Process for the preparation of pesticidally active cyclic amine compounds

Abstract

The invention relates to a process for the preparation of a compound of formula (I) wherein the substituents are as defined in claim 1. (I)

Description

[0001] 111355-FF

[0002] -1- PROCESS FOR THE PREPARATION OF PESTICIDALLY ACTIVE CYCLIC AMINE COMPOUNDS

[0003] The present invention relates to a process for the preparation of pesticidally active cyclic amine compounds, in particular insecticidally active piperazinyl pyridinyl carbonyl compounds of formula (I), and intermediates therefor.

[0004] WO2015032280, WO2019039429, JP2019077618, W02021053161, W02022070023 and WO2022207462 describe certain piperazinyl pyridinyl carbonyl compounds for use for controlling pests that damage plants.

[0005] The present invention relates to a process for preparing insecticidally active piperazinyl pyridinyl carbonyl compounds of formula (I), and intermediates therefor (see scheme 1).

[0006] The process for synthesizing the compound of formula (I) from (i) compound formula (XI), or via compound of formula (XII), and (ii) QH is highly compatible with a wide variety of QH amine compounds, rendering it a dependable and versatile approach for manufacturing. This process is unlike many classical amide coupling protocols found in literature, which typically involve the use of coupling agents (e.g., DCC, DIC, T3P, HOBt) known for generating stoichiometric amounts of waste.

[0007] Further, synthesizing the compound of formula (IX) from the compound of formula (V) uses eco-friendly solvents and is ideal in terms of atom economy, as it utilizes environmentally friendly reaction processes with simple building blocks such as molecular bromine, formaldehyde, and phosgene.

[0008] The reaction intermediates (X) and (XII) are not isolated and are involved in one-pot processes. This ultimately improves yields by preventing material loss during isolation. Additionally, the process allows for solvent savings since there is no need for workup to recover these intermediates. The process used is mild and does not generate byproducts, making it compatible with functionalities present on the substrates (IV), (V), and (IX). In addition, conducting one-pot processes generally offer reduced costs because lesser requirement for materials, solvents, equipment, and labour.

[0009] Another benefit of the process of the invention is the exclusive O-selectivity in the reaction between compound of formula (IV) and compound of formula (IX) taking into consideration the potential existence of the tautomeric form of the compound of formula (IV) but also due to various factors such as the nature of the leaving group of compound of formula (IX), the solvent, the temperature of the reaction or the electronics of compound of formula (IV), its alkylation in the presence of (IX) may lead to N-alkylation instead of the desired O-alkylation111355-FF

[0010] -2-

[0011]

[0012] Scheme 1: Process route for the preparation of compound of formula (I)111355-FF

[0013] -3-

[0014] The substituents noted in Scheme 1 are defined hereinafter.

[0015] Accordingly, in a first aspect, the present invention relates to a process for the preparation of a compound of formula (I),

[0016]

[0017] (I)

[0018] comprising

[0019] 1) reacting a compound of formula (XI)

[0020]

[0021] (XI)

[0022] with phosgene, triphosgene, oxalyl chloride, or thionyl chloride; and

[0023] 2) adding an amine derivative QH in presence of a base;

[0024] wherein, in respect of formula (I) and formula (XI):

[0025] R1is CN;

[0026] R2is H, Ci-Ce-alkyl, or Ci-Ce-haloalkyl;

[0027] R3a, R3b, and R3care independently selected from hydrogen, halogen, Ci-Ce-alkyl, C1-C6-haloalkyl, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfonyl, and Ci-Ce-haloalkylsulfanyl, or R3aand R3btogether form a Ci-C2haloalkylenedioxy substituent substituted on adjacent atoms on the phenyl ring forming together with the carbons of the phenyl ring a 5- or 6-membered ring, with the proviso that R3aand R3bare not hydrogen; and

[0028] Q is a cyclic amine represented by the formula XXa or a cyclic amine represented by the formulae XXb,

[0029] (XXa)

[0030]

[0031] (XXb)111355-FF

[0032] -4-wherein the arrow indicates the connection to the carbonyl group (in relation to formula (I)); and connection to the hydrogen (in relation to the amine derivative QH);

[0033] p1is 0, or 1 and indicates the number of methylene groups;

[0034] p2is 0, or 1 and indicates the number of methylene groups;

[0035] X is hydrogen, hydroxyl, or alkoxy;

[0036] Y is cyano, Ci-Ce-alkoxy-Ci-Ce-alkyl, Ci-Ce-alkylsulfanyl-Ci-Ce-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, Ci-C6-alkylsulfonyl-Ci-C6-alkyl, RaRbNC(O), RcC(O)NRd, ReSO2NRf, RgO-N=CRh, RjRkNSO2, 4 to 6 membered non-aromatic heterocyclic ring system in which one or two carbons are replaced independently by nitrogen, oxygen, sulfur, or sulfonyl, phenyl, phenyl substituted with 1 to 3 substituents independently selected R4, 5 or 6 membered monocyclic heteroaryl having 1 to 3 carbon atoms replaced independently by nitrogen, sulfur, or oxygen, or 5 or 6 membered monocyclic heteroaryl having 1 to 3 carbon atoms replaced independently by nitrogen, sulfur, or oxygen, substituted with 1 to 3 independently selected substituents R5;

[0037] A is cyano, C1-C6-cyanoalkyl, RiSO2, RjRkNSO2, phenyl, phenyl substituted with 1 to 3 independently selected substituents R6, or heteroaryl substituted with 1 to 3 independently selected substituents R7; wherein the said heteroaryl is either a 5 or 6 membered monocyclic or a 9 or 10 membered bicyclic, each having 1 to 3 carbon atoms replaced independently by nitrogen, sulfur, or oxygen;

[0038] Ra, Rb, Rc, Rd, Rf, Rg, Rh, Riand Rkare independently selected from hydrogen, and Ci-Ce-alkyl;

[0039] Reand Rlare independently C1-C6-alkyl; and

[0040] R4, R5, R6and R7are independently selected from halogen, Ci-Ce-alkyl, Ci-Ce-haloalkyl;

[0041] or an agrochemically acceptable salt, stereoisomer, and tautomer of the compound of formula (I).

[0042] In an embodiment, the present invention relates to the process as defined in the first aspect wherein the compound of formula (XII) is formed in situ after step h)

[0043]

[0044] (XII) wherein R1, R2, and R3a, R3b, and R3care as defined in the first aspect.

[0045] In a second aspect, the present invention relates to a process for the preparation of a compound of formula (XI), as defined in scheme 1, comprising

[0046] 1) converting a compound of formula (X) in a presence of a base;111355-FF

[0047] -5-

[0048]

[0049] wherein R1, R2, R3a, R3b, and R3c(for both formulae (XI) and (X)) are as defined in the first aspect, and R10is Ci-Ce-alkyl; or

[0050] 2) reacting compound of formula (IV), or its tautomeric form, with a compound of formula (IX), under basic conditions in the presence of a catalyst, via concomitant in-situ hydrolysis of formed compound of formula (X);

[0051]

[0052] (IV) or tautomeric form and wherein R1, R2, R3a, R3b, and R3care as defined in the first aspect, and R10is Ci-Ce-alkyl.

[0053] In a third aspect, the present invention relates to a process for the preparation of compound of formula (IV) as defined in scheme 1, comprising reacting compounds formulae (III) and (III’)

[0054] R1°a

[0055]

[0056] (HI’) in the presence of metallic sodium with an alcohol (such Ci-Ce-alcohol, preferably ethanol), or a sodium alkoxide salt to yield the compound of formula (IV), wherein R1, and R2are as defined in the first aspect, R10is Ci-Ce-alkyl (preferably ethyl), and R10ais Ci-Ce-alkoxy (preferably ethoxy) or N(CH3)2.

[0057] In a fourth aspect, the present invention relates to a process for the preparation of compound of formula (IX), as defined in scheme 1, comprising reacting a compound of formula (VIII)

[0058]

[0059] 111355-FF

[0060] -6-with one of (i) phosgene, (ii) triphosgene, (iii) oxalyl chloride, (iv) an equimolar use of CCl4 and PPh3, (v)POCl3, (vi) DCDMH (1,3-dichloro-5,5-dimethylhydantoin), (vii) thionyl chloride, or (viii) an equimolar use of NCS and PPh3; wherein R3a, R3b, and R3care as defined in the first aspect.

[0061] In a fifth aspect, the present invention relates to a process for the preparation of compound of formula (VIII), as defined in scheme 1, comprising

[0062] 1) reacting compound of formula (VII)

[0063] ,3c

[0064]

[0065] with a hydride source, such as sodium borohydride, sodium cyanoborohydride, ammonia-borane complex, or lithium aluminum hydride; or

[0066] 2) reacting a compound of formula (VI)

[0067]

[0068] with one of (i) isopropylmagnesium chloride, (ii) isopropylmagnesium chloride lithium chloride complex (also known as Turbo Grignard), or (iii) magnesium metal, and using the newly formed intermediate compound of formula (VI’)

[0069]

[0070] in the presence of formaldehyde or paraformaldehyde; whereby the compound of formula (VI ”B) is formed in-situ,

[0071] BrMg

[0072] A or B

[0073] .3c

[0074]

[0075] VI"A: RA= NMe2

[0076] VI"B: RB = H

[0077] wherein R3a, R3b, and R3care as defined in the first aspect.111355-FF

[0078] -7-

[0079] In a sixth aspect, the present invention relates to a process for the preparation of compound of formula (VI), as defined in scheme 1, comprising reacting a compound of formula (V)

[0080]

[0081] in the presence of an electrophilic bromine source, wherein R3a, R3b, and R3care as defined in the first aspect.

[0082] In a seventh aspect, the present invention relates to a process for the preparation of compound of formula (VII), as defined in scheme 1, comprising reacting a compound of formula (VI)

[0083]

[0084] with one of (i) isopropylmagnesium chloride, (ii) isopropylmagnesium chloride lithium chloride complex (also known as Turbo Grignard), or (iii) magnesium metal, and using the newly formed intermediate compound of formula (VI’)

[0085]

[0086] in the presence of A / , A / -dimethylformamide, whereby the compound of formula (VI”A) is formed in-situ,

[0087]

[0088] VI"A: RA= NMe2

[0089] VI"B: RB= H

[0090] wherein R3a, R3b, and R3care as defined in the first aspect.

[0091] The preparation of compound of formula (VII), can also be carried out by reacting a compound of formula (VI) with one of (i) isopropylmagnesium chloride, (ii) isopropylmagnesium chloride lithium chloride complex (also known as Turbo Grignard), or (iii) magnesium metal, and using the newly formed intermediate compound of formula (VI’) in the presence of triethyl orthoformate.111355-FF

[0092] -8- In an eighth aspect, the present invention relates to a compound a compound formula (XII),

[0093]

[0094] (XII) wherein

[0095] R1is CN;

[0096] R2is H, Ci-Ce-alkyl, or Ci-Ce-haloalkyl;

[0097] R3a, R3b, and R3care independently selected from hydrogen, halogen, Ci-Ce-alkyl, Ci-Ce-haloalkyl, Ci-Ce-alkoxy, O-Ce-haloalkoxy, Ci-Ce-alkylsulfonyl, and Ci-Ce-haloalkylsulfanyl, or R3aand R3btogether form a Ci-C2haloalkylenedioxy substituent substituted on adjacent atoms on the phenyl ring forming together with the carbons of the phenyl ring a 5- or 6-membered ring, with the proviso that R3aand R3bare not hydrogen.

[0098] In a ninth aspect, the present invention relates to a process for the preparation of a compound of formula (I), wherein the compound of formula (I) is as defined in the first aspect, comprising reacting a compound of formula (XII)

[0099]

[0100] (XII) wherein

[0101] R1, R2, R3a, R3b, and R3care as defined in the first aspect, with amine derivative (QH), wherein Q is as defined in the first aspect.

[0102] In a tenth aspect, the present invention relates to a process for the preparation of a compound of formula (XII), as defined in scheme 1, comprising reacting a compound of formula (XI)

[0103] O

[0104]

[0105] 111355-FF

[0106] -9-wherein R1, R2, R3a, R3b, and R3c(for both formulae (XII) and (XI) are as defined in the first aspect; with one of (i) phosgene, (ii) triphosgene, (iii) oxalyl chloride, (iv) thionyl chloride, or (v) POCl3, to deliver compound of formula (XII).

[0107] The compounds of formula (I) are in free form, in oxidized form as a N-oxide or in salt form, e.g. an agronomically usable salt form.

[0108] N-oxides are oxidized forms of tertiary amines or oxidized forms of nitrogen containing heteroaromatic compounds. They are described for instance in the book “Heterocyclic N-oxides” by A. Albini and S. Pietra, CRC Press, Boca Raton 1991.

[0109] The compounds of formula (I) according to the invention also include hydrates which may be formed during the salt formation.

[0110] The term " Ci-Cn-alkyl” as used herein refers to a saturated straight-chain or branched hydrocarbon radical attached via any of the carbon atoms having 1 to n carbon atoms, for example, any one of the radicals methyl, ethyl, n-propyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1 -ethylpropyl, n-hexyl, n-pentyl, 1,1-dimethylpropyl, 1, 2-dimethylpropyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1 -dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1 -methylpropyl, or 1-ethyl-2-methylpropyl.

[0111] The term " Ci-Cn-alkoxy" as used herein refers to a straight-chain or branched saturated alkyl radical having 1 to n carbon atoms (as mentioned above) which is attached via an oxygen atom, i.e., for example, any one of the radicals methoxy, ethoxy, n-propoxy, 1 -methylethoxy, n-butoxy, 1 -methylpropoxy, 2-methylpropoxy or 1,1 -dimethylethoxy. The term “haloCi-Cn-alkoxy" as used herein refers to a Ci-Cn-alkoxy radical where one or more hydrogen atoms on the alkyl radical is replaced by the same or different halo atom(s) - examples include trifluoromethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 3,3,3-trifluoropropoxy, 4-chlorobutoxy. Two neighboring substituents of a phenyl ring may form together with the carbons of the phenyl ring a 5- or 6-membered ring. Examples are -OCF2O-, -OCF2CF2O-.

[0112] The term “Ci-Cn-alkylsulfanyl” as used herein refers to a radical of the formula -SRa wherein Ra is a C1-Cn-alkyl radical as generally defined above.

[0113] The term “Ci-Cn-alkylsulfinyl” as used herein refers to a radical of the formula -S(O)Ra wherein Ra is a Ci-Cn-alkyl radical as generally defined above.

[0114] The term “Ci-Cn-alkylsulfonyl” as used herein refers to a radical of the formula -S(O)2Ra wherein Ra is a Ci-Cn-alkyl radical as generally defined above.111355-FF

[0115] -10- Halogen is generally fluorine, chlorine, bromine or iodine. This also applies, correspondingly, to halogen in combination with other meanings, such as haloalky I.

[0116] The term " Ci-Cn-haloalkyl" as used herein refers to a straight-chain or branched saturated alkyl radical attached via any of the carbon atoms having 1 to n carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these radicals may be replaced by fluorine, chlorine, bromine and / or iodine, i.e., for example, any one of chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl, 3,3,3-trichloropropy I, 2, 2, 3, 3, 3- pentafluoropropyl, heptafluoropropyl, 1 -(fluoromethyl)-2-fluoroethyl, 1 -(chloromethyl)-2-chloroethyl, 1 -(bromomethy l)-2-bromoethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl or nonafluorobutyl. According to a term " Ci-C2fluoroalkyl" would refer to a Ci-C2alkyl radical which carries 1, 2, 3, 4, or 5 fluorine atoms, for example, any one of difluoromethyl, trifluoromethyl, 1 -fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl or pentafluoroethyl.

[0117] The term “Ci-Cn-cyanoalkyl” as used herein refers to Ci-Cn-alkyl radical having 1 to n carbon atoms (as mentioned above), where one of the hydrogen atoms in the radical is be replaced by a cyano group: for example, cyanomethyl, 2-cyanoethyl, 2-cyanopropyl, 3-cyanopropyl, 1-(cyanomethyl)-2-ethyl, 1-(methyl)-2-cyanoethyl, 4-cyanobutyl, and the like.

[0118] The term “Ci-Cn-alkylsulfanyl-Ci-Cn-alkyl” as used herein refers to an alkyl radical wherein one of the carbon atoms is replaced by a sulfur atom.

[0119] The term “Ci-Cn-alky Isulfiny l-Ci-Cn-alky I” as used herein refers to an alkyl radical wherein one of the carbon atoms is replaced by a S(=O) group.

[0120] The term “Ci-Cn-alkylsulfonyl-Ci-Cn-alkyl” as used herein refers to an alkyl radical wherein one of the carbon atoms is replaced by a S(=O)2 group.

[0121] The term “4 to 6 membered non-aromatic heterocyclic ring system in which one or two carbons is replaced by nitrogen, oxygen, sulfur, or sulfonyl,” as used herein refers to a cyclic group where one or two carbon atoms in the ring are replaced independently by nitrogen, oxygen, sulfur, or sulfonyl, and the ring is attached via a carbon, or a nitrogen atom to remainder of the compound. Examples are azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, 2-oxopyrrolidinyl, 2-oxotetrahydrofuranyl, 1,1-dioxo-1,2-thiazolidinyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 2-oxooxazolidinyl, piperidinyl, tetrahydropyranyl, 2-oxopiperidinyl, 1,1-dioxothiazinanyl, 2-oxotetrahydropyranyl, 1,3-dioxolanyl, 1,3-dithianyl, 2-oxo-1,3-oxazinanyl.111355-FF

[0122] -11-

[0123] The term “5 or 6 membered monocyclic heteroaryl” as used herein refers to a 5 or 6 membered aromatic ring having 1 to 3 carbon atoms replaced independently by nitrogen, sulfur, or oxygen. Examples are pyridyl (or pyridinyl), pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl (e.g. 1.2.4 triazoyl), furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl.

[0124] The term “9 or 10 membered bicyclic heteroaryl” as used herein refers to a 9 or 10 membered aromatic ring made up of two rings, having 1 to 3 carbon atoms replaced independently by nitrogen, sulfur, or oxygen (the heteroatoms can be in one ring or distributed amongst the two). Examples are purinyl, quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl and benzothiazolyl.

[0125] The term “Ci-Cn-alkoxy-Ci-Cn-alkyl” as used herein refers to an alkyl radical substituted with Ci-Cn-alkoxy group. Examples are methoxymethyl, methoxyethyl, ethoxymethyl and propoxymethyl.

[0126] The term “Ci-Cnhaloalkylenedioxy“ as used herein refers to a substituent having a Ci-Cnhaloalkylene group connected to two oxygen atoms, which is attached, via the two oxygen atoms. Examples are -OCHFO-, -OCF2O-, -OCHFCHFO-, and -OCF2CF2O-.

[0127] The term “neat” as used herein means that does not contain a co-solvent or a diluent.

[0128] The term “room temperature” or “RT” or “rt” or “ambient temperature” as used herein refers to a temperature of about 15° C to about 35° C. For example, rt can refer to a temperature of about 20° C to about 30° C.

[0129] In an embodiment of each aspect of the invention, R2is

[0130] A. hydrogen, Ci-C4-alkyl, or Ci-C4-haloalkyl; or

[0131] B. hydrogen, Ci-Cs-alkyl, or Ci-Cs-haloalkyl; or

[0132] C. hydrogen, Ci-C2-alkyl, or Ci-C2-haloalkyl; or

[0133] D. hydrogen, methyl, ethyl, difluoromethyl, trifluoromethyl, or pentafluoroethyl; or

[0134] E. methyl, difluoromethyl, trifluoromethyl; or

[0135] F. difluoromethyl.

[0136] In an embodiment of each aspect of the invention, R3a, R3b, and R3care independently selected from A. hydrogen, halogen, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, C1-C4- alkylsulfonyl, and Ci-C4-haloalkylsulfanyl, or R3aand R3btogether form a C1- C2haloalkylenedioxy substituent substituted on adjacent atoms on the phenyl ring forming together with the carbons of the phenyl ring a 5- or 6-membered ring, with the proviso that R3aand R3bare not hydrogen; or

[0137] B. R3a, R3b, and R3care independently selected from hydrogen, halogen, Ci-Cs-haloalkyl, C1-C3- haloalkoxy, or R3aand R3btogether form a Ci-C2haloalkylenedioxy substituent substituted on111355-FF

[0138] -12- adjacent atoms on the phenyl ring forming together with the carbons of the phenyl ring a 5- or 6-membered ring, with the proviso that R3aand R3bare not hydrogen; or

[0139] C. R3cis hydrogen or halogen, and R3aand R3bare independently selected from hydrogen, halogen, trifluoromethyl, trifluoromethoxy, or R3aand R3btogether form with the carbons of the phenyl ring a 5-membered ring consisting of -OCF2O- with the proviso that R3aand R3bare not hydrogen; or

[0140] D. R3cis hydrogen or halogen, and R3aand R3bare independently selected from halogen, or R3aand R3btogether form with the carbons of the phenyl ring a 5-membered ring consisting of - OCF2O-; or

[0141] E. R3a, R3b, and R3care independently selected from halogen; or

[0142] F. R3a, R3b, and R3care each fluorine; or

[0143] G. R3cis hydrogen, and R3aand R3btogether form with the carbons of the phenyl ring a 5- membered ring consisting of -OCF2O-.

[0144] In an embodiment of each aspect of the invention, Q is

[0145] A. a cyclic amine represented by the formula XXa,

[0146] ,2

[0147]

[0148] (XXa)

[0149] wherein the arrow indicates the connection to the carbonyl group (in relation to formula (I)), or to hydrogen (in relation to the amine QH);

[0150] p1is 0, or 1 and indicates the number of methylene groups;

[0151] p2is 0, or 1 and indicates the number of methylene groups;

[0152] X is hydrogen, hydroxyl, or alkoxy;

[0153] Y is cyano, Ci-C4-alkoxy-Ci-C4-alkyl, Ci-C4-alkylsulfanyl-Ci-C4-alkyl, Ci-C4-alkylsulfinyl-Ci-C4- alkyl, Ci-C4-alkylsulfonyl-Ci-C4-alkyl, RaRbNC(O), RcC(O)NRd, ReSO2NRf, RgO-N=CRh, RjRkNSO2, 4 to 6 membered non-aromatic heterocyclic ring system in which one or two carbons are replaced independently by nitrogen, oxygen, sulfur, or sulfonyl, phenyl, phenyl substituted with 1 to 3 substituents independently selected R4, 5 or 6 membered monocyclic heteroaryl having 1 to 3 carbon atoms replaced independently by nitrogen, sulfur, or oxygen, or 5 or 6 membered monocyclic heteroaryl having 1 to 3 carbon atoms replaced independently by nitrogen, sulfur, or oxygen, substituted with 1 to 3 independently selected substituents R5; Ra, Rb, Rc, Rd, Rf, Rg, and Rh, are independently selected from hydrogen, and Ci-C4-alkyl; Reis Ci-C4-alkyl;

[0154] R4and R5are independently selected from halogen, Ci-Ce-alkyl, and Ci-Ce-haloalkyl; or B. A cyclic amine represented by the formula XXa1111355-FF

[0155] -13-

[0156]

[0157] (XXa1),

[0158] wherein the arrow indicates the connection to the carbonyl group (in relation to formula (I)), or to hydrogen (in relation to the amine QH);

[0159] Y is a 5 or 6 membered monocyclic heteroaryl having 1 to 3 carbon atoms replaced independently by nitrogen, sulfur, or oxygen, substituted with 1 to 3 independently selected substituents R5; and

[0160] R5is Ci-Ce-alkyl; or

[0161] C. a cyclic amine represented by the formula XXa1, wherein Y is an oxadiazole, or a triazole; substituted with a single substituent R5; and R5, is methyl; or

[0162] D. a cyclic amine represented by the formula XXa1, wherein Y is an oxadiazole substituted with a single substituent R5; and R5is methyl; or

[0163] E. a cyclic amine represented by the formula XXa1, wherein Y is 4-methyloxazol-2-yl; or

[0164] F. a cyclic amine represented by the formulae XXb,

[0165]

[0166] wherein the arrow indicates the connection to the carbonyl group (in relation to formula (I)), or to hydrogen (in relation to the amine QH);

[0167] A is cyano, C1-C4-cyanoalkyl, RjSO2, RjRkNSO2, phenyl, phenyl substituted with 1 to 3 independently selected substituents R6, or heteroaryl substituted with 1 to 3 independently selected substituents R7; wherein the said heteroaryl is either a 5 or 6 membered monocyclic or a 9 or 10 membered bicyclic, each having 1 to 3 carbon atoms replaced independently by nitrogen, sulfur, or oxygen;

[0168] R and Rkare independently selected from hydrogen, and Ci-C4-alkyl;

[0169] R' is independently Ci-C4-alkyl;

[0170] R6and R7are independently selected from halogen, Ci-C4-alkyl, and Ci-C4-haloalkyl; or G. a cyclic amine represented by the formulae XXb, wherein A is RRkNSO2; R is hydrogen; and Rkis Ci-C4-alkyl; or

[0171] H. a cyclic amine represented by the formulae XXb, wherein A is RRkNSO2; R is hydrogen; and Rkis ethyl.

[0172] In an embodiment of each aspect of the invention, R10is

[0173] A. Ci-Csalkyl; or

[0174] B. methyl or ethyl; or

[0175] C. ethyl.111355-FF

[0176] -14-

[0177] In an embodiment of each aspect of the invention, R10ais

[0178] A. Ci-Csalkoxy or N(CH3)2; or

[0179] B. ethoxy or N(CH3)2.

[0180] The present invention, accordingly, makes available a process for preparing a compound of the invention having the substituents R1, R2, R3a, R3b, R3cand Q as defined above in all combinations / each permutation. Accordingly, made available, for example, is a compound of formula (I) with R1being the first aspect (i.e. R1is CN); R2being embodiment B (i.e. R2is hydrogen, Ci-Cs-alkyl, or Ci-Cs-haloalkyl); R3a, R3b, and R3cbeing embodiment G (i.e. R3cis hydrogen, and R3aand R3btogether form with the carbons of the phenyl ring a 5-membered ring consisting of –OCF2O-.); and Q being embodiment G (i.e. Q is a cyclic amine represented by the formulae XXb, wherein A is RjRkNSO2; Rjis hydrogen; and Rkis C1-C4-alkyl).

[0181] In an embodiment of each aspect of the invention, the compounds described herein (such as formulae (I) to (XII)) have (if applicable)) as R1cyano; as R2difluoromethyl; as R3chydrogen; as R3aand R3btogether form with the carbons of the phenyl ring a 5-membered ring consisting of –OCF2O-; as Q cyclic amine represented by the formulae XXb, wherein A is RjRkNSO2, Rjis hydrogen, and Rkis ethyl; as R10ethyl; and as R10aethoxy or N(CH3)2.

[0182] In an embodiment of each aspect of the invention, the compounds described herein (such as formulae (I) to (XII)) have (if applicable) as R1cyano; as R2difluoromethyl; as R3chydrogen; as R3aand R3btogether form with the carbons of the phenyl ring a 5-membered ring consisting of –OCF2O-; as Q cyclic amine represented by the formulae XXa, wherein X is hydrogen, and Y is 4-methyloxazol-2-yl; as R10ethyl; and as R10aethoxy or N(CH3)2.

[0183] In an embodiment of each aspect of the invention, the compounds described herein (such as formulae (such as formulae (I) to (XII)) have (if applicable) as R1cyano; as R2difluoromethyl; as R3a, R3band R3ceach fluorine; as Q cyclic amine represented by the formulae XXa, wherein X is hydrogen, and Y is 4-methyloxazol-2-yl; as R10ethyl; and as R10aethoxy or N(CH3)2.

[0184] Preferred embodiments of the process for the preparation of compounds of the invention is further detailed below:

[0185] Process step a) for the preparation of compound of formula (III):

[0186] The compound of formula (II) may be converted to compound of formula (III) by reacting it with an orthoester (e.g triethyl orthoformate or an A / , A / -dimethylformamide dialkylacetal (e.g. N, N-dimethylformamide dimethylacetal or DMF-DMA). Preferably using triethylorthoformate (1.0-3.0 equiv., preferably 1.0-2.0 equiv. with respect to substrate of formula (II)). Acetic anhydride (3.0-15.0 equiv., preferably 3.0-10 equiv,, even more preferably 3.0-0.7 equiv.) may be used as co-reagent which could serve as scavenger for the ethanol by-product produced and water which may be present.111355-FF

[0187] -15-

[0188] The reaction could be carried out at temperatures ranging from 20 °C to the boiling point of the reaction mixture, preferably at temperatures ranging from 80 °C to 150 °C.

[0189] Isolation of compound of formula (III) could be carried out by removing the volatiles generated in the transformation or volatiles remaining. Generally, the reaction could be run at standard pressure, elevated pressure or reduced pressure as defined in WO2011113789. In the present case, the reaction was preferably carried out at standard pressure. However, the reaction could be performed at pressure from 0 to 750 mbar, preferably 0 to 500 mbar to ensure removal of ethanol released in the reaction and to lower the amount of acetic anhydride co-reagent need.

[0190] Preferably, the compound of formula (III) is not isolated and is of sufficient purity to be used as us for the next step (Process step b)).

[0191] Process step b) for the preparation of compound of formula (IV):

[0192] To obtain the compound of interest, / .e the compound of formula (IV), compounds of formula (III) can be subjected to a condensation reaction with acetic amide derivative (III’) (1.0-5.0 molar equivalent (or equiv.) with respect to (III) preferably 1.0-2.5 equiv.), in the presence of a base such as sodium ethoxide, lithium ethoxide, sodium hydride, lithium hydride, sodium amide, lithium amide, sodium metal, lithium metal (preferably metallic sodium associated with ethanol and sodium ethoxide (1.0-2.0 equiv., preferably 1.0-1.5 equiv.), to furnish compound of formula (IV) or its tautomer, depending of the pH or the nature of the solvent where it is solvated.

[0193] The reaction may be carried out in methanol, ethanol, 2-butoxyethanol, 2-ethoxyethanol, 2-methoxyethanol, propanol, isopropanol, 1-15 butanol, 2-butanol, isobutanol, tert-butanol, pentanols, hexanols, heptanols, octanols, isoamyl alcohol, cyclohexanol, 1,3-butanediol, 1,4-butanediol, more preferred are water-miscible alcohols, preferably ethanol or isopropanol.

[0194] The temperature can vary from -10 °C to 35 °C, preferably from 0 °C to 25 °C.

[0195] Isolation of compound of formula (IV) could be achieved by acidifying the reaction mixture to a pH lower than 2 using a solution of acid (aqueous HCI, sulfuric acid, preferably aqueous HCI 33 to 37%). Filtration and washes of the filtrate using isopropanol could deliver the desired compound of formula (IV).

[0196] In an embodiment, the process for the preparation of compound of formula (IV) carried out with metallic sodium associated with ethanol or with sodium ethoxide in ethanol or in isopropanol at the temperature between 0°C to 25°C.

[0197] Process step c) for the preparation of compound of formula (VI):

[0198] The process of aromatic bromination of compound of formula (V) may be accomplished by using molecular bromine, A / -Bromosuccinimide, or 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) (1.0-2.0111355-FF

[0199] -16-equiv. with respect to (V), preferably 1.0-1.5 equiv. of molecular bromine). The process may be carried out in the presence of stoichiometric FeBr3, or an inorganic acid such as hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid or an organic acid such as formic acid, acetic acid, propionic acid, citric acid, oxalic acid, methanesulfonic acid or p-toluenesulfonic acid. Preferably without an additive. The temperature of the reaction can vary from 20 °C to 100 °C, preferably from 80 °C to 90 °C.

[0200] Preferred solvents would be chloroform, carbon tetrachloride, dichloromethane, tetrachloroethylene, nitromethane, acetic acid, acetone, N. N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), nitrobenzene, (add polar solvents) water and acetonitrile, preferably water.

[0201] After completion of the reaction, excess of brominating agent is reduced or neutralized by using a solution of Na2S2O3and diluted with ethyl acetate. Filtration of resulting mixture and extraction of the compound of interest using an organic solvent (i.e. ethyl acetate) could be carried out to recover compound of formula (VI). Washed of the organic layer using a basic solution e.g. saturated solution of sodium bicarbonate (NaHCO3) to neutralize the acidic medium could be performed. Distillation at standard or reduced pressure (preferably reduced, between 0 to 800 mbar, preferably ranging from 0 to 100 mbar) would be the purification of choice to isolate compound of formula (VI).

[0202] In an embodiment, the process for the preparation of compound of formula (VI) is carried out with molecular bromine in water at the temperature between 80 °C to 90 °C.

[0203] Process steps d) and d-a) for the preparation of compounds of formulae (VII) and (VIII):

[0204] The aim was to access compounds of a specific formula rapidly and cost-effectively. To achieve this, various methods (such as chloromethylation, Friedel-Crafts carbonylation, interrupted Pummerer reaction) were explored, but none were successful. The lack of reactivity or decomposition of the difluordioxolone moiety in formula (V) (when R3aand R3btogether form with the carbons of the phenyl ring a 5- membered ring consisting of-OCF2O-) prompted to consider other options.

[0205] Consequently, a more reliable alternative was identfied, which involved creating an organohalide (VI') to serve as a substrate for a Grignard reaction (Scheme 2a). Subsequently, this would be reacted with the appropriate carbonyl source to produce either a compound of formula (VII) if the carbonyl source is a compound of formula (VI”A), or a compound of formula (VIII) if the carbonyl source is a compound of formula (VI”B) (Scheme 2b).

[0206] Thus, by reacting compound of formula (VI) with carbonyl sources such as formamides, we could obtain compound of formula (VII) via intermediate of formula (VI”A). Alternatively, subjecting compound of formula (VI) to Grignard conditions followed by a Barbier reaction with formaldehyde or its polymeric form (paraformaldehyde) could lead to compound of formula (VIII) via intermediate of formula (VI ”B) (Scheme 2b).111355-FF

[0207] -17-

[0208] The process would commence by forming an organomagnesium species (VI’). Therefore, exposing compound of formula (VI) to isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex (also known as Turbo Grignard), or magnesium metal would initiate the process (1.0-1.5 equiv., preferably 1.0-1.2 equiv.).

[0209]

[0210] (VI')

[0211] Scheme 2a: Grignard reagent (VI’) resulting from compound of formula (VI)

[0212] o

[0213] VI‘A: RA= NMe2

[0214]

[0215] VI‘B: RB= H

[0216] Scheme 2b: Barbier intermediate

[0217] The magnesium metal used in this invention can take any of the forms typically employed in Grignard-type reactions. For instance, it may exist as a powder, flakes, granules, chips, turnings, lumps, or shavings. The contact between the magnesium metal and the aryl bromide should occur in standard glassware or reactors suitable for conducting Grignard-type reactions. The atmosphere within the reactor or glassware must be inert to optimize the reaction yields. Therefore, under the preferred conditions of the proposed process, the reactor or glassware should be purged and blanketed with an inert atmosphere such as argon or molecular nitrogen.

[0218] Suitable solvents for synthesizing the Grignard reagent include dialkyl ethers such as dimethyl ether, diethyl ether, ethyl methyl ether, n-butylmethyl ether, n-butyl ethyl ether, di-n-buty I ether, di-isobutyl ether, isobutylmethyl ether, isobutylethyl ether, tetrahydrofuran, and methyl tetrahydrofuran, with a preference for tetrahydrofuran.

[0219] The Grignard generation can be carried out at a temperature ranging from -10 °C to 35 °C, preferably at room temperature, between 0 °C to 25 °C.

[0220] The arylmagnesium bromide produced in tetrahydrofuran is then used in the presence of a carbonyl derivative:111355-FF

[0221] -18- • Combining arylmagnesium bromide (compound of formula VI’) with gaseous monomeric formaldehyde or its polymeric form can result in the compound of formula VI ”B.

[0222] • Combining arylmagnesium bromide (compound of formula VI’) with formamide derivatives can result in the compound of formula VI”A.

[0223] The carbonyl reactants can be dissolved in the aforementioned suitable solvents for the reaction and added dropwise to the in-situ formed Grignard reagent.

[0224] Isolation of the compound of formula (VII) can be achieved by quenching the mixture with a slow addition of ice water, followed by a saturated solution of ammonium chloride or 1M hydrochloric acid. Alternatively, the reaction can be quenched by adding it dropwise to a stirring solution of 1M citric acid or a mixture of a saturated solution of ammonium chloride and ethyl acetate. The extraction of the aqueous phase could proceed using an organic solvent (such as ethyl acetate) with at least three iterations, and the combined organic layers could be washed with brine. The combined layers could be dried over sodium sulfate or magnesium sulfate, filtered, and evaporated under vacuum to obtain a crude sample. Purification can be performed by column chromatography or distillation to yield the compound of formula (VI I) or compound of formula (VIII).

[0225] In an embodiment, the process for the preparation of compound of formula (VIII) is carried out in tetra hydrofuran at the temperature between 0 °C to 25 °C.

[0226] Process step d-b) for the preparation of compound of formula (VIII):

[0227] The compound of formula (VIII) can be obtained by employing commonly established conditions for the reduction of carbonyls to alcohols. These conditions utilize hydride sources such as sodium borohydride, sodium cyanoborohydride, ammonia-borane complex, and lithium aluminum hydride. Preferably, sodium borohydride (0.3-1.0 equiv., preferably 0.3-0.5 equiv.) is used. Alcoholic solvents such as methanol, ethanol, 2-butoxyethanol, 2-ethoxyethanol, 2-methoxyethanol, propanol, isopropanol, 1 -butanol, 2-butanol, isobutanol, tert-butanol, pentanols, hexanols, heptanols, octanols, isoamyl alcohol, cyclohexanol, 1,3-butanediol, and 1,4-butanediol are the solvents of choice. Mixtures of solvents including water and organic solvents such as tetra hydrofuran, diethoxymethane, dimethoxyethane, dioxane, ethylene glycol diethyl ether, and diethylenediglycol dialkylethers such as 1-Methoxy-2-(2-methoxy-ethoxy)-ethane (diglyme) can also be used. Preferably, the reaction is carried out in aliphatic and linear alcoholic solvents with a Ci-C4alkyl chain in.

[0228] The temperature can vary from -10 °C to 30 °C, preferably from 0 °C to 25 °C.

[0229] The compound of formula (VIII) can be isolated from the reaction mixture by quenching the reaction mixture under acidic conditions (dilute aqueous HCI solutions or a saturated solution of ammonium chloride) and then extracting using an organic solvent. The organic solution can be treated with a drying111355-FF

[0230] -19-agent (such as magnesium sulfate or sodium sulfate) and concentrated in vacuo to yield the compound of formula (VIII) without any further purification.

[0231] In an embodiment, the process forthe preparation of compound offormula (VIII) is carried out with sodium borohydride in aliphatic and linear alcoholic solvents with the alkyl chain in Ci-C4alkyl at the temperature between 0 °C to 25 °C.

[0232] Process step e) forthe preparation of compound of formula (IX):

[0233] To prepare the compound with the formula (IX), the compound with the formula (VIII) is reacted with an electrophilic chlorine source. Numerous literature reports are available for the direct conversion of benzyl alcohols to benzylic chlorides.

[0234] The compound offormula (IX) can be smoothly synthesized using chlorinating agents such as phosgene (COCl2) or triphosgene OC(OCCl3)2, oxalyl chloride (COCl)2, a combination of N-Chlorosuccinimide (NCS) and triphenylphosphine (PPhs), phosphorus oxychloride (POCI3), 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), a combination of triphenyl phosphine and carbon tetrachloride (PPhs and CCk), or thionyl chloride (SOCl2); preferably thionyl chloride or phosgene (1.0 equiv.-2.0 equiv., preferably 1.0-1.5 equiv.) or triphosgene (phosgene’s surrogate) ((0.35 to 0.6 equiv., preferable 0.35 to 0.4 equiv.). The reaction could be conducted using different types of solvents:

[0235] The chlorination step is compatible with various solvents. Examples are “optionally halogenated aromatic hydrocarbon solvents" such as benzene, toluene, ethylbenzene, xylenes, chlorobenzene, and dichlorobenzene, as well as mesitylene; cyclic ethers, such as methoxycyclopentane, CPME, tetrahydrofuran, and methyl tetrahydrofuran; ether solvents include diethoxymethane, dimethoxyethane, dioxane, ethylene glycol diethyl ether, diethylenediglycol dialkylethers such as 1-Methoxy-2-(2-methoxy-ethoxy)-ethane (diglyme), 1-Ethoxy-2-(2-ethoxy-ethoxy)-ethane, triglyme, anisole, diphenyl ether, and MTBE; ester solvents, such as ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate; and carbonylated solvents like acetone, methyl ethyl ketone, diethylketone, methylpropyl ketone. Preferably methyl tetrahydrofuran.

[0236] The reaction is preferably carried out at a temperature ranging from -10 °C to 35 °C, preferably from 0 °C to 25 °C (or at room temperature).

[0237] Isolation of the compound offormula (IX) can be achieved by quenching the mixture with a slow addition of a saturated solution of potassium carbonate followed by the addition of water. The medium can be extracted using ethyl acetate. The combined organic layers can be washed using brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting product was passed through silica-gel to afford compound of formula (IX).111355-FF

[0238] -20- In an embodiment, the process for the preparation of compound of formula (IX) is carried out with phosgene, triphosgene, or thionyl chloride in methyl tetra hydrofuran at the temperature between 0 °C to 25 °C.

[0239] Process steps step f) and g) for the preparation of compound of formulae (X) and (XI):

[0240] The strong advantage of this route is the development of a more attractive sequence by encompassing 2 steps into one process. While attempting to determine the optimal conditions for this bond formation, we initially investigated this chemistry using leaving groups more prone to depart. The reaction proceeded with remarkable efficiency under conventional conditions employing polar solvents, resulting in excellent yields (exceeding 90%) of the target compound. However, the process encountered challenges when the leaving group was changed from bromide to chloride, leading to a less favorable outcome. The yield decreased, the reaction time was extended, and the formation of byproducts increased. The Williamson ether synthesis using basic conditions could be taken advantage of saponifying the ester required to pursue the next step. Thus, compound of formula (XI) could be obtained by reacting compound of formula (IX) (1.0-1.5 equiv., preferably 1.0-1.2 equiv. with respect to compound of formula (IV)) with compound of formula (IV) or its tautomer in the presence of a base (e.g. K2CO3, KOH, ZnO, CU2O, NaOtBu, NaOH, triethylamine, DIPEA, CaO, Na3PO4, aqueous NaOH (50% in water) (1.0 equiv. -1.5 equiv., preferably solid NaOH or KOH 1.0-1.2 equiv.). The involvement of an additive was crucial for successful concomitant hydrolysis. Additive which could be applicable are TBAB, TMAB, CTAB, TBAC, TEAB, Aliquat 336, NaBr, Nal, KBr, KI; preferably KBr (0.05 equiv. -0.3 equiv., preferably 0.05 to 0.2 equiv.).

[0241] Suitable solvents include aromatic solvents such as benzene, toluene, ethylbenzene, xylenes, and chlorobenzene, and polar solvents. Preferably polar solvents such as DMF, DMA, DMSO, DMPU, ethylene carbonate, GVL, acetonitrile, acetone, diethyl ketone, MIBK, diethyl ketone, Ci-C4alkyl ketone, sulpholane, and more preferably sulpholane.

[0242] The reaction could proceed at temperature ranging from 40 to 90 °C. Preferably from 50 °C to 70 °C. Isolation of the compound of formula (X) was not necessary in the present work but could proceed by flash column chromatography, for the purpose of isolating pure material for alternative applications.

[0243] The concomitant ester saponification of in-situ generated compound of formula (X) could be carried out by addition of a base (e.g. K2CO3, KOH, ZnO, CU2O, NaOtBu, NaOH (50%), triethylamine, DIPEA, CaO, Na3PO4, K3PO4, aqueous NaOH (50% in water) (1.0 equiv. -1.5 equiv., preferably NaOH 1.0-1.2 equiv.), in the presence of water upon complete full or quasi full consumption of the compound of formula (X) and in the same solvent as stated above. The saponification could proceed optimally without affecting the newly formed ether bond at temperature preferably ranging from 0 °C to 25 °C (or at room temperature). Compound of formula (XI) could be recovered by adjusting the pH of the reaction mixture to 0.5 to 4, preferably 0.5 to 1.5 and using HCI (6N aqueous solution). The medium could be filtered and the recovered solid, recrystallized using a mixture of solvents (water and alcoholic solvents).111355-FF

[0244] -21- Process step f) for the preparation of compound of formula (X) starting from compound of formula (IV’):

[0245] O

[0246]

[0247] R ' hr ^OM

[0248] (IV’) wherein M is a counterion

[0249] Compound of formula (X) could be obtained by subjecting compound of formula (IX) and compound of formula (IV’). The conditions defined in Process step f) above apply to compound of formula (IV’) which is a salt of compound of formula (IV). Compound of formula (IV’) may be generated upon treatment of the compound of formula (IV) with inorganic bases such as NaOH or KOH (1.0 equiv.-1.5 equiv., preferably NaOH 1.0-1.2 equiv.), Solvents for the preparation of compound of formula (IV’) include MeCN, n-BuCN, diethoxymethane, dimethoxyethane, dioxane, diethyl ether, MTBE, CPME, tetrahydrofuran, and methyl tetrahydrofuran. Preferably MeCN. The deprotonation could proceed at temperatures ranging from 0 to 25 °C, preferably from 10 °C to 25 °C.

[0250] Compound of formula (IV’) could be isolated by filtration and used without further purification under the same conditions as stated in the Williamson ether synthesis to prepare compound of formula (X) using the same base base (e.g. K2CO3, KOH, ZnO, Cu2O, NaOtBu, NaOH, triethylamine, DIPEA, CaO, Na3PO4, aqueous NaOH (50% in water) (1.0 equiv. -1.5 equiv., preferably NaOH or KOH 1.0-1.2 equiv.) and catalyst (e.g. TBAB, TMAB, CTAB, TBAC, TEAB, Aliquat 336, NaBr, Nal, KBr, KI; preferably KBr (0.05 equiv. -0.3 equiv., preferably 0.05 to 0.2 equiv.)).

[0251] The same lineup of solvents as for Process step f) above could be used too. These solvents include polar solvents like DMF, DMA DMSO, DMPU, ethylene carbonate, GVL, acetonitrile, acetone, diethyl ketone, MIBK, diethyl ketone, C1-C4alkyl ketone, and sulpholane (preferably sulpholane). Aromatic hydrocarbon solvents include benzene, toluene, ethylbenzene, xylenes, and chlorobenzene. The reaction could proceed at temperatures ranging from 40 to 90 °C, preferably from 50 °C to 70 °C. The preferred solvent is sulpholane.

[0252] Isolation of the compound of formula (X) by neutralizing the reaction medium using for example an aqueous solution of dilute HCI (1 to 2M) and flash column chromatography for purification purposes.

[0253] Process step q) for the preparation of compound of formula (XI)

[0254] Like the aforementioned step, the saponification reaction could be done on compound of formula (X) by subjecting the latter to a base under aqueous conditions. The challenge of this step was to find conditions which would not cleave the benzyloxy- part of the structure and other functionalities of the structure. These side reactions can take place at temperature above 35 °C. It was crucial to find appropriate conditions which would allow to operate at room temperature.111355-FF

[0255] -22- It was found that bases suitable with the present step include LiOtBu, NaOtBu, KOtBu, NaOH (25 to 50% weight in water), KOH (25 to 50% weight in water); preferably NaOH (50% weight in water) (1.0 equiv. -1.5 equiv., preferably 1.0-1.2 equiv.). The method requires a binary solvent system comprising water and an organic solvent. The latter can be sulpholane, diethoxymethane, dimethoxyethane, dioxane, ethylene glycol diethyl ether, and diethylenediglycol dialkylethers such as 1-methoxy-2-(2-methoxy-ethoxy)-ethane (diglyme), dialkyl ethers such as dimethyl ether, diethyl ether, ethyl methyl ether, n-butylmethyl ether, n-butyl ethyl ether, di-n-butyl ether, di-isobutyl ether, isobutylmethyl ether, isobutylethyl ether, tetrahydrofuran, methyl tetrahydrofuran, methanol, ethanol, 2-butoxyethanol, 2-ethoxyethanol, n-propanol, isopropanol, 1 -butanol, 2-butanol, isobutanol, tert-butanol, pentanols, hexanols, heptanols, octanols, isoamyl alcohol, 1,3-butanediol, 1,4-butanediol; with a preference for sulpholane.

[0256] The reaction is preferably carried out at a temperature ranging from -10 °C to 35 °C, preferably from 0 °C to 25 °C (or at room temperature).

[0257] The compound with the formula (XI) can be recovered during the workup process by adding water and adjusting the pH to neutralize the reaction medium, thereby protonating the carboxylate to its carboxylic acid form. The pH should be adjusted to below 1.5 but must remain above 0.7 by adding an aqueous solution of 6N HCI at room temperature. The resulting precipitated solid can be filtered and washed with water to obtain the crude material, which can then be crystallized using an appropriate solvent mixture.

[0258] The purification of the compound with the formula (XI) cannot be generalized, as it will depend on the functionality of the compound and its solubility in the crystallizing solvent. However, crystallization using a binary solvent system comprising water and alcoholic solvents (such as ethanol, methanol, and isopropanol) in a ratio of 1:1 to 4, preferably 1:1, can be performed to isolate the compound with the formula (XI).

[0259] Process steps h) and i) for the preparation of compounds of formula (XII) and (I):

[0260] The Schotten-Baumann reaction has found widespread use in industrial settings due to its reliability and efficiency in amide bond formation (US20060155143, EP3055292, EP2888226). There are various reasons for this popularity: The Schotten-Baumann reaction typically occurs under mild conditions, which can be advantageous for sensitive substrates or functional groups that may be prone to degradation under harsher conditions. The reaction is relatively straightforward and can be performed using standard laboratory equipment, making it accessible for many chemists. This method can be applied to both small-scale and large-scale synthesis, making it versatile for different applications and scales of production. When optimized, the Schotten-Baumann reaction can provide high yields and excellent selectivity, reducing the formation of unwanted by-products and only generating alkali metal salt counterpart. The significant advantage of this process is that it allows for the avoidance of coupling agents, thereby favoring the atom economy of the reaction and preventing the handling of stoichiometric amount of organic byproduct formation. Coupling agents such as DCC, DIC, HOBt / DIC, HBTU, TBTU, T3P, or DIC / HOAt could be considered as options for facilitating the formation of amide bonds through the introduction of111355-FF

[0261] -23-activated ester intermediates. However, since the method also necessitates the use of an expensive condensing agent and does not yield high results, it leads to increased production costs.

[0262] The Schotten-Baumann proceeds by first, generating an acyl chloride compound (hereby, compound of formula (XII)), generated by reacting compound of formula (XI) in the presence of a chlorinating agent, as depicted in Scheme 3. The chlorination is usually catalyzed by a formamide derivative such as N, N-dimethyl formamide (DMF) or A / , A / -dimethyacetamide (DMA). Preferably DMF (0.1 -0.2 equiv. with respect to compound of formula (XI)). DMF or similar substituted formamides form a complex with the chlorinating agent, called the Vilsmeier reagent. The latter is the actual catalytic species in the chlorination of acids.

[0263]

[0264] Scheme 3: A) General representation of the formation of the Vilsmeier reagent - B) Application to a carboxylic acid substrate (XI)

[0265] This process could be carried out using various reagents chlorinating agents such as phosgene (COCl2), triphosgene OC(OCCl3)2, oxalyl chloride (COCl)2, or thionyl chloride (SOCl2), preferably thionyl chloride or phosgene (1.0 equiv. -2.0 equiv., preferably 1.0-1.5 equiv. or triphospgene (phosgene’s surrogate) ((0.35 to 0.6 equiv., preferable 0.35 to 0.4 equiv.). Our selected reactants essentially generate gases as byproducts, resulting in a low waste and green process (Scheme 3).

[0266] A wide scope of amine pronucleophiles (formula QH) (1.0-1.5 equiv., preferably 1.0-1.2 equiv. with respect to compound of formula (XI)) can be used to deliver the corresponding amide product or compound of formula (I).

[0267] The chlorination step is compatible with various solvents. Examples are “optionally halogenated aromatic hydrocarbon solvents" include benzene, toluene, ethylbenzene, xylenes, chlorobenzene, and dichlorobenzene, as well as mesitylene; cyclic ethers, such as methoxycyclopentane, tetrahydrofuran, and methyl tetrahydrofuran; ester solvents include ethyl acetate. Isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate; and carbonylated solvents like acetone, methyl ethyl ketone, diethylketone, methylpropyl ketone. Preferably methyl tetra hydrofuran.

[0268] An aqueous solution of sodium hydroxide (NaOH) is utilized to adjust the pH in the reaction and, depending on whether ammonium salts are used, a neutralization is carried out using 1.0-2.0 equiv., excess of base, preferably 1.2- 1.5 equiv. of NaOH (50% weight in water) solution. The adjustment of the111355-FF

[0269] -24-pH throughout the reaction was crucial to avoid the formation of byproduct of the reaction step. The concentration of the aqueous sodium hydroxide solution ranges from 30 to 50% by weight, preferably 50% by weight in water. The pH value is determined using a pH meter.

[0270] The preferred pH value is not less than 8 and not more than 11.5. The pH is adjusted by the careful addition of NaOH (50% weight in water).

[0271] The temperature of the reaction can be generally defined as ranging between - 10 and +35 °C. Preferably ranging from 0 to 25 °C.

[0272] Isolation of compound of formula (I) cannot be generalized as it will depend on the nature of the amine counterpart QH. However, isolation by crystallization could usually be carried out by using a mixture of binary solvent system (water and alcoholic solvents, preferably water:ethanol).

[0273] Abbreviations:

[0274] 2-MeTHF: 2-Methyltetrahydrofuran

[0275] Aliquat 336: Tricaprylylmethylammonium chloride

[0276] CPME: Cyclopentyl methyl ether

[0277] CTAB: Cetyltrimethylammonium bromide

[0278] DCC: N, N'-Dicyclohexylcarbodiimide

[0279] DBDMH: 1,3-Dibromo-5,5-dimethylhydantoin

[0280] DCDMH: 1,3-Dichloro-5,5-dimethylhydantoin

[0281] DCM: Dichloromethane (as you noted)

[0282] DIC: N, N'-Diisopropylcarbodiimide

[0283] DIPEA: N, N-Diisopropylethylamine

[0284] DMA: N, N-Dimethylacetamide (as you noted)

[0285] DMF: N, N-Dimethylformamide (slight correction: not formaldehyde)

[0286] DMF-DMA: N, N-Dimethylformamide dimethyl acetal

[0287] DMPU: N, N'-Dimethylpropyleneurea (as you noted)

[0288] DMSO: Dimethylsulfoxide (as you noted)

[0289] GCMS: Gas chromatography-mass spectrometry (as you noted)

[0290] GVL: γ-Valerolactone

[0291] HBTU: O-(Benzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate

[0292] HOAt: 1 -Hydroxy-7-azabenzotriazole

[0293] HOBt: Hydroxybenzotriazole

[0294] LCMS: Liquid chromatography-mass spectrometry (as you noted)

[0295] MIBK: Methyl isobutyl ketone

[0296] MTBE: Methyl tert-butyl ether

[0297] Rt: Retention time (as you noted)111355-FF

[0298] -25- NMR: Nuclear Magnetic Resonance (as you noted)

[0299] tBME: tert-Butyl methyl ether (as you noted)

[0300] T3P: Propylphosphonic anhydride

[0301] TBAB: Tetrabutylammonium bromide

[0302] TBAC: Tetrabutylammonium chloride

[0303] TEAB: Tetraethylammonium bromide

[0304] TMAB: Tetramethylammonium bromide

[0305] TBTU: O-(Benzotriazol-1-yl)-N, N, N', N'-tetramethyluronium tetrafluoroborate

[0306] UPLC: Ultra Performance Liquid Chromatography (as you noted)

[0307] EXAMPLES

[0308] Preparatory Examples:

[0309] “mp” means melting point in °C.1H NMR spectra were recorded on a Brucker 400 MHz spectrometer, chemical shifts are given in ppm relevant to a TMS standard. Spectra were measured in deuterated solvents as indicated. Either one of the LCMS / GCMS methods given below was used to characterize the compounds. The characteristic LCMS / GCMS values obtained for each compound were the retention time (“Rt”, recorded in minutes) and are measured in either molecular ion (M) or (M+H)+or (M-H)-.

[0310] GCMS method:

[0311] Spectra were recorded on SHIMADZU GCMS-QP2010 Ultra mass spectrometer equipped with an electron impact (El) ion source. Ion Source Temperature: 200 °C, Interface Temperature: 220 °C, Scan speed: 2500, Carrier Gas: Helium, Mass range: 50 to 650 Da and GC-2010 PLUS from Shimadzu, Capillary Column: SH-Rxi- 17 Sil MS, Column Length: 30 m, Internal diameter: 0.25 mm, Film Thickness: 0.25 um, Column oven Temperature: 40 °C, Combi-PAL autosampler, Injector Temperature: 250 °C, Injection Mode: Split, Split Ratio: 30:1, Flow Control Mode: Pressure, Total Flow (mL / min): 33.0, Column Flow (mL / min): 1.0, Purge Flow (mL / min): 2.0, Runtime: 15 min, Temperature Programme: Initial temperature 40 °C for 1 min, then 40-280 °C with constant rate of 25 °C per min, Temperature hold at 280 °C for 4.4 min.

[0312] LCMS method:

[0313] Spectra were recorded on Waters (SQD2 or QDA Single quadrupole mass spectrometer) mass spectrometer equipped with an electrospray source (Polarity: Positive and Negative Polarity Switch), Capillary: 0.8-3.00 kV, Cone range: 25 Source Temperature: 120-150 °C, Desolvation Temperature: 500-600 °C, Cone Gas Flow: 50 L / h, Desolvation Gas Flow: 1000 L / h, Mass range: 110 to 850 Da and an Acquity UPLC from Waters: Quaternary solvent manager, heated column compartment, diode-array detector. Column: Acquity UPLC HSS T3 C18, 1.8 pm, 30 x 2.1 mm, Temp: 40 °C, DAD Wavelength range (nm): 200 to 400, Solvent Gradient: A = water + 5% Acetonitrile + 0.1% HCOOH, B= Acetonitrile + 0.05% HCOOH: gradient: 0 min 10% B; 0.-0.2 min 10-50% B; 0.2-0.6 min 50-100% B; 0.6-1.3 min 100% B; 1.3-1.4 min 100-10% B; 1.4-1.6 min 10% B; Flow (mL / min) 0.6.111355-FF

[0314] -26- NMR:

[0315] Spectra were recorded on a Bruker AVANCE Neo 400 MHz spectrometer equipped with an iProbe with z-gradients at 300 K. The operating frequencies for different nuclei were as follows: 1H NMR: 400 MHz; 13C NMR: 100 MHz; 19F NMR: 376 MHz. 2D NMR experiments (COSY, HSQC, HMBC) were also performed on the same instrument.

[0316] Procedure for the preparation of compound of formula (III) from compound of formula (II) - Step

[0317]

[0318] Preparation of ethyl (2Z)-2-(ethoxymethylene)-4,4-difluoro-3-oxo-butanoate (compound of formula (Illa))

[0319]

[0320] Example 1

[0321] 8.80 g (58.2 mmol) of triethyl orthoformate were charged in a round bottom flask equipped with a condenser. 4.01 g (29.10 mmol) of ethyl 4,4-difluoroacetoacetate followed by 24.00 g (233.00 mmol) of acetic anhydride were added to the reaction medium. The resulting solution was heated up to 140 °C, at standard pressure. Afterwards, the medium was cooled down to room temperature and concentrated in vacuo to afford compound of formula (Ila) as a clear solution (7.27 g, 100% yield).

[0322] Analytical data:

[0323] 1H NMR (400 MHz, CDCl3) δ ppm 7.74 - 7.97 (m, 1 H), 6.14 - 6.70 (m, 1 H), 4.18 - 4.51 (m, 4 H), 1.25 -1.61 (m, 7 H)

[0324] 19F NMR (377 MHz, CDCl3) δ ppm -127.69 (s, 1 F), -129.05 (s, 1 F).

[0325] Example 2

[0326] 25.94 g (171.56 mmol) of triethyl orthoformate were charged in a round bottom flask equipped with a condenser. 15.00 g (85.78 mmol) of ethyl 4,4-difluoroacetoacetate followed by 70.76 g (686.24 mmol) of acetic anhydride were added to the reaction medium. The resulting solution was heated up to 140 °C, at111355-FF

[0327] -27-standard pressure. Afterwards, the medium was cooled down to room temperature and concentrated in vacuo to afford compound of formula (Ila) as a clear solution (19.99 g, 98% yield).

[0328] Example 3

[0329] 34.59 g (228.75 mmol) of triethyl orthoformate were charged in a round bottom flask equipped with a condenser. 20.00 g (114.37 mmol) of ethyl 4,4-difluoroacetoacetate followed by 82.56 g (800.61 mmol) of acetic anhydride were added to the reaction medium. The resulting solution was heated up to 140 °C, at standard pressure. Afterwards, the medium was cooled down to room temperature and concentrated in vacuo to afford compound of formula (Ila) as a clear solution (26.6 g, 100% yield).

[0330] General procedure for the preparation of compound of formula (IV) or its tautomer from compound of formula (III) - Step b)

[0331]

[0332] (IV)

[0333] To a round bottom flask under an argon atmosphere, 2-cyanoacetamide (2.00 equiv.) in isopropyl alcohol (4.5 mL / g of compound of formula (III)) and sodium ethanolate (1.50 equiv.) were added. The reaction mixture was cooled to 0°C. At 0°C, compound of formula (III) (1.00 equiv.) was added to the reaction mixture. The reaction was quenched by adding 5M HCI (2 mL / g). The formed precipitate was diluted with isopropyl alcohol, filtered off, and dried to afford compound of formula (IV) as a yellow-orange solid.

[0334] Preparation of ethyl 5-cvano-2-(difluoromethyl)-6-hvdroxy-pyridine-3-carboxylate (or isomer) (compound of formula (IVa))

[0335]

[0336] (IVa)

[0337] Example 4

[0338] To a 50 mL round bottom flask under an argon atmosphere was charged with 2-cyanoacetamide (0.620 g, 7.381 mmol, 2.00 equiv.) in ethanol (4.42 mL, 3.50 g, 76.00 mmol, 21.00 equiv.) and sodium ethoxide (0.396 g, 5.535 mmol, 1.50 equiv.). The reaction mixture was cooled to 0°C. At 0°C, compound of formula (Illa) (1.00 g, 3.69 mmol, 1.00 equiv.) was added to the reaction mixture. The reaction was quenched by adding 5M HCI (2 mL). The formed precipitate was diluted with propan-2-ol, filtered off, and dried to afford compound of formula (IVa) as a yellow-orange solid (1.02 g, 93% yield).

[0339] Analytical data:111355-FF

[0340] -28- LCMS: Rt= 0.72 min, m / z (M+H)+= 243.

[0341] 19F NMR (377 MHz, DMSO-d6) δ ppm -119.13 (s, 2 F).

[0342] 1H NMR (400 MHz, DMSO-d6) δ ppm ) 1.28 - 1.37 (t, 3 H) 4.23 - 4.34 (q, 2 H), 7.29 - 7.66 (t, 1 H) 8.49 -8.60 (s, 1 H).

[0343] Example 5

[0344] To a 50 mL round bottom flask under an argon atmosphere was charged with 2-cyanoacetamide (0.621 g, 7.386 mmol, 2.00 equiv.) in isopropyl alcohol (4.5 mL) and sodium ethoxide (0.397 g, 5.542 mmol, 1.50 equiv.). The reaction mixture was cooled to 0°C. At 0°C, compound of formula (Illa) (1.00 g, 3.70 mmol, 1.00 equiv.) was added to the reaction mixture. The reaction was quenched by adding 5M HCI (2 mL). The formed precipitate was diluted with isopropyl alcohol (40 mL), filtered off, and dried to afford compound of formula (IVa) as a yellow-orange solid. (1.154 g, 96% yield)

[0345] Example 6 (Comparative example)

[0346] To a 50 mL round bottom flask under an argon atmosphere was charged with 2-cyanoacetamide (2.178 g, 25.91 mmol, 2.00 equiv.) in ethanol (15.54 mL, 12 g, 270 mmol, 21 equiv.) and compound of formula (Illa) (3.308 g, 12.95 mmol, 1.00 equiv.) was added to the reaction mixture. The reaction was then heated to room temperature and stirred at this temperature for 2 hours. The reaction was quenched by adding 5M HCI (2 mL). The formed precipitate was filtered off, washed once with cold water (10 mL), ethanol (10 mL), and tBME (10 mL), and dried. The crude product was diluted with 40 mL of isopropanol and stirred for 1 hour. The resulting suspension was filtered and washed twice with isopropanol (10 mL) to afford compound of formula (IVa) as a yellow solid (2.213 g, 42% yield).

[0347] General procedure for the preparation of compound of formula (VI) from compound of formula (V) - Step c)

[0348]

[0349] To a round bottom flask equipped with a water condenser and a thermometer, were charged compound of formula (V) (1.00 equiv.) and water (2.11 mL / g). Molecular bromine (2.00 equiv.) was then added dropwise over 30 minutes while slowly increasing the temperature to reach 85°C. After full addition, the temperature was further increased until reaching 85°C. The mixture was allowed to reach room temperature over 6 hours while stirring under Argon-flow, and then stirred at room temperature overnight. The mixture was added dropwise to a stirring mixture of ethyl acetate and 10% solution of Na2S2O3, filtrated, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with NaHCO3saturated solution, dried over sodium sulfate, filtrated, and evaporated in vacuo. Distillation under reduced pressure of the crude (5 mbar, 78-80 °C) afforded compound of formula (VI).111355-FF

[0350] -29- Preparation of 5-bromo-2,2-difluoro-1,3-benzodioxole (compound of formula (Via))

[0351]

[0352] (Via)

[0353] Example 7

[0354] In a 250 mL 3-neck round bottom flask equipped with a water condenser and a thermometer, compound of formula (Va) (25.00 g, 19.115 mL, 143 mmol, 1.00 equiv.) and water (0.37 mL / mmol, 52.8 mL, 2900 mmol, 20.3 equiv.) were charged. Molecular bromine (15.0 mL, 286 mmol, 2.00 equiv.) was then added dropwise for 30 minutes while slowly increasing the temperature to reach 85°C. After full addition, the temperature was further increased until reaching 85°C. The mixture was allowed to reach room temperature over 6 hours and 30 minutes while stirring under Argon-flow, and then stirred at room temperature overnight. The mixture was added dropwise to a stirring mixture of ethyl acetate and 10% solution of Na2S2O3, filtrated, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with NaHCO3saturated solution, dried over sodium sulfate, filtrated, and evaporated to dry and affording the crude material as brown. Distillation under reduced pressure (5 mbar, 78-80 °C) afforded compound of formula (Via) as a colorless oil (28.44 g, 84% yield).

[0355] Example 8 (Comparative example)

[0356] A 100 mL 3-neck round bottom flask equipped with a water condenser, bubbler, thermometer, and NaOH-trap. To a mixture of 2,2-difluoro-1,3-benzodioxole compound of formula (Va) (6 g, 4.59 mL, 34.3 mmol, 1.00eq.) in water (12.7 mL, 697 mmol, 20.3 eq.), molecular bromine (2.52 mL, 48.0 mmol, 1.40 eq.) was added dropwise for 15 minutes while slowly increasing the temperature to reach 85°C. After full addition (temperature: 52°C), the temperature was further increased to 85°C and the mixture was stirred for 6 hours and 20 minutes. An additional 0.6 equiv. of molecular bromine was added dropwise at 85°C, and the mixture was stirred at 85°C for 1.5 hours. The mixture was then allowed to reach room temperature and was left stirring at room temperature overnight. The mixture was added dropwise to a stirring mixture of ethyl acetate and a 10% solution of Na2S2O3. The mixture was then filtered, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated NaHCO3solution, dried over sodium sulfate, filtered, and evaporated in vacuo. The remaining suspension was then filtered, and the solid was washed with ethyl acetate. The filtrate was evaporated in vacuo to afford a brown liquid as crude product. The crude material was distilled at approximately 5 mbar (boiling point of about 75 °C) to afford the compound of formula (Via) as a colorless liquid (5.72 g, 71% yield).

[0357] Example 9 (Comparative example)

[0358] In a 100 mL 3-neck round bottom flask equipped with a water condenser, bubbler, thermometer, and NaOH-trap, a mixture of 2, 2-difluoro-1,3-benzodioxole compound of formula (Va) (6 g, 4.59 mL, 34.3111355-FF

[0359] -30-mmol, 1.00 equiv.) in water (18.8 mL) was added dropwise at room temperature for 15 minutes, along with molecular bromine (3.59 mL, 68.5 mmol, 2.00 equiv.). The mixture was then stirred at 85°C overnight. The mixture was added dropwise to a stirring mixture of ethyl acetate and a 10% solution of Na2S2O3. The mixture was then filtered, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated NaHCO3solution, dried over sodium sulfate, filtered, and evaporated in vacuo. The remaining suspension was then filtered, and the solid was washed with ethyl acetate. The filtrate was evaporated in vacuo, affording brown liquid. The crude material was purified by column chromatography to afford the compound of formula (Via) as a colorless liquid (3.341 g, 38% yield).

[0360] Analytical data:

[0361] 1H NMR (400 MHz, CDCl3) δ ppm 6.95 - 6.99 (dd, 1 H) 7.22 - 7.27 (m, 2 H).

[0362] 19F NMR (377 MHz, CDCl3) δ ppm -49.88 (s).

[0363] General procedure for the preparation of compound of formula (VII) from compound of formula (VI) - Step d-a)

[0364]

[0365] To a solution of isopropylmagnesium chloride in THF (2.0 M, 1.2 equiv.) was added compound of formula (VI) (1.0 equiv.) was added dropwise at room temperature for 5 minutes (exothermic). After complete addition, the resulting solution was stirred at room temperature until complete formation of the Grignard intermediate. A / , A / -dimethylformamide (1.1 equiv.) was then added dropwise for 5 minutes at room temperature (exothermic, temperature rose to 32°C again) to the stirring mixture. The mixture was added dropwise to a mixture of saturated ammonium chloride solution and ethyl acetate. The aqueous layer was then extracted four times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo, affording compound of formula (VII).

[0366] Preparation of 2,2-difluoro-1,3-benzodioxole-5-carbaldehyde (compound of formula (Vila))

[0367]

[0368] Example 10

[0369] A vial charged with isopropylmagnesium chloride (2.0 mol / L) in THF (1.2 equiv., 3.8 mL, 7.6 mmol, 1.2 equiv.) was used. Compound of formula (VI) (1.5 g, 0.86 mL, 6.3 mmol, 1.0eq.) was added dropwise at room temperature for 5 minutes (exothermic). After complete addition, the resulting brownish clear solution was stirred at room temperature for 1 hour and 10 minutes. A / , A / -dimethylformamide (1.1 equiv.,111355-FF

[0370] -31- 0.54 mL, 7.0 mmol) was then added dropwise for 5 minutes at room temperature (exothermic, temperature rose to 32°C again), and the mixture was kept stirring at room temperature. The mixture was added dropwise to a mixture of saturated ammonium chloride solution and ethyl acetate. The aqueous layer was then extracted four times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo, affording compound of formula (Vila) (1.306 g, 91% yield).

[0371] Analytical data:

[0372] LCMS: Rt= 0.89 min, m / z (M+H)+ = 187

[0373] 1H NMR (400 MHz, CDCl₃) δ ppm 9.93 (s, 1 H), 7.68 (dd, J=8.4, 1.45 Hz, 1 H), 7.62 (d, J=1.5 Hz, 1 H), 7.24 (d, J=8.0 Hz, 1 H).

[0374] 19F NMR (377 MHz, Solvent) δ ppm -49.80 (s, 2F).

[0375] Example 11 (Comparative example)

[0376] A 3-neck round bottom flask equipped with a septum, thermometer, and Argon-flow was charged with magnesium (0.12 g., 5.1 mmol, 1.2 equiv.) and the flask was then dried under vacuum using a heat gun. Then, tetra hydrofuran (0.34 mL) and 1 drop of 1,2-dibromoethane were added, and the mixture was heated to reflux to activate the magnesium. Subsequently, compound of formula (Via) (1.0 g, 0.57 mL, 4.2 mmol, 1.0 equiv.) dissolved in tetra hydrofuran (3.9 mL) was added dropwise. The addition was completed, and the temperature rose to 40°C during addition. The brown solution with magnesium was then left stirring at 40°C for 1 hour. Then, A / , A / -dimethylformamide (0.39 mL, 5.1 mmol, 1.2 equiv.) was added dropwise for 5 minutes at room temperature (exothermic, temperature rose to 36°C), and the mixture was kept stirring at room temperature for 1.5 hours. The mixture was quenched by adding ice water, followed by ammonium chloride saturated solution. The aqueous layer was then extracted four times with ethyl acetate. As there was still product in the aqueous layer due to bad layer separation, HCI 2 M was added until reaching pH 1 and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo, affording compound of formula (Vila) as a yellowish oil (0.729 g, 71% yield).

[0377] Example 12 (Comparative example)

[0378] In a Supelco Vial under argon, a solution of compound of formula (Via) (253.4 mg, 0.146 mL, 1.048 mmol, 1.0 equiv.) dissolved in tetrahydrofuran (1.048 mL) was added at 0°C, followed by isopropylmagnesium bromide (0.44 mL, 0.436 mmol, 0.416 equiv.). The mixture was then left stirring at 0°C for 10 minutes. Then, butyllithium (0.35 mL, 0.8697 mmol, 0.83 equiv.) was added dropwise for 5 minutes, and the mixture was kept stirring at 0°C for 50 minutes. The mixture was then cooled to -10°C, and N, N-dimethylformamide (0.0877 mL, 1.132 mmol, 1.08 eq.) dissolved in tetrahydrofuran (1.132 mL, 14 mmol, 13 equiv.) was added dropwise for 5 minutes. The mixture was then allowed to reach room temperature and was stirred at this temperature for 1 hour. The mixture was added dropwise to a 1 M citric acid solution while stirring. The aqueous phase was then extracted twice with DCM. The combined organic phases were then evaporated together with toluene, affording 336 mg of yellow oil, which still contains DMF. The111355-FF

[0379] -32-crude was therefore washed 2 times with 10% LiCI solution, followed by water. The organic phase was then evaporated again with toluene, affording compound of formula (Vila) as a yellow oil (0.168 g, 16% yield).

[0380] Alternative methods for the synthesis of compound of formula (Vila) from compound of formula (Va)

[0381] Example 13

[0382] To a mixture of Iron(lll) chloride (1.17 equiv., 1.34 mmol, 1.17 equiv.) and dichloromethane (0.5 mL / mmol) was added dropwise compound of formula (Va) (200 mg, 1.14 mmol, 1.0 equiv.) for 2 min at -10°C dissolved in dichloromethane (0.170 mL / mmol). The resulting mixture was left stirring at -10°C for 5 min. Then, 1-(dichloromethoxy)butane (0.202 mL, 1.38 mmol, 1.21 equiv.) dissolved in dichloromethane (0.170 mL / mmol) was added dropwise for 3 min at -10°C, and the mixture was then allowed to reach room temperature while stirring. After 1 hour, the mixture was added dropwise to a mixture of HCI (2M) and ethyl acetate while stirring. The aqueous layer was separated and extracted once with ethyl acetate. The combined organic layers were washed with water and filtrated over celite. The resulting filtrate was then dried over sodium sulfate, filtrated, and evaporated in vacuo. The crude material was purified by reversed column chromatography. The desired compound of formula (Vila) was not observed, but a byproduct compound of formula (Vllaa) (33 mg, 10% yield) was isolated.

[0383]

[0384] (Vllaa)

[0385] Analytical data

[0386] LCMS: Rt= 1.02 min, m / z (M-H)- = 293

[0387] 1H NMR (600 MHz, CDCl₃): δ ppm 4.86 - 5.92 (m, 1 H) 6.99 (t, J=7.3 Hz, 1 H) 7.04 (d, J=8.1 Hz, 1 H) 7.17 (d, J=4.6 Hz, 1 H) 7.18 (d, J=4.8Hz, 1 H) 7.21 (d, J=8.4 Hz, 1 H) 7.91 (s, 1 H) 8.05 - 8.15 (m, 1 H) 19F NMR (565 MHz, CDCl₃): δ ppm -49.7 (s, 2F).

[0388] General procedure for the preparation of compound of formula (VIII) from compound of formula (VI) - Step d)

[0389]

[0390] In a sulfonation flask was added isopropylmagnesium chloride (2.0 M, 1.2 equiv.) in THF was added. Then, compound of formula (VI) (1.0 equiv.) was added dropwise at room temperature (exothermic, temperature rose to 30 C) while stirring. The mixture was then left stirring at room temperature until111355-FF

[0391] -33-complete Grignard formation. In a separate 3-neck round bottom flask, Polyoxymethylene-Homopolymer (7 equiv.) was added, and the solid was heated slowly to 150°C while stirring. Gas-Infusion was initiated, and after 1 hour of gas infusion, the heating of paraformaldehyde was stopped, and the apparatus was allowed to reach room temperature. The mixture was quenched by adding ice water, followed by a saturated solution of ammonium chloride. The aqueous layer was then extracted two times with TBME. Subsequently, HCI 1 M was added until reaching pH 1, and the aqueous layer was extracted once more with TBME. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo, affording compound of formula (VIII).

[0392] Preparation of 2,2-difluoro-1,3-benzodioxol-5-yl)methanol (compound of formula (Villa))

[0393]

[0394] (Villa)

[0395] Example 14

[0396] In a sulfonation flask, isopropylmagnesium chloride (2.0 M) in THF (9.9 mL, 20 mmol, 1.2 equiv.) was added. Then, compound of formula (Via) (4.0 g, 2.3 mL, 17 mmol, 1.0 equiv.) was added dropwise at room temperature (exothermic, temperature rose to 30°C) while stirring. The mixture was then left stirring at room temperature for 45 minutes. An additional 0.2 equiv. of isopropylmagnesium chloride (2.0 M) in THF (9.9 mL, 20 mmol, 1.2 equiv.) was added, and the mixture was kept stirring at room temperature for 15 minutes. In a separate 3-neck round bottom flask, Polyoxymethylene-Homopolymer (7 equiv., 120 mmol, 7.0 equiv.) was added, and the solid was heated slowly to 150°C while stirring. Gas-Infusion was initiated, and after 1 hour of gas infusion, the heating of Paraformaldehyde was stopped, and the apparatus was allowed to reach room temperature. The mixture was quenched by adding ice water, followed by a saturated solution of ammonium chloride. The aqueous layer was then extracted two times with TBME. Subsequently, HC1 1 M was added until reaching pH 1, and the aqueous layer was extracted once more with TBME. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo, affording compound of formula (Villa) as orange oil. (3.176 g, 62% yield).

[0397] Analytical data

[0398] 1H NMR (400 MHz, CDCl₃) δ ppm 4.83 (d, J=6.9 Hz, 2 H) 6.92 (d, J=8.4 Hz, 1 H) 7.32 (d, J=8.4 Hz, 1 H).

[0399] 19F NMR (376 MHz, CDCl₃) δ ppm - 49.39 (s, 2F).

[0400] Example 15 (Comparative example)

[0401] A 3-neck round bottom flask with a thermometer, bubbler, argon valve, security trap, and three-way valve, as well as a syringe for gas infusion, and a sulfonation flask equipped with a thermometer, stirring bar, septa, bubbler, and security trap with a water trap were used. In a sulfonation flask, compound of formula111355-FF

[0402] -34- (Via) (2.0 g, 1.1 mL, 8.3 mmol, 1.0 equiv.) was added. Then, isopropylmagnesium chloride (2.0 mol / L) in THF (5.0 mL, 10 mmol, 1.2 equiv.) was added dropwise at room temperature (exothermic, temperature rose to 40°C) while stirring. The mixture was then left stirring at room temperature for 1 hour. In a separate 3-neck round bottom flask, Polyoxymethylene-Homopolymer (10.0 g, 110 mmol, 13 equiv.) was added, and the solid was heated slowly to 150°C while stirring. Gas infusion was started. Gas infusion was stopped after 25 minutes due to polymerization in the apparatus, which led to clogging of apparatus / tubes / inlets. Polyoxymethylene-Homopolymer (1.6 g, 17 mmol, 2.0 equiv.) was added directly into the reaction mixture and was then stirred at 40°C for 3.5 hours, allowed to reach room temperature, and left stirring at room temperature overnight. The mixture was quenched by adding ice water, followed by ammonium chloride saturated solution. The aqueous layer was then extracted two times with TBME. Then, HC1 1 M was added until reaching pH 1 (clear solution), and the aqueous layer was extracted once more with TBME. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo to afford the compound of formula (Villa) as a yellow oil (2.308 g, 54% yield).

[0403] Example 16 (Comparative example)

[0404] To a Supelco Vial charged with isopropylmagnesium chloride (2.0 mol / L) in THF (1.2 mL, 2.50 mmol, 1.2 equiv.) was added under argon dropwise at room temperature compound of formula (Via) (500 mg, 0.287 mL, 2.08 mmol, 1.0 equiv.) for 5 minutes (exothermic). The resulting solution was stirred at room temperature for 1 hour and 10 minutes. In the meantime, a separate flask was charged with polyoxymethylene-homopolymer (0.790 g., 8.33 mmol, 4.0 equiv.) and tetra hydrofuran (1.04 mL). The previously prepared Grignard reagent was then added dropwise for 5 minutes to the above-mentioned mixture while stirring (slightly exothermic, temperature rose to 28°C). After 4 hours at room temperature, the mixture was heated to 40°C and stirred for 2 hours at this temperature. The mixture was added dropwise to a mixture of saturated ammonium chloride solution and TBME. The aqueous layer was then extracted three times with TBME. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo to afford the compound of formula (Villa) as a yellow oil (0.746 g, 50% yield).

[0405] Alternative method for the synthesis of compound of formula (Villa) from compound of formula (Via)

[0406] Example 17 (Comparative example)

[0407] To a Supelco Vial charged with isopropylmagnesium chloride (2.0 mol / L) in THF (1.2 mL, 2.48 mmol, 1.2 equiv.) was added dropwise at room temperature compound of formula (Via) (500 mg, 0.287 mL, 2.067 mmol, 1.0 equiv.) for 5 minutes (slightly exothermic). After complete addition, the resulting solution was then stirred at room temperature for 1 hour. In the meantime, a separate flask was charged with 1,3,5-trioxane (0.568 mL, 8.270 mmol, 4.0 equiv.) and tetra hydrofuran (1.033 mL). The previously prepared Grignard reagent was then added dropwise for 5 minutes to the above-mentioned mixture while stirring (slightly exothermic). The reaction mixture was stirred for 2 hours at room temperature and then heated111355-FF

[0408] -35-to 40°C. The mixture was allowed to reach room temperature. The mixture was added dropwise to a mixture of saturated ammonium chloride solution and TBME. The aqueous layer was then extracted three times with TBME. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo. The material mostly consisted of debrominated compound of formula (Via) and trioxane, with no desired compound of formula (Villa).

[0409] General procedure for the reduction of compound of formula (VII) to compound of formula (VIII) - Step d-b)

[0410]

[0411] To a round bottom flask of appropriate volume, charge with methanol (5mL / g) was added compound of formula (VI I) (1.0 equiv.). The reaction medium was then cooled down to 2-5 °C and sodium borohydride (0.3 equiv.) was added portion-wise (10 portions). After 2 hours at room temperature, the reaction was carefully quenched with 150 mL of ammonium chloride saturated solution (75 g in 150 mL). The resulting mixture was concentrated in vacuo and the residual crude was extracted with ethyl acetate (150 mL x 2). The combined organic layers were dried over sodium sulfate filtered and evaporated in vacuo to afford compound of formula (VIII)

[0412] Preparation of 2,2-difluoro-1,3-benzodioxol-5-yl)methanol (compound of formula (Villa))

[0413]

[0414] (Villa)

[0415] Example 18

[0416] To a 2 L reaction flask, charge with methanol (750 mL, 5mL / g) was added compound of formula (Vila) (150 g, 105.5 mL, 234.53 mmol, 1.0 equiv.). The reaction medium was then cooled down to 2-5 °C and sodium borohydride (0.3 equiv.) was added portion-wise (10 portions). After 2 hours at room temperature, the reaction was carefully quenched with 150 mL of ammonium chloride saturated solution (75 g in 150 mL). The resulting mixture was concentrated in vacuo and the residual crude was extracted with ethyl acetate (150 mL x 2). The combined organic layers were dried over sodium sulfate filtered and evaporated in vacuo to afford compound of formula (Villa) as a clear oil (156.0 g, 96% yield).

[0417] Analytical data matched the data mentioned above.

[0418] Example 19 (Comparative example)

[0419] A 3-neck round bottom flask equipped with a thermometer and under Argon-flow was charged with compound of formula (Vila) (1.10 g, 5.60 mmol, 1.0 equiv.) and methanol (5.32 mL) and cooled to 0°C. Subsequently, 22.7 mg (1 / 3 of the total amount) of sodium borohydride was added at 0°C, causing the111355-FF

[0420] -36-temperature to rise to 10°C. This process was repeated twice more, each time adding 22.7 mg (1 / 3 of the total amount) of sodium borohydride at 0°C, with the temperature rising to 10°C and 8°C, respectively. The mixture was then allowed to reach room temperature while stirring. The reaction mixture was quenched by adding a saturated ammonium chloride solution at 0°C and subsequently extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and evaporated in vacuo to afford compound of formula (Villa) as a clear yellow liquid (962.0 mg, 80% yield).

[0421] Example 20 (Comparative example)

[0422] A vial charged with compound of formula (Vila) (300 mg, 1.58 mmol, 1.0 equiv.) and methanol (1.50 mL) was cooled to 0°C. Subsequently, sodium borohydride (0.0183 g, 0.473 mmol, 0.30 equiv.) was added in one portion and the mixture was stirred at 0°C. The reaction mixture was quenched by adding ammonium chloride saturated solution at 0°C. The resulting mixture was then extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The crude material was diluted with ethyl acetate, and the solid that precipitated during evaporation was removed by filtration using a Pasteur pipette filled with cotton, celite, and sodium sulfate. The filtrate was evaporated in vacuo, to afford compound of formula (Villa) as a clear yellow liquid (293.0 mg, 85% yield).

[0423] General procedure for the preparation of compound of formula (IX) from compound of formula (VIII) - Step e)

[0424]

[0425] Compound of formula (VIII) (1.0 equiv.) was dissolved in trifluoromethylbenzene (5 mL / g). Thionyl chloride (2.0 equiv.) was added dropwise at 0°C. The reaction mixture was stirred in the slowly warming up ice bath overnight, resulting in a colorless solution with no mass in LCMS and a new spot by TLC. The reaction mixture was then evaporated and cooled to 0°C. It was carefully quenched with a saturated solution of potassium carbonate followed by the addition of water and extracted using ethyl acetate. The organic layers were combined and washed using brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting product was passed through silica-gel to afford compound of formula (IX).

[0426] Preparation of 5-(chloromethyl)-2,2-difluoro-1,3-benzodioxole (compound of formula (IXa))

[0427]

[0428] (IXa)

[0429] Example 21 (Comparative example)111355-FF

[0430] -37- A 10 mL 2-neck round bottom flask was charged with compound of formula (Villa) (962 mg, 4.20 mmol, 1.0 equiv.) and trifluoromethylbenzene (0.546 mL, 4.44 mmol, 1.06 equiv.) and cooled to 0°C. Thionyl chloride (2 equiv., 0.619 mL, 8.41 mmol, 2.00eq.) was then added dropwise for 5 minutes, and the mixture was allowed to reach room temperature while stirring. The mixture was left stirring at room temperature overnight. After 24 hours of stirring, the reaction mixture was evaporated in vacuo and then quenched by adding a saturated solution of K2CO3at 0°C. The mixture was then extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and evaporated in vacuo, affording compound of formula (IXa) as a yellow liquid (977 mg, 92% yield).

[0431] Example 22

[0432] Compound of formula (Villa) (83 g, 414 mmol, 1.0 equiv.) was dissolved in trifluoromethylbenzene (415 mL, 5 mL / g, 3371 mmol). Thionyl chloride (60.4 mL, 828 mmol, 2.0 equiv.) was added dropwise at 0°C. The reaction mixture was stirred in the slowly warming up ice bath overnight, resulting in a colorless solution with no mass in LCMS and a new spot by TLC. The reaction mixture was then evaporated and cooled to 0°C. It was carefully quenched with 8 ml of saturated K2CO3solution followed by the addition of water (100 mL) and extracted using ethyl acetate (75 ml x 2). The organic layers were combined and washed using brine (50 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting product was passed through silica-gel to afford compound of formula (IXa) as a clear oil (89 g, 97% yield).

[0433] Analytical data:

[0434] 1H NMR (400 MHz, CDCl₃) δ ppm 4.57 (s, 2 H) 7.03 (d, J=7.99 Hz, 1 H) 7.10 (dd, J=7.99, 1.45 Hz, 1 H) 7.14 (d, J=1.45 Hz, 1 H).

[0435] 19F NMR (377 MHz, CDCl₃) δ ppm -49.99 (s).

[0436] Alternative method for the preparation of compound of formula (IX) via chloromethylation of compound of formula (V)

[0437] Preparation of 5-(chloromethyl)-2,2-difluoro-1,3-benzodioxole (compound of formula (IXa))

[0438]

[0439] (IXa)

[0440] Example 23:

[0441] To a round-bottom flask charged with paraformaldehyde (0.40 g, 4.3 mmol, 1.5 equiv.) in DCE (1.0 mL), was added thionyl chloride (0.25 mL, 0.41 g, 3.4 mmol, 1.2 equiv.) at 20°C under stirring. To this mixture, sulfuric acid (0.18 mL, 0.32 g, 3.1 mmol, 1.1 equiv.) was added, followed by compound of formula (Va) (0.45 g, 2.8 mmol, 1.0 equiv.) in 1,2-dichloroethane (0.19 mL) over a period of 18 minutes at 20°C. After 18 hours, the reaction was stopped by adding water (10 mL). The mixture was diluted with MTBE (50 mL). The organic layer was washed three times with water (10 mL). The organic phase was washed once111355-FF

[0442] -38-with brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography furnished compound of formula (IXa) as a clear oil (720 mg, 31% yield).

[0443] Preparation of 1-(chloromethyl)-2,4,5-trifluoro-benzene compound of formula (IXb)

[0444] Cl

[0445]

[0446] (IXb)

[0447] Example 24

[0448] To a round bottom flask charged with paraformaldehyde (0.522 g, 5.51 mmol, 1.5 equiv.) in DCE (1.84 mL) was added 1,2,4-trifluorobenzene (0.391 mL, 0.500 g, 3.67 mmol, 1.0 equiv.), followed by the addition of oxalyl chloride (0.386 mL, 0.571 g, 4.41 mmol, 1.2 equiv.) at rt. To this mixture, sulfuric acid (0.228 mL, 0.417 g, 4.04 mmol, 1.1 equiv.) was added. Then the reaction mixture was heated to 40°C. Sulfuric acid (0.228 mL, 0.417 g, 4.04 mmol, 1.10 equiv.) was added to the reaction mixture at 60°C. After 5 hours, the reaction was stopped by adding water (10 mL) at room temperature and diluted with MTBE (10 mL). The organic layer was washed three times with water (10 mL). The organic phase was washed once with brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (cyclohexane:ethyl acetate) furnished the title compound of formula (IXa) as a clear oil (1.20 mg, 69% yield).

[0449] Analytical data:

[0450] 1H NMR (400 MHz CDCl₃) δ ppm 4.57 (s, 2 H) 6.97 (td, J=9.40, 6.20 Hz, 1 H) 7.24 - 7.32 (m, 1 H).19F NMR (377 MHz, CDCl₃) δ ppm -141.71 (dd, J=21.37, 15.31 Hz, 1 F) -132.23 (dd, J=21.37, 4.49 Hz, 1 F).

[0451] General procedure for the preparation of compound of formula (XI) from compound of formula (IX) and compound of formula (IV) and tautomer-Step f) and q)

[0452]

[0453] (XI)

[0454] To a stirred suspension of compound (IV) (1 equiv.) in sulfolane (5 mL / g) was added powered sodium hydroxide (4.33 equiv.) at room temperature and stirring was continued at same temperature for 1 h. To the above reaction mixture was added potassium bromide (0.1 equiv.) at room temperature and heat to 60-65 °C. Then a solution of compound of formula (IX) (1.2 equiv.) in sulpholane (1 mL / g) was added111355-FF

[0455] -39-over a period of 3 h at 60-65 °C and stirring was continued at the same temperature for another 6 h. The reaction mixture was then cooled to room temperature. To the above reaction mixture was added a solution of NaOH (1.10 equiv.) in water (16 mL / g) at room temperature over a period of 1 h and stirring was continued for another 1 h, at same temperature. Water (25 mL / g) was added, and pH was adjusted to -0.9-1 by addition of 6N aq. HCI at room temperature and stirring was continued for another 30 min at the same temperature. The precipitated solid was filtered, and the solid was washed with water to afford the crude material which was crystallised the appropriate solvent mixture to afford compound of formula (XI).

[0456] Preparation of 5-cyano-6-[(2,2-difluoro-1,3-benzodioxol-5-yl)methoxyl-2-(difluoromethyl)pyridine-3-carboxylic acid (compound of formula (Xia))

[0457] O

[0458]

[0459] (Xia)

[0460] Example 25

[0461] To a stirred suspension of compound of formula (IVa) (14.7 g, 60.7 mmol) in sulfolane (75.0 mL) was added powered sodium hydroxide (2.54 g, 63.73 mmol) at room temperature and stirring was continued at same temperature for 1 h. To the above reaction mixture was added potassium bromide (0.721 g, 6.070 mmol) at room temperature and heat to 60-65 °C. Then a solution of compound of formula (IXa) (15.07 g, 72.84 mmol) in sulpholane (15 mL) was added over a period of 3 h at 60-65 °C and stirring was continued at the same temperature for another 6 h. The reaction mixture was then cooled to room temperature. To the above reaction mixture was added a solution of NaOH (2.67 g, 66.77 mmol) in water (45mL) at room temperature over a period of 1 h and stirring was continued for another 1 h, at same temperature. Water (360 mL) was added, and pH was adjusted to -0.9-1 by addition of 6N aq. HCI at room temperature and stirring was continued for another 30 min at the same temperature. The precipitated solid was filtered and the solid was washed with water to afford 22.70 gm crude product. Resultant crude solid product was crystallised from Water: IPA (1:1) (4 mL / g) at 20-75 °C. The solid was filtered and washed with Water: IPA (1:1) (5 mL / g) under string at room temperature to provide desired pure compound of formula (Xia) (18.29 g, 78% yield).

[0462] Analytical data:

[0463] LCMS: Rt= 1.04 min, m / z (M-H)- = 383.

[0464] 1H-NMR (400 MHz, DMSO-d₆) δ ppm 5.58 (s, 2 H) 7.41-7.46 (m, 2 H) 7.58-7.71 (m, 2 H) 8.79 (s, 1 H) 14.11 (br s, 1 H).

[0465] 13C NMR (101 MHz, DMSO-d₆) δ ppm 69.33, 98.68, 110.54, 111.24, 114.28, 121.06, 125.77, 129.13, 131.64, 132.65, 143.20, 143.20, 147.81, 153.71, 163.98, 164.79.111355-FF

[0466] -40-19F NMR (376 MHz, DMSO-d₆) δ ppm -118.89 (s, 1 F) -49.00 (s, 1 F).

[0467] Example 26 (Comparative example)

[0468] A 3-neck 50 mL round-bottom flask, with a thermometer connected to an N2 inlet was charged with compound of formula (IVa) (1.0 g, 4.05 mmol, 1.0 equiv.) and sodium hydroxide (0.182 g, 4.45 mmol, 1.1 equiv.) in sulpholane (4.0 mL). The reaction mixture was stirred at 24°C for 1 hour. Potassium bromide (0.048 g, 0.405 mmol, 0.1 equiv.) was then added to the reaction mixture at 24°C. The reaction mixture was heated to 90°C and then was a solution of compound of formula (IXa) (0.693 mL, 4.86 mmol, 1.2 equiv.) in sulfolane (1.00 mL) was added over 2 hours using a syringe pump. The reaction was continued at 70°C for the next 3 hours. The reaction was then cooled. To the same reaction mixture, a solution of sodium hydroxide (0.182 g, 4.46 mmol, 1.1 equiv.) in water (2.5 mL,) was added over a period of 1 hour using a syringe pump at room temperature. The reaction mixture was stirred for 1 hour. Water (20 mL) was added to the reaction mass and stirred for 15 minutes, resulting in a clear solution with a pH of 13.3.

[0469] 6N HCI was added dropwise until the pH reached approximately 0.9-1.0. The precipitate was filtered and dried, yielding a white powder as crude product. To crude was stirred for 30 minutes with water (15mL / g) and then filtered through a sintered funnel. The product was dried on a rotary evaporator affording compound of formula (Xia) as a white powder (1.30 g, 78% yield).

[0470] General procedure for the preparation of compound of formula (X) from compound of formula (IX) and compound of formula (IV) - Step f)

[0471] O

[0472]

[0473] To a three-neck round bottom flasked charged with compound of formula (IV) (1.0 equiv.) and sodium hydroxide or potassium hydroxide (1.05 equiv.) in sulpholane (10 mL / g) under an inert atmosphere. The reaction mixture was stirred at 24°C. compound of formula (IX) (1.2 equiv.) was added to the reaction mixture, and the stirring continued for 1 hour at 24°C, followed by stirring at 70°C. The reaction was then stopped and taken for workup. The reaction mass was cooled to 24°C and added to cold water (40 mL / g). The reaction mass precipitated out. The reaction mass was filtered, and the residue was dried under reduced pressure to obtain crude compound of formula (X) as solid. Purification by column chromatography (cyclohexane:ethyl acetate) delivered the desired compound of formula (XI).111355-FF

[0474] -41- Preparation of ethyl 5-cvano-6-[(2,2-difluoro-1,3-benzodioxol-5-yl)methoxyl-2- (difluoromethyl)pyridine-3-carboxylate (compound of formula (Xa))

[0475] O

[0476]

[0477] (Xa)

[0478] Example 27

[0479] In a 3-neck 25 mL round-bottom flask, the flask was charged with compound of formula (IVa) (1.00 g, 4.01 mmol) and potassium hydroxide (0.278 g, 4.21 mmol, 1.05 equiv.) in sulpholane (10 mL / g) under an inert atmosphere. The reaction mixture was stirred at 24°C. compound of formula (IXa) (1.2 equiv., 4.81 mmol) was added to the reaction mixture, and the stirring continued for 1 hour at 24°C, followed by stirring at 70°C. The reaction was then stopped and taken for workup. The reaction mass was cooled to room temperature and added to cold water (40 mL). The reaction mass precipitated out. The reaction mass was filtered, and the residue was dried under reduced pressure to obtain compound of formula (Xa) as a white solid (1.76 g, 84% yield).

[0480] Analytical data:

[0481] 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (t, J=7.08 Hz, 3 H) 4.35 (q, J=7.27 Hz, 2 H) 7.36 - 7.54 (m, 3 H) 7.60 - 7.63 (m, 1 H) 8.83 (s, 1 H).

[0482] 19F NMR (377 MHz, DMSO-d₆) δ ppm -118.83 (s, 1 F) -49.05 (s, 1 F).

[0483] Example 28 (Comparative example)

[0484] A 20 mL vial, under an argon atmosphere, equipped with a stirrer bar, magnetic stirrer, and heat-on plate was used for the following procedure. The flask was charged with compound of formula (IVa) (0.10 g, 0.41 mmol, 1.0 equiv.) and potassium carbonate (0.171 g, 1.24 mmol, 3.0 equiv.) in ethylene carbonate (1.0 mL, 1.321 g, 14.7 mmol, 35.6 equiv.) at 20°C, followed by the addition of compound of formula (IXa) (0.063 mL, 0.094 g, 0.45 mmol, 1.1 equiv.). The reaction mixture was then heated to 60°C and stirred overnight at this temperature. Potassium carbonate (0.029 g, 0.21 mmol, 0.5 equiv.) was added to the reaction mixture and stirred for a further 2 hours. The reaction was stopped by adding a saturated HCI solution (0.5 mL). The mixture was then diluted with toluene (10 mL). The organic layer was washed 3 times with an aqueous HCI solution 1 M. The aqueous layer was extracted three times with toluene. The organic phase was washed once with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford compound of formula (Xa) as a yellow gum / solid. (0.173 g, 49% yield).

[0485] Example 29 (Comparative example)

[0486] A 10 mL vial, under an argon atmosphere, equipped with a stirrer bar, magnetic stirrer, and heat-on plate was used for the following procedure. The vial was charged with compound of formula (IVa) (0.05 g,111355-FF

[0487] -42- 0.206 mmol, 1.0 equiv.), potassium carbonate (0.086 g, 0.619 mmol, 3.0 equiv.), and CTAB (0.0076 g, 0.0206 mmol, 0.10 equiv.) in A / , A / -dimethylacetamide (0.5 mL) at20°C, followed by the addition compound of formula (IXa) (0.032 mL, 0.048 g, 0.23 mmol, 1.1 equiv.). The reaction mixture was then heated to 80°C and stirred for 7 hours. The reaction was stopped by adding a saturated HCI solution (2 mL) and water (2 mL). The mixture was diluted with tBME (10 mL). The organic layer was washed once with an aqueous HCI solution 1 M and water. The aqueous layer was extracted once with tBME. The organic phase was washed once with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford compound of formula (Xa) as a yellow gum (0.053 g, 28% yield).

[0488] Example 30 (Comparative example)

[0489] A 10 mL 2-neck flask, equipped with a stirrer bar, magnetic stirrer, and heat-on plate, was used for the following procedure. The flask was charged with compound of formula (IVa) 0.159 g, 0.459 mmol, 1.0 equiv.) and calcium oxide (0.024 mL, 0.078 g, 1.38 mmol, 3.0 equiv.) in acetone (1 mL). The reaction mixture was heated to 60°C. Tetrabutylammonium chloride (0.013 g, 0.046 mmol, 0.1 equiv.) was added, followed by the addition of compound of formula (IXa) (0.0671 mL, 0.1 g, 0.459 mmol, 1.0 equiv.). The reaction mixture was stirred overnight and then cooled to room temperature. The reaction was stopped by adding ice-cold water (2 mL). An aqueous 2M HCI solution (2 mL) was added. The mixture was diluted with ethyl acetate (5 mL). The aqueous layer was extracted 2 times with ethyl acetate (5 mL). The organic phase was washed once with brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the compound of formula (Xa) as a brown gum (0.214 g, 59% yield).

[0490] Example 31 (Comparative example)

[0491] In a 7 mL vial with a stirrer bar, compound of formula (IVa) (0.063 g, 0.26 mmol, 1.1 equiv.) and zinc oxide (0.058 g, 0.711 mmol, 3.0 equiv.) in acetone (0.5 mL) were charged. The reaction mixture was heated to 60°C. Tetrabutylammonium chloride (0.0069 g, 0.0237 mmol, 0.1 equiv.) was added, followed by the addition of compound of formula (IXa) (0.0336 mL, 0.237 mmol, 1.0 equiv.). The reaction mixture was stirred for 24 hours at 60°C. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (3 mL) and filtered to remove the ZnO. Water (2 mL) and an aqueous 2M HCI solution (2 mL) were added to the filtrate. The mixture was diluted with ethyl acetate (10 mL). The organic layer was washed 2 times with an aqueous HCI solution 2M (2 mL) and water (5 mL). The organic phase was washed once with brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the compound of formula (Xa) as an orange solid (0.089 g, 63% yield).

[0492] Example 32 (Comparative example)

[0493] The 5 mL microwave vial with a stirrer bar was charged with compound of formula (IVa) (0.159 g, 0.459 mmol, 1.0 equiv.) and calcium oxide (0.0391 g, 0.68 mmol, 1.5 equiv.) in acetone (0.75 mL). The reaction mixture was heated to 60°C. Tetrabutylammonium bromide (0.0454 g, 0.137 mmol, 0.3 equiv.) was added, followed by the addition of compound of formula (IXa) (0.0671 mL, 0.1 g, 0.459 mmol, 1.0 equiv.). The reaction mixture was stirred overnight and then cooled to room temperature. The reaction was111355-FF

[0494] -43-stopped by adding ice-cold water (2 mL) and an aqueous 2M HCI solution (4 mL). The mixture was diluted with ethyl acetate (5 mL). The aqueous layer was extracted 2 times with ethyl acetate (5 mL). The aqueous layer was extracted 2 times with ethyl acetate (5 mL). The organic phase was washed once with brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the compound of formula (Xa) as a brown gum (0.252 g, 86% yield).

[0495] General procedure for the preparation of compound of formula (X) from compound of formula (IX) and compound of formula (IV’) - Step f)

[0496] Step 1: preparation of the salt of formula IV’ from compound of formula IV, to be used as nucleophile to deliver compound of formula (X)

[0497] O

[0498] R ' NT OM

[0499]

[0500] (IV’)

[0501] Preparation of sodium;3-cvano-6-(difluoromethyl)-5-ethoxycarbonyl-pyridin-2-olate (compound of formula (IV’a))

[0502] O

[0503] Hu||

[0504] F^«^XN;::;^ONa

[0505]

[0506] F(IV’a)

[0507] Example 33

[0508] A 250 mL round-bottom flask equipped with a reflux condenser, and under inert atmosphere was charged with compound of formula IV (5.00 g, 20.2 mmol, 1.00 equiv.). Acetonitrile (100 mL) was added, followed by sodium hydroxide (0.981 g, 24.3 mmol, 1.2 equiv.) at 20-25°C. The mixture was stirred for 60 minutes at 20-24°C. The resultant reaction suspension was filtered on a sintered funnel under a nitrogen atmosphere. The solid cake was washed with acetonitrile two times. The solid was dried on a rotary evaporator at 45°C under N2 atmosphere to afford compound of formula (IV’) as an off white solid (4.4 g, 77% yield).

[0509] Analytical data:

[0510] 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, J=7.13 Hz, 3 H) 4.30 (q, J=7.09 Hz, 2 H) 7.15 - 7.76 (m, 1 H) 8.63 (s, 1 H).

[0511] 19F NMR (377 MHz, DMSO-d₆) δ ppm -119.09 (s, 1 F).111355-FF

[0512] -44- Example 34

[0513] Compound of formula (IV) (10.00 g, 40.47 mmol) and acetonitrile (25 mL / g, 4780 mmol) were added, followed by sodium hydroxide (1.2 equiv., 48.56 mmol) at 20-25°C. The mixture was stirred for 60 minutes at 20-24°C, resulting in a thick white suspension.

[0514] After 1 hour of stirring, the resultant reaction suspension was filtered on a sintered funnel under a nitrogen atmosphere. The solid was washed with acetonitrile (30 mL x 2). The solid was concentrated by rotary evaporation at 45°C under N2 atmosphere to afford compound of formula (IV’) as an off-white solid (10.05 g, 88% yield).

[0515] Step 2: Use of salt of formula (IV’a) as nucleophile to deliver compound of formula (Xa)

[0516] Example 35

[0517] To a three-neck 50 mL round-bottom flask, compound of formula (IV’a) (1.0 g, 3.5 mmol) was added, followed by sulpholane (5 mL / g). Then, compound of formula (IXa) (1.20 equiv., 4.2 mmol) was added to the reaction mixture, and the reaction was stirred at 70°C. After stirring for 22 hours at 70°C, the reaction was cooled to room temperature and used as such for the next step. To the same reaction mixture, a solution of sodium hydroxide (1.1 equiv., 4.0 mmol) in water (2.5 mL) was added at room temperature, and the reaction mixture was stirred at 24°C. After 30 minutes of stirring, the reaction was completed. Water (20 mL / g with respect to sulfolane 1:4) was added to the reaction mixture at 24°C and stirred for 10-15 minutes. Then, 6N HCI was added dropwise to the resultant mixture until the pH was approximately 1 (before that, the reaction mass had a pH of approximately 12). White solid precipitation was observed, which was stirred for another 15 minutes at room temperature. The precipitated solid product was filtered over a sintered funnel and then dried on a rotary evaporator to obtain the compound of formula (Xa) as a solid (1.23 g, 82% yield). Analytical data matched the example 27.

[0518] Preparation of ethyl 5-cvano-6-[(2,2-difluoro-1,3-benzodioxol-5-yl)methoxyl-2-(difluoromethyl)pyridine-3-carboxylate (compound of formula (Xb))

[0519] O

[0520]

[0521] Example 36

[0522] To a round-bottom flask charged with compound of formula (IVa) (0.100 g, 0.41 mmol, 1.00 eq) and K2CO3(0.171 g, 1.24 mmol, 3.00 eq) in DMF (1.00 mL) at 20°C, followed by the addition of compound of formula (IXb) (0.05 mL, 0.08 g, 0.45 mmol, 1.10 eq). The reaction mixture was then heated to 60°C and subsequently cooled to room temperature. The reaction was stopped by adding water (10 mL) and diluted with 15 mL of MTBE. The organic layer was washed using a solution of HCI 1N (3x5 mL). Then,111355-FF

[0523] -45-the aqueous phase was extracted with MTBE (10 mL) and washed with brine. The combined organic phases were dried over sodium sulfate, and the solvent was removed under reduced pressure. Purification by column chromatography (cyclohexane:ethyl acetate) resulted in the desired compound of formula (Xb) as a light brown solid (0.24 mg, 64% yield).

[0524] Analytical data:

[0525] LCMS: Rt= 1.15 min, m / z (M+H)+ = 387

[0526] 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (t, J=7.2 Hz, 3 H) 4.35 (q, J=7.2 Hz, 2 H) 5.59 (s, 2 H) 7.7 (td, J=9.8, 6.7 Hz, 1 H) 7.77 (ddd, J=10.5, 9.1, 6.7 Hz, 1 H) 8.82 (s, 1 H).

[0527] 19F NMR (377 MHz, DMSO-d₆) δ ppm -143.12 (dd, J=22.7, 15.7 Hz, 1 F) -133.11 (dd, J=22.7, 4.9 Hz, 1 F) -118.91 (s, 1 F) -117.97 (dd, J=15.7, 4.9 Hz, 1 F).

[0528] Example 37:

[0529] To a round bottom flask was charged compound of formula (IVa) (0.200 g, 0.826 mmol, 1.0 eq) and potassium carbonate (0.343 g, 2.48 mmol, 3.0 equiv) in DMF (2.00 mL) at 20°C followed by the addition of 1-(bromomethyl)-2,4,5-trifluoro-benzene (0.123 mL, 0.211 g, 0.908 mmol, 1.1 equiv). Then the reaction mixture was heated to 60°C. The reaction was cooled to rt and quenched upon addition of HCI in H2O (2 mL, 2 mmol, 2.4 equiv). The mixture was diluted with toluene (10 mL). The aqueous layer was extracted three times with toluene (20 mL). The organic phase was washed once with brine (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by reverse-phase flash column chromatography (water: MeCN +0.1% formic acid) afforded compound of formula (Xb) as an off-white solid (717 mg, 94% yield).

[0530] General procedure for the preparation of compound of formula (XI) from compound of formula (X) - Step q)

[0531] HO

[0532] R2

[0533]

[0534] (XI)

[0535] To a dried 100 mL round-bottom flask equipped with a reflux condenser, under inert atmosphere and charged with compound of formula (X) (1 equiv.) was added sulpholane (0.4 mL / g) and the resulting solution was stirred at room temperature. Sodium hydroxide (1.1 equiv.) in water (2 mL / g) was dosed over a period of 1 hour. The mixture was stirred for 2 hours at room temperature. Water (20 mL) was added to the reaction mass and stirred for 15 minutes (pH=13).

[0536] 6N HCI was added until the pH reached 4, causing the reaction mass to completely precipitate out. Subsequently, water and 6N HCI were added until the pH reached 1. The precipitate was filtered to obtain a compound of formula (XI).111355-FF

[0537] -46- Preparation of 5-cyano-6-[(2,2-difluoro-1,3-benzodioxol-5-yl)methoxyl-2- (difluoromethyl)pyridine-3-carboxylic acid (compound of formula (Xia)

[0538] O

[0539]

[0540] (Xia)

[0541] Example 38 (Comparative example)

[0542] A 25 mL flask, under an argon atmosphere, equipped with a stirrer bar, magnetic stirrer, and heat-on plate, was used for the following procedure. To compound of formula (Xa) (0.58 g, 1.09 mmol, 1.0 equiv.) was added 2-methyltetrahydrofuran (2.194 mL, 22 mmol, 20.0 equiv.) followed by the addition of lithium hydroxide (0.067 g, 2.743 mmol, 2.5 equiv.) and water (2.194 mL) at room temperature. The mixture was stirred for 5 hours at room temperature. The reaction mixture was then acidified with an aqueous HCI solution (1.4 mL, 1M) (pH=2). The aqueous phase was extracted with ethyl acetate and washed with brine. The combined organic phases were dried over sodium sulfate, and the solvent was removed under reduced pressure to afford the desired compound of formula (Xia) as a yellow gum (0.496 g, 97% yield).

[0543] Example 39

[0544] To a dried 100 mL round-bottom flask equipped with a reflux condenser, under inert atmosphere and charged with compound of formula (Xa) (5.00 g, 11.92 mmol, 1.0 equiv.) was added sulpholane (2 mL) and the resulting solution was stirred at room temperature. Sodium hydroxide (0.535 g, 13.11 mmol, 1.1 equiv.) in water (1.0 mL) was dosed over a period of 1 hour. The mixture was stirred for 2 hours at room temperature. Water (20 mL) was added to the reaction mass and stirred for 15 minutes (pH=13.3).

[0545] 6N HCI was added until the pH reached 4.37, causing the reaction mass to completely precipitate out. Subsequently, 10 mL of water and 6N HCI were added until the pH reached 1.6. The precipitate was filtered to obtain compound of formula (Xia) as a white powder (4.3 g, 91% yield).

[0546] Analytical data:

[0547] LCMS: Rt= 1.04 min, m / z (M-H)- = 383.

[0548] 1H-NMR (400 MHz, DMSO-d₆) δ ppm 5.58 (s, 2 H) 7.41-7.46 (m, 2 H) 7.58-7.71 (m, 2 H) 8.79 (s, 1 H) 14.11 (br s, 1 H).

[0549] 13C NMR (101 MHz, DMSO-d₆) δ ppm 69.33, 98.68, 110.54, 111.24, 114.28, 121.06, 125.77, 129.13, 131.64, 132.65, 143.20, 143.20, 147.81, 153.71, 163.98, 164.79.

[0550] 19F NMR (376 MHz, DMSO-d₆) δ ppm -118.89 (s, 1 F) -49.00 (s, 1 F).111355-FF

[0551] -47- General procedure for the preparation of compound of formula (I) from compound of formula (XI) - Steps h) and i)

[0552] O

[0553]

[0554] A suspension of compound of formula (XI) (1.00 equiv.) and dimethylformamide (0.10 equiv.) in Me-THF (60 mL 3.11 mL / g) was heated to 60 °C under nitrogen atmosphere. To the above mixture was added thionyl chloride (1.30 equiv.) over 1 h. and the stirring was continued at same temperature for another 1 h. The reaction mixture was cooled to room temperature.

[0555] Intermediate formed: compound of formula (XII).

[0556]

[0557] (XII)

[0558] The above reaction mixture was added to a mixture of A / -ethylpiperazin-4-ium-1-sulfonamide;chloride (1.1 equiv.) and 4.5 M aq. NaOH (1.5 equiv.) in Me-THF (2 mL / g of compound of formula XI) at 0-5 °C over a period of 1 h while maintaining the pH of the reaction mixture between 8-11.5 by the occasional addition of aq. NaOH solution (4.5 M) and stirring was continued at the same temperature for another 0.5 h. Then the reaction mixture was diluted with water (60 mL) and Me-THF layer was separated. The organic layer was concentrated in vacuo and was purified by column chromatography or recrystallization to afford desired compound of formula (I).111355-FF

[0559] -48- Preparation of 4-[5-cyano-6-[(2,2-difluoro-1,3-benzodioxol-5-yl)methoxyl-2-(difluoromethyl)pyridine-3-carbonyll-N-ethyl-piperazine-1 -sulfonamide (compound of formula (la))

[0560]

[0561] (la)

[0562] Example 40

[0563] A suspension of compound of formula (Xia) (19.26 g, 50.1 mmol) and dimethylformamide (0.366 g, 5.01 mmol) in Me-THF (60 mL) was heated to 60 °C under nitrogen atmosphere. To the above mixture was added thionyl chloride (7.75 g, 65.2 mmol) over 1 h. and the stirring was continued at same temperature for another 1 h. The reaction mixture was cooled to room temperature.

[0564] Intermediate formed: 5-cyano-6-[(2,2-difluoro-1,3-benzodioxol-5-yl)methoxy]-2-(difluoromethyl)pyridine-3-carbonyl chloride compound of formula (Xlla)

[0565] O

[0566]

[0567] (Xlla)

[0568] The above reaction mixture was added to a mixture of A / -ethylpiperazin-4-ium-1-sulfonamide;chloride (12.63 g, 55.1 mmol) and 4.5 M aq. NaOH (16.7 mL, 75.2 mmol) in Me-THF (100 mL) at 0-5 °C over a period of 1 h while maintaining the pH of the reaction mixture between 8-11.5 by the occasional addition of aq. NaOH solution (4.5 M) and stirring was continued at the same temperature for another 0.5 h. Then the reaction mixture was diluted with water (60 mL) and Me-THF layer was separated. The organic layer was concentrated upto 90-95%. To the concentrated reaction mass was added EtOH / Water (5:2) mixture (140 mL) and heated to 70-75 °C. The mixture was then gradually cooled to room temperature and the solid obtained was filtered through sinter funnel under reduced pressure. The obtained solid was further washed with EtOH / Water (5:2) mixture (140 mL) at room temperature and filtered through sinter funnel under reduced pressure. The solid obtained was dried under reduced pressure to afford desired 4-[5-111355-FF

[0569] -49-cyano-6-[(2,2-difluoro-1,3-benzodioxol-5-yl)methoxy]-2-(difluoromethyl)pyridine-3-carbonyl]-~{N}-ethyl-piperazine-1 -sulfonamide (compound of formula (la)) (26.03 g, 92% yield).

[0570] Example 41 (Comparative example)

[0571] A 250 mL reactor under a nitrogen atmosphere was charged with 5-cyano-6-[(2,2-difluoro-1,3-benzodioxol-5-yl)methoxy]-2-(difluoromethyl)pyridine-3-carboxylic acid (compound of formula X) (20.0 g, 50.1 mmol, 1.00 equiv.) in 2-methyltetrahydrofuran (60 mL), followed by the addition of N, N-dimethylformamide (0.392 mL, 5.01 mmol, 0.1 equiv.). The reaction mixture was stirred at 50°C. Thionyl chloride (4.84 mL, 65.2 mmol, 1.3 equiv.) was dosed to the reaction mixture with constant monitoring of the conversion at this temperature. After complete addition, the reaction mixture was stirred at 50°C for 1 hour. The resulting reaction mixture was cooled to room temperature and transferred to a dropping funnel and used in the next step as such.

[0572] Intermediate formed: 5-cyano-6-[(2,2-difluoro-1,3-benzodioxol-5-yl)methoxy]-2-(difluoromethyl)pyridine-3-carbonyl chloride compound of formula (Xlla).

[0573] Analytical data

[0574] 1H NMR (400 MHz, C6D6) δ ppm 7.68 (s, 1 H), 6.55 - 6.89 (m, 1 H), 6.40 (d, J=8.0 Hz, 1 H), 4.91 (s, 2 H).

[0575] 19F NMR (377 MHz, C6D6) δ ppm -49.98 (s, 2 F) -119.99 (s, 2 F).

[0576] In a 250 mL reactor attached with a pH meter, N-ethylpiperazin-4-ium-1-sulfonamide chloride (13.3 g, 55.1 mmol, 1.1 equiv.) was charged with 2-methyltetradydrofuran (100 mL). The reaction mixture was cooled to 0°C, followed by the dropwise addition of aqueous sodium hydroxide (16.7 mL, 75.2 mmol, 1.5 equiv.). The resulting mixture was stirred for 15 minutes at the same temperature. The reaction mixture of Step 1 was added dropwise to the reaction mixture of Step 2 over 1 hour while maintaining the pH of the reaction between 8-11.5 by the occasional dropwise addition of NaOH solution (4.5 M aq.) (Total 50 mL was added). The reaction mixture was stirred at the same temperature for another 30 minutes. The reaction was stopped by adding water (60 g) and transferred to a separating funnel. A clear layer was formed between the aqueous and organic layers. The organic layer was separated and washed with 2N HCI (60 mL) to remove unreacted amine. The organic phase was concentrated under reduced pressure up to 90-95%. Purification: The crude compound obtained was crystallized with EtOH and water at 70-75°C. A solution of ethanol (5 mL / g) and water (2 mL / g) (7 mL / g) was added and refluxed at 70-75°C. The clear solution was stirred for 30 minutes at 70-75°C, then gradually cooled to room temperature with constant stirring (at 50°C it starts precipitating out). The precipitate was stirred at room temperature for 30 minutes, then filtered with a sintered funnel and washed with 7 mL / g of a 5:2 ethanol and water mixture. The product obtained was dried on a rotary evaporator to afford the desired 4-[5-cyano-6-[(2,2-difluoro-1,3-benzodioxol-5-yl)methoxy]-2-(difluoromethyl)pyridine-3-carbonyl]-N-ethyl-piperazine-1 -sulfonamide compound of formula (la) as a white solid (26.03 g, 92% yield).

[0577] Example 42 (Comparative example)111355-FF

[0578] -50- A 25 mL flask, under an argon atmosphere, was charged with compound of formula (Xia) (0.202 g, 0.325 mmol, 1.00 equiv.) in toluene (0.651 mL), followed by the addition of A / , A / -dimethylformamide (0.00255 mL, 0.00240651 g, 0.0325 mmol, 0.10 equiv.). The reaction mixture was stirred at 70°C. Thionyl chloride (0.0360 mL, 0.0587g, 0.4889 mmol, 1.50 equiv.) was added to the reaction mixture slowly at this temperature. The reaction mixture was stirred at 75°C for 2.5 hours. Subsequently, the reaction mixture was cooled to room temperature, Intermediate formed: 5-cyano-6-[(2,2-difluoro-1,3-benzodioxol-5-yl)methoxy]-2-(difluoromethyl)pyridine-3-carbonyl chloride compound of formula (Xlla).

[0579] The above reaction mixture was added to a 25 mL flask charged with N-ethylpiperazine-1 -sulfonamide (0.0779 g, 0.391 mmol, 1.20 equiv.) and sodium hydroxide (0.0200 g, 0.488 mmol, 1.50 equiv.) in toluene (1.30 mL) at 0°C. The pH of the had to be between 7-10 by the occasional dropwise addition of NaOH solution (4.5 M aq.). The reaction mixture was stirred for 1.30 hours at room temperature. The reaction was stopped by adding water (1 mL) and toluene (1 mL) and further basifying by adding NaOH aq. sol. (0.4 mL 4.5M). The pH of the aqueous phase was 11. The aqueous layer was separated. The organic phase was extracted three times with toluene (10 mL). The organic phase was acidified by adding 1M HCI (10 mL) and diluted with water (5 mL). The organic phase was washed once. It was then dried over sodium sulfate, and the solvent was removed under reduced pressure to afford desired compound of formula (la) as a yellow gum (0.251 g, 94% yield).

[0580] Analytical data

[0581] 1H NMR (400 MHz, DMSO-d6): δ ppm 8.58 (s, 1H), 7.59 (s, 1 H), 7.42 (m, 2H), 7.36 (t, J = 5.7 Hz, 1H), 7.00 (t, J = 56.0 Hz, 1 H), 5.54 (s, 2H), 3.64-3.77 (m, 2H), 3.26-3.38 (m, 2H), 3.16 (br s, 2H), 2.91-3.08 (m, 4H), 1.07 ppm (t, J = 7.2 Hz, 3H).

[0582] 13C NMR (101 MHz, DMSO-d6): δ ppm 163.5, 162.1, 149.4, 149.2, 149.0, 144.4, 142.8, 142.7, 133.7, 132.3, 131.2, 128.7, 125.1, 124.5, 124.4, 114.1, 113.7, 111.3, 110.6, 110.0, 108.9, 98.5, 68.5, 46.2, 45.3, 45.1, 41.0, 37.8, 15.0.

[0583] 19F NMR (377 MHz, DMSO-d6) δ ppm -49.99 (s, 2F), -117.23 ppm (s, 2F).

[0584] LCMS: Rt= 1.20 min, m / z (M+H)+ = 560.

[0585] Example 43 (Comparative example)

[0586] A 25 mL flask, under an argon atmosphere, was charged with compound of formula ((1.0 g, 2.5 mmol, 1.00 equiv.) in 2-methyltetrahydrofuran (10 mL), followed by the addition of A / , A / -dimethylformamide (0.02 mL, 0.25 mmol, 0.1 equiv.). The reaction mixture was stirred at 50°C. Then, thionyl chloride (0.28 mL, 3.8 mmol, 1.5 equiv.) was added to the reaction mixture slowly at this temperature. After complete addition, the reaction mixture was stirred at 50°C for 1 hour. The resulting reaction mixture was cooled to room temperature to afford intermediate 5-cyano-6-[(2,2-difluoro-1,3-benzodioxol-5-yl)methoxy]-2-(difluoromethyl)pyridine-3-carbonyl chloride compound of formula (Xlla).

[0587] A 100 mL three-neck round-bottom flask with a thermometer, was charged with N-ethylpiperazine-1 -sulfonamide (0.62g, 3.0 mmol, 1.2 equiv.), 2-methyltetrahydrofuran (5 mL), and aqueous sodium111355-FF

[0588] -51-hydroxide (0.84 mL, 3.8 mmol, 1.5 equiv.) and the reaction mixture was cooled to 0°C. The reaction mixture of Step 1 was added slowly to the reaction mixture of Step 2 over 30 minutes while maintaining the pH of the reaction between 9-11 by the occasional dropwise addition of NaOH solution (4.5 M aq.). After complete addition, the reaction mixture was stirred at the same temperature for 30 minutes. The reaction was stopped by adding water (10 mL), and then Me-THF (20 mL) was added, followed by further basifying by adding NaOH aq. sol. (0.4 mL 4.5M). The pH of the aqueous phase was 11. A clear organic layer was observed, and a distinct layer was formed between the aqueous and organic layers. The organic layer was separated and washed with 2M HCI. The organic phases were dried over sodium sulfate, and the solvent was removed under reduced pressure to afford the desired compound of formula (la) as a solid (1.42 g, 92% yield).

[0589] Example 44 (Comparative example)

[0590] A 25 mL flask was charged with compound of formula (Xia) (1.0 g, 2.5 mmol) in 2-methyltetrahydrofuran (3 mL / g, 30 mmol) followed by the addition of A / , A / -dimethylformamide (0.1 equiv., 0.25 mmol). The reaction mixture was stirred at 50 °C, resulting in a clear solution, thionyl chloride (1.5 equiv., 3.8 mmol) was then slowly added to the reaction mixture at this temperature, leading to gas evolution and maintaining a clear solution. After complete addition, the reaction mixture was stirred at 50°C for 1 h. HPLC data recorded after 1 h showed complete conversion of acid into acid chloride. The resulting reaction mixture was cooled to room temperature and used in the next step as such.

[0591] In a 100 mL three-neck round-bottom flask attached with a thermometer, N-ethylpiperazin-4-ium-1- sulfonamide; chloride (C, 1.1 equiv., 2.8 mmol), 2-methyltetrahydrofuran (2 mL / g, 20 mmol), and aqueous sodium hydroxide (5 equiv., 13 mmol, 4.50 mol / L) were combined, resulting in a clear solution. The reaction mixture from Step 1 was then slowly added to the reaction mixture of Step 2 over 30 min while maintaining the pH of the reaction between 9-11 by the occasional dropwise addition of NaOH solution (4.5 M aq.), resulting in gas evolution. After complete addition, the reaction mixture was stirred at the same temperature for 30 minutes. HPLC and LCMS data recorded after 30 minutes showed complete conversion into the desired product. The reaction was stopped by adding water (10 mL) and then Me- THF (20 mL), followed by further basifying by adding NaOH aq. sol. (0.4 mL 4.5M), resulting in a pH of the aqueous phase of 11.

[0592] A clear organic layer was observed, and a distinct layer was formed between the aqueous and organic layers. The organic layer was separated and washed with 2M HCI to remove unreacted amine. The organic phases were dried over sodium sulfate, and the solvent was removed under reduced pressure. HPLC and LCMS data of the crude obtained suggested that diamide formation (compound of formula (laa)) along with acid starting material in significant amounts.111355-FF

[0593] -52-

[0594]

[0595] LCMS : Rt= 2.44 min, m / z (M-H)- = 960.

[0596] Preparation of 2-[(2,2-difluoro-1,3-benzodioxol-5-yl)methoxy]-6-(difluoromethyl)-5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl]pyridine-3-carbonitrile (compound of formula Ib)

[0597]

[0598] Example 45

[0599] To a 25 mL flask was charged with compound of formula (Xia) (0.29 g, 0.75 mmol, 1.00 equiv.) in toluene (1.50 mL), followed by the addition of A / , A / -dimethylformamide (0.01 mL, 0.01 g, 0.07 mmol, 0.10 equiv.). The reaction mixture was stirred at 70°C. Thionyl chloride (0.08 mL, 0.14 g, 1.12 mmol, 1.50 equiv.) was added to the reaction mixture slowly.

[0600] The reaction to form intermediate of formula (XI la) was completed after 2 hours. Afterwards, the reaction mixture was stirred at 75°C for 30 min to bubble out HCI gas. Then, the reaction mixture was cooled to room temperature.111355-FF

[0601] -53- In another 25 mL flask was charged with 5-methyl-3-piperidin-1-ium-4-yl-1,2,4-oxadiazole;chloride (0.22 g, 0.90 mmol, 1.20 equiv.) and sodium hydroxide (0.05 g, 1.12 mmol, 1.50 equiv.) in toluene (3.00 mL) at 0°C. The reaction mixture containing intermediate of formula (Xlla) was added slowly to the reaction mixture over 40 min while maintaining the pH of the reaction between 7-10 by the occasional dropwise addition of NaOH solution (4.5 M aq.). After 1 hour, the reaction was stopped by adding water (1 mL) and Toluene (1 mL) and further basifying by adding aqueous solution of NaOH (0.2 mL 4.5M) until reaching a pH of 11.

[0602] The aqueous phase was extracted using toluene (3x10 mL) and the latter was wash using water (10mL). The organic phases were combined and dried over sodium sulfate and the solvent was removed in vacuo. The titled compound of formula (lb) was obtained as a yellow gum. Purification by flash column chromatography (cyclohexane:ethyl acetate) yielded compound of formula (lb) (382 mg, 80% yield).

[0603] Analytical data:

[0604] 1H NMR (400 MHz, CDCl3) δ ppm 7.89 (s, 1 H) 7.21 - 7.32 (m, 2 H) 7.07 (d, J=8.0 Hz, 1 H) 6.55 - 6.88 (m, 1 H) 5.54 (s, 2 H) 4.45 - 4.69 (m, 1 H) 3.53 (br d, J=13.4 Hz, 1 H) 3.16 - 3.27 (m, 2 H) 3.04 - 3.16 (m, 1 H) 2.58 (s, 3 H) 2.17 (br d, J=11.3 Hz, 1 H) 1.99 (br d, J=11.6 Hz, 1 H) 1.75 - 1.95 (m, 2 H).

[0605] 13C NMR (101 MHz, CDCl3) δ ppm 176.6, 171.9, 164.0, 162.4, 143.9, 143.8, 142.6, 131.0, 124.6, 124.4, 113.3, 111.3, 110.2, 109.4, 99.1, 69.1, 46.8, 41.4, 33.4, 29.3, 28.9, 12.3.

[0606] 19F NMR (377 MHz, CDCl3) δ ppm -49.91 (s).

[0607] Preparation of 6-(difluoromethyl)-5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl]-2-[(2,4,5-trifluorophenyl)methoxy]pyridine-3-carbonitrile (compound of formula Ic)

[0608] CH3

[0609]

[0610] Example 46111355-FF

[0611] -54- A 25 mL flask was charged with compound of formula (Xlb) (0.216 g, 0.536 mmol, 1.0 equiv.) in toluene (1.073 mL) followed by the addition of A / , A / -dimethylformamide (4.20 pL, 0.00396 g, 0.054 mmol, 0.1 equiv.). The reaction mixture was stirred at 70°C, resulting in a white suspension, thionyl chloride (0.0593 mL, 0.097 g, 0.805 mmol, 1.5 equiv.) was added to the reaction mixture slowly at this temperature, leading to gas evolution and a yellow-white suspension. The reaction mixture was then stirred at 75°C and subsequently cooled to room temperature.

[0612] 1H NMR (400 MHz, C6D6) δ ppm 7.84 - 7.97 (m, 1 H), 7.66 - 7.74 (m, 1 H), 6.96 (td, J=9.4, 6.7 Hz, 1 H), 6.70 (t, J=53.4 Hz, 1 H), 6.30 (td, J=9.5, 6.4 Hz, 1 H), 4.96 (s, 2 H).

[0613] 19F NMR (377 MHz, C6D6) δ ppm -118.16 (br dd, J=15.6, 4.8 Hz, 1 F), -119.93 (s, 1 F), -131.57 - -131.29 (m, 1 F), -142.12 (dddd, J=15.8, 1.8, 1.0 Hz, 1 F).

[0614] In a separate 25 mL flask, 5-methyl-3-piperidin-1-ium-4-yl-1,2,4-oxadiazole;chloride (0.131 g, 0.644 mmol, 1.2 equiv.) and sodium hydroxide (0.0329 g, 0.805 mmol, 1.5 equiv.) were combined in toluene (2.147 mL) at 0°C, resulting in a brown suspension. The aforementioned reaction mixture was then slowly added to the reaction mixture containing compound of formula (XI lb) over 20 min while maintaining the pH of the reaction between 7-10 by the occasional dropwise addition of NaOH solution (4.5 M aq.), resulting in gas evolution and a yellow-white suspension. The reaction was then stopped by adding water (1 mL) and toluene (1 mL), followed by further basifying by adding NaOH aq. solution (0.4 mL 4.5M), resulting in a pH of the aqueous phase of 11. The aqueous layer was separated, and the organic phase was extracted three times with toluene (8 mL). To remove any leftover amine, the organic phase was acidified by adding 1M HCI (5 mL) and diluted with water (2 mL). The organic phase was then washed once using brine (15 mL), dried over sodium sulfate, and the solvent was removed under reduced pressure.

[0615] The crude compound of formula (Ic) was obtained as a brown gum. Purification by column chromatography (cyclohexane:ethyl acetate) afforded compound of formula (Ic) as a white solid (329 mg, 97% yield).

[0616] Analytical data:

[0617] 1H NMR (400 MHz, CDCl3) δ ppm 7.90 (s, 1 H) 7.41 (ddd, J=10.0, 8.7, 6.7 Hz, 1 H) 6.98 (td, J=9.6, 6.5 Hz, 1 H) 6.70 (t, J=54.9 Hz, 1 H) 5.54 (s, 2 H) 4.56 (br d, J=5.8 Hz, 1 H) 3.52 (br d, J=13.4 Hz, 1 H) 3.15 - 3.25 (m, 2 H) 3.02 - 3.15 (m, 1 H) 2.57 (s, 3 H) 2.09 - 2.22 (m, 1 H) 1.73 - 2.04 (m, 3 H).

[0618] 13C NMR (400 MHz, CDCl3) δ ppm 176.7, 171.9, 164.0, 162.1, 142.8, 124.9, 118.6, 113.2, 111.4, 105.8, 99.1, 62.7, 62.7, 46.8, 41.4, 33.4, 29.3, 28.9, 12.3.

[0619] 19F NMR (377 MHz, DMSO-d6) δ ppm -118.50--117.36 (m, 1F), -119.27--118.56 (m, 2F), -133.26--133.13 (m, 1F), -143.42--142.82 (m, 1F).

[0620] LCMS : Rt= 1.05 min, m / z (M+H)+ = 508.

Claims

111355-FF-55- CLAIMS1. A process for the preparation of a compound of formula (I),comprising1) reacting a compound of formula (XI)(XI)with phosgene (COCl2), triphosgene OC(OCCl3)2, oxalyl chloride (COCl)2, or thionyl chloride (SOCl2); and2) adding an amine derivative QH in presence of a base;wherein, in respect of formula (I) and formula (XI):R1is CN;R2is H, Ci-Ce-alkyl, or Ci-Ce-haloalkyl;R3a, R3b, and R3care independently selected from hydrogen, halogen, Ci-Ce-alkyl, C1-C6-haloalkyl, C1-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfonyl, and Ci-Ce-haloalkylsulfanyl, or R3aand R3btogether form a Ci-C2haloalkylenedioxy substituent substituted on adjacent atoms on the phenyl ring forming together with the carbons of the phenyl ring a 5- or 6-membered ring, with the proviso that R3aand R3bare not hydrogen; andQ is a cyclic amine represented by the formula XXa or a cyclic amine represented by the formulae XXb,(XXa)(XXb)wherein the arrow indicates the connection to the carbonyl group;p1is 0, or 1 and indicates the number of methylene groups;111355-FF-56-p2is 0, or 1 and indicates the number of methylene groups;X is hydrogen, hydroxyl, or alkoxy;Y is cyano, Ci-Ce-alkoxy-Ci-Ce-alkyl, Ci-Ce-alkylsulfanyl-Ci-Ce-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, Ci-C6-alkylsulfonyl-Ci-C6-alkyl, RaRbNC(O), RcC(O)NRd, ReSO2NRf, R9O-N=CRh, RkNSO2, 4 to 6 membered non-aromatic heterocyclic ring system in which one or two carbons are replaced independently by nitrogen, oxygen, sulfur, or sulfonyl, phenyl, phenyl substituted with 1 to 3 substituents independently selected R4, 5 or 6 membered monocyclic heteroaryl having 1 to 3 carbon atoms replaced independently by nitrogen, sulfur, or oxygen, or 5 or 6 membered monocyclic heteroaryl having 1 to 3 carbon atoms replaced independently by nitrogen, sulfur, or oxygen, substituted with 1 to 3 independently selected substituents R5;A is cyano, Ci-Ce-cyanoalkyl, R'SO2, RRkNSO2, phenyl, phenyl substituted with 1 to 3 independently selected substituents R6, or heteroaryl substituted with 1 to 3 independently selected substituents R7; wherein the said heteroaryl is either a 5 or 6 membered monocyclic or a 9 or 10 membered bicyclic, each having 1 to 3 carbon atoms replaced independently by nitrogen, sulfur, or oxygen;Ra, Rb, Rc, Rd, Rf, Rs, Rh, and Rkare independently selected from hydrogen, and Ci-Ce-alkyl;Reand Rlare independently C1-C6-alkyl;R4, R5, R6and R7are independently selected from halogen, Ci-Ce-alkyl, Ci-Ce-haloalkyl,or an agrochemically acceptable salt, stereoisomer, and tautomer of the compound of formula (I).

2. The process according to claim 1 wherein the compound of formula (XII) is formed in situ after step 1)OwhereinR1, R2, and R3a, R3b, and R3care as defined in claim 1.

3. The process according to claim 1 wherein the preparation of compound of formula (XI), as defined in claim 1, comprises1) converting a compound of formula (X) in a presence of a base; or111355-FF-57-2) reacting compound of formula (IV), or its tautomeric form, with a compound of formula (IX), under basic conditions in the presence of a catalyst to form a compound of formula (X), and via concomitant in-situ hydrolysis of compound of formula (X)(IV)wherein R1, R2, R3a, R3b, and R3care as defined in claim 1, and R10is Ci-Ce-alkyl.

4. The process according to claim 3 wherein the preparation of compound of formula (IV) comprises reacting compounds formulae (III) and (III’)Oin the presence of metallic sodium with an alcohol, or a sodium alkoxide salt to yield the compound of formula (IV), wherein R1, and R2are as defined in claim 1, R10is Ci-Ce-alkyl, and R10ais Ci-Ce-alkoxy or N(CH3)2.

5. The process according to claim 3 wherein the preparation of compound of formula (IX), as defined in claim 3, comprises reacting a compound of formula (VIII)(VIII)with one of (i) phosgene, (ii) triphosgene, (iii) oxalyl chloride, (iv) an equimolar use of CCh and PPh3, (v) POCh, (vi) DCDMH (1,3-dichloro-5,5-dimethylhydantoin), (vii) thionyl chloride, or (viii) an equimolar use of NCS and PPh3; wherein R3a, R3b, and R3care as defined in claim 1.

6. The process according to claim 5 wherein the preparation of compound of formula (VIII), as defined in claim 5, comprises1) reacting compound of formula (VII)111355-FF-58-with a hydride source, such as sodium borohydride, sodium cyanoborohydride, ammonia-borane complex, or lithium aluminum hydride; or2) reacting a compound of formula (VI)with one of (i) isopropylmagnesium chloride, (ii) isopropylmagnesium chloride lithium chloride complex (also known as Turbo Grignard), or (iii) magnesium metal, and using the newly formed intermediate compound of formula (VI’)in the presence of formaldehyde or paraformaldehyde; wherein R3a, R3b, and R3care as defined in claim 1.

7. The process according to claim 6, wherein the preparation of compound of formula (VI) comprises reacting a compound of formula (V)in the presence of an electrophilic bromine source, wherein R3a, R3b, and R3care as defined in claim 1.

8. The process according to claim 6, wherein the preparation of compound of formula (VII) comprises reacting a compound of formula (VI)111355-FF-59-with one of (i) isopropylmagnesium chloride, (ii) isopropylmagnesium chloride lithium chloride complex (also known as Turbo Grignard), or (iii) magnesium metal and using the newly formed intermediate compound of formula (VI’)in the presence of A / , A / -dimethylformamide, wherein R3a, R3b, and R3care as defined in claim 1.

9. The process according to any one of claims 1 to 8 wherein Q is cyclic amine represented by the formulae XXb, wherein A is RkNSO2, Rjis hydrogen, and Rkis ethyl; R1is CN; R2is difluoromethyl; R3cis hydrogen; and R3aand R3btogether form with the carbons of the phenyl ring a 5-membered ring consisting of –OCF2O–.

10. The process for the preparation of compound of formula (I) according to claim 1, wherein the process in step 1) is carried out with thionyl chloride or phosgene in 2-methyltetrahydrofuran with N, N-dimethyl formamide at the temperature between 55°C to 65°C; and the process in step 2) is carried out with aqueous sodium hydroxide in 2-methyltetrahydrofuran at the temperature between 0°C to 25 °C, and a pH of between 8 and 11.5.

11. The process for the preparation of compound of formula (XI) according to claim 3, wherein step 1) is carried out with sodium hydroxide in sulfolane at the temperature between 0 °C to 25 °C.

12. The process for the preparation of compound of formula (XI) according to claim 3, wherein step 2) is carried out with a base selected from sodium hydroxide, an additive selected from TBAB, TMAB, CTAB, TBAC, TEAB, Aliquat 336, NaBr, Nal, KBr, and KI, and in the solvent sulfolane at the temperature between 50 °C to 70 °C.

13. The compound of formula (XII)whereinR1is CN;111355-FF-60- R2is H, Ci-Ce-alkyl, or Ci-Ce-haloalkyl;R3a, R3b, and R3care independently selected from hydrogen, halogen, Ci-Ce-alkyl, C1-C6-haloalkyl, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfonyl, and Ci-Ce-haloalkylsulfanyl, or R3aand R3btogether form a Ci-C2haloalkylenedioxy substituent substituted on adjacent atoms on the phenyl ring forming together with the carbons of the phenyl ring a 5- or 6-membered ring, with the proviso that R3aand R3bare not hydrogen.

14. The compound according to claim 13 wherein R1is CN, R2is difluoromethyl, and (a) R3cis hydrogen, and R3aand R3btogether form with the carbons of the phenyl ring a 5-membered ring consisting of –OCF2O–; or (b) R3a, R3b, and R3care each fluorine.

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