WO2024153856A1

WO2024153856A1 - Process for the preparation of 3-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide

Info

Publication number: WO2024153856A1
Application number: PCT/FI2024/050017
Authority: WO
Inventors: Rami HIRVINIEMI; Oskari KARJALAINEN; Mikko MÄKELÄ
Original assignee: Orion Corporation
Priority date: 2023-01-18
Filing date: 2024-01-17
Publication date: 2024-07-25

Abstract

The present disclosure relates to a process for the preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide, to a compound which is 3-(4,5- dichloro-2-fluorobenzamido)pyridine 1-oxide and use thereof in the preparation of 3-(4,5- dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide as well as to a compound which is 3-(5-chloro-2,4-bis(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide and use thereof as a reference substance in the control of impurities in the manufacture of 3-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1- oxide. 3-(4,5-Dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide is a NaV 1.8 blocker.

Description

PROCESS FOR THE PREPARATION OF 3-(4,5-DICHLORO-2-(4- (TRIFLUOROMETHOXY)PHENOXY)BENZAMIDO)PYRIDINE 1-OXIDE FIELD OF THE INVENTION The present disclosure relates to a process for the preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide, to a compound which is 3-(4,5- dichloro-2-fluorobenzamido)pyridine 1-oxide and use thereof in the preparation of 3-(4,5- dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide as well as to a compound which is 3-(5-chloro-2,4-bis(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide and use thereof as a reference substance in the control of impurities in the manufacture of 3-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1- oxide.3-(4,5-Dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide is a voltage-gated sodium channel (NaV) subtype 1.8 blocker. BACKGROUND OF THE INVENTION The compound 3-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1- oxide of formula (III) has been disclosed in US 2023/0303495.

3-(4,5-Dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide is a NaV 1.8 blocker. NaV 1.8 blockers have been shown to be useful in the relief of the severity, treatment and/or prevention of pain and cough. The process depicted in Scheme 1 for the preparation of the intermediate 4,5-dichloro-2- fluoro-N-(pyridin-3-yl)benzamide and 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide has been disclosed in US 2023/0303495. 5

Scheme 1 The process depicted in Scheme 2 for the preparation of 3-(4,5-dichloro-2-(4- 10 (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide has been disclosed in CA 3211594 Scheme 2 In Schemes 1 and 2, DMF, HATU, DIPEA, rt, NMP, DCM and m-CPBA are N,N- dimethylformamide, 1-(bis(dimethylamino)methylene)-1H-[1,2,3]triazolo[4,5-b]pyridine-1- ium 3-oxide hexafluorophosphate(V), N,N-diisopropyl-N-ethylamine, room temperature, 1- methylpyrrolidin-2-one, dichloromethane and 3-chlorobenzoperoxoic acid, respectively. The processes disclosed in US 2023/0303495 and CA 3211594 A1. are associated with several drawbacks. The processes involve the use of HATU. HATU is a high energetic material and using HATU imposes a risk for explosions. Additionally, the hexafluorophosphate(V) anion may cause corrosion of the manufacturing equipment. The use of HATU is thus undesirable in large-scale production. In the process disclosed in US 2023/0303495, the intermediate 4,5-dichloro-N-(pyridin-3- yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide is extracted three times with ethyl acetate and the crude intermediate is purified by column chromatography. Also, the final product 3- (4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide is extracted twice with ethyl acetate. Extraction and column chromatography are cumbersome processes and not suitable for large-scale production. Additionally, the amount of solvents required in extraction renders extraction undesirable from a sustainability point of view. SUMMARY OF THE INVENTION The present disclosure provides a process for the preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide, or a pharmaceutically acceptable salt thereof, by converting 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide to 3-(4,5- dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide and optionally converting 3-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide to a pharmaceutically acceptable salt thereof. The present disclosure also provides a process for the preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide, or a pharmaceutically acceptable salt thereof, by a) dissolving 3-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate in a first solvent, wherein the first solvent is (C2-C4)alkyl acetate; b) crystallising 3-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1- oxide; and c) optionally converting 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide to a pharmaceutically acceptable salt thereof. The present disclosure also provides 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide, or a pharmaceutically acceptable salt thereof, obtainable by a process of the disclosure. The present disclosure also provides pharmaceutical dosage forms comprising 3-(4,5- dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide, or a pharmaceutically acceptable salt thereof, obtained by a process of the disclosure. The present disclosure also provides a compound which is 3-(4,5-dichloro-2- fluorobenzamido)pyridine 1-oxide and use thereof in the preparation of 3-(4,5-dichloro-2- (4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide. The present disclosure also provides a compound which is 3-(5-chloro-2,4-bis(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide and use thereof as a reference substance in the control of impurities in the manufacture of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide. The process for the preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide provided by the present disclosure does not involve the use of HATU, extraction or column chromatography. DETAILED DESCRIPTION OF THE INVENTION The present disclosure relates to a process for the preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide of formula (III)

or a pharmaceutically acceptable salt thereof by converting 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide of formula (I)

to the compound of formula (III) and optionally converting the compound of formula (III) to a pharmaceutically acceptable salt thereof. In one embodiment, the present disclosure relates to a process, wherein the conversion of the compound of formula (I) to the compound of formula (III) is carried out by reacting the compound of formula (I) with 4-(trifluoromethoxy)phenol of formula (IIIa) to obtain the compound of formula (III). In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in the presence of an agent capable of binding the fluoride ion released, e.g., potassium trimethylsilanolate, sodium trimethylsilanolate or chlorotrimethylsilane. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in the presence of a base, e.g., KHCO3, NaOH, sodium tert-butoxide, 4-methylmorpholine, CaCO3, LiOH, KOH, Cs2CO3 or Na2CO3, such as KHCO3, sodium tert-butoxide, 4-methylmorpholine, CaCO₃, KOH, Cs₂CO₃ or Na₂CO₃, for example, NaOH, sodium tert-butoxide, 4- methylmorpholine, LiOH or KOH. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in the presence of NaOH, potassium tert-butoxide, sodium tert-butoxide, LiOH or KOH, such as NaOH, sodium tert-butoxide, LiOH or KOH. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in the presence of NaOH. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in the presence of potassium tert-butoxide. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in the presence of sodium tert-butoxide. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in the presence of LiOH. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in the presence of KOH. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in butan-2-one, tetrahydrofuran, 1-methylpyrrolidin-2-one, dimethyl sulfoxide, 2-methoxy-2- methylpropane, anisole, 4-methyl-1,3-dioxolan-2-one, acetonitrile, cyclohexanone, toluene, 1,3-dimethylimidazolidin-2-one, 1,1,3,3-tetramethylurea, 4-methylpentan-2-one, 1- butylpyrrolidin-2-one, N,N-dimethylacetamide, N,N-dimethylformamide, 1,3- dimethyltetrahydropyrimidin-2(1H)-one, tetrahydrothiophene 1,1-dioxide or a mixture thereof, e.g., butan-2-one, tetrahydrofuran, 1-methylpyrrolidin-2-one, dimethyl sulfoxide, 2- methoxy-2-methylpropane, anisole, 4-methyl-1,3-dioxolan-2-one, acetonitrile, toluene, 1,3- dimethylimidazolidin-2-one, 1,1,3,3-tetramethylurea, 4-methylpentan-2-one, 1- butylpyrrolidin-2-one, N,N-dimethylacetamide, N,N-dimethylformamide, 1,3- dimethyltetrahydropyrimidin-2(1H)-one, tetrahydrothiophene 1,1-dioxide or a mixture thereof, such as butan-2-one, tetrahydrofuran, 1-methylpyrrolidin-2-one, dimethyl sulfoxide, 2-methoxy-2-methylpropane, anisole, 4-methyl-1,3-dioxolan-2-one, acetonitrile, toluene, 1,3-dimethylimidazolidin-2-one, 1,1,3,3-tetramethylurea, 4-methylpentan-2-one, N,N- dimethylacetamide, N,N-dimethylformamide, 1,3-dimethyltetrahydropyrimidin-2(1H)-one, tetrahydrothiophene 1,1-dioxide or a mixture thereof, for example, 1-methylpyrrolidin-2- one, dimethyl sulfoxide, 4-methyl-1,3-dioxolan-2-one, acetonitrile, N,N- dimethylformamide, tetrahydrothiophene 1,1-dioxide or a mixture thereof, e.g., 1- methylpyrrolidin-2-one. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in dimethyl sulfoxide, cyclohexanone, 1,3-dimethylimidazolidin-2-one, 1,1,3,3-tetramethylurea, 1- butylpyrrolidin-2-one, N,N-dimethylacetamide, N,N-dimethylformamide or a mixture thereof, e.g., dimethyl sulfoxide, 1,3-dimethylimidazolidin-2-one, 1,1,3,3-tetramethylurea, 1-butylpyrrolidin-2-one, N,N-dimethylacetamide, N,N-dimethylformamide or a mixture thereof. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in a mixture of at least two solvents selected from butan-2-one, tetrahydrofuran, 1-methylpyrrolidin-2-one, dimethyl sulfoxide, 2-methoxy-2-methylpropane, anisole, 4-methyl-1,3-dioxolan-2-one, acetonitrile, toluene, 1,3-dimethylimidazolidin-2-one, 1,1,3,3-tetramethylurea, 4- methylpentan-2-one, N,N-dimethylacetamide, N,N-dimethylformamide, 1,3- dimethyltetrahydropyrimidin-2(1H)-one and tetrahydrothiophene 1,1-dioxide. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in a mixture of two solvents selected from butan-2-one, tetrahydrofuran, 1-methylpyrrolidin-2-one, dimethyl sulfoxide, 2-methoxy-2-methylpropane, anisole, 4-methyl-1,3-dioxolan-2-one, acetonitrile, toluene, 1,3-dimethylimidazolidin-2-one, 1,1,3,3-tetramethylurea, 4- methylpentan-2-one, N,N-dimethylacetamide, N,N-dimethylformamide, 1,3- dimethyltetrahydropyrimidin-2(1H)-one and tetrahydrothiophene 1,1-dioxide. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in a mixture of butan-2-one and tetrahydrofuran. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in a mixture of butan-2-one and 1,3-dimethylimidazolidin-2-one. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in a mixture of butan-2-one and 1,1,3,3-tetramethylurea. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in a mixture of tetrahydrofuran and dimethyl sulfoxide. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in a mixture of dimethyl sulfoxide and 2-methoxy-2-methylpropane. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in a mixture of dimethyl sulfoxide and anisole. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in a mixture of dimethyl sulfoxide and toluene. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in a mixture of dimethyl sulfoxide and 4-methylpentan-2-one. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in a mixture of anisole and 1,1,3,3-tetramethylurea. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in dimethyl sulfoxide. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in cyclohexanone. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in 1,3- dimethylimidazolidin-2-one. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in 1,1,3,3- tetramethylurea. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in 1- butylpyrrolidin-2-one. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in N,N- dimethylacetamide. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in N,N- dimethylformamide. In one embodiment, the present disclosure relates to a process, wherein the conversion of the compound of formula (I) to the compound of formula (III) is carried out by a) converting the compound of formula (I) to 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate of formula (II) ; b) isolating the compound of formula (II); and c) converting the compound of formula (II) to the compound of formula (III). 5 In one embodiment, the present disclosure relates to a process, wherein the compound of formula (I) is prepared by converting 4,5-dichloro-2-fluorobenzoic acid of formula (Ia)

to the compound of formula (I). 10 In one embodiment, the present disclosure relates to a process, wherein the conversion of the compound of formula (Ia) to the compound of formula (I) is carried out by reacting the compound of formula (Ia) with 3-aminopyridine 1-oxide of formula (Ib)

or a salt thereof, ¹⁵ e.g., 3-aminopyridine 1-oxide hydrochloride of formula (Ic)

, to obtain the compound of formula (I). In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (Ia) with the compound of formula (Ib) is carried out in the presence of a coupling reagent other than 1-(bis(dimethylamino)methylene)-1H-[1,2,3]triazolo[4,5- b]pyridine-1-ium 3-oxide hexafluorophosphate(V) (HATU). In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (Ia) with the compound of formula (Ib) is carried out in the presence of a coupling reagent which is 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P). In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (Ia) with the compound of formula (Ib) is carried out in the presence of an organic base, e.g., 4-methylmorpholine, triethylamine, N,N-diisopropyl-N-ethylamine or pyridine, such as N,N-diisopropyl-N-ethylamine. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (Ia) with the compound of formula (Ib) is carried out in the presence of T3P and the organic base. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (Ia) with the compound of formula (Ib) is carried out in the presence of 50 % T3P in ethyl acetate. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (Ia) with the compound of formula (Ib) is carried out in a polar aprotic solvent, e.g., acetone, dimethyl sulfoxide, 1-methylpyrrolidin-2-one, ethyl acetate, N,N-dimethylformamide, isopropyl acetate, tetrahydrofuran, acetonitrile, dichloromethane or a mixture thereof, such as ethyl acetate, acetonitrile or a mixture thereof, for example, acetonitrile. In one embodiment, the present disclosure relates to a process, wherein the conversion of the compound of formula (Ia) to the compound of formula (I) is carried out by converting the compound of formula (Ia) to 4,5-dichloro-2-fluorobenzoyl chloride of formula (Id)

and subsequently converting the compound of formula (Id) to the compound of formula (I). In one embodiment, the present disclosure relates to a process, wherein the conversion of the compound of formula (Ia) to the compound of formula (Id) is carried out by reacting the compound of formula (Ia) with oxalyl chloride in toluene. In one embodiment, the present disclosure relates to a process, wherein the conversion of the compound of formula (Ia) to the compound of formula (Id) is carried out in the presence of a compound of formula (Ie)

wherein R1 is H or methyl; R2 is (C1-C4)alkyl; R3 is (C1-C4)alkyl; or R2 and R3 form, together with the atom marked with an asterisk, a 5-, 6- or 7- membered saturated or partially unsaturated heterocyclic ring containing, in addition to the atom marked with an asterisk, 0 or 1 ring heteroatom(s) selected from N, O and S, wherein said heterocyclic ring is unsubstituted, e.g., N,N-dimethylformamide, N,N-dimethylacetamide or morpholine-4-carbaldehyde, such as N,N-dimethylformamide or morpholine-4-carbaldehyde, for example, N,N- dimethylformamide. In one embodiment, the present disclosure relates to a process, wherein the conversion of the compound of formula (Id) to the compound of formula (I) is carried out by reacting the compound of formula (Id) with 3-aminopyridine 1-oxide of formula (Ib) or a salt thereof, e.g., 3-aminopyridine 1-oxide hydrochloride of formula (Ic)

, to obtain the compound of formula (I). In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (Id) with the compound of formula (Ib) is carried out in the presence of a base, e.g., N,N-diisopropyl-N-ethylamine, pyridine, Cs2CO3, 4-methylmorpholine or NaOH, such as N,N-diisopropyl-N-ethylamine, Cs2CO3 or NaOH. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (Id) with the compound of formula (Ib) is carried out in the presence of N,N-diisopropyl-N-ethylamine, pyridine or 4-methylmorpholine, e.g., N,N-diisopropyl-N- ethylamine. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (Id) with the compound of formula (Ib) is carried out in pyridine, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, toluene, acetone or a mixture thereof, e.g., pyridine, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, toluene or a mixture thereof, such as dimethyl sulfoxide, tetrahydrofuran, acetonitrile, toluene or a mixture thereof. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (Id) with the compound of formula (Ib) is carried out in acetonitrile, acetone or a mixture thereof. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (Id) with the compound of formula (Ib) is carried out in acetonitrile. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (Id) with the compound of formula (Ib) is carried out in acetone. In one embodiment, the present disclosure relates to a process, wherein the compound of formula (I) is prepared by converting 4,5-dichloro-2-fluoro-N-(pyridin-3-yl)benzamide of formula (If)

to the compound of formula (I). In one embodiment, the present disclosure relates to a process, wherein the conversion of the compound of formula (If) to the compound of formula (I) is carried out in the presence of an oxidising agent, e.g., hydrogen peroxide, ethaneperoxoic acid, 3-chlorobenzoperoxoic acid or O₂, such as hydrogen peroxide. In one embodiment, the present disclosure relates to a process, wherein the conversion of the compound of formula (If) to the compound of formula (I) is carried out in toluene, ethyl acetate, acetonitrile, dichloromethane or a mixture thereof, e.g., acetonitrile. In one embodiment, the present disclosure relates to a process, wherein the compound of formula (If) is prepared by converting 4,5-dichloro-2-fluorobenzoic acid of formula (Ia)

to 4,5-dichloro-2-fluorobenzoyl chloride of formula (Id)

and subsequently converting the compound of formula (Id) to the compound of formula (If). In one embodiment, the present disclosure relates to a process, wherein the conversion of the compound of formula (Id) to the compound of formula (If) is carried out by reacting the compound of formula (Id) with pyridin-3-amine of formula (Ig)

or a salt thereof, to obtain the compound of formula (If). In one embodiment, the present disclosure relates to a process, wherein the conversion of the compound of formula (Id) to the compound of formula (If) is carried out by reacting the compound of formula (Id) with pyridin-3-amine free base. In one embodiment, the present disclosure relates to a process, wherein the conversion of the compound of formula (Id) to the compound of formula (If) is carried out by reacting the compound of formula (Id) with pyridin-3-amine hydrochloride of formula (Ih)

. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (Id) with the compound of formula (Ig) is carried out in the presence of a base, e.g., N,N-diisopropyl-N-ethylamine, triethylamine or 4-methylmorpholine, such as N,N-diisopropyl-N-ethylamine. In one embodiment, the present disclosure relates to a process, wherein the reaction of the compound of formula (Id) with the compound of formula (Ig) is carried out in acetonitrile, chlorobenzene, chloro(C1-2)alkane or a mixture thereof, e.g., acetonitrile, chlorobenzene, dichloromethane, trichloromethane, 1,2-dichloroethane or a mixture thereof, such as acetonitrile. The present disclosure also relates to a process for the preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide of formula (III) or a pharmaceutically acceptable salt thereof comprising the steps of a) dissolving 3-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate of formula (II)

in a first solvent, wherein the first solvent is (C2-C4)alkyl acetate, e.g., ethyl acetate or n- butyl acetate; b) crystallising the compound of formula (III); and c) optionally converting the compound of formula (III) to a pharmaceutically acceptable salt thereof. In one embodiment, the present disclosure relates to a process, wherein the compound of formula (II) is dissolved in ethyl acetate. In one embodiment, the present disclosure relates to a process, wherein the compound of formula (II) is dissolved in n-butyl acetate. In one embodiment, the present disclosure relates to a process, wherein the compound of formula (II) is dissolved in a mixture of the first solvent and a second solvent, wherein the second solvent is toluene, o-xylene, m-xylene, p-xylene or a mixture thereof, e.g., toluene. 5 In one embodiment, the present disclosure relates to 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide of formula (III)

or a pharmaceutically acceptable salt thereof obtainable by a process of the disclosure. 10 In one embodiment, the present disclosure relates to use of 4,5-dichloro-2-fluoro-N- (pyridin-3-yl)benzamide obtainable by a process of the disclosure and use thereof in the preparation of 3-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide

. 15 In one embodiment, the present disclosure relates to a compound which is 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide of formula (I)

. 5 In one embodiment, the present disclosure relates to use of a compound which is 3-(4,5- dichloro-2-fluorobenzamido)pyridine 1-oxide in the preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide of formula (III)

. 10 The process of the present disclosure yields 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide with high purity. In one embodiment, the present disclosure relates to 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide of formula (III) 15

or a pharmaceutically acceptable salt thereof obtainable by a process of the disclosure, wherein said 3-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide contains less than 0.1 % by weight of 3-(5-chloro-2,4-bis(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide. In one embodiment, the present disclosure relates to 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide of formula (III)

or a pharmaceutically acceptable salt thereof obtainable by a process of the disclosure, wherein said 3-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide contains less than 0.1 % by weight of 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide. In one embodiment, the present disclosure relates to 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide obtainable by a process of the disclosure, wherein said 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide contains less than 0.1 % by weight of 3-(5-chloro-2,4-bis(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide and less than 0.1 % by weight of 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide. The impurity 3-(5-chloro-2,4-bis(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide can be prepared as described in Example 25. By controlling impurities in drug products, product quality and safety can be ensured.3-(5- Chloro-2,4-bis(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide is useful as a reference substance in the control of impurities in the manufacture of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide. In one embodiment, the present disclosure relates to a compound which is 3-(5-chloro-2,4-bis(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide of formula

. Purity can be assessed with a method known in the art. Suitable methods include, but are not limited to, gas chromatography, column chromatography, liquid chromatography, high- pressure liquid chromatography, thin layer chromatography, mass spectrometry and high- resolution mass spectrometry. When describing the embodiments of the present invention, the combinations and permutations of all possible embodiments have not been explicitly described. Nevertheless, the mere fact that certain measures are recited in mutually different dependent claims or described in different embodiments does not indicate that a combination of these measures cannot be used to advantage. The present invention envisages all possible combinations and permutations of the described embodiments. The terms employed herein have the meanings indicated below. The term “polar aprotic solvent”, as employed herein, refers to a solvent that is polar and lacks an acidic proton thus not being able to serve as a proton donor in hydrogen bonding. Representative examples of polar aprotic solvents include, but are not limited to, acetone, dimethyl sulfoxide, 1-methylpyrrolidin-2-one, ethyl acetate, N,N-dimethylformamide, isopropyl acetate, tetrahydrofuran, acetonitrile and dichloromethane. The term “(C₁-C₄)alkyl”, as employed herein, refers to a straight or branched chain saturated hydrocarbon group having 1, 2, 3 or 4 carbon atom(s). Representative examples of (C1- C4)alkyl include, but are not limited to, methyl, ethyl, isopropyl and n-butyl. The term “chloro(C_1-2)alkane” as employed herein, refers to at least one chlorine appended to methane or ethane. When there are several chlorines, the chlorines can be attached to different carbon atoms or several chlorines can be attached to the same carbon atom. Representative examples of chloro(C_1-2)alkane include, but are not limited to, dichloromethane, trichloromethane and 1,2-dichloroethane. The term “(C₂-C₄)alkyl”, as employed herein, refers to a straight or branched chain saturated hydrocarbon group having 2, 3 or 4 carbon atoms. Representative examples of (C2-C4)alkyl include, but are not limited to, ethyl, isopropyl and n-butyl. The process for the preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide provided by the present disclosure does not involve the use of HATU, extraction or column chromatography. 3-(4,5-Dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide, or a pharmaceutically acceptable salt thereof, obtained by a process of the present disclosure is useful as a medicament and can be formulated into pharmaceutical dosage forms, such as tablets, capsules, powders or suspensions, by mixing with pharmaceutical excipients known in the art. Suitable excipients include, but are not limited to, fillers, binders, disintegrating agents, lubricants, solvents, gel forming agents, emulsifiers, stabilizers, colourants and preservatives. When describing the embodiments of the present disclosure, the combinations and permutations of all possible embodiments have not been explicitly described. Nevertheless, the mere fact that certain measures are described in different embodiments does not indicate that a combination of these measures cannot be used to advantage. The present disclosure envisages all possible combinations and permutations of the described embodiments. The present disclosure is explained in more detail by the following examples. The examples are meant for illustrating purposes only and do not limit the scope of the invention defined in the claims. The abbreviations have the meanings indicated below. a-% high-performance liquid chromatography area-% ACN acetonitrile DIPEA N,N-diisopropyl-N-ethylamine DMA N,N-dimethylacetamide DMF N,N-dimethylformamide DMI 1,3-dimethylimidazolidin-2-one DMSO dimethyl sulfoxide EtOAc ethyl acetate EtOH ethanol IPA propan-2-ol KOTMS potassium trimethylsilanolate MEK butan-2-one MeOH methanol NMP 1-methylpyrrolidin-2-one rt room temperature THF tetrahydrofuran w-% weight-% NMR spectrum multiplicities have the meanings indicated below. d doublet dd doublet of doublet ddd doublet of doublet of doublet m multiplet s singlet t triplet Example 1: Preparation of 4,5-dichloro-2-fluoro-N-(pyridin-3-yl)benzamide To a vessel inerted with nitrogen was added toluene (40 ml) and 4,5-dichloro-2- fluorobenzoic acid (10.0 g). The temperature was adjusted to 40 °C and a catalytic amount of DMF (27 µl) was added. Oxalyl chloride (5.1 ml) was added dropwise over about 30 min. The solution was stirred at 40 ± 5 °C until the reaction was complete (about 1 h). Excess oxalyl chloride and part of the remaining toluene was distilled off under vacuum (150 mbar, 100 ml). The mixture was cooled to rt. To another vessel inerted with nitrogen was added pyridin-3-amine (4.6 g), ACN (30 ml) and DIPEA (7.1 ml). The mixture was warmed to about 35 °C after which the previously prepared 4,5-dichloro-2-fluorobenzoyl chloride solution was added dropwise to the mixture while keeping the temperature at about 35 °C. After the addition, the solution was stirred until the reaction was complete (about 1 h). Water (10 ml) and acetic acid (44.7 ml) were added at 35 ± 5 °C and the mixture was heated to 70 °C. Water (20 ml) was added at 70 °C and the mixture was stirred for 30 min. Another water addition was done at 70 °C and the mixture was stirred for 30 min. The solution was cooled to 20 °C and stirred for 30 min. The product was isolated by filtration, washed with MeOH:water (1:1) mixture (30 ml) and MeOH (30 ml) and dried under vacuum at 60 °C. Yield: 10.4 g at 99.16 a-% purity. Example 2: Preparation of 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide To a vessel inerted with nitrogen was added ACN (660 ml), 4,5-dichloro-2-fluorobenzoic acid (110 g) and 3-aminopyridine 1-oxide hydrochloride (81 g). DIPEA (321 ml) was added while keeping the temperature <35 °C. Then the temperature was adjusted to 35 ± 5 °C. To the resulting solution was added T3P (50 % in EtOAc, 407 ml) while controlling the temperature at 35 ± 5 °C (over about 45 min). The mixture was stirred until the reaction was complete (about 1 h). Water (660 ml) was added over about 30 min. The resulting mixture was stirred for about 1 h and the product was collected by filtration. The filter cake was washed twice with MeOH (400 ml) and dried under vacuum at 50 °C. Yield: 138 g at 99.8 a-% purity.¹H NMR (400 MHz, DMSO-d6): δ 10.91 (s, 1H), 8.71 (s, 1H), 8.05 (d, J = 6.7 Hz, 1H), 8.04 (m, 1H), 7.94 (d, J = 9.7 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 8.4, 6.4 Hz, 1H). Example 3: Preparation of 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide To a vessel inerted with nitrogen was added toluene (70 ml) and 4,5-dichloro-2- fluorobenzoic acid (10.0 g). Part of the toluene was distilled off (20 ml) to dry the equipment. The temperature was adjusted to 30 °C and a catalytic amount of DMF (~20 µl) was added. Oxalyl chloride (4.5 ml) was added dropwise at <35 °C. The solution was stirred at 30 ± 5 °C until the reaction was complete (about 2 h). Excess oxalyl chloride and part of the remaining toluene was distilled off under vacuum (150 mbar, 20 ml). The mixture was cooled to rt. To another vessel inerted with nitrogen was added 3-aminopyridine 1-oxide hydrochloride (7.1 g), ACN (50 ml) and DIPEA (18.5 ml). The mixture was cooled to <10 °C after which the previously prepared 4,5-dichloro-2-fluorobenzoyl chloride solution was added dropwise to the mixture while keeping the temperature <20 °C. After the addition, the temperature was adjusted to 35 °C and the mixture was stirred until the reaction was complete (about 1 h). Water (50 ml) was added at 35 ± 5 °C. The mixture was stirred for 1 h. The product was collected by filtration, washed with water (30 ml) and MeOH (30 ml) and dried under vacuum at 50 °C. Yield: 12.3 g at 99.4 a-% purity. Example 4: Preparation of 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide To a vessel inerted with nitrogen was added toluene (200 ml) and 4,5-dichloro-2- fluorobenzoic acid (50.0 g). The temperature was adjusted to 40 °C and a catalytic amount of DMF (0.14 ml) was added. Oxalyl chloride (25.7 ml) was added dropwise over about 1 h. The solution was stirred at 40 ± 5 °C until the reaction was complete (about 1h). Excess oxalyl chloride and part of the remaining toluene was distilled off under vacuum (150 mbar, 100 ml). The mixture was cooled to rt. To another vessel inerted with nitrogen was added 3-aminopyridine 1-oxide hydrochloride (35.2 g), acetone (200 ml) and DIPEA (49.8 ml). The temperature was adjusted to 35 ± 5 °C. The previously prepared 4,5-dichloro-2-fluorobenzoyl chloride solution was added dropwise over about 1 h. Acetic acid (225 ml) and water (50 ml) were added. The mixture was heated to 70 ± 5 °C and water (100 ml) was added. The temperature was adjusted to 65 ± 5 °C and the mixture was stirred for 30 min. More water (125 ml) was added at 65 ± 5 °C over 1 h and then the mixture was stirred for 1 h. The slurry was cooled to 20 °C at the rate of 10 °C/min. The product was filtered, washed twice with MeOH:water (1:1) mixture (150 ml) and dried under vacuum at 50 °C. Yield: 63.0 g at 99.4 a-% purity. Example 5: Preparation of 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide To a vessel inerted with nitrogen was added toluene (70 ml) and 4,5-dichloro-2- fluorobenzoic acid (10.0 g). Part of the toluene was distilled off (20 ml) to dry the equipment. The temperature was adjusted to 30 °C and a catalytic amount of DMF (~20 µl) was added. Oxalyl chloride (4.5 ml) was added dropwise at <35 °C. The solution was stirred at 30 ± 5 °C until the reaction was complete (about 2 h). Excess oxalyl chloride and part of the remaining toluene was distilled off under vacuum (150 mbar, 20 ml). The mixture was cooled to rt. To another vessel inerted with nitrogen was added 3-aminopyridine 1-oxide hydrochloride (7.3 g), acetone (40 ml) and DIPEA (18.5 ml). The previously prepared 4,5-dichloro-2- fluorobenzoyl chloride solution was added dropwise to the mixture while keeping the temperature <35 °C. After the addition, the temperature was adjusted to 35 °C and the mixture was stirred until the reaction was complete (about 1h). Acetic acid (45 ml) and water (10 ml) were added and the mixture was heated to 75 ± 5 °C. Water (50 ml) was added over about 30 min. The mixture was allowed to cool to rt and the product was collected by filtration. The filter cake was washed with water (30 ml) and MeOH (30 ml) and dried under vacuum at 50 °C. Yield: 13.3 g at 99.5 a-% purity. Example 6: Preparation of 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide To vessel inerted with nitrogen was added 4,5-dichloro-2-fluoro-N-(pyridin-3-yl)benzamide (3 g), ACN (12 ml), acetic acid (1,2 ml) and a catalytic amount of sodium tungstate dihydrate (173.5 mg). The solution was heated to 75 °C and hydrogen peroxide (35 w-%) was added. The mixture was stirred for 7 h at 75 °C and then cooled to 20 °C. Aqueous NaHSO3 solution (39 w-%, 1.5 g) was added and the solution was cooled to 0 °C. The product was collected by filtration, washed twice with ACN (5 ml) and dried under vacuum at 40 °C. Yield: 3.2 g at 98.23 a-%. Example 7: Preparation of 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide To a vessel inerted with nitrogen was added toluene (400 ml), a catalytic amount of DMF (278 µl) and 4,5-dichloro-2-fluorobenzoic acid (100.0 g). The temperature was adjusted to 35 ± 5 °C. Oxalyl chloride (51.3 ml) was added dropwise at 35 ± 5 °C. The solution was stirred at 35 ± 5 °C until the reaction was complete (about 1 h). Excess oxalyl chloride and part of the remaining toluene was distilled off under vacuum (150 mbar, 200 ml). The mixture was cooled to rt and used as such. To another vessel under nitrogen was added 3-aminopyridine 1-oxide hydrochloride (36.0 g), ACN (150 ml) and DIPEA (23.0 ml). The temperature was adjusted to 35 ± 5 °C. Half of the previously prepared 4,5-dichloro-2-fluorobenzoyl chloride solution was added while keeping the temperature at 35 ± 5°C. The mixture was stirred until the reaction was complete (about 1 h). Water (150 ml) and acetic acid (100 ml) were added and the mixture was heated to 70 ± 5 °C and then adjusted to 60 °C. If the product was fully dissolved during the heating, the mixture was seeded with the product at this point. The mixture was stirred for 1 h and water (150 ml) was added over about 30 min. The mixture was cooled to rt and the product was isolated by filtration. The filter cake was washed with MeOH:water (1:1) mixture (60 ml) and MeOH (60 ml) and dried under vacuum at 60 °C. Yield: 63.3 g at 99.8 a-% purity. Example 8: Preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate To a vessel inerted with nitrogen was charged NMP (80 ml) and the contents were cooled to 5 ± 5 °C. Sodium tert-butoxide (13.7 g) was added and the mixture was stirred until the sodium tert-butoxide was fully dissolved.4-(Trifluoromethoxy)phenol (12.9 ml) was added dropwise while keeping the temperature <30 °C. Then chlorotrimethylsilane (9.3 ml) was added while controlling the temperature at <40 °C. The resulting mixture was stirred for 30 min at 30 °C.3-(4,5-Dichloro-2-fluorobenzamido)pyridine 1-oxide (20.0 g) was charged and the mixture heated to 85 °C. After completion of the reaction (about 3 h), the mixture was cooled to 35 °C. IPA (20 ml) was added followed by water (60 ml) at 35 ± 5 °C. The mixture was seeded and then more water (40 ml) was added at 35 ± 5 °C. The mixture was cooled to 0 °C over several hours. The product was collected by filtration, washed twice with IPA:water (1:1) mixture (40 ml) and dried under vacuum at 40 °C. Yield: 25.1 g at 98.9 a-% purity. Example 9: Preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate To a vessel inerted with nitrogen was charged NMP (260 ml). KOTMS (26.9 g, 90 % purity) was added and the mixture was stirred until the KOTMS was fully dissolved.4- (Trifluoromethoxy)phenol (33.3 ml) was added dropwise while keeping the temperature <30 °C. Then 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide (51.6 g) was charged and the mixture heated to 85 °C. After completion of the reaction (about 3 h), the mixture was cooled to 35 °C. IPA (130 ml) was added followed by water (160 ml) at 35 ± 5 °C. The mixture was seeded and then more water (150 ml) was added at 35 ± 5 °C. The mixture was cooled to rt over several hours. The product was collected by filtration, washed twice with IPA:water (1:1) mixture (100 ml) and dried under vacuum at 40 °C. Yield: 61.6 g at 99.5 a- % purity. Example 10: Preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate To a vessel inerted with nitrogen was charged DMSO (80 ml), 4-(trifluoromethoxy)phenol (17.8 g), 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide (20 g) and flux-calcined high permeability diatomaceous earth (Clarcel^® DIT2R, 6 g). Aqueous NaOH (50 %, 4.0 ml) was added and the mixture was heated to 85 ± 3 °C. The mixture was stirred until the reaction was complete (about 5 h) after which it was filtered. The filter cake was washed with toluene (10 ml) and IPA (30 ml). The temperature of the filtrate was adjusted to 35 °C and water (60 ml) was added while maintaining the temperature at 35 ± 5 °C. The mixture was seeded and then more water (40 ml) was added at 35 ± 5 °C. The mixture was cooled to 20 °C over several hours and the product was collected by filtration. The filter cake was washed twice with IPA:water (1:1) mixture (40 ml) and dried under vacuum at 40 °C. Yield: 23.9 g at 99.23 a-% purity and 97 % assay. Example 11: Preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate To a vessel inerted with nitrogen was charged DMSO (120 ml), 4-(trifluoromethoxy)phenol (20.1 g) and 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide (20 g). LiOH (1.75 g) was added and the mixture was heated to 85 ± 3 °C. The mixture was stirred until the reaction was complete (about 8 h). The temperature was adjusted to 35 °C and toluene (10 ml) and IPA (30 ml) were added. Water (80 ml) was added while maintaining the temperature at 35 ± 5 °C. The mixture was seeded and then more water (60 ml) was added at 35 ± 5 °C. The mixture was cooled to 20 °C over several hours and the product was collected by filtration. The filter cake was washed twice with IPA:water (1:1) mixture (40 ml) and dried under vacuum at 40 °C. Yield: 26.1 g at 99.11 a-% purity and 95 % assay. Example 12: Preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate To a pressure vessel inerted with nitrogen was charged DMI (26 ml), MEK (54 ml), 4- (triluoromethoxy)phenol (17.8 g) and 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide (20 g). Aqueous NaOH (50 %, 4.0 ml) was added and the mixture was heated to 100 ± 3 °C. The mixture was stirred until the reaction was complete (about 3 h). The mixture was cooled to about 50 °C and the pressure was vented. The mixture was filtered and the filter cake was washed with MEK (20 ml). Part of the MEK was distilled off (40 ml) and the temperature was adjusted to 35 °C. IPA (20 ml) was added. Water (100 ml) was added while maintaining the temperature at 35 ± 5 °C. The mixture was cooled to 20 °C over several hours and the product was collected by filtration. The filter cake was washed twice with IPA:water (1:1) mixture (40 ml) and dried under vacuum at 40 °C. Yield: 22.7 g at 99.28 a- % purity and 97 % assay. Example 13: Preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate To a vessel inerted with nitrogen was charged DMSO (20 ml) and 3-(4,5-dichloro-2- fluorobenzamido)pyridine 1-oxide (5 g).4-(Trifluoromethoxy)phenol (2.96 ml) was added followed by aqueous KOH (48 %, 1.51 ml). The mixture was heated to 85 ± 5 °C. After completion of the reaction (about 5 h), the mixture was cooled to 35 °C. IPA (5 ml) was added followed by toluene (7.5 ml) at 35 ± 5 °C. Then water (25 ml) was slowly added at 35 ± 5 °C. The mixture was seeded after about 50 % of the water had been added. The mixture was cooled to rt over several hours. The product was collected by filtration, washed twice with IPA:water (1:1) mixture (20 ml) and dried under vacuum at 40 °C. Yield: 5.36 g at 99.1 a-% purity and 98.4 % assay. Example 14: Preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate To a vessel inerted with nitrogen was charged DMSO (80 ml) and 3-(4,5-dichloro-2- fluorobenzamido)pyridine 1-oxide (20 g).4-(Trifluoromethoxy)phenol (12.9 ml) was added followed by aqueous NaOH (48 %, 4.02 ml). The mixture was heated to 85 ± 5 °C. After completion of the reaction (about 4 h), the mixture was cooled to 50 °C and filtered through a filter precoated with a filter aid (flux-calcined high permeability diatomaceous earth, Clarcel^® DIT2R). The filter cake was washed with a mixture of toluene (10 ml) and IPA (30 ml). The temperature of the filtrate was adjusted to 35 ± 5 °C and water (60 ml) was slowly added at 35 ± 5 °C. The mixture was seeded and then more water (40 ml) was added at 35 ± 5 °C. The mixture was cooled to rt over several hours. The product was collected by filtration, washed twice with IPA:water (1:1) mixture (40 ml) and dried under vacuum at 40 °C. Yield: 23.9 g at 99.2 a-% purity and 97.0 % assay. Example 15: Preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate To a vessel inerted with nitrogen was charged DMF (50 ml) and 4-(trifluoromethoxy)phenol (2.96 ml). Sodium tert-butoxide (4.79 g) was added and the resulting solution was stirred for about 15 min.3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide (10 g) was added. The mixture was heated to 80 °C, stirred until the reaction was complete (about 2-3 h) and then cooled to 35 °C. IPA (20 ml) was added followed by water (30 ml) at 35 ± 5 °C. The mixture was seeded and then water (20 ml) was slowly added at 35 ± 5 °C. The mixture was cooled to rt over several hours. The product was collected by filtration, washed twice with IPA:water (1:1) mixture (20 ml) and dried under vacuum at 40 °C. Yield: 11.6 g at 99.0 a-% purity. Example 16: Preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate To a vessel inerted with nitrogen was charged DMA (40 ml) and 3-(4,5-dichloro-2- fluorobenzamido)pyridine 1-oxide (10 g).4-(Trifluoromethoxy)phenol (6.45 ml) was added followed by aqueous NaOH (48 %, 2.01 ml). The mixture was heated to 85 ± 5 °C. After completion of the reaction (about 4 h), the mixture was cooled to 35 °C. Water (50 ml) was slowly added at 35 ± 5 °C. The mixture was seeded after about 50 % of the water had been added. The mixture was cooled to rt over several hours. The product was collected by filtration, washed twice with IPA:water (1:1) mixture (40 ml) and dried under vacuum at 40 °C. Yield: 13.3 g at 99.2 a-% purity and 99.0 % assay. Example 17: Preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate To a vessel inerted with nitrogen was charged DMA (40 ml) and 3-(4,5-dichloro-2- fluorobenzamido)pyridine 1-oxide (5 g).4-(Trifluoromethoxy)phenol (6.45 ml) was added followed by aqueous KOH (48 %, 1.51 ml). The mixture was heated to 85 ± 5 °C. After completion of the reaction (about 4 h), the mixture was cooled to 35 °C. Water (50 ml) was slowly added at 35 ± 5 °C. The mixture was seeded after about 50 % of the water had been added. The mixture was cooled to rt over several hours. The product was collected by filtration, washed twice with IPA:water (1:1) mixture (10 ml) and dried under vacuum at 40 °C. Yield: 6.65 g at 99.2 a-% purity and 99.0 % assay. Example 18: Preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate To a vessel inerted with nitrogen was charged DMI (40 ml) and 3-(4,5-dichloro-2- fluorobenzamido)pyridine 1-oxide (10 g).4-(Trifluoromethoxy)phenol (6.45 ml) was added followed by aqueous NaOH (48 %, 2.01 ml). The mixture was heated to 85 ± 5 °C. After completion of the reaction (about 5 h), the mixture was cooled to 35 °C. Water (50 ml) was slowly added at 35 ± 5 °C. The mixture was seeded after about 50 % of the water had been added. The mixture was cooled to rt over several hours. The product was collected by filtration, washed twice with IPA:water (1:1) mixture (40 ml) and dried under vacuum at 40 °C. Yield: 13.7 g at 99.2 a-% purity and 92.1 % assay. Example 19: Preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate To a pressure vessel was charged 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide (30 g), 4-(trifluoromethoxy)phenol (30.2 g), THF (120 ml) and DMSO (60 ml). The vessel was flushed with nitrogen and then aqueous KOH (46 %, 9.66 ml) was added. The vessel was pressurised with 2 bar nitrogen and then sealed. The mixture was heated to 100 °C and stirred for 3 h. The mixture was cooled to 35 °C and the pressure was vented. Water (180 ml) was added over 60 min at 35 °C. The resulting mixture was cooled to 20 °C over about 1 h. More water (60 ml) was added over 30 min and then the mixture was cooled to 10 °C. The product was collected by filtration, washed with IPA:water (1:1) mixture and dried under vacuum at 40 °C. Yield: 22.2 g. Example 20: Preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate To a vessel inerted with nitrogen was charged 1-butylpyrrolidin-2-one (40 ml) and 3-(4,5- dichloro-2-fluorobenzamido)pyridine 1-oxide (10 g).4-(Trifluoromethoxy)phenol (8.15 ml) was added followed by aqueous KOH (48 %, 3.02 ml). The mixture was heated to 85 ± 5 °C. After completion of the reaction (about 4 h), the mixture was cooled to 35 °C. Water (70 ml) was slowly added at 35 ± 5 °C. The mixture was seeded after about 50 % of the water had been added. The mixture was cooled to 0 °C over several hours. The product was collected by filtration, washed twice with IPA:water (1:1) mixture (10 ml) and dried under vacuum at 40 °C. Yield: 12.2 g at 99.4 a-% purity. Example 21: Preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate To a vessel inerted with nitrogen was charged solid KOH (85 w-%, 4.93 g), cyclohexanone (150 ml) and 4-(trifluoromethoxy)phenol (8.15 ml). The mixture was stirred until most KOH was dissolved.3-(4,5-Dichloro-2-fluorobenzamido)pyridine 1-oxide (20 g) was added and the mixture was heated to 95 °C. After completion of the reaction, about 110 ml of the solvent was distilled off under vacuum. Acetone (80 ml) was added and the temperature was adjusted to 30 °C. Water (120 ml) was slowly added at 30 ± 5 °C. The mixture was seeded after about 50 % of the water had been added. The mixture was cooled to 0 °C over several hours. The product was collected by filtration, washed twice with IPA:water (1:1) mixture (20 ml) and dried under vacuum at 40 °C. Yield: 24.9 g at 99.6 a-% purity. Example 22: Preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide To a vessel inerted with nitrogen was charged n-butyl acetate (170 ml) followed by 3-(4,5- dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate (28 g, 86 % assay). Part of the solvent (30 ml) was distilled off and the temperature was adjusted to 85 °C. Activated charcoal (Norit^® SX ultra, 2.1 g) and diatomaceous earth (Celite^® 545, 2.1 g) were added. The mixture was stirred for 1 h and then filtered. The filter cake was washed with preheated n-butyl acetate (30 ml). Toluene (56 ml) was added. The temperature was adjusted to 60 °C and the mixture was seeded. After seeding, the mixture was stirred for about 30 min and then cooled to 0 °C over several hours with ripening. The product was collected by filtration, washed with cold n-butyl acetate (30 ml) and dried under vacuum at 50-60 °C. Yield: 22.6 g at 99.8 a-% purity and 100.8 % assay. Example 23: Preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide To a vessel inerted with nitrogen was charged EtOH (280 ml) followed by 3-(4,5-dichloro- 2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate (27.7 g). The temperature was adjusted to 50 °C. Activated charcoal (Norit^® SX ultra, 2.8 g) and diatomaceous earth (Celite^® 545, 5.6 g) were added. The mixture was stirred for about 1 h and then filtered.180 ml of the solvent was distilled off. n-Butyl acetate (225 ml) was added and the distillation was continued until further 210 ml had been collected (internal temperature >127 °C). The temperature was adjusted to 70 °C. Toluene (56 ml) was added and the mixture was seeded. After seeding, the mixture was stirred for about 30 min and cooled to 0 °C over 5 h. The product was collected by filtration, washed twice with cold n- butyl acetate (30 ml) and dried under vacuum at 50-60 °C. Yield: 22.4 g at 99.7 a-% purity. Example 24: Preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide To a vessel inerted with nitrogen was charged EtOAc (480 ml) followed by 3-(4,5-dichloro- 2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate (60.0 g). The mixture was heated until a solution was obtained (about 60 °C). Activated charcoal (Norit^® SX ultra, 6.0 g) and diatomaceous earth (Celite^® 545, 6.0 g) were added. The mixture was stirred for 1 h and then filtered. The filter cake was washed twice with preheated EtOAc (60 ml).370 ml of the solvent was distilled off. Toluene (253 ml) was added and the temperature was adjusted to 55 °C. The mixture was seeded and stirred for about 30 min. The mass was cooled to 0 °C over 6 h. The product was collected by filtration, washed twice with cold EtOAc (60 ml) and dried under vacuum at 60 °C. Yield: 50.9 g. Example 25: Preparation of the impurity 3-(5-chloro-2,4-bis(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide To a vessel inerted with nitrogen was charged 4,5-dichloro-2-fluorobenzoic acid (20.0 g), EtOH (100 ml) and sulfuric acid (98 w-%, 2.6 ml). The mixture was heated to reflux, stirred for 7 h and then cooled to rt. To the crystallised mass was added dilute ammonia (15 ml of ammonia (25 %) diluted with 100 ml of water) until pH >8.5 (consumption 74 ml of dilute ammonia). The product ethyl 4,5-dichloro-2-fluorobenzoate was filtered, washed twice with water (50 ml) and dried under vacuum at 30 °C. Yield: 20.1 g. To a vessel inerted with nitrogen was added ethyl 4,5-dichloro-2-fluorobenzoate (10.0 g), Cs2CO3 (34.4 g), DMSO (150 ml) and 4-(trifluoromethoxy)phenol (16.7 ml). The mixture was heated to 100 °C. After 3 h, the mixture was cooled to 70 °C. Water (50 ml) was added over 15 min. Aqueous NaOH (48 %, 9 ml) was added and the mixture was stirred for 1 h at 70 °C. The mixture was cooled to rt and pH was adjusted to 2.8 using HCl (30 %, ~34ml). The product 5-chloro-2,4-bis(4-(trifluoromethoxy)phenoxy)benzoic acid was collected, washed with water and dried under vacuum at 40 °C. Yield: 17.8 g at 98.8 a-% purity. To a vessel inerted with nitrogen was charged 5-chloro-2,4-bis(4- (trifluoromethoxy)phenoxy)benzoic acid (5.0 g) and 3-aminopyridine 1-oxide hydrochloride (1.7 g) followed by ACN (40 ml) and DIPEA (5.14 ml). The resulting solution was heated to 30 °C after which T3P (50 % in EtOAc, 7.89 ml) was added dropwise over about 15 min. After stirring for 15 min, water (40 ml) was added and the mixture was allowed to cool to rt. Mixing was stopped and the product was allowed to slowly crystallise over the weekend. Large crystals, which were washed with water, were collected which prompted further crystallisation from the mother liquor. The second crop of crystals was also collected and combined with the first one. The product was dissolved in EtOAc (40 ml) at 40 °C. Heptane (25 ml) was added after which water droplets became apparent in the mixture.10 ml of the solvent was distilled off at ambient pressure and the mixture was allowed to cool to rt. The product 3-(5-chloro-2,4-bis(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide, which was powdery, was collected, washed with heptane and dried under vacuum at 40 °C. Yield: 4.0 g at 98.4 a-% purity.¹H NMR (400 MHz, DMSO-d6): δ 10.78 (s, 1H), 8.65 (t, J = 1.8 Hz, 1H), 8.02 (s, 1H), 8.00 (ddd, J = 6.3 Hz, 1.8 Hz, 1.0 Hz, 1H), 7.50 (ddd, J = 8.5 Hz, 1.9 Hz, 0.9 Hz, 1H), 7.43-7.30 (m, 5H), 7.23-7.12 (m, 4H), 6.78 (s, 1H). A person skilled in the art will appreciate that the embodiments described in the present disclosure can be modified without departing from the inventive concept. A person skilled in the art also understands that the present disclosure is not limited to the particular embodiments disclosed but is intended to also cover modifications of the embodiments that are within the spirit and scope of the present disclosure.

Claims

CLAIMS 1. A process for the preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide of formula (III) 5

to the compound of formula (III) 10 and optionally converting the compound of formula (III) to a pharmaceutically acceptable salt thereof.

2. The process according to claim 1, wherein the conversion of the compound of formula (I) to the compound of formula (III) is carried out by reacting the compound of formula (I) with 4-(trifluoromethoxy)phenol of formula (IIIa) 15

to obtain the compound of formula (III).

3. The process according to claim 2, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in the presence of an agent capable of binding the fluoride ion released.

4. The process according to claim 3, wherein the agent capable of binding the fluoride ion released is potassium trimethylsilanolate, sodium trimethylsilanolate or chlorotrimethylsilane.

5. The process according to any one of claims 2 to 4, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in the presence of a base.

6. The process according to claim 5, wherein the base is NaOH, potassium tert- butoxide, sodium tert-butoxide, LiOH or KOH.

7. The process according to claim 6, wherein the base is NaOH.

8. The process according to claim 6, wherein the base is potassium tert-butoxide.

9. The process according to claim 6, wherein the base is sodium tert-butoxide.

10. The process according to claim 6, wherein the base is LiOH.

11. The process according to claim 6, wherein the base is KOH.

12. The process according to any one of claims 2 to 11, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in butan-2-one, tetrahydrofuran, 1-methylpyrrolidin-2-one, dimethyl sulfoxide, 2- methoxy-2-methylpropane, anisole, 4-methyl-1,3-dioxolan-2-one, acetonitrile, cyclohexanone, toluene, 1,3-dimethylimidazolidin-2-one, 1,1,3,3- tetramethylurea, 4-methylpentan-2-one, 1-butylpyrrolidin-2-one, N,N- dimethylacetamide, N,N-dimethylformamide, 1,3-dimethyltetrahydropyrimidin- 2(1H)-one, tetrahydrothiophene 1,1-dioxide or a mixture thereof.

13. The process according to claim 12, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in dimethyl sulfoxide, cyclohexanone, 1,3-dimethylimidazolidin-2-one, 1,1,3,3- tetramethylurea, 1-butylpyrrolidin-2-one, N,N-dimethylacetamide, N,N- dimethylformamide or a mixture thereof.

14. The process according to claim 13, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in dimethyl sulfoxide.

15. The process according to claim 13, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in cyclohexanone.

16. The process according to claim 13, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in 1,3- dimethylimidazolidin-2-one.

17. The process according to claim 13, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in 1,1,3,3- tetramethylurea.

18. The process according to claim 13, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in 1- butylpyrrolidin-2-one.

19. The process according to claim 13, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in N,N- dimethylacetamide.

20. The process according to claim 13, wherein the reaction of the compound of formula (I) with the compound of formula (IIIa) is carried out in N,N- dimethylformamide.

21. The process according to any one of claims 1 to 20, wherein the conversion of the compound of formula (I) to the compound of formula (III) is carried out by a) converting the compound of formula (I) to 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate of formula (II) ; b) isolating the compound of formula (II); and c) converting the compound of formula (II) to the compound of formula (III).

22. The process according to any one of claims 1 to 21, wherein the compound of 5 formula (I) is prepared by converting 4,5-dichloro-2-fluorobenzoic acid of formula (Ia)

to the compound of formula (I).

23. The process according to claim 22, wherein the conversion of the compound of 10 formula (Ia) to the compound of formula (I) is carried out by reacting the compound of formula (Ia) with 3-aminopyridine 1-oxide of formula (Ib)

or a salt thereof to obtain the compound of formula (I). ¹⁵

24. The process according to claim 23, wherein the reaction of the compound of formula (Ia) with the compound of formula (Ib) is carried out in the presence of a coupling reagent other than 1-(bis(dimethylamino)methylene)-1H- [1,2,3]triazolo[4,5-b]pyridine-1-ium 3-oxide hexafluorophosphate(V) (HATU).

25. The process according to claim 24, wherein the reaction of the compound of formula (Ia) with the compound of formula (Ib) is carried out in the presence of a coupling reagent which is 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6- trioxide (T3P).

26. The process according to according to any one of claims 23 or 25, wherein the reaction of the compound of formula (Ia) with the compound of formula (Ib) is carried out in the presence of an organic base.

27. The process according to claim 26, wherein the reaction of the compound of formula (Ia) with the compound of formula (Ib) is carried out in the presence of T3P and an organic base.

28. The process according to any one of claims 25 or 27, wherein the reaction of the compound of formula (Ia) with the compound of formula (Ib) is carried out in the presence of 50 % T3P in ethyl acetate.

29. The process according to any one of claims 26 or 27, wherein the organic base is 4-methylmorpholine, triethylamine, N,N-diisopropyl-N-ethylamine or pyridine.

30. The process according to claim 29, wherein the organic base is N,N-diisopropyl- N-ethylamine.

31. The process according to any one of claims 23 to 30, wherein the reaction of the compound of formula (Ia) with the compound of formula (Ib) is carried out in a polar aprotic solvent.

32. The process according to claim 31, wherein the polar aprotic solvent is acetone, dimethyl sulfoxide, 1-methylpyrrolidin-2-one, ethyl acetate, N,N- dimethylformamide, isopropyl acetate, tetrahydrofuran, acetonitrile, dichloromethane or a mixture thereof.

33. The process according to claim 32, wherein the polar aprotic solvent is ethyl acetate, acetonitrile or a mixture thereof.

34. The process according to claim 33, wherein the polar aprotic solvent is acetonitrile.

35. The process according to any one of claims 23 to 34, wherein the conversion of the compound of formula (Ia) to the compound of formula (I) is carried out by reacting the compound of formula (Ia) with 3-aminopyridine 1-oxide hydrochloride of formula (Ic)

.

36. The process according to claim 22, wherein the conversion of the compound of formula (Ia) to the compound of formula (I) is carried out by converting the compound of formula (Ia) to 4,5-dichloro-2-fluorobenzoyl chloride of formula

and subsequently converting the compound of formula (Id) to the compound of formula (I).

37. The process according to claim 36, wherein the conversion of the compound of formula (Ia) to the compound of formula (Id) is carried out by reacting the compound of formula (Ia) with oxalyl chloride in toluene.

38. The process according to claim 37, wherein the conversion of the compound of formula (Ia) to the compound of formula (Id) is carried out in the presence of a compound of formula (Ie)

wherein R1 is H or methyl; R₂ is (C₁-C₄)alkyl; R₃ is (C₁-C₄)alkyl; or R2 and R3 form, together with the atom marked with an asterisk, a 5-, 6- or 7- membered saturated or partially unsaturated heterocyclic ring containing, in addition to the atom marked with an asterisk, 0 or 1 ring heteroatom(s) selected from N, O and S, wherein said heterocyclic ring is unsubstituted.

39. The process according to claim 38, wherein the compound of formula (Ie) is N,N- dimethylformamide, N,N-dimethylacetamide or morpholine-4-carbaldehyde.

40. The process according to claim 39, wherein the compound of formula (Ie) is N,N- dimethylformamide or morpholine-4-carbaldehyde.

41. The process according to claim 40, wherein the compound of formula (Ie) is N,N- dimethylformamide.

42. The process according to any one of claims 36 to 41, wherein the conversion of the compound of formula (Id) to the compound of formula (I) is carried out by reacting the compound of formula (Id) with 3-aminopyridine 1-oxide of formula

or a salt thereof to obtain the compound of formula (I).

43. The process according to claim 42, wherein the reaction of the compound of formula (Id) with the compound of formula (Ib) is carried out in the presence of a base.

44. The process according to claim 43, wherein the base is N,N-diisopropyl-N- ethylamine, pyridine or 4-methylmorpholine.

45. The process according to claim 44, wherein the base is N,N-diisopropyl-N- ethylamine.

46. The process according to any one of claims 42 to 45, wherein the reaction of the compound of formula (Id) with the compound of formula (Ib) is carried out in pyridine, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, toluene, acetone or a mixture thereof.

47. The process according to claim 46, wherein the reaction of the compound of formula (Id) with the compound of formula (Ib) is carried out in acetonitrile, acetone or a mixture thereof.

48. The process according to claim 47, wherein the reaction of the compound of formula (Id) with the compound of formula (Ib) is carried out in acetonitrile.

49. The process according to claim 47, wherein the reaction of the compound of formula (Id) with the compound of formula (Ib) is carried out in acetone.

50. The process according to any one of claims 42 to 49, wherein the conversion of the compound of formula (Id) to the compound of formula (I) is carried out by reacting the compound of formula (Id) with 3-aminopyridine 1-oxide hydrochloride of formula (Ic)

.

51. The process according to any one of claims 1 to 21, wherein the compound of formula (I) is prepared by converting 4,5-dichloro-2-fluoro-N-(pyridin-3- yl)benzamide of formula (If)

to the compound of formula (I).

52. The process according to claim 51, wherein the conversion of the compound of formula (If) to the compound of formula (I) is carried out in the presence of an oxidising agent.

53. The process according to claim 52, wherein the oxidising agent is hydrogen peroxide, ethaneperoxoic acid, 3-chlorobenzoperoxoic acid or O2.

54. The process according to claim 53, wherein the oxidising agent is hydrogen peroxide.

55. The process according to any one of claims 51 to 54, wherein the conversion of the compound of formula (If) to the compound of formula (I) is carried out in toluene, ethyl acetate, acetonitrile, dichloromethane or a mixture thereof.

56. The process according to claim 55, wherein the conversion of the compound of formula (If) to the compound of formula (I) is carried out in acetonitrile.

57. The process according to any one of claims 51 to 56, wherein the compound of formula (If) is prepared by converting 4,5-dichloro-2-fluorobenzoic acid of formula (Ia)

to 4,5-dichloro-2-fluorobenzoyl chloride of formula (Id)

and subsequently converting the compound of formula (Id) to the compound of formula (If).

58. The process according to claim 57, wherein the conversion of the compound of formula (Ia) to the compound of formula (Id) is carried out by reacting the compound of formula (Ia) with oxalyl chloride in toluene.

59. The process according to claim 58, wherein the conversion of the compound of formula (Ia) to the compound of formula (Id) is carried out in the presence of a compound of formula (Ie) wherein R1 is H or methyl; R₂ is (C₁-C₄)alkyl; R3 is (C1-C4)alkyl; or R2 and R3 form, together with the atom marked with an asterisk, a 5-, 6- or 7- membered saturated or partially unsaturated heterocyclic ring containing, in addition to the atom marked with an asterisk, 0 or 1 ring heteroatom(s) selected from N, O and S, wherein said heterocyclic ring is unsubstituted.

60. The process according to claim 59, wherein the compound of formula (Ie) is N,N- dimethylformamide, N,N-dimethylacetamide or morpholine-4-carbaldehyde.

61. The process according to claim 60, wherein the compound of formula (Ie) is N,N- dimethylformamide or morpholine-4-carbaldehyde.

62. The process according to claim 61, wherein the compound of formula (Ie) is N,N- dimethylformamide.

63. The process according to any one of claims 57 to 62, wherein the conversion of the compound of formula (Id) to the compound of formula (If) is carried out by reacting the compound of formula (Id) with pyridin-3-amine of formula (Ig)

or a salt thereof to obtain the compound of formula (If).

64. The process according to claim 63, wherein the reaction of the compound of formula (Id) with the compound of formula (Ig) is carried out in the presence of a base.

65. The process according to claim 64, wherein the base is N,N-diisopropyl-N- ethylamine, triethylamine or 4-methylmorpholine.

66. The process according to claim 65, wherein the base is N,N-diisopropyl-N- ethylamine.

67. The process according to any one of claims 63 to 66, wherein the reaction of the compound of formula (Id) with the compound of formula (Ig) is carried out in acetonitrile, chlorobenzene, chloro(C1-2)alkane or a mixture thereof.

68. The process according to claim 67, wherein the reaction of the compound of formula (Id) with the compound of formula (Ig) is carried out in acetonitrile, chlorobenzene, dichloromethane, trichloromethane, 1,2-dichloroethane or a mixture thereof.

69. The process according to claim 68, wherein the reaction of the compound of formula (Id) with the compound of formula (Ig) is carried out in acetonitrile.

70. The process according to any one of claims 63 to 69, wherein the conversion of the compound of formula (Id) to the compound of formula (I) is carried out by reacting the compound of formula (Id) with pyridin-3-amine free base.

71. The process according to any one of claims 63 to 69, wherein the conversion of the compound of formula (Id) to the compound of formula (I) is carried out by reacting the compound of formula (Id) with pyridin-3-amine hydrochloride of formula (Ih)

.

72. A process for the preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide of formula (III) or a pharmaceutically acceptable salt thereof comprising the steps of a) dissolving 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide hydrate of formula (II)

in a first solvent, wherein the first solvent is (C2-C4)alkyl acetate; b) crystallising the compound of formula (III); and c) optionally converting the compound of formula (III) to a pharmaceutically acceptable salt thereof.

73. The process according to claim 72, wherein the compound of formula (II) is dissolved in a mixture of the first solvent and a second solvent, wherein the second solvent is toluene, o-xylene, m-xylene, p-xylene or a mixture thereof.

74. The process according to claim 73, wherein the second solvent is toluene.

75. The process according to any one of claims 72 to 74, wherein the first solvent is ethyl acetate or n-butyl acetate.

76. The process according to claim 75, wherein the first solvent is ethyl acetate.

77. The process according to claim 75, wherein the first solvent is n-butyl acetate.

78. A process for the preparation of 4,5-dichloro-2-fluoro-N-(pyridin-3-yl)benzamide of formula (If)

5 or a salt thereof by converting 4,5-dichloro-2-fluorobenzoic acid of formula (Ia)

to 4,5-dichloro-2-fluorobenzoyl chloride of formula (Id)

10 and subsequently converting the compound of formula (Id) to the compound of formula (If) and optionally converting the compound of formula (If) to a salt thereof.

79. Use of 4,5-dichloro-2-fluoro-N-(pyridin-3-yl)benzamide of formula (If)

15 prepared according to claim 78 in the preparation of 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide of formula (III)

.

80.3-(4,5-Dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide of 5

or a pharmaceutically acceptable salt thereof obtainable by the process according to any one of claims 1 to 71 or the process according to any one of claims 72 to 77.

81.3-(4,5-Dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide10 according to claim 80, wherein said 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide contains less than 0.1 % by weight of 3-(5-chloro-2,4-bis(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide.

82.3-(4,5-Dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide¹⁵ according to claim 80, wherein said 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide contains less than 0.1 % by weight of 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide.

83.3-(4,5-Dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide according to any one of claims 81 or 82, wherein said 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide contains less than 0.1 % by weight of 3-(5-chloro-2,4-bis(4- 5 (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide and less than 0.1 % by weight of 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide.

84. A pharmaceutical dosage form comprising the 3-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide of any one of claims 80 to 83 and at least one pharmaceutically acceptable excipient. ¹⁰ 85. A compound which is 3-(4,5-dichloro-2-fluorobenzamido)pyridine 1-oxide of formula (I)

.