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WO2017175161A1 - Formes solides de lumacaftor et de ses sels, et procédés associés - Google Patents

Formes solides de lumacaftor et de ses sels, et procédés associés Download PDF

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Publication number
WO2017175161A1
WO2017175161A1 PCT/IB2017/051970 IB2017051970W WO2017175161A1 WO 2017175161 A1 WO2017175161 A1 WO 2017175161A1 IB 2017051970 W IB2017051970 W IB 2017051970W WO 2017175161 A1 WO2017175161 A1 WO 2017175161A1
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Prior art keywords
lumacaftor
formula
crystalline form
preparation
mixture
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Inventor
Vilas Hareshwar Dahanukar
Srinivas ORUGANTI
Pallavi Rao
Ramesh Chakka
Mohammed Azeezulla Baig
Sunitha Vyala
Venkata Narasayya SALADI
Vishweshwar Peddy
Raviram Chandrasekhar Elati
Saravanan Mohanarangam
Gopal RAJ
Phani MAMIDIPALLI
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Dr Reddys Laboratories Ltd
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Dr Reddys Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • aspects of the present application relate to solid forms of Lumacaftor, its salts and processes thereof. Specific aspects of the present application relate to alternate processes for the preparation of Lumacaftor and intermediates thereof.
  • the drug compound having the adopted name "Lumacaftor” has chemical name: 3- ⁇ 6- ⁇ [1 -(2,2-Difluoro-1 ,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino ⁇ -3- methylpyridin-2-yl ⁇ benzoic acid as below.
  • Lumacaftor partially corrects the fundamental molecular defect caused by F508del-CFTR to increase the amount of functional F508del-CFTR at the cell surface, resulting in enhanced chloride transport.
  • the channel gating activity of F508del-CFTR delivered to the cell surface by Lumacaftor can be potentiated by Ivacaftor to further enhance chloride transport.
  • Ivacaftor When added to F508del/F508del- HBE, the magnitude of chloride transport observed with the combination of Lumacaftor and either acute or chronic Ivacaftor treatment was greater than that observed with Lumacaftor alone. Orkambi is approved in US and Europe as a fixed dose combination (FDC) pink immediate-release film-coated tablet for oral administration.
  • Orkambi contains 200 mg of Lumacaftor and 125 mg of Ivacaftor as active substances. US FDA label prescribes two tablets to be taken orally every 12 hours for the treatment of cystic fibrosis (CF) in patients age 12 years and older who are homozygous for the F508del mutation in the CFTR gene.
  • CF cystic fibrosis
  • US 8993600 B2 discloses Lumacaftor as compound-396, its pharmaceutical use for the treatment of cystic fibrosis. Further, it discloses preparative methods for the preparation of compounds disclosed therein including Lumacaftor by reacting N-(6-chloro-5-methylpyridin-2-yl)-1 -(2,2- difluorobenzo[d][1 ,3]dioxol-5-yl)cyclopropanecarboxamide (which is obtained by the N-acylation of 2-chloro-3-methyl pyridine amine with (2,2-difluorobenzo[d][1 ,3] dioxol-5-yl)cyclopropane carboxylic acid chloride) with 3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzoic acid as depicted in scheme-1 .
  • US 8124781 B2 describes a process for the preparation of Lumacaftor by reacting t-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate with 1 -(2,2-difluoro-l,3- benzodioxol-5-yl)-cyclopropanecarbonylchloride in the presence of triethyl amine (TEA) to obtain t-butyl ester of Lumacaftor, which is either hydrolyzed directly to its free carboxylic acid form i.e. , Lumacaftor or converted to its HCI salt and then neutralized to afford Lumacaftor as depicted in scheme-2.
  • TAA triethyl amine
  • US 8507534 B2 discloses a similar approach as in scheme-2 for the synthesis of Lumacaftor and discloses a crystalline Form I of Lumacaftor, which was prepared either by dispersing or dissolving a salt form, such as HCI, of Lumacaftor in an appropriate solvent for an effective amount of time (or) directly by treating t-butyl ester intermediate of Lumacaftor with an appropriate acid, such as formic acid.
  • a salt form such as HCI
  • US 8507687 B2 discloses the crystalline solvate Form A of Lumacaftor, which is an isostructural solvate.
  • Solvate Form A includes, but not limited to methanol, ethanol, 2-propanol, acetone, acetonitrile, tetrahydrofuran, methyl acetate, 2-butanone, ethyl formate, 2-methyl tetrahydrofuran and a crystalline Form A of Lumcaftor HCI salt.
  • the physicochemical properties of a solid form is a critical parameter in the development of pharmaceutical dosage forms of and these properties can affect the bioavailability, stability and process ability of the active pharmaceutical ingredient. It is known that a solid active pharmaceutical ingredient can exist in amorphous and crystalline state. Crystalline solids may further exist as various polymorphs and solvates.
  • the present application provides a process for the preparation of Lumacaftor, comprising the step of reacting the cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) to obtain 5-methylpyridin-2- amine of formula (V).
  • Ri is selected from hydrogen, any leaving group such as halogen or a phenyl group of formula (A);
  • R 2 is any leaving group such as halogen and R 3 is hydrogen or a group selected from cyano, carboxylic acid or carboxylic ester.
  • the present application provides a process for the preparation of Lumacaftor, comprising the step of halogenating 3-methylpyridine of formula (VI I I) to obtain 2-halo 5-methylpyridine of formula (IV), wherein R-i , R 2 and R 3 are same as defined above.
  • the present application provides a process for the preparation of Lumacaftor, comprising the step of halogenating 3-methylpyridine of formula (VII I) through N-oxide formation to obtain 2-halo 5-methylpyridine of formula (IV) as depicted below, wherein R-i , R 2 and R 3 are same as defined above.
  • the present application provides a process for the preparation of Lumacaftor, comprising the step of halogenation through diazotization of 5-methylpyridin-2-amine of formula (IX) as depicted below; wherein R-i , R 2 and R 3 are same as defined above.
  • the present application provides a process for the preparation of Lumacaftor, comprising the step of halogenating 3-methylpyridine of formula (IVc) to obtain 2-halo 3-methylpyridine of formula (IV), wherein X is any halogen
  • R 2 may be any halogen, amino group which is optionally protected or amide group of formula (C).
  • the present application provides a process for the preparation of Lumacaftor, comprising the step of halogenating 2-aminopyridine of formula (VI) through N-oxide formation to obtain 6-halo pyridine-2-amine of formula
  • R 4 is selected from hydrogen, a amine protecting group or a group of formula (B)
  • the present application provides a process for the preparation of Lumacaftor, comprising the step of amination of 3-methylpyridine of formula (VIII) through N-oxide formation to obtain 5-methyl pyridine-2-amine of formula (IX) as depicted below, wh halogen.
  • the present application provides an improved process for the preparation of Lumacaftor of formula or ester thereof, comprising the step of reacting N-(6-bromo pyridin-2-yl) cyclopropyl carboxamide of formula (XI) with borolanyl benzene of formula (XII) or its derivatives thereof; wherein R 3 is same as defined above and R' and R" may be same or different selected from hydrogen, alkyl, aryl or both together form a ring with C2 to C6 aliphatic chain.
  • the present application provides novel and alternative intermediates of formula (III), (XI) and (IVa) useful in the preparation of Lumacaftor, its esters or salts thereof, wherein R 2 is leaving group such as halogen and R 3 is hydrogen or a group selected from cyano, carboxylic acid or carbox lic ester.
  • the present application provides N-oxides of intermediates of formula (VI) and (VIII) useful in the preparation of Lumacaftor, its esters or salts thereof,
  • Ri is any leaving group such as halogen and R 4 is selected from hydrogen or a group of formula (
  • the present application provides a hydrobromide salt of Lumacaftor.
  • the present application provides a process for the preparation of hydrobromide salt of Lumcaftor comprising the step of contacting hydrobromic acid with Lumacaftor.
  • the present application provides a process for the preparation of Lumacaftor, comprising the step of converting hydrobromide salt of Lumcaftor to its free form.
  • the present application provides a pharmaceutical composition comprising salts of Lumacaftor with hydrobromic acid.
  • the present application provides a process for the preparation of Lumacaftor or salts thereof, comprising the step of reacting 3- boronobenzoic acid or a derivative thereof with N-(6-halo-5-methylpyridin-2-yl)-1 - (2,2-difluorobenzo[d][1 ,3]dioxol-5-yl)cyclopropanecarboxamide in presence of an inert solvent selected from the group comprising of water, dimethylformamide, dimethoxyethane, 1 ,4-dioxane, 2-propanol, n-butanol, 2-butanol, tert. Butanol or mixtures thereof.
  • the present application provides a crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.52, 9.30, 10.45, 10.73, 1 1 .88, 17.19, 19.46, 20.28 and 24.7 ⁇ 0.2° 2 ⁇ .
  • the application provides crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern having one or more additional peaks at about, 8.88, 1 1 .10, 16.08, 16.63, 16.85, 17.82, 18.73, 19.79 and 21 .54 ⁇ 0.2° 2 ⁇ .
  • the present application provides a crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.67, 10.74, 1 1 .32, 13.85, 19.25, 20.34, 26.47 and 27.25 ⁇ 0.2° 2 ⁇ .
  • the application provides crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern having one or more additional peaks at about 16.45, 17.84, 18.77, 21 .64 and 22.43 ⁇ 0.2° 2 ⁇ .
  • the present application provides a crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.13, 12.19, 12.83, 17.08, 22.78, 24.20, 25.47, 26.39 and 28.02 ⁇ 0.2° 2 ⁇ .
  • the application provides crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern having one or more additional peaks at about 14.87, 15.22, 16.53, 17.85, 18.43, 19.68, 20.44, 21 .56 and 22.10 ⁇ 0.2° 2 ⁇ .
  • the present application provides a crystalline form SV4 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.39, 12.91 , 14.23, 15.98, 23.69, 27.12 and 27.95 ⁇ 0.2° 2 ⁇ .
  • the application provides crystalline form SV4 of Lumacaftor, characterized by a PXRD pattern having one or more additional peaks at about 7.80, 15.58, 18.71 and 21 .6 ⁇ 0.2° 2 ⁇ .
  • the present application provides a process for the preparation of crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.52, 9.30, 10.45, 10.73, 1 1 .88, 17.19,
  • the present application provides a process for the preparation of crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.67, 10.74, 1 1 .32, 13.85, 19.25, 20.34, 26.47 and 27.25 ⁇ 0.2° 2 ⁇ , comprising the step of drying crystalline form SV1 of Lumacaftor.
  • the present application provides a process for the preparation of crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.13, 12.19, 12.83, 17.08, 22.78, 24.20,
  • the present application provides a process for the preparation of crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.13, 12.19, 12.83, 17.08, 22.78, 24.20, 25.47, 26.39 and 28.02 ⁇ 0.2° 2 ⁇ , comprising the step of suspending Lumacaftor in a solvent selected from the group comprising of nitromethane, 1 ,2-dimethoxy ethane and hexane.
  • the present application provides a process for the preparation of crystalline form SV4 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.39, 12.91 , 14.23, 15.98, 23.69, 27.12 and 27.95 ⁇ 0.2° 2 ⁇ , comprising the step of crystallizing Lumacaftor from solvent or mixture of solvents comprising 1 ,2-dimethoxy ethane.
  • the present application provides a process of converting crystalline form SV1 of Lumacaftor to crystalline form SV3 of Lumacaftor.
  • the present application provides a process for the preparation of crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.52, 9.30, 10.45, 10.73, 1 1 .88, 17.19, 19.46, 20.28 and 24.7 ⁇ 0.2° 2 ⁇ comprising the step of treating Lumacaftor with 1 ,4-dioxane or a mixture thereof.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline Form of Lumacaftor selected from the group comprising form SV1 , form SV2, form SV3, form SV4 or mixtures thereof together with atleast one pharmaceutically acceptable excipient.
  • Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Form SV1 of Lumacaftor prepared by the method of Example-31 .
  • Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline Form SV2 of Lumacaftor prepared by the method of Example-32.
  • Figure 3 is an illustrative X-ray powder diffraction pattern of crystalline Form SV3 of Lumacaftor prepared by the method of Example-35.
  • Figure 4 is an illustrative X-ray powder diffraction pattern of crystalline Form SV4 of Lumacaftor prepared by the method of Example-37.
  • Figure 5 is an illustrative X-ray powder diffraction pattern of crystalline Form SV3 of Lumacaftor prepared by the method of Example-38.
  • Figure 6 is an illustrative X-ray powder diffraction pattern of crystalline Form SV1 of Lumacaftor prepared by the method of Example-39.
  • Figure 7 is an illustrative X-ray powder diffraction pattern of crystalline Form SV1 of Lumacaftor prepared by the method of Example-40.
  • Figure 8 is an illustrative X-ray powder diffraction pattern of crystalline Form SV2 of Lumacaftor prepared by the method of Example-41 .
  • Figure 9 is an illustrative PXRD pattern of hydrobromic acid salt of Lumacaftor prepared by the method of example No 30.
  • Figure 10 is an illustrative DSC thermogram of hydrobromic acid salt of Lumacaftor prepared by the method of example No 30.
  • Figure 1 1 is an illustrative PXRD pattern of Lumacaftor prepared by the method of example 20.
  • Figure 12 is an illustrative DSC thermogram of Lumacaftor prepared by the method of example No 20.
  • the present application provides a process for the preparation of Lumacaftor, comprising the step of reacting the cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) to obtain 5-methylpyridin-2- amine of formula V).
  • R-i is selected from hydrogen, any leaving group such as halogen or a phenyl group of formula (A);
  • R 2 is any leaving group such as halogen and R 3 is hydrogen or a group selected from cyano, carboxylic acid or carboxylic ester.
  • the reaction of cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) may be carried out in the presence of a catalyst.
  • Catalyst are those which can facilitate C-N bond-forming such as palladium catalysts in the presence of a ligand and palladium catalyst may include, but not limited to Palladium acetate [Pd(OAc) 2 ] Tris(dibenzylideneacetone) dipalladium (O)-chloroform adduct [Pd 2 (dba) 3 .
  • reaction of cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) may be carried out in the presence of a ligand such as Xantphos (X-phos), BrettPhos, DavePhos or the like.
  • a ligand such as Xantphos (X-phos), BrettPhos, DavePhos or the like.
  • the reaction may be carried out according to a copper-catalyzed method such as in the presence of a combination of copper iodide and ⁇ , ⁇ '- dimethyl ethylenediamine.
  • reaction of cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) may be carried out under suitable coupling conditions known in the art such as Buchwald et al, (Org. Lett. , 2000, 2 (8), pp 1 101-1 104 and Org. Lett. , 2003, 5 (20), pp 3667-3669)
  • reaction may be carried out between cyclopropyl carboxamide of formula (III) and 3-methylpyridine of formula (IV), wherein R 2 is a leaving group such as halogen like Chlorine, Bromine, Iodine; O-triflates; sulphonate or the like.
  • R 2 is a leaving group such as halogen like Chlorine, Bromine, Iodine; O-triflates; sulphonate or the like.
  • reaction of cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) may be carried out in a mole ratio of cyclopropyl carboxamide of formula (III) to 3-methylpyridine of formula (IV) of 1 : 0.5 to 0.5: 1 .
  • the reaction of cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) may be carried out in the presence of a base.
  • Base may include but not limited to an organic base such as organic amines, alkoxides or an inorganic base such as carbonates, bicarbonates, alkoxides and hydroxides.
  • the reaction may be carried out in the presence of Cesium carbonate, potassium carbonate or sodium tert butoxide.
  • reaction of cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) may be carried out in the presence of a suitable solvent or mixture of solvents.
  • suitable solvents may include but not limited to tert-butanol, dioxane, tetrahydrofuran, toluene, 2-propanol, n-butanol or the like.
  • reaction of cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) may be carried out at suitable temperature of about 50°C and above for atleast 10 hours and more. In an embodiment, the reaction of cyclopropyl carboxamide of formula (III) with 3-methylpyridine of formula (IV) may be carried out at 80°C to 120°C for atleast 15 hours or more.
  • reaction conditions may be altered depending on the other parameters used.
  • R-i is a phenyl group of formula (A)
  • the process for the preparation of Lumacaftor or a ester thereof comprising the step of reacting the cyclopropyl carboxamide of formula (II I) with 3-methylpyridine of formula (IVa) to afford Lumacaftor intermediate of formula (Va), wherein R 3 is selected from hydrogen or a group selected from cyano, carboxylic acid or carboxylic ester.
  • the process further comprises the step of converting intermediate of formula (Va) to Lumacaftor, its ester or salts thereof according to methods known in the art or procedures described or exemplified in the instant application.
  • esters of Lumacaftor may be hydrolyzed according to suitable conditions known in the art or according to methods or procedures described or exemplified in the instant applications.
  • ester of Lumacaftor may be hydrolyzed under acidic, neutral or basic conditions.
  • 3-methylpyridine of formula (IV) may be prepared employing a process comprising the step of halogenating 3-methylpyridine of formula (VIII) to obtain 2-halo 3-methylpyridine of formula (IV), wherein R-i , R 2 and R 3 are same as defined above.
  • 3-methylpyridine of formula (IV) may be prepared employing a process comprising the step of halogenating 3-methylpyridine of formula (VIII) through N-oxide formation as depicted below, wherein R-i , R 2 and R 3 are same as defined above.
  • obtain 3-methylpyridine of formula (IV) may be also prepared employing a process comprising the step of halogenating 3- methylpyridine of formula (IVc) as depicted below; wherein X is any halogen and R 2 may be any leaving group such as halogen.
  • 3-methylpyridine of formula (IV) may be also prepared employing a process comprising the step of halogenation through diazotization of 5-methylpyridin-2-amine of formula (IX) as depicted below; wherein R-i and R 2 are same as defined above.
  • 3-methylpyridine of formula (IV) may be prepared according to any method known in the art or procedures described in any aspect or exemplified in the present application.
  • cyclopropyl carboxamide of formula (III) may be prepared employing a process comprising the step of hydrolysis of cyclopropyl nitrile of formula (XIII) to corresponding amide as depicted below.
  • cyclopropyl nitrile of formula (XIII) may be hydrolyzed to corresponding amide either in the presence of an acid or a base catalyst.
  • Suitable acid catalyst may include, but not limited to hydrogen halides such as HCI, HBr, HI; sulphuric acid, phosphoric acid, nitric acid or the like and a suitbale base catalyst may include, but not limited to hydroxides such as NaOH, KOH, Mg(OH) 2 ,Ca(OH) 2 or the like; alkoxides such as methoxides, ethoxides, t- butoxides or the like ; carbonates such as NaC0 3 , KC0 3 or the like.
  • hydrolysis of cyclopropyl nitrile of formula (XIII) may be carried out in the presence of an inert solvent which include, but not limited to alcohols such as tert-butanol or the like; ketones such as methyl tert-butyl ketone or the like and hydrocarbons such as toluene or the like.
  • an inert solvent include, but not limited to alcohols such as tert-butanol or the like; ketones such as methyl tert-butyl ketone or the like and hydrocarbons such as toluene or the like.
  • cyclopropyl carboxamide of formula (III) may be prepared according to any method known in the art or procedures described in any aspect or exemplified in the present application.
  • the present application provides a process for the preparation of Lumacaftor, comprising the step of halogenating 3-methylpyridine of formula (VIII) to obta -halo 3-methylpyridine of formula (IV),
  • R-i is, hydrogen, any leaving group such as halogen or a phenyl group of formula (A);
  • R 2 is any halogen and R 3 is hydrogen or a group selected from cyano, carboxylic acid or carboxylic ester.
  • halogenating 3-methylpyridine of formula (VIII) may be carried out under suitable conditions known in the art.
  • halogenation may be carried out by reacting 3-methylpyridine of formula (VIII) with halogen source such as chlorine (Cl 2) , Bromine (Br 2 ), Iodine (l 2 ) in the presence of suitable catalyst that include, but not limited to n-Bu Li / di Isopropyl amine; n-Bu Li / dimethyl amino ethanol; PdCI 2 /CCI 4 or the like.
  • halogenation may be carried out by reacting 3- methylpyridine of formula (VIII) in an inert atmosphere at suitable temperature of about 0°C or below, optionally the presence of an inert solvent such as hexane or the like.
  • 3- methylpyridine of formula (IVa) may be prepared following a process comprising the steps of halogenating 3-methylpyridine of formula (Villa) as depicted below.
  • the process further comprises the step of converting 3- methylpyridine of formula (IVa) to Lumacaftor, salt or an ester thereof.
  • 3-methylpyridine of formula (IVa) may be reacted with cyclopropyl carboxamide of formula (III) according to conditions or methods described at any aspect or exemplified in the instant application.
  • Ri is any leaving group (X) such as halogen
  • 3- methylpyridine of formula (IVb) may be prepared following a process comprising the steps of halogenating 3-methylpyridine of formula (Vlllb) as depicted below.
  • the process further comprises the step of converting 2- halo 3-methylpyridine of formula (IV) to Lumacaftor.
  • 2-halo 3-methylpyridine of formula (IV) obtained by the process of this aspect may be isolated or taken directly to the next step for the preparation of Lumacaftor.
  • 2-halo 3-methylpyridine of formula (IV) may be converted to Lumacaftor according to any of the methods known in the art or procedures described at any aspect or exemplified in the instant application.
  • the present application provides a process for the preparation of Lumacaftor, comprising the step of halogenating 3-methylpyridine of formula (VIII) through N-oxide formation to obtain 2-halo 3-methylpyridine of formula (IV),
  • R 2 is any halogen and R 3 is hydrogen or a group selected from cyano, carboxylic acid or carboxylic ester.
  • halogenation of 3-methylpyridine of formula (VIII) may be carried out through the formation of corresponding N-oxide followed by its halogenation.
  • the N-oxide may be either isolated or continued for the halogenation directly without isolating it.
  • N-oxide of 3-methylpyridine of formula (VIII) may be carried out in the presence of an oxidation agent including, but not limited to peroxides or per acids such as hydrogen peroxide, per acetic acid perphtalic acids (magnesium- monoperphtalate (MMPP)), performic acid, pertrifuoricacetic acid, peroxymonosulfuric acid, bromate, metal oxidants such as chromic acid and permanganate, perphosphoric acid, permaleinic acid, urea- hydrogen peroxide (UHP), urea-hydrogen peroxide / phthalic anhydride , m-chloro Perbenzoic acid (m-CPBA) or the like.
  • peroxides or per acids such as hydrogen peroxide, per acetic acid perphtalic acids (magnesium- monoperphtalate (MMPP)), performic acid, pertrifuoricacetic acid, peroxymonosulfuric acid, bromate, metal oxid
  • N-oxide formation may be carried out in a mole ratio of 3-methylpyridine of formula (VIII) to oxidation agent of 2: 1 to 1 :2.
  • N-oxide formation may be carried out at suitable temperature of about 30°C and above for sufficient time of atleast 30 minutes or more.
  • N-oxide formation may be carried out according to conditions known in the art or methods described at any aspect or exemplified in the instant application.
  • N-oxide obtained according to the process of this aspect may be halogenated using suitable halogen source which may include but not limited to phosphorus oxyhalide such as POCI3, POBr 3 ; thionyl halides such as SOCI2; Oxalyl halides such as (COCI) 2.
  • suitable halogen source may include but not limited to phosphorus oxyhalide such as POCI3, POBr 3 ; thionyl halides such as SOCI2; Oxalyl halides such as (COCI) 2.
  • halogenation of N-oxide may be carried out in a mole ratio of 3-methylpyridine of formula (VIII) to halogen source of 1 : 1 to 1 :2.
  • halogenation of N-oxide may be carried out in the presence of a base such as triethyl amine, diisopropyl amine, diisopropyl ethyl amine or the like.
  • halogenation of N-oxide may be carried out in the presence of an inert solvent such as halogenated hydrocarbons such dichloromethane.
  • halogenation of N-oxide may be carried out at suitable temperature of about 30°C and above for sufficient time of atleast 30 minutes or more.
  • 3- methylpyridine of formula (IVa) may be prepared following a process comprising the steps of halogenating 3-methylpyridine of formula (Villa) as depicted below.
  • Ri is any leaving group (X) such as halogen
  • 3- methylpyridine of formula (IVb) may be prepared following a process comprising the steps of halogenating 3-methylpyridine of formula (Vlllb) as depicted below.
  • the process further comprises the step of converting 2- halo 3-methylpyridine of formula (IV) to Lumacaftor.
  • 2-halo 3-methylpyridine of formula (IV) obtained by the process of this aspect may be isolated or taken directly to the next step for the preparation of Lumacaftor.
  • 2-halo 3-methylpyridine of formula (IV) may be converted to Lumacaftor according to any of the methods known in the art or procedures described at any aspect or exemplified in the instant application.
  • the present application provides a process for the preparation of Lumacaftor, comprising the step of diazotization of 5-methylpyridin- 2-amine of formula (IX) as depicted below;
  • R 2 is any halogen and R 3 is hydrogen or a group selected from cyano, carboxylic acid or carboxylic ester.
  • diazotization of 5-methylpyridin-2-amine of formula (IX) may be carried out using nitrites including, but not limited to sodium nitrite or other nitrites such as methyl nitrite, nitrosyl chloride or the like to obtain corresponding diazo derivative.
  • diazo derivative is prepared insitu and taken directly for the halogenation step.
  • Diazotization of 5-methylpyridin-2-amine of formula (IX) may be carried out under conditions known in the art or procedures described or exemplified in the instant application. Diazotization may be carried out at suitable temperature of about 0°C or below.
  • the diazo derivative obtain above may be treated with the halogenating agent with its isolation.
  • the diazotization may be carried out in the presence of halogenating agent.
  • Suitable halogenating agents may include, but not limited to Hydrogen halides such as HCI, HBr, HI; Br 2 , I2, Cl 2 or the like.
  • halogenation of diazo derivative may be carried out in the presence of an acid such as sulphuric acid or a hydrogen halide either in concentrated or diluted form.
  • Diazotization and / or halogenation of 5-methylpyridin-2-amine of formula (IX) may be carried out under conditions known in the art or procedures described or exemplified in the instant application.
  • the process of this aspect may be carried out at suitable temperature of about 0°C or below, preferably at a temperature between -10°C and -30°C.
  • 3-methylpyridine of formula (IVa) may be prepared employing a process comprising the step of diazotization of 5-methylpyridin-2- amine of formula (IXa) as depicted below.
  • 3-methylpyridine of formula (IVb) may be prepared employing a process comprising the step of diazotization of 5-methylpyridin-2- amine of formula (IXb) as depicted below.
  • the process further comprises the step of converting 2- halo 3-methylpyridine of formula (IV) to Lumacaftor.
  • 2-halo 3-methylpyridine of formula (IV) obtained by the process of this aspect may be isolated or taken directly to the next step for the preparation of Lumacaftor.
  • the processes for the preparation of 3-methylpyridine of formula (IVa) in any of the aspects further comprises the step of converting 3- methylpyridine of formula (IVa) to Lumacaftor, salt or an ester thereof.
  • 3-methylpyridine of formula (IVa) may be reacted with cyclopropyl carboxamide of formula (III) according to conditions or methods described at any aspect or exemplified in the instant application.
  • the processes for the preparation of 3-methylpyridine of formula (IVb) in any of the aspects further comprises the step of converting 3- methylpyridine of formula (IVb) to Lumacaftor, salt or an ester thereof.
  • 3-methylpyridine of formula (IVb) may be reacted with cyclopropyl carboxamide of formula (III) or with borolanyl benzene of formula (XII) or its derivative thereof according to methods known in the art or procedures described at an aspect or exemplified in the instant application as depicted below.
  • 2-halo 3-methylpyridine of formula (IV) may be converted to Lumacaftor according to any of the methods known in the art or procedures described at any aspect or exemplified in the instant application.
  • the present application provides a process for the preparation of Lumacaftor, comprising the step of halogenating 3-methylpyridine of formula (IVc) to obtain 2-halo 3-meth lpyridine of formula (IV),
  • R 2 may be any halogen, amino group which is optionally protected or amide grou of formula (C).
  • halogenating 3-methylpyridine of formula (IVc) may be carried out under suitable conditions known in the art.
  • halogenation may be carried out by reacting 3-methylpyridine of formula (IVc) with halogen source such as chlorine (Cl 2 ), Bromine (Br 2 ), Iodine (l 2 ) in the presence of suitable catalyst that include, but not limited to n-Bu Li / di Isopropyl amine; n-Bu Li / dimethyl amino ethanol; PdCI 2 /CCI 4 or the like.
  • halogenation may be carried out by reacting 3- methylpyridine of formula (IVc) in an inert atmosphere at suitable temperature of about 0°C or below, optionally the presence of an inert solvent such as hexane or the like.
  • 3-methylpyridine of formula (IVb) may be obtained following a process comprising the step of halogenating 3- methylpyridine of formula IVc) as depicted below.
  • 3-methylpyridine of formula (Vb) may be obtained following a process comprising the step of halogenating 3-methylpyridine of formula (Vc) as depicted below.
  • 3- methylpyridine of formula (VI lb) may be obtained following a process comprising the step of halogenating 3-methylpyridine of formula (Vlb) as depicted below; wherein R 4 is hydrogen or amine rotectin rou .
  • the process further comprises the step of converting 2- halo 3-methylpyridine of formula (IV) of this aspect to Lumacaftor.
  • 2-halo 3- methylpyridine of formula (IV) obtained by the process of this aspect may be isolated or taken directly to the next step for the preparation of Lumacaftor.
  • 2-halo 3-methylpyridine of formula (IV) may be converted to Lumacaftor according to any of the methods known in the art or procedures described at any aspect or exemplified in the instant application.
  • the present application provides a process for the preparation of Lumacaftor, comprising the step of halogenating 2-aminopyridine of form -halo pyridine-2-amine of formula (VII),
  • R 4 is selected from hydrogen, a amine protecting group or group B and X is a halogen.
  • halogenation of 3-methylpyridine of formula (VI) may be carried out through the formation of corresponding N-oxide followed by its halogenation.
  • the N-oxide may be either isolated or continued for the halogenation directly without isolating it.
  • N-oxide formation and subsequent halogenation may be carried out according to previous aspects for the preparation of 3- methylpyridine of formula (IV).
  • halogenation of 2-aminopyridine of formula (Vc) to obtain 6-halo pyridine-2-amine of formula (Vb), may be carried out as depicted below, wherein X is a halogen.
  • N-oxide of 2-aminopyridine of formula (Vc) may be prepared as depicted below according any methods known in the art or procedures described in any aspect or exemplified in the instant application.
  • halogenation of 2-aminopyridine of formula (VI) to obtain 6-halo pyridine-2-amine of formula (VII) may be carried out according to any method known in the art or procedures described in any aspect or exemplified in the present application.
  • the process for the preparation of 6-halo pyridines- amine of formula (VII) in any of the aspects further comprises the step of converting 6-halo pyridine-2 -amine of formula (VII) to Lumacaftor, salt or ester thereof.
  • 6-halo pyridine-2-amine of formula (VII) may be reacted with borolanyl benzene of formula (XII) or its derivative, wherein R', R" and R 3 are same as defined in other aspects, according to any methods known in the art or procedures described at any aspect or exemplified in the instant application.
  • 6-halo pyridine-2-amine of formula (VII) may be reacted with cyclopropyl carboxylic acid of formula (X), its derivatives or with borolanyl benzene of formula (XII) or its derivatives thereof as depicted below.
  • the present application provides a process for the preparation of Lumacaftor, comprising the step of amination of 3-methylpyridine of formula (VIII) through the formation of N-oxide to obtain 5-methyl pyridines- amine of formula (IX), wherein R-i is any leaving group such as halogen.
  • amination of 3-methylpyridine of formula (VIII) may be carried out through the formation of corresponding N-oxide followed by its amination.
  • the N-oxide may be either isolated or continued for the amination directly without isolating it.
  • N-oxide formation may be carried out according to previous aspects for the preparation of 3-methylpyridine of formula (IV).
  • amination of N-oxide of 3-methylpyridine of formula (VII I) may be carried out under suitable conditions for Chichibabin amination of pyridines known in the art such as in Lawin, Phillip B. et al (WO 9600216)
  • amination of N-oxide may be carried out by reacting with a suitable amine compound which include, but not limited to ammonia; organic amines such as alkyl amines; such as methyl amine, ethyl amine, ethanol amine, propyl amine, propanol amine, butyl amine, butanol amine; aryl amines such as 4-tolyl amine; inorganic amines such as sodamide, potassamide or the like.
  • a suitable amine compound which include, but not limited to ammonia; organic amines such as alkyl amines; such as methyl amine, ethyl amine, ethanol amine, propyl amine, propanol amine, butyl amine, butanol amine; aryl amines such as 4-tolyl amine; inorganic amines such as sodamide, potassamide or the like.
  • the amination of N-oxide may be carried out in the presence of an inert solvent such as acetonitrile, toluene or the like.
  • the amination of N-oxide may be carried out at suitable temperature of about 50°C and above for sufficient time for atleast 30 minutes.
  • pyridine-2-amine of formula (IX) may be reacted with cyclopropyl carboxylic acid of formula (X), reactive derivatives thereof or with borolanyl benzene of formula (XII) or its derivative thereof according to methods known in the art or procedures described at any aspect or exemplified in the instant application.
  • the present application provides an improved process for the preparation of Lumacaftor or intermediate thereof, comprising the step of reacting N-(6-bromo pyridin-2-yl) cyclopropyl carboxamide of formula (XI) with borolanyl benzene of formula (XII) or its derivatives thereof; wherein R 3 is same as defined above and R' and R" may be same or different selected from hydrogen, alkyl, aryl or both together form a ring with C 2 to C 6 aliphatic chain.
  • N-(6-bromo 5-methyl pyridin-2-yl) cyclopropyl carboxamide of formula (XI) may be prepared according to any of the methods known in the art or procedures described in any aspect or exemplified in the instant application.
  • the N-(6-bromo 5-methyl pyridin-2-yl) cyclopropyl carboxamide of formula (XI) may be optionally purified before using by any methods known in the art such as column chromatography, fractional distillation, recrystallization or the like, before using.
  • N-(6-bromo pyridin-2-yl) cyclopropyl carboxamide of formula (XI) may be reacted with borolanyl benzene of formula (XII) or its derivative thereof in the presence of suitable catalyst.
  • Catalyst may include but not limited to palladium catalyst such as palladium acetate (Pd(OAc) 2 ), Dichloro-[1 , 1 -bis(diphenylphosphino) ferrocene]palladium(ll) (Pd(dppf)CI 2 ), Tetrakis(triphenylphosphine)palladium (0) (Pd(PPh 3 ) 4 ) or the like.
  • palladium catalyst such as palladium acetate (Pd(OAc) 2 ), Dichloro-[1 , 1 -bis(diphenylphosphino) ferrocene]palladium(ll) (Pd(dppf)CI 2 ), Tetrakis(triphenylphosphine)palladium (0) (Pd(PPh 3 ) 4 ) or the like.
  • this coupling reaction may be carried out under Suzuki coupling conditions known in the art.
  • mole ratio of N-(6-bromo 5-methyl pyridin-2-yl) cyclopropyl carboxamide of formula (XI) to borolanyl benzene of formula (XII) may vary from 0.5: 2 to 2:0.5
  • the reaction may be carried out in the presence of an inert solvent including, but not limited to an aprotic solvent such as dimethyl formamide, dioxane, N-methyl pyrrolidone, dimethyl sulfoxide, toluene, acetonitrile, dimethyl acetamide, dichloromethane or the like.
  • an aprotic solvent such as dimethyl formamide, dioxane, N-methyl pyrrolidone, dimethyl sulfoxide, toluene, acetonitrile, dimethyl acetamide, dichloromethane or the like.
  • the reaction may be carried out at suitable temperature of about 0°C and above for sufficient time for atleast 15 minutes.
  • the process further comprises the step converting the obtained intermediate to Lumacaftor , its esters or salt thereof under suitable condition known in the art or procedures described at any aspect or exemplified in the present application.
  • the present application provides novel and alternative intermediates of formula (III), (XI) and (IVa) useful in the preparation of Lumacaftor, its esters or salts thereof, wherein R 2 is leaving group such as halogen and R 3 is hydrogen or a group selected from cyano, carboxylic acid or carboxylic ester.
  • the present application provides N-oxides of intermediates of formula (VI) and (VIII) useful in the preparation of Lumacaftor, its esters or salts thereof,
  • R-i is any leaving group such as halogen and R 4 is selected from hydrogen or a group of formula (
  • Starting materials used in any aspect of the instant application may be obtained from either commercially available sources or prepared according to the methods known in the art. Starting materials used in any aspect of the instant application may be purified according to the methods known in the art such as recrystallization, acid - base treatment, chromatography, fractional distillation, slurrying or the like, before using.
  • Lumacaftor obtained according to any aspects of the instant patent application may be purified according to any of the methods known in the art recrystallization, acid - base treatment, chromatography or the like. Further, Lumacaftor may be dried under suitable drying conditions such as air drying or vacuum drying.
  • the present application provides a salt of Lumacaftor with hydrobromic acid.
  • the salt of this aspect may contain Lumacaftor and the hydrobromic acid in any stoichiometric ratio.
  • the salt may be in crystalline or an amorphous form. In preferred embodiment, the salt may be in crystalline form.
  • the present application provides a hydrobromic acid salt of Lumcaftor.
  • the hydrobromic acid salt is in crystalline form, characterized by a PXRD pattern of figure 9 and / or a DSC thermogram of figure 10.
  • the present application provides a process for the preparation of hydrobromic acid salt of Lumacaftor comprising the step of contacting hydrobromic acid with Lumacaftor.
  • Lumacaftor may be contacted with hydrobromic acid in a mole ratio of about 1 : 0.8 to 1 : 1 .6.
  • Lumacaftor may be contacted with hydrobromic acid in a heterogeneous or homogenous phase. In an embodiment, Lumacaftor may be contacted with hydrobromic acid in homogeneous phase. In an embodiment, solution comprising Lumacaftor in an inert solvent may be contacted with hydrobromic acid.
  • the hydrobromic acid may be used either in concentrated or diluted form before contacting with Lumacaftor.
  • Lumacaftor may be contacted with hydrobromic acid at a suitable temperature at about 0°C and above for time sufficient for salt formation.
  • the reaction mixture comprising Lumacaftor and the hydrobromic acid may be stirred for sufficient time and at suitable temperature for the completion of salt formation.
  • reaction mixture comprising Lumacaftor and the acid may be concentrated and / or cooled to suitable temperature before isolating the salt of Lumcaftor.
  • suitable anti-solvent may be added to the reaction mixture comprising Lumacaftor and hydrobromic acid before isolating the salt of Lumcaftor.
  • salt of Lumacaftor may be carried out by any methods known in the art or procedures described in the present application.
  • salt of Lumacaftor may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
  • drying salt of Lumacaftor may be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
  • Lumacaftor may be purified through the formation of a suitable salt followed by its neutralization to free from.
  • salts may be optionally purified by any method known in the art including recrystallization, before neutralization, unlike the free forms.
  • the salt forms are generally regarded as superior in terms of solubility compared to respective free forms and may be conveniently recrystallized from suitable solvents according to techniques known in the art such cooling crystallization, anti-solvent addition, or the like.
  • the present application provides a purification process for Lumacaftor, comprising the step of converting a salt of Lumacaftor obtained according any of the previous aspects into its free form.
  • the present application provides a process for the preparation of Lumacaftor, comprising the step of converting a salt of Lumacaftor to its free form, wherein the salt may be hydrobromide salt.
  • the salt of Lumacaftor may be converted to Lumacaftor in free form by neutralization.
  • the salt may be neutralized in the presence of a suitable base.
  • Base may be used directly or may diluted form in water or any inert suitable solvent, before using.
  • Suitable base may include, but not limited to: hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide; carbonates such sodium carbonate, potassium carbonate, ammonium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate; an organic base like amines such as triethyl amine, diisopropyl amine, diisopropyl ethyl amine; alkoxides such as methoxide, ethoxide, isopropoxide, tert. Butoxide; N- heterocyclic Compounds; tetraalkylammonium and phosphonium hydroxides; Amides; metal silanoates; and the like.
  • hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide
  • carbonates such sodium carbonate, potassium carbonate, ammonium carbonate
  • bicarbonates such as sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate
  • the salt of Lumacaftor may be converted to its free form by subjecting the salt to suitable conditions which may include, but not limited to: suspending the salt of Lumacaftor in a suitable solvent optionally at elevated temperatures.
  • the free form of Lumcaftor obtained according to the process of this aspect may be either in crystalline form or amorphous form. In an embodiment, the free form of Lumacaftor may be in crystalline form.
  • the present application provides a pharmaceutical composition comprising salt of Lumacaftor with hydrobromic acid.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • the present application provides a process for the preparation of Lumacaftor or salts thereof, comprising the step of reacting 3- boronobenzoic acid or a derivative thereof with N-(6-halo-5-methylpyridin-2-yl)-1 - (2,2-difluorobenzo[d][1 ,3]dioxol-5-yl)cyclo propanecarboxamide in presence of an inert solvent selected from the group comprising of water, dimethylformamide, dimethoxyethane, 1 ,4-dioxane, 2-propanol, n-butanol, 2-butanol, tert. Butanol or mixtures thereof.
  • the reaction between 3-boronobenzoic acid or a derivative thereof and N-(6-halo-5-methyl pyridin-2-yl)-1 -(2,2- difluorobenzo[d][1 ,3]dioxol-5-yl)cyclopropanecarboxamide may be carried out in the presence of a suitable catalyst selected from the group comprising of palladium acetate; dichloro-[1 , 1 -bis(diphenylphosphino) ferrocene]palladium(ll) (Pd(dppf)CI 2 ); palladium acetate / triphenyl phosphine; Tetrakis(triphenylphosphine)palladium (0) (Pd(PPh 3 ) 4 ) or the like.
  • a suitable catalyst selected from the group comprising of palladium acetate; dichloro-[1 , 1 -bis(diphenylphosphino) ferrocene]palladium(ll)
  • the reaction between 3-boronobenzoic acid or a derivative thereof and N-(6-halo-5-methyl pyridin-2-yl)-1 -(2,2- difluorobenzo[d][1 ,3]dioxol-5-yl)cyclopropanecarboxamide may be carried out in the presence of a suitable base selected from the group comprising of hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide; carbonates such sodium carbonate, potassium carbonate, ammonium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate; Potassium phosphate tribasic (K 3 P0 4 ); an organic base like amines such as triethyl amine, diisopropyl amine, diisopropyl ethyl amine; alkoxides such as methoxide, ethoxide, isopropoxide, tert. Butoxide; N-heterocyclic
  • 3-boronobenzoic acid may reacted directly or its derivatives such as 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoic acid or the like may be reacted with N-(6-halo-5-methylpyridin-2-yl)-1 -(2,2- difluorobenzo[d][1 ,3]dioxol-5-yl)cyclopropanecarboxamide.
  • the mole ratio of 3-boronobenzoic acid or a derivative thereof to N-(6-halo-5-methyl pyridin-2-yl)-1 -(2,2-difluorobenzo[d][1 ,3]dioxol-5- yl)cyclopropanecarboxamide that may be used is about 1 : 0.8 to 1 : 1 .2.
  • the reaction between 3-boronobenzoic acid or a derivative thereof and N-(6-halo-5-methylpyridin-2-yl)-1 -(2,2-difluoro benzo[d][1 ,3]dioxol-5yl)cyclopropane carboxamide may be carried out at a suitable temperature of about 0°C to reflux temperature of the reaction mixture.
  • the reaction between 3-boronobenzoic acid or a derivative thereof and N-(6-halo-5-methylpyridin-2-yl)-1 -(2,2-difluoro benzo[d][1 ,3]dioxol-5yl)cyclopropane carboxamide may be carried out for sufficient time to complete the formation of Lumacaftor or salts thereof for about 1 hour or more.
  • Lumacaftor that is obtained according to the process of this aspect may be purified through the formation of any salt described in the instant application.
  • Starting materials or Lumacaftor used in any aspect of the instant application may be purified according to the methods known in the art such as recrystallization, acid - base treatment, chromatography, fractional distillation, slurrying or the like, before using.
  • Starting materials used for the preparation of Lumacaftor may be obtained from either commercially available sources or prepared according to the methods known in the art.
  • Lumacaftor used as starting material for the preparation of any salt of the present application may be obtained according to the methods known in the art or according to the procedure described or exemplified in the present application.
  • Lumacaftor obtained according to any aspects of the instant patent application may be further purified according to any of the methods known in the art recrystallization, acid - base treatment, chromatography or the like. Further, Lumacaftor may be dried under suitable drying conditions such as air drying or vacuum drying.
  • the present application provides a pharmaceutical composition comprising Lumacaftor obtained according any of the previous aspects and atleast one additional pharmaceutically acceptable excipient.
  • the present application provides a pharmaceutical composition comprising Lumacaftor obtained according any of the previous aspects and atleast one additional pharmaceutically acceptable excipient.
  • Lumacaftor that is used as starting material for the preparation of any of the solid forms of present application may be purified before using employing any of the purification techniques known in the art such as recrystallization, slurrying or chromatography or according to the procedures described or exemplified in the instant application.
  • Starting material may be either in a crystalline or amorphous state.
  • crystalline form of Lumacaftor may include but not limited to crystalline form I or solvate form A of Lumacaftor or an alternate crystalline form of Lumacaftor known in the art.
  • the present application provides a crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.52, 9.30, 10.45, 10.73, 1 1 .88, 17.19, 19.46, 20.28 and 24.7 ⁇ 0.2° 2 ⁇ .
  • the application provides crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern having one or more additional peaks at about, 8.88, 1 1 .10, 16.08, 16.63, 16.85, 17.82, 18.73, 19.79 and 21 .54 ⁇ 0.2° 2 ⁇ .
  • the present application provides crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern substantially as shown in figure 1 .
  • the present application provides a crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.67, 10.74, 1 1 .32, 13.85, 19.25, 20.34, 26.47 and 27.25 ⁇ 0.2° 2 ⁇ .
  • the application provides crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern having one or more additional peaks at about 16.45, 17.84, 18.77, 21 .64 and 22.43 ⁇ 0.2° 2 ⁇ .
  • the present application provides crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern substantially as shown in figure 2.
  • the present application provides crystalline form SV2 of Lumacaftor, which is stable for atleast 3 months under packed condition when stored ambient temperature.
  • crystalline form SV2 of Lumacaftor is stable for more than 3 months when stored in an amber colored bottle and stored at 25°C - 30°C.
  • the present application provides a crystalline form SV2 of Lumacaftor.
  • the crystalline form SV2 is stable under humidity of about 60% RH, under both closed or packed and open conditions.
  • the crystalline form SV2 of Lumacaftor is stable for atleast a week when placed under open atmospheric conditions.
  • the present application provides a crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.13, 12.19, 12.83, 17.08, 22.78, 24.20, 25.47, 26.39 and 28.02 ⁇ 0.2° 2 ⁇ .
  • the application provides crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern having one or more additional peaks at about 14.87, 15.22, 16.53, 17.85, 18.43, 19.68, 20.44, 21 .56 and 22.10 ⁇ 0.2° 2 ⁇ .
  • the present application provides crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern substantially as shown in figure 3.
  • the present application provides a crystalline form SV4 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.39, 12.91 , 14.23, 15.98, 23.69, 27.12 and 27.95 ⁇ 0.2° 2 ⁇ .
  • the application provides crystalline form SV4 of Lumacaftor, characterized by a PXRD pattern having one or more additional peaks at about 7.80, 15.58, 18.71 and 21 .6 ⁇ 0.2° 2 ⁇ .
  • the present application provides crystalline form SV4 of Lumacaftor, characterized by a PXRD pattern substantially as shown in figure 4.
  • Lumacaftor that is used as starting material for the preparation of any of the solid forms of present application may be purified before using employing any of the purification techniques known in the art such as recrystallization, slurrying or chromatography or according to the procedures described or exemplified in the instant application.
  • Starting material may be either in a crystalline or amorphous state.
  • crystalline form of Lumacaftor may include but not limited to crystalline form I or solvate form A of Lumacaftor or an alternate crystalline form of Lumacaftor known in the art.
  • the present application provides a process for the preparation of crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.52, 9.30, 10.45, 10.73, 1 1 .88, 17.19, 19.46, 20.28 and 24.7 ⁇ 0.2° 2 ⁇ comprising the step of crystallizing Lumacaftor form SV1 from the solution comprising Lumacaftor and 1 ,4-dioxane.
  • solution comprising Lumacaftor and 1 ,4-dioxane may obtained by dissolving Lumacaftor in a solvent or mixture of solvents comprising 1 ,4-dioxane, optionally by heating.
  • dissolution of Lumacaftor may be carried out by optionally heating a mixture of Lumacaftor and a solvent or mixture of solvents comprising 1 ,4- dioxane at about 30°C to reflux temperature of the solvent.
  • the solution may be made particle free by filtering the solution, optionally the solution may be treated with carbon, hydrose or any decolorizing agent before filtration.
  • crystallization of Lumacaftor form SV1 may be carried out according to any methods known in the art for the reduction of solubility of Lumacaftor such as lowering the temperature (i.e. , cooling crystallization) of the solution; adding anti-solvent to the solution; evaporating the solvent from the solution; or the combinations thereof.
  • crystallization of Lumacaftor form SV1 may be carried out by lowering the temperature of the solution comprising Lumacaftor and 1 ,4- dioxane to a suitable temperature of about 25°C and below. In an embodiment, crystallization may be carried out by lowering the temperature of the solution to 0°C and below.
  • temperature lowering may be carried out slowly or drastically.
  • drastic lowering of temperature may be effected by placing the solution in a pre-cooled bath.
  • temperature lowering may be carried out in gradually in single step or stepwise in multiple steps.
  • the solution comprising Lumacaftor and 1 ,4-dioxane may be stirred at the same temperature for time sufficient to obtain crystalline form SV1 of Lumacaftor.
  • Isolation of crystalline form SV1 of Lumacaftor may be carried out by any methods known in the art or procedures described in the present application.
  • crystalline form SV1 may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
  • the present application provides a process for the preparation of crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.67, 10.74, 1 1 .32, 13.85, 19.25, 20.34, 26.47 and 27.25 ⁇ 0.2° 2 ⁇ , comprising the step of drying crystalline form SV1 of Lumacaftor.
  • drying crystalline form SV1 of Lumacaftor may be carried out in suitable drying equipment such as a tray drier optionally under reduced pressure or other drying conditions known in the art such as Buchi rotavapour vacuum drying, rotatory cone vacuum drying; fluid bed drying optionally under nitrogen atmosphere, thin film drying; or the like.
  • suitable drying equipment such as a tray drier optionally under reduced pressure or other drying conditions known in the art such as Buchi rotavapour vacuum drying, rotatory cone vacuum drying; fluid bed drying optionally under nitrogen atmosphere, thin film drying; or the like.
  • drying crystalline form SV1 of Lumacaftor may be carried out at suitable temperatures of about 25°C and above, optionally under reduced pressure. In an embodiment, drying may be carried out at about 100°C and above.
  • drying crystalline form SV1 of Lumacaftor may be carried out for sufficient time to complete its conversion to crystalline form SV2 of Lumacaftor. Drying can be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
  • the present application provides a process for the preparation of crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.13, 12.19, 12.83, 17.08, 22.78, 24.20, 25.47, 26.39 and 28.02 ⁇ 0.2° 2 ⁇ , comprising the step of treating Lumacaftor with solvent or solvent mixture comprising acetic acid.
  • crystalline form SV3 of Lumacaftor may be obtained by treating Lumacaftor with solvent or solvent mixture comprising acetic acid, wherein the mixture of Lumacaftor and the solvent is either heterogeneous or homogeneous.
  • crystalline form SV3 of Lumacaftor may be obtained by suspending Lumacaftor in a solvent or mixture of solvents comprising acetic acid for at suitable temperature and sufficient time.
  • crystalline form SV3 of Lumacaftor may be obtained by crystallizing it from the solution comprising Lumacaftor and solvent or mixture of solvents comprising acetic acid.
  • crystallization of Lumacaftor form SV3 may be carried out according to any method known in the art for the reduction of solubility of Lumacaftor such as lowering the temperature (i.e. , cooling crystallization) of the solution; adding anti-solvent to the solution; evaporating the solvent from the solution; or the combinations thereof. Crystallization may be carried out by any method described in any aspect or according to procedures exemplified in the instant application.
  • crystallization of Lumacaftor form SV3 may be carried out by lowering the temperature of the solution comprising Lumacaftor and solvent or mixture of solvents comprising acetic acid to a suitable temperature of about 25°C and below. In an embodiment, crystallization may be carried out by lowering the temperature of the solution to 0°C and below.
  • temperature lowering may be carried out slowly or drastically.
  • drastic lowering of temperature may be effected by placing the solution in a pre-cooled bath.
  • temperature lowering may be carried out in gradually in single step or stepwise in multiple steps.
  • the solution comprising Lumacaftor and solvent or mixture of solvents comprising acetic acid may be stirred at the same temperature for time sufficient to obtain crystalline form SV3 of Lumacaftor.
  • Isolation of crystalline form SV3 of Lumacaftor may be carried out by any methods known in the art or procedures described in the present application.
  • crystalline form SV3 may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
  • isolated crystalline form SV3 of Lumacaftor may be optionally dried in a suitable drying equipment for times sufficient to achieve desired quality of product at suitable temperatures.
  • the present application provides a process for the preparation of crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.13, 12.19, 12.83, 17.08, 22.78, 24.20, 25.47, 26.39 and 28.02 ⁇ 0.2° 2 ⁇ , comprising the step of suspending Lumacaftor in a solvent or mixture of solvents, wherein solvent is selected from the group comprising of nitromethane, ,2-dimethoxy ethane and hexane.
  • crystalline form SV3 of Lumacaftor may be obtained by suspending Lumacaftor in the solvent with suitable concentrations such that the mixture of Lumacaftor and the solvent remain heterogeneous throughout the transformation.
  • crystalline form SV3 of Lumacaftor may be obtained by suspending Lumacaftor in the solvent at suitable temperature of about 0°C and above for sufficient time to complete the formation of crystalline form SV3, for atleast 1 hour or more.
  • crystalline form SV3 of Lumacaftor may be obtained by suspending Lumacaftor in the solvent at 25°C and above for sufficient time to complete the formation of crystalline form SV3, for more than 10 hours.
  • the present application provides a process for the preparation of crystalline form SV4 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.39, 12.91 , 14.23, 15.98, 23.69, 27.12 and 27.95 ⁇ 0.2° 2 ⁇ , comprising the step of crystallizing Lumacaftor from solvent or mixture of solvents comprising 1 ,2-dimethoxy ethane.
  • solution comprising Lumacaftor and solvent or mixture of solvents comprising 1 ,2-dimethoxy ethane may obtained by dissolving Lumacaftor in a solvent or mixture of solvents, optionally by heating.
  • dissolution of Lumacaftor may be carried out by optionally heating a mixture of Lumacaftor and a solvent or mixture of solvents comprising 1 ,2- dimethoxy ethane at about 30°C to reflux temperature of the solvent.
  • the solution may be made particle free by filtering the solution, optionally the solution may be treated with carbon, hydrose or any decolorizing agent before filtration.
  • crystallization of Lumacaftor form SV4 may be carried out according to any methods known in the art for the reduction of solubility of Lumacaftor such as lowering the temperature (i.e. , cooling crystallization) of the solution; adding anti-solvent to the solution; evaporating the solvent from the solution; or the combinations thereof.
  • crystallization of Lumacaftor form SV4 may be carried out by lowering the temperature of the solution comprising Lumacaftor and 1 ,2- dimethoxy ethane to a suitable temperature of about 25°C and below. In an embodiment, crystallization may be carried out by lowering the temperature of the solution to 0°C and below.
  • temperature lowering may be carried out slowly or drastically.
  • drastic lowering of temperature may be effected by placing the solution in a pre-cooled bath.
  • temperature lowering may be carried out in gradually in single step or stepwise in multiple steps.
  • the solution comprising Lumacaftor and 1 ,2-dimethoxy ethane may be stirred at the same temperature for time sufficient to obtain crystalline form SV4 of Lumacaftor.
  • Isolation of crystalline form SV4 of Lumacaftor may be carried out by any methods known in the art or procedures described in the present application.
  • crystalline form SV4 may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
  • the present application provides a process of converting crystalline form SV1 of Lumacaftor to crystalline form SV3 of Lumacaftor.
  • the conversion of crystalline form SV1 may be carried out by holding crystalline form SV1 under closed condition at suitable temperature of about 0°C to 40°C. In an embodiment, crystalline form SV1 may be held under closed condition for sufficient time to complete the conversion for atleast 24 hours or more. In an embodiment, crystalline form SV1 may be held under suitable packing condition.
  • the present application provides crystalline form SV3 of Lumacaftor obtained according to the process of this aspect may be, characterized by a PXRD pattern substantially as shown in figure 5.
  • the present application provides a process for the preparation of crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.52, 9.30, 10.45, 10.73, 1 1 .88, 17.19, 19.46, 20.28 and 24.7 ⁇ 0.2° 2 ⁇ comprising the step of treating Lumacaftor with 1 ,4- dioxane or a mixture thereof.
  • treating Lumacaftor with 1 ,4-dioxane or a mixture thereof may be carried out by combining Lumacaftor and 1 ,4-dioxane or a mixture thereof.
  • the mixture of Lumacaftor and 1 ,4-dioxane or a mixture thereof may form a homogeneous or heterogeneous mixture. In an embodiment, the mixture of Lumacaftor and 1 ,4-dioxane or a mixture thereof is a heterogeneous mixture in the form a suspension.
  • crystalline form SV1 of Lumacaftor may be obtained by treating Lumacaftor with a mixture of 1 , 4-dioxane and atleast one additional solvent.
  • additional solvent may be selected from the group comprising of water, methanol, ethanol, 2-propanol, acetone, methyl isobutyl ketone, diethyl ether, di isopropyl ether, methyl tert. butyl ether or a mixture thereof.
  • combining Lumacaftor with 1 ,4-dioxane or a mixture thereof may be carried out optionally by heating a mixture of Lumacaftor and 1 ,4- dioxane or a mixture thereof at about 30°C to reflux temperature.
  • the mixture of Lumacaftor and 1 ,4-dioxane or a mixture thereof may be stirred for sufficient time to complete the formation of form SV1 and at suitable temperature where crystalline form SV1 is stable and do not convert to any other form of Lumacaftor.
  • seeds of crystalline form SV1 of Lumacaftor may be added to the mixture of Lumacaftor and 1 ,4-dioxane or a mixture thereof, in case the mixture forms a homogenous solution.
  • seeds may be added at a suitable temperature and sufficient quantity such that the seeds are not dissolved.
  • the mixture of Lumacaftor and 1 ,4-dioxane or a mixture thereof may be stirred for atleast one hour or more. In an embodiment, the mixture of Lumacaftor and 1 ,4-dioxane or a mixture thereof may be stirred at a temperature of about 0°C to reflux temperature.
  • anti-solvent may be added to the mixture of Lumacaftor and 1 ,4-dioxane or a mixture thereof, in case the mixture forms a homogenous solution.
  • the anti-solvent may be a solvent in which Lumacaftor has low solubility and which include, but not limited to water; hydrocarbons like n- pentane, n-hexane, n-heptane, cyclohexane, methyl cyclohexane; ethers like diethyl ether, di isopropyl ether or mixtures thereof.
  • the mixture of Lumacaftor and 1 ,4-dioxane or a mixture may be optionally cooled to a suitable temperature before or after formation of Form SV1 .
  • the mixture of Lumacaftor and 1 ,4-dioxane or a mixture thereof may be cooled to a relatively lower temperature.
  • the mixture comprising Lumacaftor and 1 ,4-dioxane or a mixture thereof may be stirred at the same temperature for time sufficient to obtain crystalline form SV1 of Lumacaftor.
  • Isolation of crystalline form SV1 of Lumacaftor may be carried out by any methods known in the art or procedures described in the present application.
  • crystalline form SV1 may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline Form of Lumacaftor selected from the group comprising form SV1 , form SV2, form SV3, form SV4 or mixtures thereof together with atleast one pharmaceutically acceptable excipient.
  • the present application provides Lumacaftor, its salt, crystalline forms thereof or their pharmaceutical compositions comprising Lumacaftor having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
  • the present application provides Lumacaftor, its salt, crystalline forms thereof or their pharmaceutical compositions, wherein particle size (D90) of Lumacaftor may be less than 100 microns or less than 50 microns or less than 20 microns.
  • inert solvent when used in the present application is a solvent that does not react with the reactants or reagent s under conditions that cause the chemical reaction indicated to take place.
  • C1 -C6 alcohols include, but are not limited to, methanol, ethanol, ethylene glycol, diethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1 - butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, 1 -, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
  • aliphatic hydrocarbon is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds.
  • a liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called “aromatic.”
  • C5-C8aliphatic or aromatic hydrocarbons include, but are not limited to, n-pentane, isopentane, neopentane, n- hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4- dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n- octane, iso
  • C3-C6esters include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
  • ether is an organic compound containing an oxygen atom -0- bonded to two other carbon atoms.
  • C2-C6 ethers include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2- methyltetrahydrofuran, 1 ,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
  • a "halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen.
  • Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 , 1 , 1 - trichloroethane, 1 ,1 ,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
  • C3-C6 ketones include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
  • a “nitrile” is an organic compound containing a cyano -(C ⁇ N) bonded to another carbon atom.
  • C2-C6Nitriles include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.
  • crystalline form indicates that the Lumacaftor is present in substantially crystalline Form.
  • substantially crystalline denotes that atleast 80 %, preferably 90 % or 95 %, more preferably all of the Lumacaftor is crystalline form.
  • crystalline form of Lumacaftor denotes Lumacaftor, which does not contain substantial amounts, preferably does not contain noticeable amounts, of any other crystalline portions of Lumacaftor e.g. measurable upon X-ray powder diffraction analysis.
  • X-ray powder diffraction patterns described herein were generated using a Bruker AXS D8 Advance powder X-ray diffractometer with a copper K-alpha radiation source.
  • a diffraction angle (2 ⁇ ) in powder X-ray diffractometry may have an error in the range of ⁇ 0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ⁇ 0.2°.
  • the present invention includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ⁇ 0.2°.
  • the phrase "having a diffraction peak at a diffraction angle (2 ⁇ ) ⁇ 0.2° of 6.3°” means “having a diffraction peak at a diffraction angle (2 ⁇ ) of 6.1 ° to 6.5°.
  • the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peak relationships and the peak locations are characteristic for a specific polymorphic form.
  • the relative intensities of the PXRD peaks may vary somewhat, depending on factors such as the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrumental variation and other factors may slightly affect the 2-theta values.
  • the term "substantially" in the context of PXRD is meant to encompass that peak assignments may vary by plus or minus about 0.2°. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a filter is used or not).
  • Example-1 Preparation of tert-butyl ester of Lumacaftor (or) tert-butyl 3-(6-(1 - (2,2-difluorobenzo[d][1 ,3]dioxol-5-yl)cyclopropane-1 -carboxamido)-3- methylpyridin-2-yl)benzoate.
  • the reaction mixture was degassed with nitrogen for 30 minutes at 27°C.
  • the reaction mixture was heated at 100°C for 21 hours. Cooled the reaction mixture to 27° and filtered on celite bed.
  • the celite bed was washed with tert-butanol (10 ml_).
  • the organic filtrate was evaporated at 45°C under reduced pressure to obtain pale yellow liquid.
  • the compound was purified by column chromatography using 60-120 silica mesh using 20% ethyl acetate / hexane as eluent to obtain title compound as brown solid.
  • Example-2 Preparation of Lumacaftor.
  • Example-4 Preparation of 1 -(2,2-difluorobenzo[d][1 ,3]dioxol-5-yl)cyclopropane-1 - carboxamide
  • 2-bromo 3-methyl pyridine 25 g was dissolved in dichloromethane (250 mL) at 30°C and cooled to 0°C.
  • m-chloroperbenzoic acid 65.58 g was added to the above solution slowly portion wise in 20 minutes at 0°C.
  • the reaction mixture was warmed to 30°C and stirred for 16 hours.
  • the reaction mixture was quenched with saturated sodium sulfite (2 x 50 mL) and extracted with dichloromethane (200 mL).
  • Example-8 Preparation of tert-butyl 3-(6-bromo-3-methylpyridin-2-yl)benzoate and 3-(6-bromo-3-methylpyridin-2-yl)benzoic acid
  • the crude product was purified by column chromatography using (10% to 50%) ethyl acetate / hexane as eluent to obtain 185 mg of tert-butyl 3-(6- bromo-3-methylpyridin-2-yl)benzoate as a colorless liquid with 96.07% purity by HPLC and 1 .0 g of 3-(6-bromo-3-methylpyridin-2-yl)benzoic acid as a white solid with 98.36% purity by HPLC.
  • Example-11 Preparation of 6-bromo 5-methyl pyridin-2-amine and 2-bromo 3- methyl pyridin-4-amine.
  • the reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic solution was dried over sodium sulfate and concentrated under reduced pressure to obtain crude product.
  • the crude product was purified by column chromatography using 60-120 mesh and 20-30% ethyl acetate / hexane as eluent to obtain 0.32 g of 6-bromo 5-methyl pyridin-2-amine with 93.41 % purity by HPLC as a brown solid and 0.34 g of 2-bromo 3-methyl pyridin-4-amine with 97.94% purity by HPLC as a brown solid.
  • Example-12 Preparation of N-(6-bromo-5-methylpyridin-2-yl)-1 -(2,2- difluorobenzo[d][1 ,3]dioxol-5-yl)cyclopropane-1 -carboxamide
  • 6-bromo 5-methyl pyridin-2-amine (0.1 g) was dissolved in dichloromethane (1 mL) under nitrogen atmosphere. The solution was cooled to 0°C and triethyl amine (0.149 mL) was added. 1 -(2,2-difluorobenzo[d][1 ,3]dioxol-5- yl)cyclopropane-1 -carbonyl chloride (0.209 g) in dichloromethane (0.5 mL) was added drop wise into the reaction mixture in 5 minutes. The reaction mixture was warmed to 30°C and stirred for 18 hours at the same temperature. Quenched the reaction mixture with saturated potassium hydroxide solution (30 mL) and extracted with dichloromethane (30 mL).
  • Example-13 Preparation of N-(5-methylpyridin-2-yl)-1 -(2,2- difluorobenz -5-yl)cyclopropane-1 -carboxamide
  • 5-methyl pyridin-2-amine (2.0 g) was suspended in toluene (20 mL) under nitrogen atmosphere at 29°C.
  • Triethyl amine (7.79 mL) and 4- dimethylaminopyridine (45 mg) were added to the reaction mixture and stirred for 10 minutes.
  • 1 -(2,2-difluorobenzo[d][1 ,3]dioxol-5-yl)cyclopropane-1 -carbonyl chloride (7.71 g) in toluene (4 mL) was added drop wise into the reaction mixture at 29°C in 15 minutes and stirred for 3 hours at the same temperature.
  • N-(5-methylpyridin-2-yl)-1 -(2,2-difluorobenzo[d][1 ,3]dioxol-5-yl)cyclopropane-1 - carboxamide (1 g) was dissolved in ethyl acetate (10 mL) and water (0.3 mL).
  • urea - hydrogen peroxide (566 mg) was added and then phthalic anhydride (891 mg) was added portion wise in 20 minutes at 27°C.
  • the reaction mixture was heated to 55°C and stirred at the same temperature for 16 hours. Cooled the reaction mixture to 27°C and diluted with ethyl acetate (10 mL) and water (10 mL).
  • Example-16 Preparation of N-oxide of N-(5-methylpyridin-2-yl)-1 -(2,2- difluorobenz -5-yl)cyclopropane-1 -carboxamide
  • N-oxide of 5-methyl pyridin-2-amine hydrochloride (0.3 g) was dissolved in dichloromethane (6 mL) under nitrogen atmosphere. The solution was cooled to 5°C and triethyl amine (0.78 mL) was added. 1 -(2,2-difluorobenzo[d][1 ,3]dioxol-5- yl)cyclopropane-1 -carbonyl chloride (0.486 g) in dichloromethane (3 mL) was added drop wise into the reaction mixture. The reaction mixture was warmed to 30°C and stirred for 3 hours at the same temperature. Quenched the reaction mixture with water (10 mL) and extracted with dichloromethane (2 x 5 mL).
  • Example-17 Preparation of N-(6-chloro-5-methylpyridin-2-yl)-1 -(2,2- difluorobenzo[d][1 ,3]dioxol-5-yl)cyclopropane-1 -carboxamide cyclopropane-1 -carboxamide (200 mg) was dissolved in dichloromethane (5 mL) and cooled to 0°C. Triethylamine (0.12 mL) and Phosphorous oxychloride (0.079 mL) were added to the reaction mixture at 0°C. Then the reaction mixture was heated to 45°C and stirred at the same temperature for 16 hours and cooled to 29°C.
  • the reaction mixture was filtered and the filtrate was concentrated by evaporating n- butanol under reduced pressure at 56°C and water (200 mL) was added.
  • the aqueous layer was washed with toluene (200 mL) and the pH was adjusted to 2 using concentrated hydrochloric acid.
  • the reaction mixture was extracted with ethyl acetate (500 mL) and the organic layer was washed with water (200 mL).
  • the organic layer was washed with 5% sodium bicarbonate solution (100 mL) and then with water (200 mL).
  • the solvent was removed from the organic layer completely by evaporation under reduced pressure at 50°C.
  • Example-20 Preparation of Lumacaftor from Lumacaftor hydrobromide salt.
  • Example-21 Preparation of Lumacaftor N-(6-bromo-5-methylpyndin-2-yl)-1 -(2,2-difluorobenzo[d][1 ,3]dioxol-5-yl) cyclopropanecarboxamide (20 g) and 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzoic acid (14.48 g) were added to a mixture of potassium carbonate (32.3 g) in dimethylformamide (100 ml_) and water (20 ml_) at 26°C.
  • Lumacaftor (1 g) was dissolved in isopropyl alcohol (10 ml_) at 72°C and cooled to 60°C. Hydrobromic acid (0.268 g) was added at 60°C into the above solution and cooled to 26°C. Stirred the reaction mixture for 3 hours at same temperature and the solid was filtered. The cake was washed with isopropyl alcohol (3 ml_) and dried under vacuum at 60°C for 1 1 .5 hours to obtain the title compound. Yield: 786 mg.
  • Example-31 Preparation of crystalline form SV1 of Lumacaftor.
  • Lumacaftor (3 g) was dissolved in 1 ,4-dioxane (15 mL) at 50°C and rapidly cooled to -78°C to precipitate solid. The reaction mixture was allowed to attain 25°C and solid was filtered to obtain 1 .6 g of the title compound.
  • Crystalline form SV1 of Lumcaftor (0.8 g) obtained in example-34 was dried under vacuum at 100°C for 1 hour to obtain the title compound.
  • Example-33 Preparation of crystalline form SV1 of Lumacaftor.
  • Lumacaftor (0.5 g) was dissolved in 1 ,4-dioxane (2 mL) at 25°C and rapidly cooled to -78°C to precipitate solid. The precipitated solid was allowed to attain
  • Crystalline form SV1 of Lumacaftor that was obtained in example- 37 was heated to 140°C and cooled to 25°C in a thermo gravimetric analyzer to obtain title compound.
  • Example-35 Preparation of crystalline form SV3 of Lumacaftor
  • Lumacaftor (2 g) was dissolved in acetic acid (20 mL) at 60°C and rapidly cooled to -78°C. The reaction mixture was then allowed to attain 26°C and maintained for
  • Example-36 Preparation of crystalline form SV3 of Lumacaftor
  • Lumacaftor (3 x 0.1 g) was stirred with 0.7 mL of each solvent (i.e., Nitromethane,
  • Lumacaftor (0.5 g) was dissolved in 1 ,2-dimethoxy ethane (10 mL) at 60°C and rapidly cooled to -70°C and maintained for 10 minutes at the same temperature.
  • Crystalline form SV1 of Lumacaftor obtained at example-34 was packed in an amber colour glass vial and stored for 12 days at 25°C to obtain the title compound.
  • Example-39 Preparation of crystalline form SV1 of Lumacaftor.
  • Lumacaftor (1 g) was dissolved in a mixture of 1 ,4-dioxane (5 mL) and water (1 mL) and a crystalline form SV1 seed (100 mg) at 26°C. The mixture was stirred for 5.5 hours at the same temperature and the solid was filtered to obtain the title compound.
  • Example-40 Preparation of crystalline form SV1 of Lumacaftor.
  • Example-41 Preparation of crystalline form SV2 of Lumacaftor
  • Crystalline form SV1 (100 mg) was heated to 100°C in 1 hour under reduced pressure in a tray drier to obtain the title compound.
  • Example-42 Preparation of crystalline form SV2 of Lumacaftor
  • Crystalline form SV1 (100 mg) was dried in tray drier at 70°C for 13 hours under reduced pressure to obtain the title compound.
  • Lumacaftor (5.02 g) was dissolved in 1 ,4-dioxane (25 mL) at 52°C and the solution was filtered to make it particle free. The filtrate was cooled to -78°C rapidly and stirred at the same temperature for 1 hour. Reaction mass was allowed to reach 26°C and filtered the solid under nitrogen pressure in nutsche filter to obtain crystalline form SV1 of Lumacaftor. This solid was dried under nitrogen pressure for 1 hour in the nutsche filter and dried further in a tray drier under reduced pressure at 70°C for 12 hours to obtain 2.5 g of title compound.

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Abstract

La présente invention concerne, selon divers aspects, des formes solides de lumacaftor et de ses sels, ainsi que des procédés associés. Des aspects spécifiques de la présente invention concernent d'autres procédés pour la préparation de lumacaftor et d'intermédiaires de celui-ci. La présente invention concerne, en outre, ces formes solides de lumacaftor et de ses sels.
PCT/IB2017/051970 2016-04-07 2017-04-06 Formes solides de lumacaftor et de ses sels, et procédés associés Ceased WO2017175161A1 (fr)

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Publication number Priority date Publication date Assignee Title
EP4434581A2 (fr) 2017-01-09 2024-09-25 Laurus Labs Limited Procédé et formes cristallines de lumacaftor

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007056341A1 (fr) * 2005-11-08 2007-05-18 Vertex Pharmaceuticals Incorporated MODULATEURS HÉTÉROCYCLIQUES DE TRANSPORTEURS À CASSETTE LIANT l’ATP

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007056341A1 (fr) * 2005-11-08 2007-05-18 Vertex Pharmaceuticals Incorporated MODULATEURS HÉTÉROCYCLIQUES DE TRANSPORTEURS À CASSETTE LIANT l’ATP

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4434581A2 (fr) 2017-01-09 2024-09-25 Laurus Labs Limited Procédé et formes cristallines de lumacaftor

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