WO2014161850A1

WO2014161850A1 - Process for the preparation of amides from hindered anilines containing a perhaloalkyl group

Info

Publication number: WO2014161850A1
Application number: PCT/EP2014/056518
Authority: WO
Inventors: Helmars Smits; Thomas Pitterna; Ottmar Franz Hueter; Andrew Edmunds; André Stoller; Pierre Joseph Marcel Jung
Original assignee: Syngenta Participations Ag
Priority date: 2013-04-02
Filing date: 2014-04-01
Publication date: 2014-10-09
Also published as: JP6352389B2; CN105102421A; JP2016520543A; EP2981519A1; EP2981519B1; US20160168097A1; CN105102421B; DK2981519T3; US9598369B2

Abstract

The present invention provides a novel and improved process for the production of the production of hindered anilines containing perfluoroalky groups in good yield any by using close to stoichiometric amounts of acylating agent.

Description

Process for the preparation of amides from hindered anilines containing a perhaloalkyl group

Hindered anilines containing perhaloalkyl groups are known to have low reactivity towards acylating agents. Standard methods of acylation such as treatment with acid chloride or anhydride in the presence of base and a nucleophilic catalyst proceed only in low yields, the major side reaction being double acylation. It is possible to obtain these amides in modest yield by using two equivalents of acylating agent followed by hydrolytic cleavage of one acyl group. However this method involves sacrificing at least one equivalent of often valuable acylating partner (see for example

WO2008000438 and WO2010127928).

It is clear that a significant disadvantage of the prior art process is the sacrificial use of an excess acylating agent, which makes this this process uneconomical and especially unsuitable for a large- scale production.

A method for enhancing the reactivity has now surprisingly been found that allows the preparation of the desired amides in good yield and by using close to stoichiometric amounts of acylating agent.

The aim of the present invention relates therefore to provide a novel and improved process for the acylation of hindered anilines containing perhaloalkyl groups.

Therefore the present invention relates to a process for the preparation of compounds of formula VI

comprising at least the following steps a) to c):

Step a)

reacting a compound of formula (I) with a compound of formula (II) to obtain a compound of formula (III):

Step b)

reacting the compound of formula (III) with a compound of formula (IV) to obtain a compound of formula (V):

wherein Xi and X₂ each independently are halogen, C₁-C4 alkyl, C₁-C4 haloalkyl, C₁-C4 alkoxy, C₁-C4 haloalkoxy, C₁-C4 alkoxymethyl, Ci-C4-alkylsulphonyl, Ci-C4-haloalkylsulphonyl, C₁-C4- alkylsulphinyl, Ci-C4-haloalkylsulphinyl, Ci-C4-alkylthio, Ci-C4-haloalkylthio,

X₃ is heptafluoroprop-2-yl, l-[chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl, 1- [bromo(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl; X₄ is a leaving group selected from halogen, Ci-C6-alkyl-C(0)0-, phenyl-C(0)0-, Ci-C6-alkoxy-

C(0)0-, phenoxy-C(0)0-, benzyloxy-C(0)0- and imidazol-l-yl;

Ri is H, C₁-C4 alkyl, C_rC₄ haloalkyl;

R₂ is H or C_rC₄-alkyl;

R3 is H, fluorine, methoxy;

R_3a is H or CN,

Qi is 4-cyano-phenyl, 2-methyl-4-cyano-phenyl, 3-pyridyl or 4-pyridyl;

Preferably Xi and X₂ each independently are halogen, C₁-C4 alkyl, C₁-C4 haloalkyl, C₁-C4 alkoxy, C C4 haloalkoxy, C₁-C4 alkoxymethyl, Ci-C4-alkylsulphonyl, Ci-C4-haloalkylsulphonyl, C₁-C4- alkylsulphinyl, Ci-C4-haloalkylsulphinyl, Ci-C4-alkylthio, Ci-C4-haloalkylthio,

X3 is heptafluoroprop-2-yl, l-[chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl, 1- [bromo(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

X₄ is a leaving group selected from halogen, Ci-C6-alkyl-C(0)0-, phenyl-C(0)0-, Ci-C6-alkoxy-

C(0)0-, phenoxy-C(0)0-, benzyloxy-C(0)0- and imidazol-l-yl;

Ri is H, C₁-C4 alkyl, C_rC₄ haloalkyl;

R₂ is H or C_rC₄-alkyl;

R3 is H, fluorine, methoxy;

R_3a is H or CN,

Qi is 4-cyano-phenyl, 2-methyl-4-cyano-phenyl, 3-pyridyl or 4-pyridyl;

provided that R₃ is H when R_3a is CN, and that R₃ is fluorine or methoxy when R_3a is H;

More preferably Xi and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkoxymethyl, Ci-C₄-alkylsulphonyl, Ci-C₄-haloalkylsulphonyl, Ci C₄-alkylsulphinyl, Ci-C₄-haloalkylsulphinyl, Ci-C₄-alkylthio, Ci-C₄-haloalkylthio,

X₃ is heptafluoroprop-2-yl, l-[chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl, 1- [bromo(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

C(0)0-, phenoxy-C(0)0-, benzyloxy-C(0)0- and imidazol-l-yl;

Ri is H, C₁-C4 alkyl, C_rC₄ haloalkyl;

R₂ is H or C_rC₄-alkyl;

R₃ is H, fluorine, methoxy;

R_3a is H or CN,

Qi is 4-cyano-phenyl, 2-methyl-4-cyano-phenyl, 3-pyridyl or 4-pyridyl;

provided that not both R₃ and R_3a are H;

and provided that R₃ is H when R_3a is CN, and that R₃ is fluorine or methoxy when R_3a is H; The above reaction steps are described in more detail below.

The present invention further relates to compounds according to formula (III)

wherein Xi and X₂ each independently are halogen, C₁-C4 alkyl, C₁-C4 haloalkyl, C₁-C4 alkoxy, C₁-C4 haloalkoxy, C₁-C4 alkoxymethyl, Ci-C4-alkylsulphonyl, Ci-C4-haloalkylsulphonyl, C₁-C4- alkylsulphinyl, Ci-C4-haloalkylsulphinyl, Ci-C4-alkylthio, Ci-C4-haloalkylthio;

X₃ is heptafluoroprop-2-yl, l -[chloro(difluoro)methyl]- l ,2,2,2-tetrafluoro-ethyl, 1 - [bromo(difluoro)methyl]-l ,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

Ri is H, C₁-C4 alkyl, C_rC₄ haloalkyl;

The present invention further relates to compounds according to formula (IV)

wherein X₄ is a leaving group selected from halogen, Ci-C₆-alkyl-C(0)0-, phenyl-C(0)0-, Ci-C₆- alkoxy-C(0)0-, phenoxy-C(0)0-, benzyloxy-C(0)0- and imidazol-l -yl;

R₂ is C_rC₄-alkyl;

R₃ is H, fluorine or methoxy;

R_3a is H or CN;

Qi is 2-methyl-4-cyano-phenyl, 3-pyridyl or 4-pyridyl;

provided that not both R₃ and R3_a are H;

Preferably in the compounds according to formula (IV) X₄ is a leaving group selected from halogen,

Ci-C₆-alkyl-C(0)0-, phenyl-C(0)0-, C_rC₆-alkoxy-C(0)0-, phenoxy-C(0)0-, benzyloxy-C(0)0- and imidazol-l -yl;

R₂ is C_rC₄-alkyl;

R₃ is H, fluorine or methoxy;

R_3a is H or CN; Qi is 2-methyl-4-cyano-phenyl, 3-pyridyl or 4-pyridyl;

provided that not both R₃ and R3_a are H;

and provided that R₃ is H when R_3a is CN, and that R₃ is fluorine or methoxy when R_3a is H; The present invention further relates to compounds according to formula (V)

X₃ is heptafluoroprop-2-yl, l -[chloro(difluoro)methyl]- l,2,2,2-tetrafluoro-ethyl, 1-

[bromo(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

Ri is H, C₁-C4 alkyl, C_rC₄ haloalkyl;

R₂ is H or C_rC₄-alkyl;

R₃ is H, fluorine, methoxy;

R_3a is H or CN,

provided that R₃ is H when R_3a is CN;

Qi is 4-cyano-phenyl, 2-methyl-4-cyano-phenyl, 3-pyridyl or 4-pyridyl;

The compounds according to the invention, namely the compounds of formula (III), (IV) and (V), and the compounds mentioned in the method according to the invention may exist in different geometric or optical isomers or tautomeric forms.

This invention covers all such isomers and tautomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds.

The invention also covers salts of all compounds of the invention.

In particularly preferred embodiments for the methods and compounds of the invention (namely the compounds of formula (III), (IV) and (V)) and the compounds mentioned in the method according to the invention, the preferred groups for Xi, X₂, X3, X₄, Ri, R₂, R3, I¾_a and Qi in any combination thereof, are as set out below.

In one preferred embodiment R₃ is H, fluorine or methoxy

In one preferred embodiment R₃ is H;

In another preferred embodiment R₃ is fluorine;

In still another preferred embodiment R₃ is methoxy.

In one preferred embodiment R_3a is H or cyano

In one preferred embodiment R_3a is H;

In another preferred embodiment R_3a is cyano;

In one preferred embodiment R₃ is H and R_3a is H

In one preferred embodiment R₃ is fluorine and R_3a is H

In one preferred embodiment R₃ is methoxy and R_3a is H

In one preferred embodiment R₃ is H and R_3a is CN

Preferably Xi and X₂ each independently are halogen, C₁-C4 alkyl, C₁-C4 haloalkyl, C₁-C4 alkoxy, Cp C4 haloalkoxy, C₁-C4 alkoxymethyl;

More preferred Xi and X₂ each independently are halogen, C₁-C4 alkyl, C₁-C4 haloalkyl, C₁-C4 haloalkoxy;

Most preferred Xi and X₂ each independently are halogen, methyl, ethyl, trifluoromethyl or difluoromethoxy. Preferably X₃ is heptafluoroprop-2-yl, l-[chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl, 1- [bromo(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

More preferred X₃ are heptafluoroprop-2-yl, l-[chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl or 1- [bromo(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl.

Even more preferred X₃ are heptafluoroprop-2-yl or l-[bromo(difluoro)methyl]-l,2,2,2-tetrafluoro- ethyl.

Preferably X₄ is a leaving group selected from halogen, Ci-C₆-alkyl-C(0)0-, phenyl-C(0)0-, Ci-C₆- alkoxy-C(0)0-;

More preferred X₄ is a leaving group selected from halogen, Ci-C₆-alkyl-C(0)0-;

Even more preferred X₄ is a leaving group selected from halogen;

Most preferred X₄ is a chloride. Preferably Ri is H, C_rC₄ alkyl;

More preferred Ri is H, methyl;

Most preferred Ri is methyl. Preferably R₂ is H, methyl or ethyl;

More preferred R₂ is H or ethyl.

Preferably Qi is 4-cyano-phenyl, 2-methyl-4-cyano-phenyl or 4-pyridyl;

In a more preferred embodiment Qi is 2-methyl-4-cyano-phenyl or 4-pyridyl;

In a further more preferred embodiment Qi is 4-cyano-phenyl;

In an even more preferred embodiment Qi is 4-pyridyl;

In a further even more preferred embodiment Qi is 2-methyl-4-cyano-phenyl.

In one preferred embodiment (A) R₃ is H, fluorine or methoxy and R3_a is H;

Most preferred Xi and X₂ each independently are halogen, methyl, ethyl, trifluoromethyl or difluoromethoxy.

Preferably X₃ is heptafluoroprop-2-yl, l-[chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl, 1- [bromo(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

More preferred X3 are heptafluoroprop-2-yl, l-[chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl or 1- [bromo(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl.

Even more preferred X3 are heptafluoroprop-2-yl or l-[bromo(difluoro)methyl]-l,2,2,2-tetrafluoro- ethyl.

Preferrably X₄ is a leaving group selected from halogen, Ci-C₆-alkyl-C(0)0-, phenyl-C(0)0-, Ci-C₆- alkoxy-C(0)0-;

Even more preferred X₄ is a leaving group selected from halogen;

Most preferred X₄ is a chloride. Preferably Ri is H or C₁-C4 alkyl;

More preferred Ri is H or methyl;

Most preferred Ri is methyl. Preferably R₂ is methyl or ethyl;

More preferred R₂ is ethyl.

Preferably Qi is 4-cyano-phenyl or 4-pyridyl;

Further preferred Qi is 4-pyridyl;

Further preferred Qi is 4-cyano-phenyl

Further preferred Qi is 3-pyridyl or 4-pyridyl.

In one preferred embodiment (B) R₃ is H and R_3a is H;;

Preferably Xi and X₂ each independently are halogen, C₁-C4 alkyl, C₁-C4 haloalkyl, C₁-C4 alkoxy, C C4 haloalkoxy, C₁-C4 alkoxymethyl;

Most preferred Xi and X₂ each independently are halogen, methyl, ethyl, trifluoromethyl ordifluoromethoxy.

Preferably X₃ is heptafluoroprop-2-yl, l -[chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl, 1- [bromo(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

More preferred X₃ are heptafluoroprop-2-yl, l -[chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl or [bromo(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl.

Even more preferred X3 are heptafluoroprop-2-yl or l -[bromo(difluoro)methyl]-l,2,2,2-tetrafluoro- ethyl.

Even more preferred X₄ is a leaving group selected from halogen;

Most preferred X₄ is a chloride.

Preferably Ri is H or C₁-C4 alkyl;

More preferred Ri is H or methyl;

Most preferred Ri is methyl.

Preferably R₂ is methyl or ethyl;

More preferred R₂ is ethyl. Preferably Qi is 4-cyano-phenyl or 4-pyridyl;

Further preferred Qi is 4-pyridyl;

Further preferred Qi is 4-cyano-phenyl

Further preferred Qi is 3-pyridyl or 4-pyridyl;

In one preferred embodiment (C) R₃ is fluorine and R_3a is H;

More preferred Xi and X₂ each independently are halogen, C₁-C4 alkyl, C₁-C4 haloalkyl or C₁-C4 haloalkoxy;

Even more preferred X₄ is a leaving group selected from halogen;

Most preferred X₄ is a chloride.

Preferably Ri is H or C₁-C4 alkyl;

More preferred Ri is H or methyl;

Most preferred Ri is methyl.

Preferably R₂ is methyl or ethyl;

More preferred R₂ is ethyl.

Preferably Qi is 4-cyano-phenyl or 4-pyridyl;

Further preferred Qi is 4-pyridyl;

Further preferred Qi is 4-cyano-phenyl;

Further preferred Qi is 3-pyridyl or 4-pyridyl; In one preferred embodiment (D) R₃ is methoxy and P3_a is H;

Preferably Xi and X₂ each independently are halogen, C₁-C4 alkyl, C₁-C4 haloalkyl, C₁-C4 alkoxy, C C4 haloalkoxy or C₁-C4 alkoxymethyl;

Preferrably X₄ is a leaving group selected from halogen, Ci-C₆-alkyl-C(0)0-, phenyl-C(0)0-, CpC, alkoxy-C(0)0-;

Even more preferred X₄ is a leaving group selected from halogen;

Most preferred X₄ is a chloride.

Preferably Ri is H or C₁-C4 alkyl;

More preferred Ri is H or methyl;

Most preferred Ri is methyl.

Preferably R₂ is methyl or ethyl;

More preferred R₂ is ethyl.

Preferably Qi is 4-cyano-phenyl or 4-pyridyl;

Further preferred Qi is 4-pyridyl;

Further preferred Qi is 4-cyano-phenyl

Further preferred Qi is 3-pyridyl or 4-pyridyl;

In one preferred embodiment (E) R₃ is H and R3_a is cyano; Preferably Xi and X₂ each independently are halogen, C₁-C4 alkyl, C₁-C4 haloalkyl, C₁-C4 alkoxy, C C4 haloalkoxy or C₁-C4 alkoxymethyl;

Preferrably X4 is a leaving group selected from halogen, Ci-C₆-alkyl-C(0)0-, phenyl-C(0)0-, CpC, alkoxy-C(0)0-;

Even more preferred X₄ is a leaving group selected from halogen;

Most preferred X₄ is a chloride.

Preferably Ri is H or C₁-C4 alkyl;

More preferred Ri is H or methyl;

Most preferred Ri is methyl.

Preferably R₂ is methyl or ethyl;

More preferred R₂ is ethyl.

Preferably Qi is 4-cyano-phenyl or 4-pyridyl;

Further preferred Qi is 4-pyridyl;

Further preferred Qi is 4-cyano-phenyl

Further preferred Qi is 3-pyridyl or 4-pyridyl;

In a preferred embodiment (A) Qi is 4-cyano-phenyl or 4-pyridyl;

In a further preferred embodiment (A) Qi is 4-pyridyl;

In a further preferred embodiment (A) Qi is 4-cyano-phenyl;

In a further preferred embodiment (a) Qi is 3-pyridyl or 4-pyridyl; In a preferred embodiment (B) Qi is 4-cyano-phenyl or 4-pyridyl;

In a further preferred embodiment (B) Qi is 4-pyridyl;

In a further preferred embodiment (B) Qi is 4-cyano-phenyl;

In a further preferred embodiment (B) Qi is 3-pyridyl or 4-pyridyl;

In a preferred embodiment (C) Qi is 4-cyano-phenyl or 4-pyridyl;

In a further preferred embodiment (C) Qi is 4-pyridyl;

In a further preferred embodiment (C) Qi is 4-cyano-phenyl;

In a further preferred embodiment (C) Qi is 3-pyridyl or 4-pyridyl;

In a preferred embodiment (D) Qi is 4-cyano-phenyl or 4-pyridyl;

In a further preferred embodiment (D) Qi is 4-pyridyl;

In a further preferred embodiment (D) Qi is 4-cyano-phenyl;

In a further preferred embodiment (D) Qi is 3-pyridyl or 4-pyridyl;

In a preferred embodiment (E) Qi is 4-cyano-phenyl or 4-pyridyl;

In a further preferred embodiment (E) Qi is 4-pyridyl;

In a further preferred embodiment (E) Qi is 4-cyano-phenyl;

In a further preferred embodiment (E) Qi is 3-pyridyl or 4-pyridyl;

Preferably Xi and X2 each independently are halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, Cp C4 haloalkoxy or C1-C4 alkoxymethyl;

X₃ is heptafluoroprop-2-yl, l-[chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl, 1- [bromo(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;;

X₄ is a leaving group selected from halogen, Ci-C6-alkyl-C(0)0-, phenyl-C(0)0-, Ci-C6-alkoxy- C(0)0-;

Ri is H or C_rC₄ alkyl;

R2 is methyl or ethyl;

Qi is 2- pyridyl or 4-pyridyl.

Equally preferably Xi and X2 each independently are halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, Cp C4 haloalkoxy, C1-C4 alkoxymethyl,

Ri is H, C1-C4 alkyl, R₂ is methyl or ethyl

Qi is 4-cyano-phenyl, 3- pyridyl or 4-pyridyl;

More preferred Xi and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy;

X3 is heptafluoroprop-2-yl;

X₄ is a leaving group selected from halogen, Ci-C6-alkyl-C(0)0-;

Ri is H or methyl;

R₂ is ethyl;

Qi is 4-pyridyl.

More preferred Xi and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,

X₃ is l-[chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl;

X₄ is a leaving group selected from halogen, Ci-C6-alkyl-C(0)0-;

Ri is H, methyl,

R₂ is ethyl

Qi is 4-pyridyl; More preferred Xi and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,

X₃ is l-[bromo(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl;

X₄ is a leaving group selected from halogen, Ci-C6-alkyl-C(0)0-;

Ri is H, methyl,

R₂ is ethyl

Qi is 4-pyridyl;

X₃ is nonafluorobut-2-yl;

X₄ is a leaving group selected from halogen, Ci-C6-alkyl-C(0)0-;

Ri is H, methyl,

R₂ is ethyl

Qi is 4-pyridyl;

More preferred R3 is methoxy; and R3_a is H,

More preferred R3 is fluorine; and R3_a is H, More preferred R₃ is H; and R_3a is CN,

More preferred R₃ is H; R_3a is H,

The following schemes describe the reactions of the invention in more detail. The substituent definitions are the same as defined previously:

Scheme 1

Step a)

Compounds of formula (III) can be prepared by reacting compounds of formula (I) with compounds of formula (II).

The reactions of compounds of formula (I) with compounds of formula (II) are preferably carried out in the presence of a suitable base. Suitable bases include, but are not limited to carbonates such as Na₂C0₃, K₂C0₃, hydroxides such as NaOH, nitrogen-based organic bases such as amines, pyridines and derivatives thereof, e.g. triethylamine, tri-n-propylamine, pyridine and diisopropylethylamine. The reactions of compounds of formula (I) with compounds of formula (II) are preferably carried out in the presence of a solvent. Suitable solvents include, but are not limited to organic solvents such as toluene, chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene,THF, dioxane, preferably chloroform, dichloromethane. It is also possible to conduct the reaction in a biphasic mixture of an organic solvent and water.

The reaction can be carried out at a temperature from -20°C to 100°C, preferably from 0°C to 30°C (e.g. greater than -20°C, preferably greater than 0°C, e.g. lower than 100°C, preferably lower than 30°C). The reactions of compounds of formula (I) and (II) are preferably carried out in the presence of a catalyst. Suitable catalysts include, but are not limited to nucleophilic catalysts capable of promoting acyl transfer reactions such as 4-dialkylaminopyridines, N-alkylimidazoles, phosphines,

imidazolylidene carbenes, 1 ,2-diamines, bicyclic amidines, isothioureas and guanidines, triazoles, some alcohols, iodide and cyanide salts, preferably 4-dimethylaminopyridine.

Alternatively the reaction can be carried out in the presence of a catalytic amount of a suitable acid. Suitable acids include but are not limited to mineral acids such as sulfuric acid, hydrochloric acid and organic acids such as trifluoroacetic acid.

The reactions of compounds of (I) and (II) are carried out either by using compound of formula (II) as the solvent or in the presence of suitable additional organic solvent. Suitable solvents include but are not limited to dichloromethane, dichloroethane, THF and dioxane.

The reaction can be carried out at a temperature from 0 °C to 120°C, preferably from 30°C to 100 °C (e.g. greater than 0 °C, preferably greater than 30 °C, e.g. lower than 120°C, preferably lower than 70°C).

The reaction between compounds of formula (I) and compounds of formula (II) can be carried out under acidic conditions to yield compounds of formula III. Compounds of formula III can be formed by hydrolysis of intermediate compounds of formula Ilia. It is thus preferable to treat the resulting mixture of compounds of formula (III) and diacylated intermediate (Ilia) obtained in step a, with a suitable aqueous base. Suitable bases include, but are not limited to, aqueous solutions of NaOH, LiOH, Na₂C0₃, or K₂C0₃. Suitable organic co-solvents include, but are not limited to, THF and dioxane.

Step b)

Compounds of formula (V) can be prepared by reacting compounds of formula (III) with compounds of formula (IV).

The reactions of compounds of formula (III) with compounds of formula (IV) are preferably carried out in the presence of a suitable base. Suitable bases include, but are not limited to, carbonates such as Na₂C0₃, K₂CO₃, hydroxides such as NaOH, nitrogen-based organic bases such as amines, pyridines and derivatives thereof, e.g. triethylamine, tri-n-propylamine, pyridine and diisopropylethylamine. The reactions of compounds of formula (III) with compounds of formula (IV) are preferably carried out in the presence of a solvent. Suitable solvents include, but are not limited to organic solvents such as toluene, chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene,THF, or dioxane, preferably chloroform ordichloromethane. It is also possible to conduct the reaction in a biphasic mixture of an organic solvent and water.

The reaction can be carried out at a temperature from -20°C to 100°C, preferably from 0°C to 30°C (e.g. greater than -20°C, preferably greater than 0°C, e.g. lower than 100°C, preferably lower than 30°C). The reactions of compounds of formula (III) and (IV) could be carried out in the presence of a catalyst. Suitable catalysts include, but are not limited to nucleophilic catalysts capable of promoting acyl transfer reactions such as 4-dialkylaminopyridines, N-alkylimidazoles, phosphines,

Step c)

Compounds of formula (VI) can be prepared by reacting compounds of formula (V) with a suitable base. Suitable bases include but are not limited to aqueous solutions of NaOH, LiOH or K₂CO₃. The reactions of compounds of formula (VI) with an aqueous base are preferably carried out in the presence of a suitable organic co-solvent. Suitable solvents include, but are not limited to, THF, dioxane and ethanol.

The reaction can be carried out at a temperature from -20°C to 100°C, preferably from 0°C to 30°C (e.g. greater than -20°C, preferably greater than 0°C, e.g. lower than 100°C, preferably lower than 30°C).

Alternatively the compounds of formula (VI) can be prepared in a one pot process by reacting compounds of formula (III) with compounds of formula (IV) as described for step b, followed by addition of a suitable aqueous base.

Suitable bases include, but are not limited to LiOH, NaOH, KOH, Na₂C0₃, K₂C0₃.

1) Acid halides of formula (IV), wherein R is CI, F or Br, may be made from carboxylic acids of formula (IV), wherein R is OH by treatment with thionyl chloride, oxalyl chloride or phosgene.

2) Carboxylic acids of formula (IV), wherein R is OH, may be formed from esters of formula (IV), wherein R is CpCealkoxy by treatment of the ester with an alkali hydroxide, such as lithium hydroxide, in a solvent, such as a mixture of THF and water.

3) Esters of formula (IV), wherein R is CpCealkoxy, may be made by reacting compounds of formula (VII), wherein R is CpCealkoxy, by acylation with a carboxylic acid of formula (VIII) wherein R4 is OH or with acid halide of formula (VIII) wherein R4 is CI, F or Br. When R4 is OH such reactions may be carried out in the presence of a coupling reagent, such as DCC (N,N'-dicyclohexyl- carbodiimide), EDC (l-ethyl-3-[3-dimethylamino-propyl]carbodiimide hydrochloride) or BOP-C1 (bis(2-oxo-3-oxazolidinyl)phosphonic chloride), in the presence of a base, such as pyridine, triethylamine, 4-(dimethylamino)pyridine or diisopropylethylamine, and optionally in the presence of a nucleophilic catalyst, such as hydroxybenzotriazole. When R4 is CI, such reactions may be carried out under basic conditions, for example in the presence of pyridine, triethylamine, 4- (dimethylamino)pyridine or diisopropylethylamine, and optionally in the presence of a nucleophilic catalyst. Alternatively, the reaction may be conducted in a biphasic system comprising an organic solvent, preferably ethyl acetate, and an aqueous solvent, preferably a solution of sodium bicarbonate. When R4 is CpCealkoxy the ester may be converted directly to the amide by heating the ester and amine together in a thermal process.

4) Compounds of formula (VII), wherein R is CpCealkoxy, may be made from compounds of formula (IX) by sequential treatment with an alcohol R-OH under acidic conditions and then formation of the N-R¹ bond. For example, reductive amination may be achieved by treatment of the amine with an aldehyde or ketone and a reducing agent such as sodium cyanoborohydride.

Alternatively, alkylation may be achieved by treating the amine with an alkylating agent such as an alkyl halide, optionally in the presence of a base.

R = Ci-Ce-Alkoxy

6) Alternatively, compounds of formula (VII), wherein R is CpCealkoxy, may be made from a compound of formula (X), wherein R is CpCealkoxy and LG is a leaving group, such as fluoro, chloro or sulfonate, via the displacement of the leaving group by an amine of formula R¹-NH₂ or other imine analogue followed by hydrolysis with a metal catalyst. See, for example: Chemical Communications (2009), (14), 1891-1893 or Journal of Organic Chemistry (2000), 65(8), 2612-2614.

Compounds of formula (X) and amines of formula R¹-NH₂ are either known compounds or may be made by methods known to a person skilled in the art.

6a) Alternatively, compounds of formula (VII), wherein R is CpCealkoxy, may be made from a compounds of formula (XI), wherein R is CpCealkoxy via reduction in the presence of a metal catalyst and a suitable two carbon building block such as acetaldehyde or acetonitrile. See for example: J. Org. Chem. 2007, 72, 9815 or Org. Lett. 2005, 7, 471 

80210- WO-REG-ORG-P- 1

80210- WO-REG-ORG-P- 1

80210- WO-REG-ORG-P- 1

80210- WO-REG-ORG-P- 1

80210- WO-REG-ORG-P- 1

80210- WO-REG-ORG-P- 1

80210- WO-REG-ORG-P- 1

80210- WO-REG-ORG-P- 1

Table 1 : Compounds of the formula (V) wherein Xi is CI, X₂ is CI and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 2: Compounds of the formula (V) wherein Xi is Br, X₂ is CI and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 3 : Compounds of the formula (V) wherein Xi is I, X₂ is CI and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 4: Compounds of the formula (V) wherein Xi is methyl, X₂ is CI and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 5: Compounds of the formula (V) wherein Xi is ethyl, X₂ is CI and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 6: Compounds of the formula (V) wherein Xi is trifluoromethyl, X₂ is CI and the

combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A. l to A.156 of Table A.

Table 7: Compounds of the formula (V) wherein Xi is trifluoromethoxy, X₂ is CI and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line

A.l to A.156 of Table A.

Table 8: Compounds of the formula (V) wherein Xi is difluoromethoxy, X₂ is CI and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A. l to A.156 of Table A.

Table 9: Compounds of the formula (V) wherein Xi is trifluoromethylthio, X₂ is CI and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line

A. l to A.156 of Table A.

Table 10: Compounds of the formula (V) wherein Xi is trifluoromethylsulfinyl, X₂ is CI and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line

A. l to A.156 of Table A.

Table 11 : Compounds of the formula (V) wherein Xi is Br, X₂ is Br and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A. l to A.156 of

Table A.

Table 12: Compounds of the formula (V) wherein Xi is I, X₂ is Br and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A. Table 13: Compounds of the formula (V) wherein Xi is methyl, X₂ is Br and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 14: Compounds of the formula (V) wherein Xi is ethyl, X₂ is Br and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 15: Compounds of the formula (V) wherein Xi is trifluoromethyl, X₂ is Br and the

combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line

A.l to A.156 of Table A.

Table 16: Compounds of the formula (V) wherein Xi is trifluoromethoxy, X₂ is Br and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line

A. l to A.156 of Table A.

Table 17: Compounds of the formula (V) wherein Xi is difluoromethoxy, X₂ is Br and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line

A. l to A.156 of Table A.

Table 18: Compounds of the formula (V) wherein Xi is trifluoromethylthio, X₂ is Br and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line

A. l to A.156 of Table A.

Table 19: Compounds of the formula (V) wherein Xi is trifluoromethylsulfinyl, X₂ is Br and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line

A. l to A.156 of Table A.

Table 20: Compounds of the formula (V) wherein Xi is I, X₂ is I and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of

Table A.

Table 21 : Compounds of the formula (V) wherein Xi is methyl, X₂ is I and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 22: Compounds of the formula (V) wherein Xi is ethyl, X₂ is I and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 23: Compounds of the formula (V) wherein Xi is trifluoromethyl, X₂ is I and the

A. l to A.156 of Table A.

Table 24: Compounds of the formula (V) wherein Xi is trifluoromethoxy, X₂ is I and the

A. l to A.156 of Table A. Table 25: Compounds of the formula (V) wherein Xi is difluoromethoxy, X₂ is I and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line

A. l to A.156 of Table A.

Table 26: Compounds of the formula (V) wherein Xi is trifluoromethylthio, X₂ is I and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line

A. l to A.156 of Table A.

Table 27: Compounds of the formula (V) wherein Xi is trifluoromethylsulfinyl, X₂ is I and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line

A. l to A.156 of Table A.

Table 28: Compounds of the formula (V) wherein Xi is methyl, X₂ is methyl and the

A. l to A.156 of Table A.

Table 29: Compounds of the formula (V) wherein Xi is ethyl, X₂ is methyl and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to

A.156 of Table A.

Table 30: Compounds of the formula (V) wherein Xi is trifluoromethyl, X₂ is methyl and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line

A. l to A.156 of Table A.

Table 31 : Compounds of the formula (V) wherein Xi is trifluoromethoxy, X₂ is methyl and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line

A. l to A.156 of Table A.

Table 32: Compounds of the formula (V) wherein Xi is difluoromethoxy, X₂ is methyl and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line

A. l to A.156 of Table A.

Table 33: Compounds of the formula (V) wherein Xi is trifluoromethylthio, X₂ is methyl and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 34: Compounds of the formula (V) wherein Xi is trifluoromethylsulfinyl, X₂ is methyl and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 35: Compounds of the formula (V) wherein Xi is ethyl, X₂ is ethyl and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to

A.156 of Table A.

Table 36: Compounds of the formula (V) wherein Xi is trifluoromethyl, X₂ is ethyl and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A. l to A.156 of Table A. Table 37: Compounds of the formula (V) wherein Xi is trifluoromethoxy, X₂ is ethyl and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line

A. l to A.156 of Table A.

Table 38: Compounds of the formula (V) wherein Xi is difluoromethoxy, X₂ is ethyl and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line

A. l to A.156 of Table A.

Table 39: Compounds of the formula (V) wherein Xi is trifluoromethylthio, X₂ is ethyl and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line

A. l to A.156 of Table A.

Table 40: Compounds of the formula (V) wherein Xi is trifluoromethylsulfinyl, X₂ is ethyl and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A. l to A.156 of Table A.

Table 41 : Compounds of the formula (V) wherein Xi is trifluoromethyl, X₂ is trifluoromethyl and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 42: Compounds of the formula (V) wherein Xi is trifluoromethoxy, X₂ is trifluoromethyl and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 43: Compounds of the formula (V) wherein Xi is difluoromethoxy, X₂ is trifluoromethyl and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 44: Compounds of the formula (V) wherein Xi is trifluoromethylthio, X₂ is

trifluoromethyl and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A. l to A.156 of Table A.

Table 45: Compounds of the formula (V) wherein Xi is trifluoromethylsulfinyl, X₂ is

trifluoromethyl and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 46: Compounds of the formula (V) wherein Xi is trifluoromethoxy, X₂ is

trifluoromethoxy and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 47: Compounds of the formula (V) wherein Xi is difluoromethoxy, X₂ is

Table 48: Compounds of the formula (V) wherein Xi is trifluoromethylthio, X₂ is

trifluoromethoxy and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A. Table 49: Compounds of the formula (V) wherein Xi is trifluoromethylsulfinyl, X₂ is trifluoromethoxy and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 50: Compounds of the formula (V) wherein Xi is difluoromethoxy, X₂ is difluoromethoxy and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A. l to A.156 of Table A.

Table 51 : Compounds of the formula (V) wherein Xi is trifluoromethylthio, X₂ is

difluoromethoxy and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 52: Compounds of the formula (V) wherein Xi is trifluoromethylsulfinyl, X₂ is

Table 53: Compounds of the formula (V) wherein Xi is trifluoromethylthio, X₂ is

trifluoromethylthio and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table 54: Compounds of the formula (V) wherein Xi is trifluoromethylsulfinyl, X₂ is

Table 55: Compounds of the formula (V) wherein Xi is trifluoromethylsulfinyl, X₂ is

trifluoromethylsulfinyl and the combination of the substituents X₃, Ri, R₂, R3 and Qi for each compound corresponds to a line A.l to A.156 of Table A.

Table B:

Table 56: Compounds of the formula (IV) wherein X₄ is CI and the combination of the

substituents R¾ ₃ and Qi for each compound corresponds to a line B. l to B.20 of Table B. Table 57: Compounds of the formula (IV) wherein X₄ is F and the combination of the

substituents R₂, R₃ and Qi for each compound corresponds to a line B.l to B.20 of Table B. Table 58: Compounds of the formula (IV) wherein X₄ is Br and the combination of the

substituents R₂, R₃ and Qi for each compound corresponds to a line B. l to B.20 of Table B. Table 59: Compounds of the formula (IV) wherein X₄ is I and the combination of the

substituents R₂, R₃ and Qi for each compound corresponds to a line B. l to B.20 of Table B. Table 60: Compounds of the formula (IV) wherein X is acetoxy and the combination of the substituents R₂, R₃ and Qi for each compound corresponds to a line B.l to B.20 of Table B. Table 61 : Compounds of the formula (IV) wherein X is formyloxy and the combination of the substituents R₂, R₃ and Qi for each compound corresponds to a line B. l to B.20 of Table B. Table 62: Compounds of the formula (IV) wherein X is benzoyloxy and the combination of the substituents R₂, R₃ and Qi for each compound corresponds to a line B. l to B.20 of Table B. Table 63: Compounds of the formula (IV) wherein X is methoxycarbonyloxy and the

combination of the substituents R₂, R₃ and Qi for each compound corresponds to a line B.l to

B.20 of Table B.

Table 64: Compounds of the formula (IV) wherein X is ethoxycarbonyloxy and the

combination of the substituents R₂, R₃ and Qi for each compound corresponds to a line B.l to B.20 of Table B. Table 65: Compounds of the formula (IV) wherein X₄ is isopropoxycarbonyloxy and the combination of the substituents R¾ R₃ and Qi for each compound corresponds to a line B.l to B.20 of Table B.

Table 66: Compounds of the formula (IV) wherein X₄ is phenoxycarbonyloxy and the

combination of the substituents R₂, R₃ and Qi for each compound corresponds to a line B.l to B.20 of Table B.

Table 67: Compounds of the formula (IV) wherein X₄ is benzyloxycarbonyloxy and the

Table 68: Compounds of the formula (IV) wherein X₄ is imidazol-l-yl and the combination of the substituents R₂, R₃ and Qi for each compound corresponds to a line B.l to B.20 of Table B.

Table C:

Table 69: Compounds of the formula (III) wherein X₃ is heptafluoroprop-2-yl, Ri is H and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Table 70: Compounds of the formula (III) wherein X₃ is heptafluoroprop-2-yl, Ri is methyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Table 71 : Compounds of the formula (III) wherein X₃ is heptafluoroprop-2-yl, Ri is ethyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Table 72: Compounds of the formula (III) wherein X₃ is heptafluoroprop-2-yl, Ri is isopropyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Table 73 : Compounds of the formula (III) wherein X₃ is nonafluorobut-2-yl, Ri is H and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Table 74: Compounds of the formula (III) wherein X₃ is nonafluorobut-2-yl, Ri is methyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Table 75: Compounds of the formula (III) wherein X₃ is nonafluorobut-2-yl, Ri is ethyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Table 76: Compounds of the formula (III) wherein X₃ is nonafluorobut-2-yl, Ri is isopropyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Table 77: Compounds of the formula (Ilia) wherein X₃ is heptafluoroprop-2-yl, Ri is H and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Table 78: Compounds of the formula (Ilia) wherein X₃ is heptafluoroprop-2-yl, Ri is methyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C. Table 79: Compounds of the formula (Ilia) wherein X₃ is heptafluoroprop-2-yl, Ri is ethyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C.l to C.55 of Table C.

Table 80: Compounds of the formula (Ilia) wherein X₃ is heptafluoroprop-2-yl, Ri is isopropyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C.l to C.55 of Table C.

Table 81 : Compounds of the formula (Ilia) wherein X₃ is nonafluorobut-2-yl, Ri is H and the combination of the substituents Xi and X₂ for each compound corresponds to a line C.l to C.55 of Table C.

Table 82: Compounds of the formula (Ilia) wherein X₃ is nonafluorobut-2-yl, Ri is methyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C.l to C.55 of Table C.

Table 83: Compounds of the formula (Ilia) wherein X₃ is nonafluorobut-2-yl, Ri is ethyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C.l to C.55 of Table C.

Table 84: Compounds of the formula (Ilia) wherein X₃ is nonafluorobut-2-yl, Ri is isopropyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C.l to C.55 of Table C.

Table 85: Compounds of the formula (III) wherein X₃ is l-[chloro(difluoro)methyl] -1,2,2,2- tetrafluoro-ethyl, Ri is H and the combination of the substituents Xi and X₂ for each compound corresponds to a line C.l to C.55 of Table C.

Table 86: Compounds of the formula (III) wherein X₃ is l-[chloro(difluoro)methyl] -1,2,2,2- tetrafluoro-ethyl, Ri is methyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C.l to C.55 of Table C.

Table 87: Compounds of the formula (III) wherein X₃ is l-[chloro(difluoro)methyl] -1,2,2,2- tetrafluoro-ethyl, Ri is ethyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C.l to C.55 of Table C.

Table 88: Compounds of the formula (III) wherein X₃ is l-[chloro(difluoro)methyl] -1,2,2,2- tetrafluoro-ethyl, Ri is isopropyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C.l to C.55 of Table C.

Table 89: Compounds of the formula (III) wherein X₃ is l-[bromo(difluoro)methyl] -1,2,2,2- tetrafluoro-ethyl, Ri is H and the combination of the substituents Xi and X₂ for each compound corresponds to a line C.l to C.55 of Table C.

Table 90: Compounds of the formula (III) wherein X₃ is l-[bromo(difluoro)methyl] -1,2,2,2- tetrafluoro-ethyl, Ri is methyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C.l to C.55 of Table C. Table 91 : Compounds of the formula (III) wherein X₃ is l -[bromo(difluoro)methyl] -1 ,2,2,2- tetrafluoro-ethyl, Ri is ethyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Table 92: Compounds of the formula (III) wherein X₃ is l -[bromo(difluoro)methyl] -1 ,2,2,2- tetrafluoro-ethyl, Ri is isopropyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Table 93 : Compounds of the formula (Ilia) wherein X₃ is l -[chloro(difluoro)methyl] -1 ,2,2,2- tetrafluoro-ethyl, Ri is H and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Table 94: Compounds of the formula (Ilia) wherein X₃ is l -[chloro(difluoro)methyl] -1 ,2,2,2- tetrafluoro-ethyl, Ri is methyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Table 95: Compounds of the formula (Ilia) wherein X₃ is l -[chloro(difluoro)methyl] -1 ,2,2,2- tetrafluoro-ethyl, Ri is ethyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Table 96: Compounds of the formula (Ilia) wherein X₃ is l -[chloro(difluoro)methyl] -1 ,2,2,2- tetrafluoro-ethyl, Ri is isopropyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Table 97: Compounds of the formula (Ilia) wherein X₃ is l -[bromo(difluoro)methyl] -1 ,2,2,2- tetrafluoro-ethyl, Ri is H and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Table 98: Compounds of the formula (Ilia) wherein X₃ is l -[bromo(difluoro)methyl] -1 ,2,2,2- tetrafluoro-ethyl, Ri is methyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Table 99: Compounds of the formula (Ilia) wherein X₃ is l -[bromo(difluoro)methyl] -1 ,2,2,2- tetrafluoro-ethyl, Ri is ethyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Table 100: Compounds of the formula (Ilia) wherein X₃ is l -[bromo(difluoro)methyl] -1 ,2,2,2- tetrafluoro-ethyl, Ri is isopropyl and the combination of the substituents Xi and X₂ for each compound corresponds to a line C. l to C.55 of Table C.

Preparation Examples

Examples

The following abbreviations were used throughout this section: s = singlet; bs = broad singlet; d = doublet; dd = double doublet; dt = double triplet; t = triplet, tt = triple triplet, q = quartet, sept = septet; m = multiplet; Me = methyl; Et = ethyl; Pr = propyl; Bu = butyl; M.p. = melting point. Example 1 : Meth l 3-(ethylamino)-2-methoxy-benzoate '

A pressure vial was charged with Pd/C (10%, 0.021 g) and 2-propanol (3.4 ml). A solution of ammonium formiate (0.452 g, 7.10 mmol) in water (0.35 ml) was added and the resulting mixture was stirred for 5 min. Methyl 2-methoxy-3-nitro-benzoate (0.100 g, 0.473 mmol) was added and the reaction media was cooled to 0 C. Acetaldehyde (0.105 g, 2.37 mmol) was added and the reaction media was stirred for 16 h at ambient temperature. The reaction mixture was filtered through a short pad of celite and filtrate was evaporated under reduced pressure. The residue was dissolved in dichloromethane and washed with brine. Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was further purified by column chromatography on silica gel (eluent: 0-30% EtOAc in cyclohexane) to give methyl 3-(ethylamino)-2-methoxy-benzoate (0.0839 g, 85%) as a beige oil H NMR (400 MHz, CDC1₃): 7.09 (dd, 1H), 7.01 (t, 1H), 6.77 (dd, 1H), 4.30 (bs, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.16 (q, 2H), 1.27 (t, 3H) ppm.

Example 2: Methyl 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoate

To a solution of methyl 3-(ethylamino)-2-methoxy-benzoate (0.158 g, 0.754 mmol) in dichloromethane (2.6 ml) was added triethylamine (0.233 ml, 1.66 mmol) followed by 4-cyanobenzoyl chloride (0.140 g, 0.829 mmol). After stirring at ambient temperature for 16 h the reaction was quenched by addition of saturated aqueous NH₄C1. The mixture was extracted with dichloromethane (2x) and organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was further purified by column chromatography on silica gel (eluent: 0-40%> EtOAc in cyclohexane) to give methyl 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy- benzoate (0.207 g, 81%) as a beige gum.

lH NMR (400 MHz, CDC1₃): 7.77-7.58 (m, 1H), 7.55-7.35 (m, 4H), 7.32-7.20 (m, 1H), 7.12-6.99 (m, 1H), 4.20 (bs, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.73-3.61 (m, 1H), 1.33-1.21 (m, 3H) ppm Example 3 : 3 - [(4-cyanobenzoyl)-ethyl-amino] -2-methoxy-benzoic acid

To a solution of 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoate (0.120 g, 0.354 mmol) in MeOH (1.2 ml) was added 5M NaOH (0.142 ml, 0.707 mmol). The reaction mixture was stirred for 1.5 h at ambient temperature before being quenched by addition of aqueous saturated NH₄C1. The mixture was extracted with dichloromethane (3x), combined organice layers were washed with brine, dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to obtain3-[(4-cyanobenzoyl)- ethyl-amino] -2-methoxy-benzoic acid (0.0827 g, 72%) as a white solid sufficiently pure for further chemistry.

lH NMR (400 MHz, CDC1₃): 7.98-7-78 (m, 1H), 7.68-7.29 (m, 5H), 7.25-7.10 (m, 1H), 4.30 (bs, 1H), 3.91 (s, 3H), 3.71-3.57 (m, 1H), 1.42-1.19 (m, 3H) ppm

Example 4: N- [2-bromo-6-chloro-4- [ 1 ,2,2,2-tetrafluoro- 1 -(trifluoromethyl)ethyl]phenyl] acetamide

A solution of 2-bromo-6-chloro-4-[l ,2,2,2-tetrafluoro-l -(trifluoromethyl)ethyl]aniline (5.00 g, 12.0 mmol) in acetic anhydride (30 ml) was heated to 60 C and few drops of concentrated sulfuric acid was added. The heating was continued for further 90 min and then most of acetic anhydride was evaporated under reduced pressure. The residue was taken dissolved in THF (25 ml) and aqueous 2N NaOH (35 ml) was added. The reaction mixture was stirred at ambient temperature for 2 h before being extracted with dichloromethane (3x). Combined organic layers were dried over anhydrous Na₂S0₄ and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-40% EtOAc in cyclohexane) to afford N- [2 -bromo-6-chlo ro-4-[l , 2,2,2-tetrafluoro- l-(trifluoromethyl)ethyl]phenyl]acetamide (5.00 g, 90%) as a beige solid.

lH NMR (400 MHz, CDC1₃): 7.77 (s, 1H), 7.66 (s, 1H), 7.18 (brs, 1H), 2.24 (brs, 3H) ppm. Example 5: N-acetyl-N-[2-bromo-6-chloro-4-[l ,2,2,2-tetrafluoro-l-(trifluoromethyl ethyllphenyll-3- [(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzamide

Step 1

Preparation of 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoyl chloride. To a suspension of 3- [(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoic acid (1.00 g, 3.08 mmol) in 1 ,2-dichloroethane was one drop of DMF followed by a slow addition of oxalyl chloride (0.284 ml, 3.24 mmol). The reaction mixture was stirred for further 30 min to afford a solution of 3-[(4-cyanobenzoyl)-ethyl- amino]-2-methoxy-benzoyl chloride which was used for the next step immediately.

Step 2

To a solution of N-[2-bromo-6-chloro-4-[l ,2,2,2-tetrafluoro-l-

(trifluoromethyl)ethyl]phenyl]acetamide (1.28 g, 3.08 mmol) in 1 ,2-dichlorethane (11 ml) was added triethylamine (1.08 ml, 7.70 mmol). The solution of acid chloride prepared in the step 1 was added dropwise at 0 C and the reaction mixture was stirred at room temperature for 4 h. The reaction was quenched by addition of aqueous saturated NaHC03, the aqueous phase was extracted with DCM (3x), the combined organic layers were dried over anhydrous Na2S04 and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-30% EtOAc in cyclohexane) to afford N-acetyl-N-[2-bromo-6-chloro-4-[l ,2,2,2 etrafluoro-l-(trifluoromethyl)ethyl]phenyl]-3-[(4- cyanobenzoyl)-ethyl-amino]-2-methoxy-benzamide (1.61 g, 71%) as a white solid.

lH NMR (400 MHz, CDC1₃): 7.88 (brs, 1H), 7.81-7.73 (m, 1H), 7.56-7.41 (m, 4H), 7.39-7.31 (m, 1H), 7.17-7.07 (m, 1H), 7.04-6.94 (m, 1H), 4.34-4.19 (m, 1H), 3.90 (s, 3H), 3.73-3.59 (m, 1H), 2.02-1.87 (m, 3H), 1.36-1.22 (m, 3H) ppm.

Example 6: N- [2-bromo-6-chloro-4- [1,1,1 ,2,3 ,3 ,3 -heptafluoro-prop-2-yl]phenyl] -3 - [(4- cyanobenzoyl)-ethyl-amino]-2-methoxy-benzamide

To a solution of N-acetyl-N-[2-bromo-6-chloro-4-[l,2,2,2-tetrafluoro-l- (trifluoromethyl)ethyl]phenyl]-3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzamide (0.0750 g, 0.0995 mmol) in THF (0.5 ml) was added IN NaOH (0.40 ml, 0.40 mmol) and the resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate, phases were separated and the aqueous phase was extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous Na2S04 and evaporated under reduced pressure to afford pure N-[2-bromo-6-chloro-4-[l, 1,1, 2,3,3, 3-heptafluoro-prop-2-yl]phenyl]-3-[(4-cyanobenzoyl)-ethyl- amino]-2-methoxy-benzamide (0.0706 g, 98%>) as a beige solid.

lH NMR (400 MHz, CDC1₃): 8.78 (bs, 1H), 8.04 (d, 1H), 7.81 (s, 1H), 7.70 (s, 1H), 7.55 (d, 1H), 7.40- 7.55 (m, 4H), 7.43 (t, 1H), 4.34-4.48 (m, 1H), 3.96 (s, 3H), 3.67-3.80 (m, 1H), 1.48 (t, 3H) ppm. Example 7: methyl 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoate

To a solution of methyl 3-(ethylamino)-2-methoxy-benzoate (1.168 g, 5.58 mmol) in DCM (20 ml) was added triethylamine (1.89 ml, 13.40 mmol) followed by isonicotinoyl chloride hydrochloride (1.217 g, 6.70 mmol) and the reaction mixture was stirred at 40 C for 1 h. The reaction mixture was cooled to room temperature and quenched by addition of aqueous saturated NaHC0₃ and IN NaOH was added until pH=8-9. The aqueous phase was extracted with DCM (3x), combined organic layers were dried over anhydrous Na₂S0₄ and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-100% EtOAc in cyclohexane) to afford methyl 3- [ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoate (1.644 g, 94%) as a beige oil.

lH NMR (400 MHz, CDC1₃): 8.44 (s, 2H), 7.65 (d, 1H), 7.30-7.11 (m, 3H), 7.09-6.98 (m, 1H), 4.31- 4.17 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.71-3.59 (m, 1H), 1.33-1.23 (m, 3H) ppm.

Example 8: 3 - [ethyl(pyridine-4-carbonyl)amino] -2-methoxy-benzoic acid hydrochloride

To a solution of methyl 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoate (0.108 g, 0.343 mmol) in a mixture of THF (0.82 ml) and water (0.28 ml) was added lithium hydroxide hydrate (0.0153 g, 0.36 mmol). The reaction mixture was stirred at 50 C for 1 h, cooled to room temperature and acidified with IN HCl. The reaction mixture was extracted with DCM (3x), the combined organic layers were dried over anhydrous Na₂S0₄ and evaporated under reduced pressure. Thus obtained crude 3 -[ethyl(pyridine-4-carbonyl)amino] -2-methoxy-benzoic acid hydrochloride (0.060 g, 52%) was without further purification. ^lH NMR (400 MHz, CDC1₃): 8.48 (s, 2H), 7.89 (d, 1H), 7.43-7.32 (m, 1H), 7.27-7.09 (m, 3H), 4.38- 4.24 (m, 1H), 3.92 (s, 3H), 3.70-3.58 (m, 1H), 1.40-1.27 (m, 3H) ppm.

Example 9: N- [3 - [acetyl- [2-bromo-6-chloro-4- [ 1 ,2,2,2-tetrafluoro- 1 -

(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-ethyl-pyridine-4-carboxamide

Step 1

Preparation of 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoyl chloride hydrochloride. To a suspension of 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoic acid hydrochloride (0.0985 g, 0.278 mmol) in 1 ,2-dichloroethane (0.83 ml) was added one drop of DMF followed by slow addition of oxalyl chloride (0.0256 ml, 0.292 mmol). The resulting reaction mixture was stirred at room temperature for 40 min to afford a solution of 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy- benzoyl chloride hydrochloride which was immediately used for the next step.

Step 2

To a solution of N-[2-bromo-6-chloro-4-[l ,2,2,2-tetrafluoro-l-

(trifluoromethyl)ethyl]phenyl]acetamide (0.116 g, 0.278 mmol) in 1 ,2-dichloroethane (0.83 ml) was added triethylamine (0.137 ml, 0.973 mmol) followed by a dropwise addition of the solution of acid chloride prepared in the step 1 at 0 C. The resulting reaction mixture was stirred at room temperature for 2 h and quenched by addition of aqueous saturated NaHC0₃. The aqueous phase was extracted with DCM (3x), combined organic layers were dried over anhydrous Na₂S0₄ and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-100% EtOAc in cyclohexane) to afford N- [3 -[acetyl- [2 -bromo-6-chloro-4-[l ,2,2,2-tetrafluoro-l - (trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-ethyl-pyridine-4-carboxamide (0.1 16 g, 59%) as a white solid. ^lH NMR (400 MHz, CDC1₃): 8.56-8.41 (m, 2H), 7.87 (s, 1H), 7.75 (d, 1H), 7.44-7.32 (m, 1H), 7.26- 7.08 (m, 3H), 7.05-6.93 (m, 1H), 4.34-4.20 (m, 1H), 3.91 (s, 3H), 3.71 -3.58 (m, 1H), 2.67 (d, 3H), 1.35-1.21 (m, 3H) ppm.

ExampleJ LN- [3 - [[2-bromo-6-chloro-4- [ 1 ,2,2,2-tetrafluoro- 1 -

To a solution of N-[3-[acetyl-[2-bromo-6-chloro-4-[l ,2,2,2-tetrafluoro-l -

(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-ethyl-pyridine-4-carboxamide (0.106 g, 0.152 mmol) in THF (0.76 ml) was added 1M NaOH (0.61 ml, 0.61 mmol) and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and ethyl acetate, phases were separated and the aqueous phase was extracted with ethyl acetate (3x). Combined organic layers were dried over anhydrous Na₂S0₄ and evaporated under reduced pressure to afford a pure N-[3-[[2-bromo-6-chloro-4-[l ,2,2,2-tetrafluoro-l -

(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-ethyl-pyridine-4-carboxamide (0.100 g, 96%) as a white solid.

lH NMR (400 MHz, CDC1₃): 8.79 (s, 1H), 8.47 (s, 2H), 8.06 (d, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.53- 7.47 (m, 1H), 7.35-7.27 (m, 1H), 7.23-7.13 (m, 2H), 4.46-4.33 (m, 1H), 3.96 (s, 3H), 3.76-3.64 (m, 1H), 1.48-1.38 (m, 3H) ppm. Example 11 : N-[2-bromo-4-[l -[chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl]-6- (difluoromethoxy)phenyl]acetamide

From 200 mg 2-bromo-4-[l -[chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl]-6- (difluoromethoxy)aniline, following the same procedure as described in Example 4, N-[2-bromo-4-[l- [chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl]-6-(difluoromethoxy)phenyl]acetamide was obtained (104 mg, 47%).

lH NMR (400 MHz, CDC1₃): 7.77 (s, 1H), 7.48 (s, 1H), 6.93 (brs, 1H), 6.52 (t, 1H), 2.26 (s, 3H) ppm.

Example 12: 2-bromo-4-[l-[chloro(difluoro)methyll-l,2,2,2-tetrafluoro-ethyll-6- (difluoromethoxy) aniline

2.41 g N-bromosuccinimide was slowly added to a solution of 3.88 g 4-[l-[chloro(difluoro)methyl]- l,2,2,2-tetrafluoro-ethyl]-2-(difluoromethoxy)aniline (Example 13) in 24 ml Dichloromethane at ambient temperature. A slightly exothermic reaction was observed. The mixture was stirred for 1 hour at ambient temperature. ThenlOO ml of aqueous sodium hydroxide (IN) were added. The layers were separated and the organic layer was washed with 100 ml of aqueous sodium hydroxide (IN). The aqueous phases were washed twice with 100 ml portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness. Thus, 2- bromo-4-[l -[chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl]-6-(difluoromethoxy)aniline (4.58 g, 96%) was obtained as a dark brown oil.

lH NMR (400 MHz, CDC1₃): 7.55 (s, 1H), 7.24 (s, 1H), 6.50 (t, 1H), 4.60 (brs, 2H) ppm.

Exam le 13: 4-[l-[chloro(difluoro)methyll-l,2,2,2 etrafluoro-ethyll-2-(difluoromethoxy)aniline

6.8 g Sodium hydrosulphite, 2.8 g sodium bicarbonate, 0.69 g tetrabutylammonium hydrogensulphate and 10 g 1-chloro-l, 1,2,3,3, 3-hexafluoro-2-iodo-propane were added to a solution of 4.5 g 2- (difluoromethoxy) aniline in a mixture of 41 ml 2-methoxy-2-methyl-propane and 41 ml water. The reaction mixture was stirred for 3 days at ambient temperature. Then the layers were separated, the aqueous layer was washed twice with 2-methoxy-2-methyl-propane. The combined organic layers were washed twice with 100 ml portions of aqueous hyrochloric acid (IN), twice with 100 ml portions of water, once with 100 ml of brine, dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. Thus, 4-[l-[chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl]-2- (difluoromethoxy) aniline (3.88 g, 41%) was obtained as an orange oil.

lH NMR (400 MHz, CDC1₃): 7.28 (m, 2H), 6.82 (d, 1H), 6.49 (t, 1H), 4.12 (brs, 2H) ppm.

Example 14: N 2-bromo-4 1 ^cmoro(difluoro)methyll-l,2,2,2-tetrafluoro-ethyll-6-ethyl- henyl] acetamide

From 200 mg 2-bromo-4-[l -[chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl]-6-ethyl-aniline, following the same procedure as described in Example 4, N-[2-bromo-4-[l-[chloro(difluoro)methyl]- l,2,2,2-tetrafluoro-ethyl]-6-ethyl-phenyl]acetamide was obtained (151 mg, 68%>).

lH NMR (400 MHz, CDC1₃): 7.51 (s, 1H), 7.74 (s, 1H), 6.91 (brs, 1H), 2.71 (q, 2H), 2.25 (s, 3H), 1.23 (t, 3H) ppm.

Exam le 15: 2-bromo-4-[l-[chloro(difluoro)methyll-l,2,2,2-tetrafluoro-ethyll-6-ethyl-aniline

6.67 g N-bromosuccinimide was slowly added to a solution of 9.54 g 4-[l-[chloro(difluoro)methyl]- l,2,2,2-tetrafluoro-ethyl]-2-ethyl-aniline in 67 ml dichloromethane at ambient temperature. An exothermic reaction was observed. The mixture was stirred for 1.5 hours at ambient temperature. Then 100 ml of aqueous sodium hydroxide (IN) were added. The layers were separated and the organic layer was washed with 100 ml of aqueous sodium hydroxide (IN). The combined aqueous phases were washed twice with 100 ml portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness. Thus, 2-bromo-4-[l- [chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl]-6-ethyl-aniline (12.0 g, 100%) was obtained as a dark brown oil. ^lH NMR (400 MHz, CDC1₃): 7.53 (s, 1H), 7.20 (s, 1H), 4.38 (brs, 2H), 2.56 (q, 2H), 1.27 (t, 3H) ppm.

Exam le 16: 4-[l-[chloro(difluoro methyll-l,2,2,2 etrafluoro-ethyll-2-ethyl-aniline

9.66 Sodium hydrosulphite, 3.96 g sodium bicarbonate, 0.97 g tetrabutylammonium hydrogensulphate and 13.5 g 1-chloro-l, 1,2,3,3, 3-hexafluoro-2-iodo-propane were added to a solution of 4.86 g 2- ethylaniline in a mixture of 58 ml 2-methoxy-2-methyl-propane and 58 ml water. The reaction mixture was stirred 2 hours at ambient temperature. Then the layers were separated. The aqueous layer was washed twice with 2-methoxy-2-methyl-propane. The combined organic layers were washed twice with 100 ml portions of aqueous hyrochloric acid (IN), twice with 100 ml portions of water, once with 100 ml brine, dried over sodium sulfate, filtered and evaporated under vacuum. Thus, 4-[l- [chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl]-2-ethyl-aniline (9.54 g, 79%) was obtained as an orange oil.

lH NMR (400 MHz, CDC1₃): 7.26 (m, 2H), 6.70 (d, 1H), 3.85 (brs, 2H), 2.53 (q, 2H), 1.27 (t, 3H) ppm.

Exam le 17: N-[2,6-dibromo-4-[l ,2,2,2-tetrafluoro-l -(trifluoromethyl)ethyl]phenyl]acetamide

From 1.0 g 2,6-dibromo-4-[l ,2,2,2-tetrafluoro-l -(trifluoromethyl)ethyl] aniline, following the same procedure as described in Example 4, N-[2,6-dibromo-4-[l,2,2,2-tetrafluoro-l - (trifluoromethyl)ethyl]phenyl]acetamide was obtained (0.98 g, 89%).

lH NMR (400 MHz, CDC1₃): 7.82 (s, 2H), 7.00 (brs, 1H), 2.26 (brs, 3H) ppm.

Exam le 18: N-[2,6-diethyl-4-[l ,2,2,2-tetrafluoro-l - trifluoromethyl)ethyl]phenyl]acetamide

From 1.0 g 2,6-diethyl-4-[l ,2,2,2-tetrafluoro-l-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2,6-diethyl-4-[l,2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] phenyl] acetamide was obtained (0.93 g, 82%).

lH NMR (400 MHz, CDC1₃): 7.33 (s, 2H), 6.70 (brs, 1H), 2.63 (q, 4H), 2.24 (s, 3H), 1.20 (t, 6H) ppm.

Example 19: N-[2-chloro-6-(difluoromethoxy -4-[l ,2,2,2-tetrafluoro-l- (trifluorometh l)ethyl]phenyl]acetamide

From 323 mg 2-chloro-6-(difluoromethoxy)-4-[l ,2,2,2-tetrafluoro-l-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2-chloro-6-(difluoromethoxy)-4-[ 1 ,2,2,2- tetrafluoro-l-(trifluoromethyl)ethyl]phenyl] acetamide was obtained (232 mg, 64%).

lH NMR (400 MHz, CDC1₃): 7.60 (s, 1H), 7.41 (s, 1H), 6.92 (brs, 1H), 6.53 (t, 1H), 2.24 (s, 3H) ppm.

Exam le 20: N-[2,6-dichloro-4-[l ,2,2,2-tetrafluoro-l-(trifluoromethyl)ethyl]phenyl]acetamide

From 1.0 g 2,6-dichloro-4-[l ,2,2,2-tetrafluoro-l-(trifluoromethyl)ethyl]aniline, following the procedure as described in Example 4, N-[2,6-dichloro-4-[l,2,2,2-tetrafluoro-l - (trifluoromethyl) ethyl] phenyl] acetamide was obtained (0.296 g, 26%>).

lH NMR (400 MHz, CDC1₃): 7.62 (s, 2H), 6.95 (brs, 1H), 2.25 (brs, 3H) ppm.

Example 21 : N-[2-chloro-6-methyl- - l ,2,2,2-tetrafluoro-l-(trifluoromethyl)ethyl]phenyl]acetamide

From 1.0 g 2-chloro-6-methyl-4-[l ,2,2,2-tetrafluoro-l -(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2-chloro-6-methyl-4-[l ,2,2,2-tetrafluoro-l - (trifluoromethyl) ethyl] phenyl] acetamide was obtained (1.038 g, 91%).

lH NMR (400 MHz, CDC1₃): 7.52 (s, 1H), 7.39 (s, 1H), 6.96 ppm (brs, 1H), 2.37 (s, 3H), 2.26 (s, 3H) ppm.

Exam le 22: N-[2-chloro-6-ethyl-4-[l ,2,2,2-tetrafluoro-l-(trifluoromethyl)ethyl]phenyl]acetamide

From 1.0 g 2-chloro-6-ethyl-4-[l ,2,2,2-tetrafluoro-l-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2-chloro-6-ethyl-4-[l ,2,2,2-tetrafluoro-l- (trifluoromethyl)ethyl]phenyl]acetamide was obtained (1.1 g, 97%).

lH NMR (400 MHz, CDC1₃): 7.54 (s, 1H), 7.42 (s, 1H), 6.88 (brs, 1H), 2.70 (q, 2H), 2.27 (s, 3H), 1.23 (t, 3H) ppm.

Exam le 23: 2-chloro-6-ethyl-4-[l ,2,2,2-tetrafluoro-l-(trifluoromethyl)ethyl]aniline

27.9 g l-chloropyrrolidine-2,5-dione was added in portions to a solution of 60.5 g 2-ethyl-4-[ 1 ,2,2,2- tetrafluoro-l-(trifluoromethyl)ethyl] aniline in 350 ml dichloromethane. The reaction mixture was stirred for 3 days at ambient temperature. Then, 150 ml of aqueous sodium hydroxide (IN) were slowly added, during addition an exothermic reaction was observed. The layers were separated and the organic layer was washed twice with 100 ml of aqueous sodium hydroxide (IN), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue, 64.2 g of a dark brown powder, was purified by flash chromatography using dichloromethane/cyclohexane as a solvent. Thus, 2-chloro-6- ethyl-4-[l ,2,2,2-tetrafluoro-l-(trifluoromethyl)ethyl]aniline (50.2 g, 74%>) was obtained as a pale orange solid.

lH NMR (400 MHz, CDC1₃): 7.88 (s, 1H), 7.17 (s, 1H), 4.33 brs, 2H), 2.56 (q, 2H), 1.28 (t, 3H) ppm.

Example 24: N-[2-bromo-6-ethyl-4-[l ,2,2,2-tetrafluoro-l-(trifluoromethyl)ethyl]phenyl]acetamide

From 1.0 g 2-bromo-6-ethyl-4-[l ,2,2,2-tetrafluoro-l -(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2-bromo-6-ethyl-4-[l ,2,2,2-tetrafluoro-l - (trifluoromethyl)ethyl]phenyl]acetamide was obtained (098 g, 88%).

lH NMR (400 MHz, CDC1₃): 7.70 (s, 1H), 7.45 (s, 1H), 6.87 (brs, 1H), 2.41 (q, 2H), 2.25 (s, 3H), 1.22 (t, 3H) ppm.

Example 25: N-[2-bromo-6-(difluoromethoxy -4-[l ,2,2,2-tetrafluoro-l - (trifluorometh l)ethyl]phenyl] acetamide

From 1.0 g 2-bromo-6-(difluoromethoxy)-4-[l ,2,2,2-tetrafluoro-l -(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2-bromo-6-(difluoromethoxy)-4-[l , 2,2,2- tetrafluoro-l -(trifluoromethyl)ethyl]phenyl] acetamide was obtained (954 mg, 86%).

lH NMR (400 MHz, CDC1₃): 7.75 (s, 1H), 7.46 (s, 1H), 6.95 (brs, 1H), 6.52 (t, 1H), 2.24 (s, 3H) ppm.

Example 26: N-[2-bromo-4-[l -[bromo(difluoro)methyll-l ,2,2,2-tetrafluoro-ethyll-6-ethyl- henyl] acetamide

From 500 mg 2-bromo-4-[l -[bromo(difluoro)methyl]-l ,2,2,2-tetrafluoro-ethyl]-6-ethyl-aniline, following the same procedure as described in Example 4, N-[2-bromo-4-[l -[bromo(difluoro)methyl]- l ,2,2,2-tetrafluoro-ethyl]-6-ethyl-phenyl]acetamide was obtained (520 mg, 95%>).

lH NMR (400 MHz, CDC1₃): 7.70 (s, 1H), 7.48 (s, 1H), 7.01 (brs, 1H), 2.70 (q, 2H), 2.25 (s, 3H), 1.22 (t, 3H) ppm. Example 27: N-[2,6-dibromo-4-[l -[bromo(difluoro methyll-l ,2,2,2-tetrafluoro- eth l]phenyl] acetamide

From 500 mg 2,6-dibromo-4-[l -[bromo(difluoro)methyl]-l ,2,2,2-tetrafluoro-ethyl]aniline, following the same procedure as described in Example 4, N-[2,6-dibromo-4-[l -[bromo(difluoro)methyl]-l ,2,2,2- tetrafluoro-ethyljphenyl] acetamide was obtained (340 mg, 71%).

lH NMR (400 MHz, CDC1₃): 7.84 (s, 2H), 7.01 (brs, 1H), 2.28 (s, 3H) ppm.

Example 28: N-[4-[l -[bromo(difluoro methyll-l ,2,2,2-tetrafluoro-ethyll-2,6-dichloro- henyl] acetamide

From 500 mg 4-[l -[bromo(difluoro)methyl]-l ,2,2,2-tetrafluoro-ethyl]-2,6-dichloro-aniline, following the same procedure as described in Example 4, N-[4-[l -[bromo(difluoro)methyl]-l ,2,2,2-tetrafluoro- ethyl]-2,6-dichloro-phenyl]acetamide was obtained (320 mg, 72%).

lH NMR (400 MHz, CDC1₃): 7.64 (s, 2H), 6.95 (brs, 1H), 2.27 (s, 3H) ppm.

& ampje_ 9: N- [3 - [acetyl- [2-bromo-6-(difluoromethoxy)-4- [ 1 ,2,2,2-tetrafluoro- 1 - (trifluorometh l)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4

From 760 mg N-[2-bromo-6-(difluoromethoxy)-4-[l ,2,2,2-tetrafluoro-l -(trifluoromethyl)ethyl]phenyl] acetamide and 520 mg 2-methoxy-3-[methyl(pyridine-4-carbonyl)amino]benzoyl chloride, following the same procedure as described in Example 5, Step 2, N-[3-[acetyl-[2-bromo-6-(difluoromethoxy)-4- [1 ,2,2,2-tetrafluoro- 1

pyridine-4-carboxamide was obtained (446 mg, 37%).

lH NMR (400 MHz, CDC1₃): 8.50 (brs, 2H), 7.77 (m, 1H), 7.43 (brs, 1H), 7.20-7.30 (m, broad, 4H), 7.05 (m, 1H), 6.45 (t, broad, 1H), 3.88 (s, 3H), 3.43 (brs, 3H), 1.96 (brs, 3H) ppm.

Example 30: N-r3-rr2-bromo-6-(difluoromethoxy -4-rL2,2,2-tetrafluoro-l- (trifluoromethyl)ethyl]phenyl] carbamoyl] -2-methoxy-phenyl] -N-methyl-pyridine-4-carboxamide

From 278 g N-[3-[acetyl-[2-bromo-6-(difluoromethoxy)-4-[l ,2,2,2-tetrafluoro-l- (trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4-carboxamide, following the same procedure as described in Example 6, N-[3-[[2-bromo-6-(difluoromethoxy)-4- [l,2,2,2-tetrafluoro-l-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-methyl- pyridine-4-carboxamide was obtained (259 mg, 99%).

lH NMR (400 MHz, CDC1₃): 8.73 (brs, 1H), 8.47 (brs, 2H), 8.03 (d, 1H), 7.75 (s, 1H), 7.53 (d, 1H), 7.45 (s, 1H), 7.35 (t, 1H), 7.17 (brs, 2H), 6.53 (t, 1H), 3.62 (brs, 3H), 3.58 (brs, 3H) ppm.

Claims

1. A process for the preparation of

comprising reacting a compound of formula (I) with a compound of formula (II) in the presence of acid to obtain a compound of formula (III):

then

Step b)

then

Step c)

reacting the compound of formula (V) with aqueous base to obtain a compound of formula (VI):

wherein

Xi and X₂ each independently are halogen, C₁-C4 alkyl, C₁-C4 haloalkyl, C₁-C4 alkoxy, C₁-C4 haloalkoxy, C₁-C4 alkoxymethyl, Ci-C4-alkylsulphonyl, Ci-C4-haloalkylsulphonyl, C₁-C4- alkylsulphinyl, Ci-C4-haloalkylsulphinyl, Ci-C4-alkylthio, Ci-C4-haloalkylthio,

X₃ is heptafluoroprop-2-yl, l -[chloro(difluoro)methyl]- l,2,2,2-tetrafluoro-ethyl, 1- [bromo(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

X4 is a leaving group selected from halogen, Ci-C6-alkyl-C(0)0-, phenyl-C(0)0-, Ci-C6-alkoxy-

C(0)0-, phenoxy-C(0)0-, benzyloxy-C(0)0- and imidazol-l -yl;

Ri is H, C₁-C4 alkyl, C_rC₄ haloalkyl,

R₂ is C_rC₄-alkyl

R3 is H, fluorine, methoxy;

R_3a is H or CN,

Qi is 4-cyano-phenyl, 3-pyridyl or 4-pyridyl;

2. A compound according to formula (III)

wherein

Ri is H, C₁-C4 alkyl, C_rC₄ haloalkyl,

3. A compound according to formula (IV)

wherein

X4 is a leaving group selected from halogen, Ci-C6-alkyl-C(0)0-, phenyl-C(0)0-, Ci-C6-alkoxy- C(0)0-, phenoxy-C(0)0-, benzyloxy-C(0)0- and imidazol-l -yl;

R₂ is C_rC₄-alkyl;

R3 is H, fluorine, methoxy;

R_3a is H or CN;

Qi is 3-pyridyl or 4-pyridyl;

provided that not both R₃ and R3_a are H;

4. A compound according to formula (V)

wherein

Ri is H, C₁-C4 alkyl, C_rC₄ haloalkyl,

R₂ is C_rC₄-alkyl

R3 is H, fluorine, methoxy;

R_3a is H or CN,

Qi is 4-cyano-phenyl, 3-pyridyl or 4-pyridyl;

5. A method according to claim 1 or a compound according to the claims 4 wherein Xi and X₂ each independently are halogen, C₁-C4 alkyl, C₁-C4 haloalkyl, C₁-C4 alkoxy, Cp C4 haloalkoxy, C₁-C4 alkoxymethyl,

Ri is H, C₁-C4 alkyl,

R₂ is methyl or ethyl

Qi is 4-cyano-phenyl, 3- pyridyl or 4-pyridyl;

6. A method according to claim 1 or a compound according to the claims 4 wherein

Xi and X₂ each independently are halogen, C₁-C4 alkyl, C₁-C4 haloalkyl, C₁-C4 alkoxy, Cp C4 haloalkoxy, C₁-C4 alkoxymethyl,

X₃ is l-[chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl, l-[bromo(difluoro)methyl] -1,2,2,2- tetrafluoro-ethyl;

Ri is H, C₁-C4 alkyl,

R₂ is methyl or ethyl

Qi is 3- pyridyl or 4-pyridyl;

7. A method according to claim 1 or a compound according to the claims 4 wherein

Xi and X₂ each independently are halogen, C₁-C4 alkyl, C₁-C4 haloalkyl, C₁-C4 haloalkoxy, X₃ is heptafluoroprop-2-yl;

X₄ is a leaving group selected from halogen, Ci-C6-alkyl-C(0)0-;

Ri is H, methyl,

R₂ is ethyl

Qi is 4-pyridyl;

8. A method according to claim 1 or a compound according to the claims 4 wherein

X₄ is a leaving group selected from halogen, Ci-C6-alkyl-C(0)0-;

Ri is H, methyl,

R₂ is ethyl

Qi is 4-pyridyl;

9. A method according to claim 1 or a compound according to the claims 4 wherein

Xi and X₂ each independently are halogen, C₁-C4 alkyl, C₁-C4 haloalkyl, C₁-C4 haloalkoxy, X₃ is l-[chloro(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl;

X4 is a leaving group selected from halogen, Ci-C₆-alkyl-C(0)0-;

Ri is H, methyl,

R₂ is ethyl

Qi is 4-pyridyl;

10. A method according to claim 1 or a compound according to the claims 4 wherein Xi and X₂ each independently are halogen, C₁-C4 alkyl, C₁-C4 haloalkyl, C₁-C4 haloalkoxy,

X₃ is l-[bromo(difluoro)methyl]-l,2,2,2-tetrafluoro-ethyl;

X4 is a leaving group selected from halogen, Ci-C₆-alkyl-C(0)0-;

Ri is H, methyl,

R₂ is ethyl

Qi is 4-pyridyl;

11. A method according to claim 1 or a compound according to the claims 4 wherein

Xi and X₂ each independently are halogen, C₁-C4 alkyl, C₁-C4 haloalkyl, C₁-C4 haloalkoxy, X3 is nonafluorobut-2-yl;

X4 is a leaving group selected from halogen, Ci-C₆-alkyl-C(0)0-;

Ri is H, methyl,

R₂ is ethyl

Qi is 4-pyridyl;

12. A method according to claim 1 or a compound according to the claims 3 or 4 wherein R₃ is methoxy and R_3a is H,

13. A method according to claim 1 or a compound according to the claims 3 or 4 wherein R₃ is fluorine and R_3a is H,

14. A method according to claim 1 or a compound according to the claims 3 or 4 wherein R₃ is H and R_3a is CN,

15. A method according to claim 1 or a compound according to the claims 4 wherein R₃ is H and R3_a is H.