DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of Indian provisional patent application No. 3831/CHE/2015 filed on July 27, 2015, which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION

The present invention relates to novel process for the preparation of lumacaftor useful for treating a cystic fibrosis transmembrane conductance regulator (CFTR) mediated disease such as cystic fibrosis.

BACKGROUND OF THE INVENTION

Lumacaftor, 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid having the following structure (Formula I), is useful for treating or lessening the severity of a variety of cystic fibrosis transmembrane conductance regulator (CFTR) mediated diseases.

U.S. Patent App. Pub. No. 20130245010, which is hereby incorporated by reference, discloses lumacaftor compound and process for the preparation of the same.

Further PCT App. Pub. No. WO2009076142, which is hereby incorporated by reference, discloses processes for the preparation of lumacaftor or its intermediates. Lumacaftor and its salt polymoprhs are disclosed in PCT App. Pub. Nos. WO2009073757 and WO2011127290, which are hereby incorporated by reference.

The present invention relates to a process for the preparation of lumacaftor and its pharmaceutically acceptable salts.

SUMMARY OF THE INVENTION
The present invention provides processes for the preparation of lumacaftor and its pharmaceutically acceptable salts.

In one aspect, the present invention provides a process for the preparation of lumacaftor, that may include the steps of:
a) reacting a compound of formula II with a compound of formula III to get formula Ia;

b) optionally deprotecting the compound of formula Ia to get lumacaftor.
Within the context of this scheme, X is any halogen and R is either hydrogen or a carboxylic acid protecting group, as described below.
Another aspect of the present invention encompasses processes for the preparation of lumacaftor that may include the steps of:
a) halogenating the compound of formula IV with halogenating agent to produce compound of formula V;

b) coupling the compound of formula V with a compound of formula VI to get a compound of formula Ia; and

c) optionally deprotecting the compound of formula Ia to give Lumacaftor (formula I).

Within the context of this scheme, X is any halogen and R is either hydrogen or a carboxylic acid protecting group, as described below.
In another aspect, the present invention provides a process for the preparation of a compound of formula II as shown in scheme.

Within this context, the present invention provides a process for the preparation of formula II that may include the step of converting a compound of formula IIb to compound of formula II, where X is any halogen.
In another aspect, the present invention provides additional processes for the preparation of a compound of formula II as shown in scheme.

Within this context, the present invention provides a process for the preparation of a compound of formula II that may include the step of converting compound of formula IId to compound of formula II.
In another aspect, the present invention provides a process for the preparation of a compound of formula III as shown in scheme.

Within this context, the present invention provides a process for the preparation of a compound of formula III that may include the steps of halogenating the compound of formula IIId with halogenating agent to get a compound of formula III. Within the context of this scheme, X is any halogen and R is either hydrogen or a carboxylic acid protecting group, as described below.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to process for the preparation of CFTR corrector lumacaftor or its pharmaceutically acceptable salts.
As used herein, examples of suitable “leaving groups” (LG) include, but are not limited to halogens (e.g., fluorine, chlorine, bromine, iodine), methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy, (2-nitro-benzene)-sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy, (2,4,6-tri-isopropyl-benzene)-sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, (4-tertbutyl-benzene)sulfonyloxy, benzenesulfonyloxy, (4-methoxy-benzene)sulfonyloxy, and alkoxy. The term “alkoxy,” as used herein, refers to straight chain or branched chain alkyl groups containing 1 to 6 carbons.
Suitable alkoxy groups useful within the context of the present invention include, but are not limited to, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1, 1-dimethyl ethoxy, and 1-methylpropoxy. An alkoxy group may be substituted by one or more halogens, or may be unsubstituted. In certain embodiments, methoxy, ethoxy, and trifluoromethoxy were found to be particularly effective as leaving groups.
As used herein “X” means any halogen. Suitable halogens useful within the context of the present invention include, but are not limited to, fluorine, chlorine, bromine, and iodine.
As used herein, the term “carboxylic acid protecting group” means a chemical moiety that protects a carboxylic acid residue from unwanted reaction. Suitable carboxylic acid protecting groups useful with in the context of the present invention include, but are not limited to, alkyl ester such as methyl ester, ethyl ester, t-butyl ester; arakyl ester such as benzyl ester; silyl ester, and oxazoline.
The phrase “pharmaceutically acceptable salt” is well known and understood in the art and refers to salts of pharmaceutically active agents which are suitable for use in contact with the tissues of humans and lower animals without undue adverse effects (e.g., toxicity, irritation, allergic response). Examples of pharmaceutically acceptable salts may be found in S. M. Berge, et al., J. Pharmaceutical Sciences, 66: 1-19 (1977), in which all information pertaining to the pharmaceutically acceptable salts and processes for preparation thereof are hereby incorporated by reference.
Methods for the preparation of a pharmaceutically acceptable salt of an active pharmaceutical agent is well known in the art. For example, the salts can be prepared in situ during the final isolation and purification of the compounds taught herein or separately by reacting a free base or free acid moiety on the active pharmaceutical agent with a suitable reagent. Pharmaceutically acceptable salts include, acid salts, for example, mineral acid salts such as hydrochloride, sulfates salts, nitrate salts, phosphates salts, carbonates salts, hydrogencarbonates or perchlorate; organic acid salts such as acetates, propionates, lactates, maleates, fumarates, tararic acid salts, malates, citrates salts, ascorbates, formic acid; sulfonates such as methanesulfonates, isethionates, benzenesulfonates, or p-toluenesulfonates; and acidic amino acid salts such as aspartates or glutamates.
In some embodiments, the present invention provides a process for the preparation of lumacaftor that may include the steps of:
a) reacting a compound of formula II with a compound of formula III to get formula Ia; and

b) optionally deprotecting the compound of formula Ia to get lumacaftor.

As used in this scheme, X is any halogen and R is either hydrogen or a carboxylic acid protecting group, as described above. In these embodiments of the present invention, reaction of compound of formula II with formula III may be carried out in the presence of a catalyst, a ligand, base, and a suitable solvent.
The base useful in this embodiment may be an organic base, an inorganic base, or mixtures thereof. Suitable organic bases useful for this reaction include, but are not limited to pyridine, trimethylamine, N, N-diisopropylethylamine, and mixturest thereof. Suitable inorganic bases for use in this reaction include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof. Suitable alkaline metal hydroxides for use in this reaction include, but are not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof. Suitable alkaline metal bicarbonates useful in this reaction include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Suitabel alkaline metal carbonates useful in this reaction include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. Suitable alkaline alkoxides useful in this reaction include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof. In some particularly useful embodiments, the use of cesium carbonate or sodium tert-butoxide as a base was found to be effective.
Within the context of this embodiment, the catalyst may be a palladium-containing catalyst. Suitable palladium-containing catalysts include, but are not limited to, bis(dibenzylideneacetone)palladium [Pd(dba)2], tris(dibenzylideneacetone)dipalladium [Pd2(dba)3], palladium(II) acetate [Pd(OAc)2], [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II)[Pd(dppf)Cl2], tetrakis (triphenylphosphine)palladium [Pd(PPh3)4], allylpalladium(II) chloride dimer [Pd(C3H5)Cl], and mixtures thereof. In some particularly effective embodiments, Pd(OAc)2 was found to be useful as a catalyst.
Within the context of this embodiment, the ligand does what? Suitable ligands useful for this reaction include, but are not limited to, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene [xantphos], 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [BINAP], 1,1’-bis(diphenyl phosphine) ferrocene [DPPF], 2-(diphenyl phosphine phenyl) ether [DPEphos], tri-t-butyl phosphine [Fu’s salt], 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl [DavePhos], 2-di-tert-butylphosphino-2'-(N,N-dimethylamino) biphenyl [t-BuDavePhos], triphenylphosphine, trialkyl phosphines, and mixtures thereof. In some particularly useful embodiments, the use of xantphos and BINAP as a ligand was found to be particularly effective.
Within the context of this embodiment, the solvent used may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof. Suitable non-polar solvents useful within this reaction include, but are not limited to, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane, and mixtures thereof. Suitable polar aprotic solvents useful within this reaction include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1,2-dimethoxyethane and mixtures thereof. Suitable polar protic solvents useful within this reaction include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, the use of 1,4-dioxane or toluene as a solvent was found to be particularly effective.
Within the context of this embodiment, this deprotection of formula Ia may be carried out as disclosed in PCT App. Pub. No. WO2009076142, which is hereby incorporated by reference for those process. For example, deprotection of formula Ia may be carried out in presence of acid and a suitable solvent. The acid used in the deprotection step may be an organic acid or an inorganic acid. Suitable organic acids useful in this step include, but are not limited to, formic acid, acetic acid, propanoic acid, tartaric acid, oxalic acid, maleic acid, mandellic acid, malonic acid, methane sulphonic acid, p-toluene sulphonic acid, trifluoroacetic acid, benzene sulfonic acid, and combinations thereof. Suitable inorganic acids useful in this step include, but are not limited to, hydrochloric acid, hydrobromic acid, hydro iodic acid, sulphuric acid, nitric acid, boric acid, phosphoric acid, chromic acid, and combinations thereof. In some particularly useful embodiments, formic acid or hydrochloric acid is used as the acid.
Within the context of this embodiment, the solvent may be a polar aprotic solvent or a polar protic solvent. Suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1,2-dimethoxyethane and mixtures thereof. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, acetonitrile is used as the solvent.
The present invention further provides a process for the preparation of lumacaftor that may include the steps of:
a) halogenating the compound of formula IV with a halogenating agent to produce compound of formula V;

b) coupling the compound of formula V with a compound of formula VI to get compound formula Ia.

c) optionally deprotecting the compound of formula Ia to give lumacaftor.

In these structures, X refers to any halogen and R is either hydrogen or a carboxylic acid protecting group, as described above. In this embodiment, halogenation of the compound formula IV may be carried out in presence of halogenating agent, base, and suitable solvent. Suitable halogenating agents include, but are not limited to, phosgene, oxalyl chloride, thionyl chloride, phosphorus pentachloride, phosphorous trichloride, phosphorus oxychloride, carbonyl dibromide, oxalyl bromide, thionyl bromide, phosphorous bromide, phosphorus oxybromide, chloroacetyl chloride, methane sulfonyl chloride, benzene sulfonyl chloride, p-toluene sulfonyl chloride, and mixtures thereof. The specific identity of the halogenating agent will be impacted by the specific halogen that is being attached to the compound of Formula IV. In some particularly useful embodiments, phosphorus oxychloride is used as the halogenating agent.
Within the context of this embodiment, the base may be an organic base or an inorganic base. Suitable inorganic base useful in this step include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof. Suitable alkaline metal hydroxides useful in this step include, but are not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof. Suitable alkaline metal bicarbonates useful in this step include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Suitable alkaline metal carbonates useful in this step include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. Suitable alkaline alkoxides useful in this step include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof. Suitable organic bases useful in this step include, but are not limited to, pyridine, triethylamine. N,N-diisopropylethylamine, tributyl amine, diisopropyl amine, and mixtures thereof. In some particularly useful embodiments, trimethylamine is used as the base.
Within the context of this embodiment, the solvent may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof. Suitable non-polar solvents for this step include, but are not limited to, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane, and mixtures thereof. Suitable polar aprotic solvents useful in this step include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1,2-dimethoxyethane, and mixtures thereof. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, dichloromethane is used as the solvent.
Within the context of this embodiment, coupling the compound of formula V with a compound of formula VI may be carried out in presence of a base, catalyst, and a suitable solvent to get compound formula Ia. The base may be an organic base or an inorganic base. Suitable inorganic base useful in this step include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof. Suitable alkaline metal hydroxides useful in this step include, but are not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof. Suitable alkaline metal bicarbonates useful in this step include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Suitable alkaline metal carbonates useful in this step include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. Suitable alkaline alkoxides useful in this step include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof. Suitable organic bases useful in this step include, but are not limited to, pyridine, triethylamine. N,N-diisopropylethylamine, tributyl amine, diisopropyl amine, and mixtures thereof. In some particularly useful embodiments, the base is potassium bicarbonate or sodium bicarbonate.
Suitable catalysts useful for this step include, but are not limited to, Pd(dba)2, Pd2(dba)3, Pd(OAc)2, Pd(dppf)Cl2, Pd(PPh3)4, copper, cuprous bromide, cuprous iodide, 2,2’-bis-diphenylphosphanyl[1,1’] binaphtalenyl (rac-Binap), [Pd(C3H5)Cl]2, and mixtures thereof. In some particularly useful embodiments Pd(dppf)Cl2 is used as a catalyst.
Within the context of this embodiment, the solvent may be a polar aprotic solvent or a polar protic solvent. Suitable polar aprotic solvents useful in this step include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1,2-dimethoxyethane, and mixtures thereof. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, N,N-dimethylformamide is used as a solvent.
The present invention further provides a process for the preparation of a compound of formula II as shown in the following scheme.

Within the context of this reaction, X refers to any halogen. This embodiment thus provides a process for the preparation intermediate of a compound of formula II that may include the step of converting the compound of formula IIb to compound of formula II.
Within the context of this embodiment, conversion of the compound of formula IIb to the compound of formula II may be carried out in the presence of an ammonia source and a suitable solvent. Examples of suitable ammonia sources useful in the step include, but are not limited to, ammonium hydroxide, ammonia gas, ammonium acetate, ammonium formate, and mixtures thereof. In some particularly useful embodiments, the ammonia source is ammonium hydroxide.
Within the context of this embodiment, the solvent may be a non-polar solvent. Examples of suitable non-polar solvents useful in this step include, but are not limited to 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof. In some particularly useful embodiments, the solvent is toluene.
The present invention also provides processes for the preparation of a compound of formula II as shown in the following scheme.

Within the context of this embodiment, X may be any halogen. This embodiment thus provides an in situ process for the preparation of an intermediate of the compound of formula II that may include the steps of:
a) halogenating a compound of formula IIa with halogenating agent to get a compound of formula IIb; and
b) converting the compound of formula IIb to a compound of formula II.
Within the context of this embodiment, halogenation of formula IIa may be carried out as disclosed in U.S. Patent App. Pub. No. 20080306062 and PCT App. Pub. No. WO2009076142, both of which are incorporated by reference with respect to those processes. For example, halogenation may occur in the presence of a halogenating agent and a suitable solvent. Suitable halogenating agents useful for this step include, but are not limited to, phosgene, oxalyl chloride, thionyl chloride, phosphorus pentachloride, phosphorous trichloride, phosphorus oxychloride, carbonyl dibromide, oxalyl bromide, thionyl bromide, phosphorous bromide and phosphorus oxybromide chloroacetyl chloride, methane sulfonyl chloride, benzene sulfonyl chloride, p-toluene sulfonyl chloride, and mixtures thereof. In some particularly useful embodiments, thionyl chloride was found to be effective as a halogenating agent.
The solvent used in this embodiment may be a polar aprotic solvents or a polar protic solvent. Suitable polar aprotic solvents useful within this reaction include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, acetone, N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1,2-dimethoxyethane, and mixtures thereof. Suitable polar protic solvents useful within this reaction include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, N,N-dimethylformamide was found to be effective as a solvent.
In the second step of the reaction of this embodiment, conversion compound of formula IIb to compound of formula II may be carried out in presence of an ammonia source and a suitable solvent. Suitable ammonia sources useful in this step include, but are not limited to, ammonium hydroxide, ammonia gas, ammonium acetate, ammonium formate, and mixtures thereof. In some particularly useful embodiments, ammonium hydroxide was found to be effective as an ammonia source.
The solvent useful in this step may be a non-polar solvent. Suitable non-polar solvents useful in this step include, but are not limited to 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof. In some particularly useful embodiments, toluene was found to be effective as the solvent.
In another embodiment of the present invention, an additional process for the preparation of a compound of formula II is disclosed and is shown in scheme.

This embodiment provides a process of hydrolysis of cyano compound of formula IId which may be carried out in presence an acid and a base. Additionally, peroxides (e.g., hydrogen peroxide) may optionally be utilized to get to compound of formula II. The acid used in this reaction may be an organic acid or an inorganic acid. Suitable organic acids useful in this step include, but are not limited to, formic acid, acetic acid, propanoic acid, methane sulphonic acid, p-toluene sulphonic acid, trifluoroacetic acid, and mixtures thereof. Suitable inorganic acids useful in this step include, but are not limited to, hydrochloric acid, hydrobromic acid, hydro iodic acid, sulphuric acid, nitric acid, and combinations thereof. In some particularly useful embodiments, trifluoroacetic acid, sulphuric acid, and mixtures thereof were used as the acid.
The base used in this reaction may be an organic base or an inorganic base. Suitable inorganic bases useful in this reaction include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof. Suitable alkaline metal hydroxides useful in this reaction include, but are not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof. Suitable alkaline metal bicarbonates useful in this reaction include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Suitable alkaline metal carbonates useful in this reaction include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. Suitable alkaline alkoxides useful in this reaction include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof. Suitable organic bases useful in this reaction include, but are not limited to, pyridine, triethylamine and N, N-diisopropylethylamine, tributyl amine, diisopropyl amine, and mixtures thereof. In some particularly useful embodiments, potassium carbonate was used as the base..
Within the context of this embodiment, the solvent may be a polar aprotic solvent or a polar protic solvent. Suitable polar aprotic solvents for this reaction include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1,2-dimethoxyethane and mixtures thereof. Suitable polar protic solvents useful in this reaction include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, DMSO was utilized as the solvent.
In another embodiment of the present invention, there is disclosed an additional in situ process for the preparation of a compound of formula II as depicted in scheme that may include the steps of:
a) reacting a compound of formula IIc with a compound of formula IIe to get a compound of formula IId; and
b) converting the compound of formula IId to compound of formula II.

Within this reaction scheme, LG represents leaving group, as described above. Within the context of this embodiment, a compound of formula IIc is reacted with a compound of formula IIe to get a compound of formula IId. This process may be carried out as disclosed in U.S. Patent App. Pub. No. 20080306062 and PCT App. Pub. No. WO2009076142, both of which are hereby incorporated by reference with respect to those processes.
In another embodiment, present invention provides a process for the preparation of a compound of formula III as shown in scheme.

Accordingly, this embodiment provides processes for the preparation of a compound of formula III, comprising, halogenating the compound of formula IIId with halogenating agent to get the compound of formula III. In this embodiment, halogenation a compound of formula IIId may be carried out in presence of a halogenating agent, a base, and a solvent.
Suitable halogenating agents for this reaction include, but are not limited to, phosgene, oxalyl chloride, thionyl chloride, phosphorus pentachloride, phosphorous trichloride, phosphorus oxychloride, carbonyl dibromide, oxalyl bromide, thionyl bromide, phosphorous bromide, phosphorus oxybromide, chloroacetyl chloride, methane sulfonyl chloride, benzene sulfonyl chloride, p-toluene sulfonyl chloride, and mixtures thereof. In some particularly effective embodiments, phosphorus oxychloride is used as a halogenating agent.
Within the context of this reaction, the base may be an organic base or an inorganic base. Suitable inorganic bases for this reaction include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof. Suitable alkaline metal hydroxides useful in this reaction include, but are not limited to sodium hydroxide, potassium hydroxide, and mixtures thereof. Suitable alkaline metal bicarbonates useful for this reaction include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Suitable alkaline metal carbonates useful for this reaction include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. Suitable alkaline alkoxides useful in this step include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof. Suitable organic bases useful for this reaction include, but are not limted to pyridine, trimethylamine, N,N-diisopropylethylamine, and mixtures thereof
For this reaction, the solvent may be a non-polar solvent. Suitable non-polar solvents for this reaction include, but are not limited to 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane, and mixtures thereof. In some particularly useful embodiments, dichloromethane was used as the solvent.
In a further embodiment, the present invention provides process for the preparation of a compound of formula III as shown in scheme.

Within the context of this scheme X is any halogen and R is either hydrogen or a carboxylic acid protecting group, as described above. This embodiment provides a process for the preparation of a compound of formula III, comprising the steps of:
a) coupling the compounds of formula IIIa and IIIb to get a compound of formula IIIc;
b) oxidizing the compound of formula IIIc to get a compound of formula IIId; and
c) halogenating the compound of formula IIId with a halogenating agent to get a compound of formula III.
Within the context of this embodiment, coupling the compounds of formula IIIa and IIIb may be carried out in the presence base and catalyst to get a compound of formula IIIc, followed by oxidizing the compound of formula IIIc with a suitable oxidizing agent to get a compound of formula IIId as disclosed in the PCT App. Pub. No. WO2009076142, which is hereby incorporated by reference for those processes.
The following examples are provided to illustrate the process of the present invention. They, are however, not intended to limit the scope of the present invention in any way. Several variants of these examples would be evident to person ordinarily skilled in the art.
Example 1:
Preparation of 1-(2-2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid amide

A mixture of 10 g of 1-(2-2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid 50 ml toluene, and 0.1 ml dimethylformamide (DMF) was stirred for 15 min. To the reaction mixture was added 6.4 g of thionyl chloride, then the reaction mixture was heated to 60-65 °C and maintained for 2-3 hours. After completion of reaction, the solvent was completely distilled off under vacuum. Toluene (15 ml) was added and distilled out completely under vacuum. To the residue, 25 ml toluene was added at room temperature. To the reaction mass, aqueous ammonia solution (40 mL) was slowly added at 10-15 °C and maintained for 2 hours at 25-30 °C. After completion of reaction, 20 ml of water was added to the reaction mixture, and the reaction mixture was then stirred for 15 min. The layers were separated, the aqueous layer was extracted with 40 ml toluene. The combined toluene layer was washed with water. The remaining solvent was completely removed under vacuum at 50-55 °C. The resulting residue was triturated with acetone and hexane mixture (10 mL) for 1 hour. The obtained solid was filtered and washed with hexane (5 ml). The wet material was dried under vacuum to afford 1-(2-2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid amide (6.0 g , 60.3 % yield).

Example 2:
Preparation of 1-(2-2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropane carboxylic acid amide
A mixture of 10 g of (2-2-difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile, 10 g benzyltriethylammonium chloride, and 14.8 g 1-bromo-2-chloro ethane was stirred for 15 min. To the reaction mixture was added 30 ml 50% sodium hydroxide solution at room temperature, then the reaction mixture was heated to 70-75°C and maintained for 15 hours. After completion of reaction, 100 ml ethyl acetate and 100 ml water were added at room temperature and the reaction mixture was stirred for 15 min. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layer was washed with water. The solvent was completely removed under vacuum at 50-55 °C. To the resulted residue, 50 ml trifluoroacetic acid (TFA) and 12.5 ml sulfuric acid were added slowly at room temperature, then the mixture was heated at reflux for 4-5 hours. After completion of reaction, 100 ml of ice-cold water was added to the reaction mixture. The reaction mixture was then separated, and the aqueous layer was extracted with toluene. The toluene layer was washed with water. The solvent was completely removed under vacuum at 50-55 °C. The resulting residue was triturated with acetone and hexane mixture (10 mL) for 1 hour. The solid obtained was filtered and washed with hexane (5 ml). The wet material was dried under vacuum to afford 1-(2-2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid amide (6.0 g , 49 % yield)

Example 3:
Preparation of 1-(2-2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropane carboxylic acid amide
A mixture of 10 g of (2-2-difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile, 10 g benzyltriethylammonium chloride, and 14.8 g 1-bromo-2-chloro ethane was stirred for 15 min. To the reaction mixture was added 30 ml 50% sodium hydroxide solution at room temperature, then the reaction mixture was heated to 70-75 °C and maintained for 15 hours. After completion of reaction, 100 ml ethyl acetate and 100 ml water were added at room temperature and stirred for 15 min. The layers were separated, and the aqueous layer was extracted with 25 ml ethyl acetate. The combined ethyl acetate layer was washed with water. The solvent was completely removed under vacuum at 50-55 °C. To the resulting residue, 50 ml dimethyl sulfoxide, 1.12 g potassium carbonate and 8.7 g 30% hydrogen peroxide were added at 15-20 °C. The reaction mixture was heated to 25-30 °C and maintained for 3 hours. After completion of reaction, 100 ml water, 100 ml toluene were added to the reaction mixture. The layers were seapareted, and the aqueous layer was extracted with 50 ml toluene. The toluene layer was washed with 50ml 10% sodium sulfite, followed by washing with 50 ml water. The solvent was completely removed under vacuum at 50-55 °C. The resulting residue was triturated with hexanes (50 mL) for 1 hour. The obtained solid was filtrered and washed with hexane (10 ml). The wet material was dried under vacuum to afford 1-(2-2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid amide (7.5 g , 61.3% yield)

Example 4:
Preparation of tert-butyl-3-(6-chloro-3-methylpyridine-2-yl)benzoate
a) Preparation of tert-butyl-3(3-methylpyridin-2-yl)benzoate
10 g of 2-bromo-3-methyl pyridine was dissolved in 120 ml of toluene. 38.5 g of potassium carbonate was added followed by 35 ml of water and the mixture heated to 65 °C under N2 atm for 1 hour. 13.55 g (t-butoxycarbonyl)phenylboronic acid and 0.72 g Pd(dppf)Cl2 were added. The reaction mixture was heated to 80 °C. After completion of reaction, the reaction mass was cooled, 35 ml water was added and stirred for 15 min. The layers were separated. The organic layer was washed with 35 ml water and extracted with 230 ml 10% methane sulfonic acid. The aqueous layer was basified with 50% NaOH and extracted with 100 ml ethyl acetate. The organic layer was concentrated under vacuum to afford 13 g crude tert-butyl-3(3-methylpyridin-2-yl)benzoate (83.3 % yield).

b) Preparation of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide
13 g of tert-butyl-3(3-methylpyridin-2-yl)benzoate was dissolved in 80 ml ethyl acetate, then 4 ml water and 15 g ureahydrogen peroxide were added. 22 g of phthalic anhydride was added portion wise and the reaction temperature was maintained below 45 °C. The reaction mixture was heated to 45 °C and stirred for 4 hours. After completion of reaction, the reaction mass was cooled to room temperature. 100 ml of 10% sodium sulphite solution was added slowly and the reaction mixture was stirred for 30 minutes. The layers were separated and organic layer was washed with 100 ml 10% sodium carbonate and 100 ml 10% sodium chloride solution. The organic phase is then filtered and concentrated under vacuum to afford 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (13 g , 94.8 %).

c) Preparation of tert-butyl-3-(6-Chloro-3-methylpyridine-2-yl)benzoate
10 g of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide was dissolved in 50 ml dichloromethane and 8.8 g triethylamine (TEA) was added. To the reaction mass 13.6 ml phosphorous oxychloride solution in 20 ml dichloromethane was added slowly at 0-5 °C. The reaction mass was stirred for 2-3 hours at room temperature. After the completion of reaction, chilled water was added and the reaction mass was stirred for 10 min. The layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layer washed with water. The organic layer was concentrated under reduced pressure and purified by column chromatography by using 10% ethyl acetate in hexane to afford tert-butyl-3-(6-chloro-3-methylpyridine-2-yl)benzoate (6 g , 56.6 % yield).

Example 5:
Preparation of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropane carboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate
A mixture 9.6 g 1-(2-2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid amide, 160 mg palladium acetate, 580 mg Xantphos, and 16.5 g cesium carbonate in 50 ml 1,4-dioxane were stirred for 10 min. To the reaction mixture, tert-butyl-3-(6-chloro-3-methylpyridine-2-yl)benzoate solution (10 g in 50 ml 1,4-dioxane) was added at room temperature. The reaction mixture was heated to reflux for 15 hours. After completion of the reaction, the reaction mass was cooled to room temperature. The reaction mass was filtered through Hyflo and washed with 10 ml 1,4-dioxane. Filtrate was isolated completely under vacuum. 100 ml toluene was then added and the reaction mass was stirred for 10 min. The reaction mass was washed with 20 ml of water. Toluene was distilled out completely under vacuum to afford 16 g of crude 3-(6-(1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane carboxamido) -3-methylpyridin-2-yl)-t-butylbenzoate ( 95.8% yield).

Example 6:
Preparation of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane carboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate
A mixture of 9.6 g 1-(2-2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid amide, 400 mg palladium acetate, 2 g BINAP[(±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene ], and 5 g sodium tertiary butoxide in 100 ml toluene were stirred for 10 min. To the reaction mixture tert-butyl-3-(6-chloro-3-methylpyridine-2-yl)benzoate solution (10 g in 50 ml toluene) was slowly added at room temperature. The reaction mixture was heated to reflux for 15 hours. After the completion of reaction, reaction mass was cooled to room temperature and filtered through Hyflo. Filtrate was washed with water, distilled out toluene completely under vacuum to afford 16 g of crude 3-(6-(1-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate ( 95.8% yield)
Example 7:
Preparation of N-(6-chloro-5-methylpyridine--2-yl)-1-(2,2difluorobenzo[d][1,3]
dioxol-5-yl)cyclopropanecarboximide
10 g of N-(5-methyl-1-oxy-pyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide was dissolved in 50 ml dichloromethane and 3.5 g triethylamine (TEA) was added. To the reaction mass, 5.3 g phosphorous oxychloride was added slowly at 0-5°C. The reaction mass was stirred for 2-3 hours at room temperature. After completion of reaction, 50 ml of chilled water was added slowly and the reaction mass was stirred for 10 min. The layers were separated, and the aqueous layer was extracted with 25 ml dichloromethane. The organic layer was washed with water, concentrated under reduced pressure, and purified by column chromatography by using 10% ethyl acetate in hexane to afforded N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (2 g , 18 % yield).

Example 8:
Preparation of Lumacaftor
10 g N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide was dissolved in 30 ml of N,N-dimethylformamide. To the solution, 6.8 g of 3-boronobenzoic acid, 50 ml of aqueous potassium carbonate solution and 2.1 g Pd(dppf)Cl2 were added and the reaction mass was heated to 150 °C for 15-30 min. The reaction mixture was filtered and purified by column chromatography 10% EtOAC in hexane to yield lumacaftor.

Example 9:
Preparation of Lumacaftor
A solution of 16 g of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane carboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate in 48 ml formic acid was heated to 75-80 °C and maintained for 8 hours. After the completion of reaction, the reaction mixture was cooled to room temperature, 100 ml water was added slowly to the reaction mixture which was heated to 50 °C and stirred for 2 hours. The reaction mixture was further heated to 75-80 °C and stirred for 2 hours. The reaction mass was cooled to room temperature, and the product was filtered and washed with water. The wet material was dried in a vacuum oven at 60 °C to afford lumacaftor. (12.g , 85% yield)

Example 10:
Preparation of Lumacaftor
To a slurry of 15 g of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5- yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate in 48 ml acetonitrile was added 12.5 ml water, followed by concentrated 12.5 ml aqueous HCl. The mixture was heated to 45-50 °C and maintained for 48 hours. After completion of reaction, the reaction mixture was cooled to room temperature, and 20 ml of water was added. The reaction mixture was stirred for 1 hour. The resulting product was filtered and washed with 5 ml acetonitrile. The wet material was dried in a vacuum oven at 60 °C to afford lumacaftor hydrochloride.

A slurry of 12.0 g of lumacaftor hydrochloride in 120 ml water was stirred for 30 hours at ambient temperature. The product was filtered and washed with water. The solid was dried under vacuum at 60 °C to afford lumacaftor (11 g,85% yield).
,CLAIMS:We claim:
1. A process for the preparation of lumacaftor (compound of formula I) or pharmaceutically acceptable salts thereof
,
comprising the steps of:
a) treating a compound of formula II, with a compound of formula III to give a compound of formula Ia, wherein X is a halogen and R is a hydrogen or a carboxylic acid protecting group
; and
b) optionally deprotecting the formula Ia to produce lumacaftor.
2. The process according to claim 1, wherein step a) is carried out in presence of a catalyst, a ligand, a base, and a solvent; wherein the catalyst is selected from Pd(dba)2, Pd2(dba)3, Pd(OAc)2,Pd(dppf)Cl2, Pd(C3H5)Cl, Pd(PPh3)4 and mixtures thereof; wherein the ligand is selected from Xantphos, BINAP, DPPF, DPEphos, Fu’s salt, DavePhos, t-BuDavePhos, triphenylphosphine, trialkyl phosphines and mixtures thereof; wherein the base is selected from pyridine, trimethylamine, N, N-diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide and mixtures thereof; where in the solvent is selected from 1,2- dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, methanol, ethanol, isopropyl alcohol, n-butanol and mixtures thereof.
3. The process according to claim 1, wherein the deprotection is carried out in presence of an acid and a solvent.
4. A process for the preparation of lumacaftor (a compound of formula I) or pharmaceutically acceptable salts thereof.
,
comprising the steps of:
a) halogenating the compound of formula IV with a halogenating agent to produce a compound of formula V, wherein X is a halogen;

b) coupling the compound of formula V with a compound of formula VI to get a compound of formula Ia, wherein X is a halogen and R is a hydrogen or a carboxylic acid protecting group; and

c) optionally deprotecting the compound of formula Ia to give lumacaftor.
5. The process according to claim 4, wherein the halogenating agent is selected from the group consisting of phosgene, oxalyl chloride, thionyl chloride, phosphorus pentachloride, phosphorous trichloride, phosphorus oxychloride, carbonyl dibromide, oxalyl bromide, thionyl bromide, phosphorous bromide, phosphorus oxybromide.
6. The process according to claim 4, wherein step a) is carried out in presence of a base and a solvent, wherein base is selected from pyridine, trimethylamine, N, N-diisopropylethylamine, tributyl amine, diisopropyl amine; wherein the solvent is selected from 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof .
7. The process according to claim 4, wherein step b) is carried out in presence of a base, a catalyst, and a solvent. wherein the base is selected from the sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide and mixtures thereof; wherein the catalyst is selected from Pd(dba)2, Pd2(dba)3, Pd(OAc)2, Pd(dppf)Cl2, Pd(PPh3)4, [Pd(C3H5)Cl]2, copper, cuprous bromide, cuprous iodide, 2,2’-bis-diphenylphosphanyl[1,1’] binaphtalenyl (rac-Binap), and mixtures thereof; wherein the solvent is acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide or mixtures thereof.
8. The process according to claim 4, wherein step c) is carried out in presence of an acid and a solvent.
9. A compound selected from

(i)
(wherein X is a halogen and R is a hydrogen or a carboxylic acid protecting group)
(ii)

(iii)
(wherein X is a halogen)
(iv)
10. A process for the preparation of a compound of formula II, comprising reacting a compound of formula IIb in the presence of an ammonia source and a solvent, wherein X is a halogen.

11. The process according to claim 10, wherein the ammonia source is selected from ammonium hydroxide, ammonia gas, ammonium acetate, ammonium formate, and mixtures thereof; wherein the solvent is selected from 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof.
12. A process for the preparation of a compound of formula II, comprising, hydrolyzing a cyano compound of formula IId to give the compound of formula II.

13. The process according to claim 12, wherein the hydrolyzing step is carried out in presence of an acid, a base, and optionally a peroxide; wherein the acid is selected from formic acid, acetic acid, propanoic acid, methane sulphonic acid, p-toluene sulphonic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, and their mixtures; wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide and their mixtures.
14. A process for the preparation of a compound of formula III, comprising halogenating a compound of formula IIId in the presence of a halogenating agent to give the compound of formula III, wherein R is hydrogen or a carboxylic acid protecting group.

15. The process according to claim 16, wherein the halogenating step is carried out in the presence of a base and a solvent. wherein halogenating agent is selected from phosgene, oxalyl chloride, thionyl chloride, phosphorus pentachloride, phosphorous trichloride, phosphorus oxychloride, carbonyl dibromide, oxalyl bromide, thionyl bromide, phosphorous bromide, phosphorus oxybromide, chloroacetyl chloride, methane sulfonyl chloride, benzene sulfonyl chloride, p-toluene sulfonyl chloride, and mixtures thereof; wherein the base is selected from pyridine, trimethylamine, N, N-diisopropylethylamine, and mixtures thereof; wherein the solvent is 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane or mixtures thereof.