of amorphous lumacaftor

A slurry of lumacaftor hydrobromide (5g) in ethyl acetate (500mL) and water (500mL) was stirred for about 14h at about room temperature. The two layers were separated and the organic layer was washed with water and brine solution, dried over sodium sulphate and filtered through hyflo bed. Methanol or isopropyl alcohol (120mL) was added to the filtrate and the mixture was concentrated. Methanol or isopropyl alcohol was added to the residue and the mixture was concentrated up to 500mL solution. 300mL solution was used for spray drying (Spray drying: Outer Temperature: 75-85°C, Aspirator Rate: 1200- 2000rpm and Feed Rate: 20rpm) and the remaining 700mL solution was used for complete evaporation on rotavapor under reduced pressure in five lots at about reflux temperature to give amorphous Lumacaftor.

[0187] EXAMPLE 24 Preparation of amorphous lumacaftor

A solution of lumacaftor (l lg) in methanol (440mL) was completely evaporated on rotavapor under reduced pressure in five lots at about reflux temperature to give amorphous lumacaftor. Yield: 10.5g

Stability data of amorphous lumacaftor prepared by the present invention at periodic intervals under various packaging conditions:

Stability data of amorphous lumacaftor at periodic intervals packed in LDPE bag under nitrogen followed by black LDPE bag and kept in triple laminated aluminium pouch placed in HDPE drum under various storage conditions: Time -20±5°C 5±3°C 25°C/60%RH

2 Weeks Amorphous pattern Amorphous pattern Amorphous pattern

1 Month Amorphous pattern Amorphous pattern Crystalline pattern

2 Months Amorphous pattern Amorphous pattern Crystalline pattern

3 Months Amorphous pattern Amorphous pattern Crystalline pattern

(RH is relative humidity)

The results indicate that the amorphous lumacaftor of the present invention is stable and does not undergo polymorphic conversion at temperatures -20±5°C and 5±3°C packed in LDPE bag under nitrogen followed by black LDPE bag and kept in triple laminated aluminium pouch placed in HDPE drum.

[0188] EXAMPLE 25 Preparation of amorphous lumacaftor

A solution of lumacaftor (lOg) in ethanol (400mL) was completely evaporated on rotavapor under reduced pressure at about 80°C to about 85°C to give amorphous lumacaftor. Yield: 8g

Claims

CLAIMS:

1. A process for the reparation of lumacaftor, a compound of formula I,

I

the process comprising:

(a) obtaining lumacaftor;

(b) reacting lumacaftor obtained in step (a) with hydrobromic acid to form lumacaftor hydrobromide; and

(c) converting lumacaftor hydrobromide to lumacaftor.

2. The process of claim 1 , wherein the step (b) is carried out in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof, at a temperature in the range of 10°C to 100°C.

3. The process of claim 1, wherein the step (c) of converting lumacaftor hydrobromide to lumacaftor comprises:

(i) providing a mixture of lumacaftor hydrobromide in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;

(ii) stirring the mixture obtained in step (i);

(iii) optionally, separating the aqueous and organic layers from the mixture of step (ii);

(iv) isolating lumacaftor from the mixture of step (ii) or the organic layer of step (iii).

4. The process of claim 3, wherein the step (ii) is carried out in the presence or absence of a base.

5. The process of claim 3, wherein the step (iv) of isolating lumacaftor comprises: (p) removing the solvent from the mixture of step (ii) or the organic layer of step (iii); or (q) treating the mixture of step (ii) or the organic layer of step (iii) with an anti-solvent; or

(r) partially or completely evaporating the mixture of step (ii) or the organic layer of step (iii) and adding an organic solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, or mixtures thereof to the obtained reaction mass followed by removal of the solvent; or

(s) filtering the mixture of step (ii).

6. The process of claim 1, wherein the level of any single impurity in the lumacaftor hydrobromide obtained in step (b) is less than 0.15% w/w of lumacaftor hydrobromide.

7. The process of claim 6, wherein the single impurity is represented by a compound of formula II,

I I

8. The process of claim 7, wherein the compound of formula II is less than 0.15% w/w of lumacaftor hydrobromide.

9. The process of claim 1, wherein the lumacaftor obtained in step (c) has a purity of >99.8% and wherein the level of any single impurity is less than 0.1% w/w of lumacaftor.

10. The process of claim 1, wherein the lumacaftor obtained in step (a) is prepared by a process comprising:

(i) reacting a compound of formula VIII with an oxidising agent to give a compound of formula VII,

VIII VII

wherein, X is selected from the group consisting of CI, Br, I;

(ii) aminating the compound of form a compound of formula V;

V

(iii) reacting the compound of formula V with a compound of formula TV to compound of formula II; and

(iv) reacting the compound of formula II with a com ound of formula III,

II I

wherein, R represents boronic acid, boronic acid ester,

in the presence of a metal catalyst to give lumacaftor, the compound of formula I.

11. The process of claim 10, wherein step (ii) is carried out in the presence of an activating reagent selected from the group consisting of methanesulfonic anhydride, methanesulfonyl chloride, /7-toluenesulfonic anhydride, /7-toluenesulfonyl chloride, trifluoromethansulfonic anhydride, benzenesulfonic anhydride, benzenesulfonyl chloride, trifluoroacetic anhydride.

12. The process of claim 10, wherein step (ii) is carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, dimethylaminopyridine, 2,4,6-trimethylpyridine.

13. The process of claim 10, wherein step (ii) is carried out in the presence of an aminating reagent selected from the group consisting of methanolamine, ethanolamine, propanolamine, butanolamine, pentanolamine, hexanolamine, ieri-butylamine, ammonia, sodamide.

14. The process of claim 10, wherein the compound of formula V is purified by a process comprising:

(x) reacting the compound of formula V with an acid to form an acid addition salt of the compound of formula V; and

(y) treating the acid addition salt of the compound of formula V with a base to give the compound of formula V.

15. The process of claim 14, wherein the acid addition salt is a /7-toluenesulphonic acid salt of the compound of formula V.

16. The process of claim 14, wherein the compound of formula V is obtained in a purity of >99%.

17. Lumacaftor hydrobromide.

18. The lumacaftor hydrobromide of claim 17, characterized by a proton NMR spectrum having peak positions at 9.13 (s,lH), 7.98-7.92 (m,3H), 7.84-7.82 (m,lH), 7.73-

7.70 (m,lH), 7.59-7.52 (m,2H), 7.38-7.30 (m,2H), 2.21 (s,3H), 1.51 (m,2H), 1.17 (m,2H) ppm.

19. The lumacaftor hydrobromide of claim 17, characterized by an X-ray powder diffraction (XRPD) spectrum as depicted in Figure 4.

20. The lumacaftor hydrobromide of claim 17, characterized by a TGA thermogram as depicted in Figure 5.

21. A process for the preparation of lumacaftor hydrobromide, the process comprising:

(i) providing a solution of lumacaftor in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;

(ii) adding hydrobromic acid to the solution of step (i);

(iii) obtaining lumacaftor hydrobromide from the mixture of step (ii); and

(iv) isolating lumacaftor hydrobromide.

22. The process of claim 21, wherein the level of any single impurity in the lumacaftor hydrobromide is less than 0.15% w/w of lumacaftor hydrobromide.

23. An amorphous form of lumacaftor.

24. A process for the preparation of amorphous form of lumacaftor, the process comprising:

(a) providing a mixture of lumacaftor, or salt or solvate thereof, in a suitable solvent; (b) obtaining amorphous lumacaftor from the mixture of step (a); and

(c) isolating the amorphous lumacaftor.

25. The process of claim 24, wherein the step (b) of obtaining lumacaftor in amorphous form comprises:

(i) removing the solvent from the solution obtained in step (a); or

(ii) treating the solution of step (a) with an anti-solvent.

26. The process of claim 25, wherein the solvent is removed from the solution by concentrating the solution, or completely evaporating the solvent, or removing the solvent by lyophilisation, freeze-drying, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.

27. A stable amorphous form of lumacaftor.

28. The stable amorphous form of lumacaftor of claim 27, wherein the lumacaftor has no change in the XRD pattern after storage for three months at 2°C to 8°C.

29. A process for the preparation of amorphous form of lumacaftor, the process comprising:

(a) providing a mixture of lumacaftor hydrobromide in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;

(b) stirring the mixture obtained in step (a);

(c) optionally, separating the aqueous and organic layers from the mixture of step (b); (d) isolating the amorphous lumacaftor from the mixture of step (b) or the organic layer of step (c).

30. The process of claim 29, wherein the step (b) is carried out in the presence or absence of a base.

31. The process of claim 29, wherein the step (d) of isolating the amorphous lumacaftor comprises:

(i) removing the solvent from the mixture of step (b) or the organic layer of step (c); or

(ii) treating the mixture of step (b) or the organic layer of step (c) with an anti-solvent; or

(iii) partially or completely evaporating the mixture of step (b) or the organic layer of step (c) and adding an organic solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, or mixtures thereof to the obtained reaction mass followed by removal of the solvent; or

(iv) filtering the mixture of step (b).

32. The process of claim 31, wherein the solvent is removed from the solution by concentrating the solution, or completely evaporating the solvent, or removing the solvent by lyophilisation, freeze-drying, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.

33. The process of claim 29, wherein the lumacaftor hydrobromide is prepared by a process comprising:

(i) reacting a compound of formula VIII with an oxidising agent to give a compound of formula VII,

VIII VI I

wherein, X is selected from the group consisting of CI, Br, I;

(ii) aminating the compound of form a compound of formula V;

V

(iii) reacting the compound of formula V with a compound of formula TV to give a compound of formula II and

(iv) reacting the compound of formula II with a com ound of formula III,

I I I

wherein, R represents boronic acid, boronic acid ester,

in the presence of a metal catalyst to give lumacaftor, the compound of formula I.

(v) providing a solution of lumacaftor in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;

(vi) adding hydrobromic acid to the solution of step (v);

(vii) obtaining lumacaftor hydrobromide from the mixture of step (vi); and

(viii) isolating lumacaftor hydrobromide.

34. The process of claim 33, wherein step (ii) is carried out in the presence of an activating reagent selected from the group consisting of methanesulfonic anhydride, methanesulfonyl chloride, /7-toluenesulfonic anhydride, /7-toluenesulfonyl chloride, trifluoromethansulfonic anhydride, benzenesulfonic anhydride, benzenesulfonyl chloride, trifluoroacetic anhydride.

35. The process of claim 33, wherein step (ii) is carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, dimethylaminopyridine, 2,4,6-trimethylpyridine.

36. The process of claim 33, wherein step (ii) is carried out in the presence of an aminating reagent selected from the group consisting of methanolamine, ethanolamine, propanolamine, butanolamine, pentanolamine, hexanolamine, /er/-butylamine, ammonia, sodamide.

37. The process of claim 33, wherein the compound of formula V is purified by a process comprising:

(x) reacting the compound of formula V with an acid to form an acid addition salt of the compound of formula V; and

(y) treating the acid addition salt of the compound of formula V with a base to give the compound of formula V.

38. The process of claim 37, wherein the acid addition salt is a /7-toluenesulphonic acid salt of the compound of formula V.

39. The process of claim 37, wherein the compound of formula V is obtained in a purity of >99%.

40. The process of claim 33, wherein the level of any single impurity in the lumacaftor hydrobromide is less than 0.15% w/w of lumacaftor hydrobromide.

41. The process of claim 33, wherein the amorphous lumacaftor has a purity of >99.8% and wherein the level of any single impurity is less than 0.1% w/w of lumacaftor.

42. The use of lumacaftor hydrobromide in the preparation of amorphous form of lumacaftor.

43. A process for the preparation of lumacaftor, a compound of formula I,

I

the process comprising:

(a) reacting a compound of formula VIII with an oxidising agent to give a compound of formula VII,

VIII VII

wherein, X is selected from the group consisting of CI, Br, I;

(b) aminating the compound of form a compound of formula V;

(c) reacting the compound of formula V with a compound of formula IV to give a compound of formula II and

(d) reacting the compound of formula II with a com ound of formula III,

II I

wherein, R represents boronic acid, boronic acid ester,

in the presence of a metal catalyst to give lumacaftor, the compound of formula I.

44. The process of claim 43, wherein X is Br and R is boronic acid.

45. The process of claim 43, wherein step (b) is carried out in the presence of an activating reagent selected from the group consisting of methanesulfonic anhydride, methanesulfonyl chloride, /7-toluenesulfonic anhydride, /7-toluenesulfonyl chloride, trifluoromethansulfonic anhydride, benzenesulfonic anhydride, benzenesulfonyl chloride, trifluoroacetic anhydride.

46. The process of claim 43, wherein step (b) is carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, dimethylaminopyridine, 2,4,6-trimethylpyridine.

47. The process of claim 43, wherein step (b) is carried out in the presence of an aminating reagent selected from the group consisting of methanolamine, ethanolamine, propanolamine, butanolamine, pentanolamine, hexanolamine, ieri-butylamine, ammonia, sodamide.

48. The process of claim 43, wherein the compound of formula V is purified by a process comprising:

(x) reacting the compound of formula V with an acid to form an acid addition salt of the compound of formula V; and

(y) treating the acid addition salt of the compound of formula V with a base to give the compound of formula V.

49. The process of claim 48 wherein the acid addition salt is a /7-toluenesulphonic acid salt of the compound of formula V.

50. The process of claim 48, wherein the compound of formula V is obtained in a purity of >99%.

51. The process of claim 43, wherein step (c) is carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, di- isopropyl ethylamine, dimethylaminopyridine, N-methyl morpholine.

52. The process of claim 43, wherein the metal catalyst is selected from the group consisting of Pd(PPh₃)₄, PdCl₂(PPh₃)₂, PdCl₂(dppf), Pd(OAc)₂, NiCl₂(PPh₃)₂, PdCl₂(dppb), PdCl₂(PhCN)₂, Pd(dba)₂.

53. The process of claim 43, further comprising: (i) reacting lumacaftor obtained in step (d) with an acid selected from the group of hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid in a solvent to form salt of lumacaftor; and

(ii) converting the salt of lumacaftor to lumacaftor.

54. The process of claim 53, wherein lumacaftor is reacted with hydrobromic acid to form lumacaftor hydrobromide which is converted to lumacaftor.

55. The process of claim 54, wherein the level of any single impurity in the lumacaftor hydrobromide is less than 0.15% w/w of lumacaftor hydrobromide.

56. The process of claim 54, wherein the lumacaftor has a purity of >99.8% and wherein the level of any single impurity is less than 0.1% w/w of lumacaftor.

57. A compound of formula Ila

I la