WO2009138375A1

WO2009138375A1 - Process for the preparation of amides

Info

Publication number: WO2009138375A1
Application number: PCT/EP2009/055651
Authority: WO
Inventors: Martin Charles Bowden; David Anthony Jackson; Alexandre Christian Saint-Dizier; George Robert Hodges
Original assignee: Syngenta Participations AG; Syngenta Ltd
Current assignee: Syngenta Participations AG; Syngenta Ltd
Priority date: 2008-05-14
Filing date: 2009-05-11
Publication date: 2009-11-19
Anticipated expiration: 2010-11-14
Also published as: CN102026982A; JP2011520828A; MX2010011790A; TW200950701A; US8227619B2; US20110178310A1; US20120289707A1; IL208792A0; EP2280944A1; BRPI0912558A2

Abstract

The invention relates to a process for the preparation of fungicidally active compounds such as tricyclic amine derivatives(I). The process involves coupling of a carboxylic 5 acid e.g. a compound of formula (II) with an aniline, e.g. a compound of formula(III) in the presence of a boronic acid catalystor an antimony catalyst (II)(III)(I) wherein R1, R2, R3, R4, R5, R6, R7, X, Y and Het are defined in the specification.

Description

PROCESS FOR THE PREPARATION OF AMIDES

The present invention relates to a process for the preparation of certain fungicidally active tricyclic amine derivatives and to certain fungicidally active ortho-substituted- cy clopropy 1- azolcarboxamides .

Tricyclic amine derivatives having fungicidal activity are disclosed in WO/2004/035589 and WO 2007/048556. Ortho-substituted-cyclopropyl-azolcarboxamides of the formula (IA) are disclosed in WO03/074491

(IA) wherein

Heta is a 5-or 6-membered heterocyclic ring containing one to three heteroatoms, each independently selected from oxygen, nitrogen and sulphur, the ring being substituted by groups R4a, R5a and R6a;

RIa is hydrogen or halo; R2a is hydrogen or halo;

R3a is optionally substituted C_2-12 alkyl, optionally substituted C_2-12 alkenyl, optionally substituted C_2-12 alkynyl, optionally substituted C_3-12 cycloalkyl, optionally substituted phenyl or optionally substituted heterocyclyl; and

R4a, R5a and R6a are independently selected from hydrogen, halo, cyano, nitro, Ci_₄ alkyl, Ci_4 haloalkyl, Ci_4 alkoxy(Ci_4) alkyl and Ci_4 halo alkoxy(C 1.4) alkyl, provided that at least one of R4a, R5a and R6a is not hydrogen. The compounds disclosed in WO03/074491 have microbiocidal activity, in particular fungicidal activity.

A variety of methods for the preparation of the above compounds have been described in WO2004/035589, WO 2007/048556, and WO 2003/074491.

It has now been surprisingly found that these compounds may be advantageously obtained by coupling the respective amine and carboxylic acid in the presence of a boronic acid catalyst or an antimony catalyst.

The present invention relates to a process for the preparation of compounds of the formula (I)

(I) wherein where Het is a 5- or 6-membered heterocyclic ring containing one to three heteroatoms, each independently selected from oxygen, nitrogen and sulphur, provided that the ring is not 1,2, 3-triazole, the ring being substituted by groups R8, R9 and RlO;

X is a single or double bond; Y is O, S, N(Rl 1), (CR12R13)(CR14R15)m(CR16R17)n or C=C(A)Z in which A and

Z are independently Ci_₆ alkyl or halogen; m is 0 or 1 ; n is 0 or 1 ;

Rl is hydrogen, Ci_-4 alkyl, Ci_-4 haloalkyl, Ci_-4 alkoxy, Ci_-4 haloalkoxy, CH₂C=CRl 8,

CH₂CR19=CHR20, CH=C=CH₂ or COR21; R2 and R3 are each, independently, hydrogen, halogen, Ci_₄ alkyl, Ci_₄ alkoxy or Ci_₄ haloalkoxy; R4, R5, R6 and R7 are each, independently, hydrogen, halogen, Ci_₄ alkyl, Ci_₄ haloalkyl, Ci_4 alkoxy, C_M haloalkoxy, Ci_4 alkylthio, Ci_4 halo alky It hio, hydroxymethyl, Ci_-4 alkoxymethyl, C(O)CH₃ or C(O)OCH₃;

R8, R9 and RlO are each, independently, hydrogen, halogen, cyano, nitro, Ci_4 alkyl, Ci_ 4 haloalkyl, Ci_4 alkoxy(Ci_4)alkylene or Ci_4 haloalkoxy(Ci_4)alkylene, provided that at least one of R8, R9 and RlO is not hydrogen;

Rl 1 is hydrogen, Ci_₄ alkyl, benzyl (in which the phenyl group is optionally substituted with up to three substituents, each independently selected from halogen, Ci_₄ alkyl, Ci_₄ haloalkyl and C_M alkoxy), formyl, C(O)Ci_₄ alkyl (optionally substituted by halogen or Ci_4 alkoxy), C (=O)O-Ci_6 alkyl (optionally substituted by halogen, Ci_4 alkoxy or cyano) or Ci_4 alkoxy (C 1.4) alkylene;

Rl 2, Rl 3, Rl 4, Rl 5, R16 and Rl 7 are each, independently, hydrogen, halogen, hydroxy, Ci_6 alkyl, C2-6 alkenyl [both optionally substituted by halogen, hydroxy, Ci_4 alkoxy, =0, aryl or 0-C(O)-C_M alkyl or a 3-7 membered carboxylic ring (itself optionally substituted by up to three methyl groups) ], a 3-7 membered saturated ring (optionally substituted by up to three methyl groups and optionally containing one heteroatom selected from nitrogen and oxygen) or Ci_₄ alkoxy; or R12 and Rl 3 together with the carbon atom to which they are attached form the group C=O or a 3-5 membered carbocyclic ring (optionally substituted by up to three methyl groups and optionally with up to 2 heteroatoms each independently selected from O and N); or R12 and Rl 3 together form a Ci_6 alkylidene (optionally substituted by up to three methyl groups) or a C₃_6 cycloalkylidene group (optionally substituted by up to three methyl groups); R18, R19 and R20 are each, independently, hydrogen, halogen, Ci_₄ alkyl, Ci_₄ haloalkyl or Ci_4 alkoxy(Ci_4)alkylene; and

R21 is hydrogen, Ci_6 alkyl, Q_6 haloalkyl, Ci_4 alkoxy (C_1-4) alkylene, Ci_4 alkyl-S-(Ci_ ₄) alkylene, Ci_4 alkoxy or aryl;

comprising the step of reacting a carboxylic acid of formula (II)

- A - (H) wherein Het is as defined above with an aniline of the formula (III)

wherein Rl, R2, R3, R4, R5, R6, R7, X and Y are as defined above; in the presence of a boronic acid catalyst or an antimony catalyst.

Halogen is fluoro, chloro, bromo or iodo; preferably fluoro, chloro or bromo.

Each alkyl moiety is a straight or branched chain and is, for example, methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, sec-butyl, iso-butyl, tert-butyl, neo- pentyl, n-heptyl, 1,3-dimethylbutyl, 1, 3 -dimethylpentyl,l-methyl-3 -ethyl-butyl or 1,3, 3-trimethylbutyl. Likewise, each alkylene moiety is a straight or branched chain.

Haloalkyl moieties are alkyl moieties which are substituted by one or more of the same or different halogen atoms and are, for example, CF3, CF₂Cl, CHF₂, CH₂F, CCI3, CF₃CH₂, CHF₂CH₂, CH₂FCH₂, CH₃CHF or CH₃CF₂.

Alkenyl and alkynyl moieties can be in the form of straight or branched chains.

Each alkenyl moiety, where appropriate, may be of either the (E)-or (Z)-configuration.

A 3-5 membered carbocyclic ring includes a spiro-three or five membered ring.

Aryl includes phenyl, naphthyl, anthracyl, fluorenyl and indanyl but is preferably phenyl. Alkyliden moieties may be in the form of straight or branched chains. Alkyliden includes methylidene[CH₂=], ethylidene [CH₃C(H) =], n-propylidene, i-propylidene [(CH₃)₂C=], n-butylidene, i-butylidene, 2-butylidene, n-pentylidene, i-pentylidene, neo- pentylidene, 2-pentylidene, n-hexylidene, 2-hexylidene, 3-hexylidene, i-hexylidene and neo-hexylidene.

Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Cycloalkenyl includes cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.

Cycloalkylidene includes cyclopropylidene [c(C₃H₄)=], cyclobutylidene, cyclopentylidene and cyclohexylidene.

In one aspect of the invention, Rl 1 is hydrogen, Ci_₄ alkyl, benzyl (in which the phenyl group is optionally substituted with up to three substituents, each independently selected from halogen, Ci_4 alkyl, Ci_4 haloalkyl and Ci_4 alkoxy), formyl, C(O)Ci_4 alkyl or Ci_4 alkoxy (C_1-4) alkylene.

In another aspect of the invention, R12, R13, R14, R15, R16 and R17 are each, independently, hydrogen, Ci_₄ alkyl or Ci_₄ alkoxy.

Het is preferably pyrro IyI, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidyl, pyridazinyl, 2, 3-hydro-[l, 4] oxathiine-6-yl, oxazinyl, thiazinyl or triazinyl.

Het is more preferably pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl or 2,3-dihydro-

[1, 4] oxathiine-yl.

Het is even more preferably pyrrolyl, pyrazolyl, thiazolyl or pyridinyl.

Het is most preferably pyrrolyl or pyrazolyl.

Preferably X is a single bond. In one aspect, Y is O, S, N(Rl 1), CH₂, CH₂CH₂, CH₂CH₂CH₂, C(CH₃)₂, CH (CH₃), CH

C₂H₅), C(CH₃)(C₂H₅), CH(OCH₃) or C(OCH₃)₂; more preferably N(Rl 1), O, S, CH₂, CH₂CH₂, CH₂CH₂CH₂, C(CH₃)₂, CH(CH₃) or CH(C₂H₅); even more preferably N(Rl 1), O, S, CH₂ or CH₂CH₂; and still more preferably O, CH₂ or N (Rl 1). Preferably Y is O, N(Rl 1) or (CR12R13)(CR14R15)m(CR16R17)n. More preferably Y is O or (CR12R13)(CR14R15)m(CR16R17)n. Even more preferably Y is (CR12R13)(CR14R15)m(CR16R17)n. Still more preferably Y is (CR12R13), e.g. CHCH(CH₃)CH₃.

In a further aspect, Y is C=C(A)Z in which A and Z are independently Ci_₆ alkyl or halogen. Preferably A and Z are independently halogen, more preferably both A and Z are chlorine.

Preferably n is O.

Preferably m is O.

Preferably Rl is hydrogen, CH₂C=CRl 8, CH=C=CH₂ or COR21.

More preferably Rl is hydrogen, CH₂C=CH, CH=C=CH₂, C(O)H or C(O)CH₃.

Yet more preferably Rl is hydrogen, CH₂C=CH, CH=C=CH₂ or C(O)CH₃.

Even more preferably Rl is hydrogen, CH₂C=CH or CH=C=CH₂. Most preferably Rl is hydrogen.

Preferably R2 is hydrogen, halogen or Ci_₄ alkyl. More preferably R2 is hydrogen or halogen. Most preferably R2 is hydrogen.

Preferably R3 is hydrogen or methyl. More preferably R3 is hydrogen.

Preferably R4 is hydrogen, Ci_4 alkyl, halogen, Ci_4 haloalkyl, Ci_4 alkoxy, C(O)CH₃ or C(O)OCH₃.

More preferably R4 is hydrogen, Ci_₂ alkyl, halogen, CF₃, methoxy, C(O)CH₃ or

C(O)OCH₃.

Even more preferably R4 is hydrogen, methyl, chlorine, CF₃ or methoxy. Most preferably R4 is hydrogen or methyl.

Preferably R5 is hydrogen, Ci_4 alkyl, halogen, Ci_4 haloalkyl, Ci_4 alkoxy, C(O)CH₃ or C(O)OCH₃. More preferably R5 is hydrogen, Ci_2 alkyl, chlorine, CF₃, methoxy, C(O)CH₃ or C(O)OCH₃. Most preferably R5 is hydrogen or methyl.

Preferably R6 is hydrogen, Ci_4 alkyl, Ci_4 alkoxy or C(O)CH₃. More preferably R6 is hydrogen, methyl, methoxy or C(O)CH₃. Most preferably R6 is hydrogen or methyl.

Preferably R7 is hydrogen, Ci_₄ alkyl, Ci_₄ alkoxy or C(O)CH₃. More preferably R7 is hydrogen, methyl, methoxy or C(O)CH₃. Most preferably R7 is hydrogen or methyl.

Preferably R8 is hydrogen, halogen, Ci_4 alkyl, Ci_4 haloalkyl or methoxymethylene. More preferably R8 is hydrogen, chloro, fluoro, bromo, Ci_2 alkyl, CF₃, CF₂Cl, CHF₂₅CH₂F or methoxymethylene. Even more preferably R8 is hydrogen, chloro, fluoro, Ci_₂ alkyl, CF₃, CF₂Cl, CHF₂, CH₂F or methoxymethylene. Most preferably R8 is hydrogen, chloro, fluoro, methyl, CF₃, CHF₂ or CH₂F.

Preferably R9 is hydrogen, halogen, Ci_4 alkyl or Ci_4 haloalkyl or methoxymethylene. More preferably R9 is hydrogen, chloro, fluoro, bromo, Ci_₂ alkyl, CF₃, CF₂Cl, CHF₂,

CH₂F or methoxymethylene.

Even more preferably R9 is hydrogen, chloro, fluoro, Ci_₂ alkyl, CF₃, CF₂Cl, CHF₂,

CH₂F or methoxymethylene.

Most preferably R9 is hydrogen, chloro, fluoro, methyl, CF₃, CHF₂ or CH₂F.

Preferably RlO is hydrogen, halogen, Ci_4 alkyl, Ci_4 haloalkyl or methoxymethylene.

More preferably RlO is hydrogen, chloro, fluoro, bromo, Ci_₂ alkyl, CF₃, CF₂Cl, CHF₂,

CH₂F or methoxymethylene. Even more preferably RlO is hydrogen, chloro, fluoro, Ci_2 alkyl, CF3, CF₂Cl, CHF₂,

CH₂F or methoxymethylene.

Most preferably RlO is hydrogen, chloro, fluoro, methyl, CF₃, CHF₂ or CH₂F.

In one aspect of the invention Rl 1 is hydrogen, Ci_₄ alkyl, benzyl, formyl, C(O)CH₃ or C(O)OC(CHs)₃; more preferably hydrogen or Ci_₂ alkyl. Preferably Rl 1 is Q_-4 alkyl, formyl, C(O)CH₃ or C(O)OCi_₆ alkyl (optionally substituted by halogen, CN or Ci_4 alkoxy). More preferably Rl 1 is C(O)OCi_₄ alkyl.

In one aspect of the invention R12, R13, R14, R15, R16 and R17 are each, independently, hydrogen, Ci_₂ alkyl or methoxy.

Preferably R12 and R13 are each, independently, hydrogen, halogen, Ci_₅ alkyl, Ci_₃ alkoxy, CH₂OH, CH(O), C₃_₆ cycloalkyl, CH₂O-C(=O)CH₃, CH₂-C_3-6 cycloalkyl or benzyl; or Rl 2 and Rl 3 together with the carbon atom to which they are attached form the group C=O or a 3-5 membered carbocyclic ring; or R12 and R13 together form Ci_5 alkylidene or C₃_₆ cycloalkylidene.

More preferably R12 and Rl 3 are, independently, H, CH₃, C₂H₅, n-C₃H₇, i-C₃H₇, n- C₄H₉, sec-C₄H₉, i-C₄H₉, CH(C₂Hs)₂, CH₂-cyclopropyl or cyclopentyl; or Rl 2 and Rl 3 together with the carbon atom to which they are attached form a 3-membered or 5- membered carbocyclic ring.

Preferably R14 is H or CH₃.

Preferably Rl 5 is H or CH₃.

Preferably Rl 6 is H or CH₃.

Preferably Rl 7 is H or CH3.

Preferably Rl 8 is hydrogen, chloro, bromo, methyl or methoxy. More preferably Rl 8 is hydrogen, chloro or methyl. Most preferably R18 is hydrogen.

Preferably Rl 9 is hydrogen, chloro, bromo, methyl or methoxy. More preferably Rl 9 is hydrogen, chloro or methyl. Most preferably Rl 9 is hydrogen.

Preferably R20 is hydrogen, chloro, bromo, methyl or methoxy. More preferably R20 is hydrogen, chloro or methyl. Most preferably R20 is hydrogen.

Preferably R21 is hydrogen, methyl, OC(CH₃)₃ or CH₃OCH₂.

For example,

Het is pyrrolyl or pyrazolyl, either being substituted by groups R8, R9 and RlO; X is a single bond;

Y is (CR12R13)(CR14R15)_m(CR16R17)_n or C=C(A)Z in which A and Z are independently Ci_₆ alkyl or halogen; m is 0 or 1 ; n is 0 or 1 ; Rl is hydrogen;

R2 and R3 are each, independently, hydrogen, halogen, Ci_₄ alkyl, Ci_₄ alkoxy or

Ci_4 halo alkoxy;

R4, R5, R6 and R7 are each, independently, hydrogen, halogen, Ci_₄ alkyl,

Ci_4 haloalkyl, Ci_4 alkoxy, Ci_4 haloalkoxy, Ci_4 alkylthio, Ci_4 halo alky It hio, hydroxymethyl, Ci_₄ alkoxymethyl, C(O)CH₃ or C(O)OCH₃;

R8, R9 and RlO are each, independently, hydrogen, halogen, cyano, nitro, Ci_4 alkyl,

Ci_4 haloalkyl, Ci_4 alkoxy(Ci_4)alkylene or Ci_4 haloalkoxy(Ci_4)alkylene, provided that at least one of R8, R9 and RlO is not hydrogen;

R12 and R13 are each, independently, hydrogen, halogen, Ci_₅ alkyl, Ci_₃ alkoxy, CH₂OH, CH(O), C₃_6 cycloalkyl, CH₂O-C(=O)CH₃, CH₂-C_3-6 cycloalkyl or benzyl; or Rl 2 and Rl 3 together with the carbon atom to which they are attached form the group C=O or a 3-5 membered carbocyclic ring; or R12 and R13 together form Ci_5 alkylidene or C₃_₆ cycloalkylidene; and R14, R15, R16 and R17 are each, independently, H or CH₃.

Preferably, R8, R9 and RlO are each, independently, hydrogen, chloro, fluoro, methyl, CF₃, CHF₂ or CH₂F, provided that at least one of R8, R9 and RlO is not hydrogen. Preferably, n is 0 and m is 0. Preferably, R12 and R13 are each, independently, hydrogen, Ci_₄ alkyl or Ci_₄ alkoxy. Preferably, R2 is hydrogen, halogen or Ci_₄ alkyl. Preferably, R3 is hydrogen or methyl. Preferably Het is pyrazolyl.

Preferably Het is a group of formula (VIIA)

(VIIA) in which R7a is selected from CF₃ and CHF₂;

Preferably, Rl, R2, R3, R4, R5, R6, R7 are each independently hydrogen. Preferably, X is a single bond; Preferably, Y is C=CCl₂ or CHCH(CH₃)CH₃.

For example, in one embodiment: Het is a group of formula (VIIA)

(VIIA) in which R7a is selected from CF₃ and CHF₂; Rl, R2, R3, R4, R5, R6, R7 are each independently hydrogen; X is a single bond; Y is CHCH(CH₃)CH₃; and the catalyst is a boronic acid catalyst or an antimony catalyst, e.g. boric acid or an aryl boronic acid such as 3,5-bis-(trifluoromethyl)-phenylboronic acid or 2-(N₅N- dimethylaminomethyl)phenylboronic acid, or an antimony III alkoxide such as Sb(OEt)₃. For example, the catalyst may be 3,5-bis-(trifluoromethyl)-phenylboronic acid or Sb(OEt)₃.

For example, in further embodiment: Het is a group of formula (VIIA)

(VIIA) in which R7a is selected from CF₃ and CHF₂; Rl, R2, R3, R4, R5, R6, R7 are each independently hydrogen; X is a single bond; Y is C=C(A)Z in which A and Z are, independently fluoro, chloro or bromo, preferably chloro; and the catalyst is a boronic acid catalyst or an antimony catalyst, e.g. boric acid or an aryl boronic acid such as 3,5-bis-(trifluoromethyl)-phenylboronic acid or 2-(N₅N- dimethylaminomethyl)phenylboronic acid, or an antimony III alkoxide such as Sb(OEt)₃. For example, the catalyst may be boric acid or 2-(N₅N- dimethylaminomethyl)phenylboronic acid.

According to a very highly preferred embodiment, the invention relates to a process for the preparation of a compound of formula (VI)

comprising reacting a carboxylic acid of formula (IV)

(IV) with an aniline of formula (V)

(V) in the presence of a boronic acid catalyst or an antimony catalyst, e.g. boric acid or an aryl boronic acid such as 3,5-bis-(trifluoromethyl)-phenylboronic acid or 2-(N ,N- dimethylaminomethyl)phenylboronic acid, or an antimony III alkoxide such as Sb(OEt)₃. For example, the catalyst may be 3,5-bis-(trifluoromethyl)-phenylboronic acid or Sb(OEt)₃.

According to a further highly preferred embodiment of the invention, the invention relates to a process for the preparation of a compound of formula (VIII)

(VIII)

comprising reacting a carboxylic acid of formula (IV)

(IV) with an aniline of formula (VII)

(VII) in the presence of a boronic acid catalyst or an antimony catalyst, e.g. boric acid or an aryl boronic acid such as 3,5-bis-(trifluoromethyl)-phenylboronic acid or 2-(N ,N- dimethylaminomethyl)phenylboronic acid, or an antimony III alkoxide such as Sb(OEt)₃. For example, the catalyst may be boric acid or 2-(N ,N- dimethylaminomethyl)phenylboronic acid.

In a further embodiment, the present invention provides a process for the preparation of compounds of formula (IA)

(IA) wherein

Heta is a 5 -or 6-membered heterocyclic ring containing one to three heteroatoms, each independently selected from oxygen, nitrogen and sulphur, the ring being substituted by groups R4a, R5a and R6a;

RIa is hydrogen or halogen;

R2a is hydrogen or halogen; R3a is optionally substituted C_2-12 alkyl, optionally substituted C_2-12 alkenyl, optionally substituted C_2-12 alkynyl, optionally substituted C_3-12 cycloalkyl, optionally substituted phenyl or optionally substituted heterocyclyl; and R4a, R5a and R6a are independently selected from hydrogen, halogen, cyano, nitro, Ci_₄ alkyl, Ci_4 haloalkyl, Ci_4 alkoxy(Ci_4) alkyl and Ci_4 halo alkoxy(C 1.4) alkyl, provided that at least one of R4a, R5a and R6a is not hydrogen

comprising reacting a carboxylic acid of formula (HA)

0

Heta OH

(IIA) with an aniline of the formula (IIIA)

(IIIA) in the presence of a boronic acid catalyst or an antimony catalyst.

Halogen is fluoro, chloro or bromo.

Each alkyl moiety is a straight or branched chain and is, for example, methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl or neo-pentyl.

When present, each optional substituent on an alkyl moiety is, independently, selected from halogen, hydroxy, cyano, Q_4 alkoxyC(=O), formyl, nitro, Q_4 alkoxy, C_M haloalkoxy, Q_-4 alkylthio, Q_-4 halo alky lthio, HC(OR)=N and R'R"NN=C(H); where R' and R" are, independently, hydrogen or Q_₄ alkyl.

Alkenyl and alkynyl moieties can be in the form of straight or branched chains. The alkenyl moieties, where appropriate, can be of either the (E)-or (Z)-confϊguration.

Examples are vinyl, allyl and propargyl.

When present, each optional substituent on alkenyl or on alkynyl is, independently, selected from those optional substituents given above for an alkyl moiety.

Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

When present, each optional substituent on cycloalkyl is, independently, selected from Ci_₃ alkyl and those optional substituents given above for an alkyl moiety.

The term heterocyclyl refers to a non-aromatic or aromatic ring containing up to 10 atoms including one or more (preferably one or two) heteroatoms selected, each independently, from O, S and N. Examples of such rings include 1,3-dioxolanyl, tetrahydrofuranyl, morpholinyl, thienyl and furyl.

When present, each optional substituent on phenyl or on heterocyclyl is, independently, selected from Ci_6 alkyl and those optional substituents given above for an alkyl moiety. When present, there are up to four optional substituents on phenyl, each independently selected.

When present, each optional substituent on an alkyl moiety is, independently, selected from the preferred list of halo, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, cyano and nitro.

When present, each optional substituent on alkenyl or on alkynyl is, independently, selected from the preferred list of halogen and cyano.

When present, each optional substituent on cycloalkyl is, independently, selected from the preferred list of methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy and cyano. When present, each optional substituent on phenyl or on a heterocyclyl group is, independently, selected from the preferred list of halo, hydroxy, methoxy, trifiuoromethoxy, difluoromethoxy and cyano.

It is preferred that Heta is pyrrolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, thiophenyl, furyl, isothiazolyl or isoxazolyl (more preferably pyrrolyl, pyrazolyl or thiazolyl), each being substituted by groups R4a, R5a and R6a.

Preferably Heta is pyrrolyl, pyrazolyl or thiazolyl, each being substituted by groups R4a, R5a, R6a;

RIa is hydrogen, fiuoro, chloro or bromo; R2a is hydrogen, fiuoro, chloro or bromo; R3a is optionally substituted C_2-12 alkyl, wherein, when present, each optional substituent is, independently, selected from fiuoro, chloro, bromo, hydroxy, cyano, Ci_4 alkoxyC(=O), formyl, nitro, Ci_4 alkoxy, Ci_4 haloalkoxy, Ci_4 alkylthio, Ci_4 haloalkylthio, HC(OR')=N and R'R"NN=C(H); optionally substituted C₂-I₂ alkenyl, wherein, when present, each optional substituent is, independently, selected from fiuoro, chloro, bromo, hydroxy, cyano, Ci_4 alkoxyC(=O), formyl, nitro, Ci_4-alkoxy, Ci_4 haloalkoxy, Ci_-4 alkylthio, Ci_-4 haloalkylthio, HC(OR')=N and R'R' 'NN=C(H); optionally substituted C_2-12 alkynyl, wherein, when present, each optional substituent is, independently, selected from fiuoro, chloro, bromo, hydroxy, cyano, Ci_4 alkoxyC(=O), formyl, nitro, Ci_4 alkoxy, Ci_4 haloalkoxy, Ci_4 alkylthio, Ci_4 haloalkylthio, HC(OR')=N and R'R"NN=C(H); optionally substituted C3-12 cycloalkyl, wherein, when present, each optional substituent is, independently, selected from Ci .₃ alkyl, fiuoro, chloro, bromo, hydroxy, cyano, Ci_4 alkoxyC(=O), formyl, nitro, Ci_4 alkoxy, C_M haloalkoxy, Ci_-4 alkylthio, Ci_-4 haloalkylthio, HC(OR')=N and R'R"NN=C(H); optionally substituted phenyl, wherein, when present, each optional substituent is, independently, selected from Ci_6 alkyl, fiuoro, chloro, bromo, hydroxy, cyano, Ci_4 alkoxyC(=O), formyl, nitro, Ci_4 alkoxy, Ci_4 haloalkoxy, Ci_4 alkylthio, Ci_4 haloalkylthio, HC(OR')=N and R'R"NN=C(H); or optionally substituted heterocyclyl, wherein, when present, each optional substituent is, independently, selected from Ci_₆ alkyl, fiuoro, chloro, bromo, hydroxy, cyano, Ci_4 alkoxyC(=O), formyl, nitro, Ci_4 alkoxy, Ci_₄ haloalkoxy, Ci_₄ alkylthio, Ci_₄ haloalkylthio, HC(0R')=N; R' and R" are, independently, hydrogen or Ci_₄ alkyl; and

R4a, R5a, and R6a are, independently, selected from hydrogen, fluoro, chloro, bromo, cyano, nitro, Ci_₄ alkyl, Ci_₄ haloalkyl, Ci_₄ alkoxy(Ci_₄)alkyl and Ci_₄ haloalkoxy(Ci_₄)alkyl, provided that at least one of R4a, R5a, and R6a is not hydrogen.

Preferably RIa and R2a are, independently, hydrogen or fluoro.

Preferably R3a is C2-6 alkyl, optionally substituted C3_8 cycloalkyl, phenyl, thienyl or furyl.

Preferably R4a, R5a and R6a are, independently, selected from hydrogen, halogen, C 1-4 alkyl, Ci_₄ haloalkyl and Ci_₄ alkoxy(Ci_₄)alkyl ; provided that at least one of R4a, R5a and R6a is not hydrogen. More preferably R4a, R5a, and R6a are, independently, selected from hydrogen, halogen, methyl, Ci_₂ haloalkyl and methoxymethyl; provided that at least one of R4a, R5a and R6a is not hydrogen.

Preferably, Heta is pyrazolyl. More preferably, Heta is pyrazol-4-yl. More preferably, Heta is a group of formula (VIIA)

(VIIA)

wherein R7a is selected from CF3 and CHF₂. Preferably, R7a is CHF₂.

Preferably, RIa is hydrogen. Preferably, R2a is hydrogen. More preferably, RIa and R2a are hydrogen.

Preferably, R3a is optionally substituted cycloalkyl. More preferably, R3a is optionally substituted cyclopropyl. More preferably, R3a is a group of the formula (VIIIA)

(VIIIA)

wherein R8a is H or Ci_6 alkyl. Preferably, R8a is H or Methyl. More preferably, R8a is H.

For example,

Heta is a group of formula (VIIA)

(VIIA) wherein R7a is selected from CF3 and CHF₂; RIa is R2a, and R3a are hydrogen; R3a is a group of the formula (VIIIA)

(VIIIA)

wherein R8a is H or C 1-4 alkyl, preferably H or Methyl, more preferably H; and the catalyst is a boronic acid catalyst or an antimony catalyst, e.g. boric acid or an aryl boronic acid such as 3,5-bis-(trifluoromethyl)-phenylboronic acid or 2-(N ,N- dimethylaminomethyl)phenylboronic acid, or an antimony III alkoxide such as Sb(OEt)₃. For example, the catalyst may be boric acid or 2-(N ,N- dimethylaminomethyl)phenylboronic acid. According to a very highly preferred embodiment, the invention relates to a process for the preparation of a compound of formula (IXA)

(IXA)

comprising reacting an acid of formula (XA)

with an aniline of formula (XIA)

(XIA)

in the presence of a boronic acid catalyst or an antimony catalyst, e.g. boric acid or an aryl boronic acid such as 3,5-bis-(trifluoromethyl)-phenylboronic acid or 2-(N ,N- dimethylaminomethyl)phenylboronic acid, or an antimony III alkoxide such as Sb(OEt)₃. For example, the catalyst may be boric acid or 2-(N ,N- dimethylaminomethyl)phenylboronic acid.

Ratio of reagents Preferably, the molar ratio of acid (II) or (HA) : aniline (III) or (IIIA) is in the range of from 10:1 to 1 :10. More preferably, the molar ratio of acid (II) or (HA) : aniline (III) or (IIIA) is in the range of from 5:1 to 1 :5. More preferably, the molar ratio of acid (II) or (IIA): aniline (III) or (IIIA) is in the range of from 2:1 to 1 :2. More preferably, the molar ratio of acid (II) or (IIA) : aniline (III) or (IIIA) is in the range of from 1.2: 1 to 1 : 1.2. More preferably, the molar ratio of acid (II) or (IIA): aniline (III) or (IIIA) is in the range of from 1.1 :1 to 1 :1.1.

Solvent

The reaction of the invention is optionally (and preferably) conducted in a suitable solvent. Suitable solvents include, but are not limited to, linear, branched or cyclic aliphatic hydrocarbons, such as ligroin or cyclohexane, pentane, hexane, heptane, octane, as well as aromatic solvents, such as benzene, toluene, xylene, monochlorobenzene, dichlorobenzene, trichlorobenzene.

A preferred solvent is xylene.

Temperature

The reaction of the invention may be carried out at a temperature such that an acceptable rate of reaction is attained. Preferably, the reaction is conducted at a temperature of from 0 ⁰C to 200 ⁰C. More preferably, the reaction is conducted at a temperature of from 50 ⁰C to 180 ⁰C. More preferably, the reaction is conducted at a temperature of from 100 ⁰C to 170 ⁰C. More preferably, the reaction is conducted at a temperature of from 130 ⁰C to 150 ⁰C.

Removal of Water

Preferably, provision is made for removal of water from the reaction mixture, e.g. removal of water prior to completion of the reaction. Water may be removed from the reaction continuously. A suitable method is azeotropic removal of water. Suitable apparatus for conducting azeotropic removal of water will be known to those skilled in the art. We have found that removal of water is highly desirable in order to achieve a commercially useful conversion to product.

Boronic Acid

Examples of the boronic acids include boric acid, phenylboronic acid, 2- methylphenylboronic acid, 3-methylphenylboronic acid, 4-methylphenylboronic acid, 2,3-dimethylphenylboronic acid, 4-dimethylphenylboronic acid, 2,5- dimethylphenylboronic acid, 2-ethylphenylboronic acid, 4-n-propylphenylboronic acid, 4-isopropylphenylboronic acid, 4-n-butylphenylboronic acid, 4-tert-butylphenylboronic acid, 1-naphthylboronic acid, 2-naphthylboronic acid, 2-biphenylboronic acid, 3- biphenylboronic acid, 4-biphenylboronic acid, 2-fluoro-4-biphenylboronic acid, 2- fluorenylboronic acid, 9-fluorenylboronic acid, 9-phenanthrenylboronic acid, 9- anthracenylboronic acid, 1-pyrenylboronic acid, 2-trifluoromethylphenylboronic acid, 3-trifluoromethylphenylboronic acid, 4-trifluorophenylboronic acid, 3,5- bis(trifluoromethyl)phenylboronic acid, 2-methoxyphenylboronic acid, 3- methoxyphenylboronic acid, 4-methoxyphenylboronic acid, 2,5- dimethoxyphenylboronic acid, 4,5-dimethoxyphenylboronic acid, 2,4- dimethoxyphenylboronic acid, 2-ethoxyphenylboronic acid, 3-ethoxyphenylboronic acid, 4-ethoxyphenylboronic acid, 4-phenoxyboronic acid, A- methylenedioxyphenylboronic acid, 2-fluorophenylboronic acid, 3-fluorophenylboronic acid, 4-fluorophenylboronic acid, 2,4-difluorophenylboronic acid, 2,5- difluorophenylboronic acid, 4,5-difluorophenylboronic acid, 3,5-difluorophenylboronic acid, 2-formylphenylboronic acid, 3-formylphenylboronic acid, 4-formylphenylboronic acid, 3-formyl-4-methoxyphenylboronic acid, 2-cyanophenylboronic acid, 3- cyanophenylboronic acid, 4-cyanophenylboronic acid, 3-nitrophenylboronic acid, 3- acetylphenylboronic acid, 4-acetylphenylboronic acid, 3-trifluoroacetylphenylboronic acid, 4-trifluoroacetylphenylboronic acid, 4-methylthiophenylboronic acid, A- vinylphenylboronic acid, 3-carboxyphenylboronic acid, 4-carboxyphenylboronic acid, 3-aminophenylboronic acid, 2-(N,N-dimethylamino)phenylboronic acid, 3 -(N ,N- dimethylamino)phenylboronic acid, 4-(N,N-dimethylamino)phenylboronic acid, 2- (N,N-diethylamino)phenylboronic acid, 3-(N,N-diethylamino)phenylboronic acid, A- (N,N-diethylamino)phenylboronic acid, 2-(N,N-dimethylaminomethyl)phenylboronic acid, furan-2-boronic acid, furan-3 -boronic acid, 4-formyl-2-furanboronic acid, dibenzofuran-4-boronic acid, benzo furan-2-boronic acid, thiophene-2-boronic acid, thiophene-3-boronic acid, 5-methylthiophene-2-boronic acid, 5-chlorothiophene-2- boronic acid, 4-methylthiophene-2-boronic acid, 5-methylthiophene-2-boronic acid, 2- acetylthiophene-5-boronic acid, 5-methylthiophene-2-boronic acid, benzo thiophene-2- boronic acid, dibenzothiophene-4-boronic acid, pyridine-3-boronic acid, pyridine-4- boronic acid, pyrimidine-5-boronic acid, quinoline-8-boronic acid, isoquinoline-4- boronic acid, 4-benzenebis(boronic acid), phenylboronic acid-pinacol ester, and 4- cyanophenylboronic acid-pinacol ester.

A preferred class of boronic acids are aryl boronic acids. Most preferred is 2-(N ,N- dimethylaminomethyl)phenylboronic acid and 3,5-trifluoromethylphenylboronic acid.

An alternative preferred boronic acid is boric acid.

Antimony

Antimony for use as a catalyst in the present invention may be, for example, antimony III or antimony V.

Examples of antimony for use as a catalyst include antimony complexes, e.g. organo antimony complexes such as aryl antimony complexes and saturated and unsaturated carbon chain antimony complexes, with the ligand complexed to the antimony with a suitable coordination atom, e.g. selected from O, S or N. Example of suitable antimony catalysts include: antimony halides, e.g. SbCl₃, antimony oxides, e.g. Sb₂O₃, antimony alkoxides, e.g. Sb(ORx)₃ in which Rx is alkyl, alkenyl, alkynyl, e.g. C1-C4 alkyl, C2-C4 alkenyl, e.g. C3-C4 alkynyl, in particular Sb(OEt)₃, antimony carboxylic acids, e.g. Sb(O₂CRx)₃ in which Rx is as defined above, in particular Sb(Ac)₃.

Examples of antimony V catalysts include aryl antimony complexes, such as those mentioned in Nomura et al, Chemistry Letters, The Chemical Society of Japan, 1986, pages 1901-1904. These include antimony complexed with aryl groups and carboxylates, e.g. PhSSb(O₂CRx)₂ in which Rx is as defined above, particularly Ph₃Sb(OAc)₂, and antimony oxides complexed with aryl groups, e.g. Ph₃SbO.

Catalyst recycle

Preferably the catalyst is recycled, e.g. by extracting the catalyst from the reaction solution into the aqueous phase. Extraction of the catalyst may be achieved by changing the pH of the reaction solution, e.g. to alkaline pH, so that the catalyst transfers from the organic phase to the aqueous phase. The catalyst may subsequently be transferred from the aqueous phase to fresh reactant solution by changing the pH, e.g. to acidic pH.

Boronic acid catalysts, such as 3,5-bis-(trifluoromethyl)-phenylboronic acid, are particularly suitable for catalyst recycle by extracting the catalyst from the reactant solution to aqueous phase.

Amount of Catalyst

Preferably, the amount of catalyst employed is up to 50 mol % based on the amount of carboxylic acid (II) or (HA). More preferably, the amount of catalyst employed is up to 25 mol % based on the amount of carboxylic acid (II) or (HA). More preferably, the amount of catalyst employed is up to 15 mol % based on the amount of carboxylic acid (II) or (IIA).

Preferably, the amount of catalyst employed is at least 0.01 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is at least 0.1 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is at least 1 mol % based on the amount of carboxylic acid (II) or (IIA).

Preferably, the amount of catalyst employed is between 0.01 and 50 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is between 0. 1 and 25 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is between 1 and 15 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is between 8 and 12 mol % based on the amount of carboxylic acid

(II) or (IIA).

Preferably, the amount of catalyst employed is up to 50 mol % based on the amount of aniline (III) or (III A). More preferably, the amount of catalyst employed is up to 25 mol % based on the amount of aniline (III) or (III A). More preferably, the amount of catalyst employed is up to 15 mol % based on the amount of aniline (III) or (III A).

Preferably, the amount of catalyst employed is at least 0.01 mol % based on the amount of aniline (III) or (III A). More preferably, the amount of catalyst employed is at least 0.1 mol % based on the amount of aniline (III) or (III A). More preferably, the amount of catalyst employed is at least 1 mol % based on the amount of aniline (III) or (III A).

Preferably, the amount of catalyst employed is between 0.01 and 50 mol % based on the amount of aniline (III) or (III A). More preferably, the amount of catalyst employed is between 0. 1 and 25 mol % based on the amount of aniline (III) or (III A). More preferably, the amount of catalyst employed is between 1 and 15 mol % based on the amount of aniline (III) or (III A). More preferably, the amount of catalyst employed is between 8 and 12 mol % based on the amount of aniline (III) or (III A).

Usually one type of catalyst will be used in a reaction. However, the invention also covers reactions in which more than one type of catalyst is used, e.g. either separately, sequentially or simultaneously. For example, more than one type of boronic catalyst or antimony catalyst may be used or a boronic acid catalyst and an antimony catalyst may be used.

Synthesis of Starting Materials

Suitable methods for the preparation of carboxylic acids (II) and anilines (III) are disclosed in WO04/035589 and WO 2007/048556. Suitable methods for the preparation of carboxylic acids (IIA) and anilines (HIA) are disclosed in WO03/074491. Other methods will be apparent to those skilled in the art. Workup and Isolation of Products

Workup of the reaction mixture is achieved according to well known procedures of synthetic organic chemistry. For example, an aqueous workup may be achieved by the addition of water (or other aqueous solution), and extraction of the desired product with a suitable organic solvent.

Alternatively, the product may be isolated by removing any solvent present by distillation, e.g. under reduced pressure.

Purification of the product may be achieved by any one of a number of methods, e.g. distillation, recrystallization and chromatography.

The present invention will now be described by way of the following non- limiting examples. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.

All references mentioned herein are incorporated by reference in their entirety. All aspects and preferred features of the invention may be combined with each other, except where this is evidently not possible.

Figure 1

Figure 1 shows the reaction profile of the boronic acid catalysed reaction of Example 2:

using 10 mole% catalyst, under azeotropic reflux in toluene. The X axis indicates time in hours and the Y axis indicates mole fraction. Triangles represent the acid reactant, diamonds represent the aniline reactant, circles represent product. Figure 2

Figure 2 shows a profile of mole fraction of 3,5-bis-(trifluoromethyl)-phenylboronic acid catalyst in the organic phase (toluene) versus pH. Circles represent modelled data, diamonds represent experimental data.

Examples

Example 1

Reaction sequence (absence of catalyst)

An oven-dried round bottomed flask was evacuated and refilled with nitrogen three times. The flask was fitted with a dropping funnel containing charged 3A molecular sieves, and this was connected to the nitrogen line. 3 -Difluoromethyl-1 -methyl- IH- pyrazole-4-carboxylic acid (0.36 g, 2 mmol), 9-Isopropyl- 1,2,3, 4-tetrahydro- 1,4- methano-naphthalen-5-ylamine (0.4 g, 2 mmol) were added to the flask, followed by anhydrous toluene (2 mL) via syringe. The mixture was azeotropically refluxed overnight, under nitrogen. After this time, the solution was cooled and concentrated in vacuo to give a pale brown solid. ¹H and ¹⁹F NMR and GC analyses showed only 5% conversion to amide product.

Example 2

Reaction sequence

An oven-dried flask was evacuated and refilled with nitrogen three times. The flask was fitted with a dropping funnel containing charged 3A molecular sieves. 3- Difluoromethyl-1 -methyl- lH-pyrazole-4-carboxylic acid (0.36 g, 2 mmol), 9-Isopropyl- l,2,3,4-tetrahydro-l,4-methano-naphthalen-5-ylamine (0.4 g, 2 mmol) were added to the flask, followed by 3,5-bis-(trifluoromethyl)-phenylboronic acid (26 mg, 5 mol %) and anhydrous toluene (4 mL). The mixture was heated to reflux and was azeotropically refluxed overnight under nitrogen. A sample was analysed by GC which indicated quantitative conversion to the amide and so the solution was cooled, and quenched with saturated aqueous solutions of sodium hydrogencarbonate (10 mL) and ammonium chloride (10 mL).

The aqueous layer was extracted with ethyl acetate (3 x 10 mL). Combined organic extracts were washed with water (10 mL), dried with MgSO₄ and concentrated in vacuo to give a brown solid which was identified as the amide product by ¹H and ¹⁹F NMR, and GC-MS (0.55g, 76%).

The boronic acid catalysed reaction was profiled using 10 mole% catalyst, under azeotropic reflux in toluene. The removal of water by azeotropic reflux appears to be advantageous, since without these conditions, reactions were not complete after 18 hours. See Figure 1.

Recycling of the catalyst was by extracting the boronic acid from the reaction mass with strong aqueous alkali, acidifying and then re-extracting into toluene ready for the next batch was investigated. The phase partition was modelled using the calculated LogP (3.013) and pKa (6.57) and the experimental values are close although show a slight tail at the higher pH possibly due to the high ionic strength. See Figure 2.

Catalyst recycle would significantly reduce the cost contribution of catalyst to the product.

Example 3

Reaction sequence

An oven-dried flask was evacuated and refilled with nitrogen three times. The flask was fitted with a dropping funnel containing charged 3A molecular sieves. 3- Difluoromethyl-1 -methyl- lH-pyrazole-4-carboxylic acid (0.36 g, 2 mmol), 9-Isopropyl- l,2,3,4-tetrahydro-l,4-methano-naphthalen-5-ylamine (0.4 g, 2 mmol) were added to the flask, followed by antimony (III) ethoxide (34 μL, 5 mol %) and anhydrous toluene (4 mL). The reaction was refluxed azeotropically overnight, under an atmosphere of nitrogen. A sample was analysed by GC which indicated quantitative conversion to the amide and so the solution was quenched with methanol (5 mL), and a solid crashed out of the resulting solution. This suspension was filtered through a pad of Celite, washing with 50/50 ethyl acetate/acetone (10 mL). The resulting solution was concentrated in vacuo to yield a yellow solid which was identified by ¹H and ¹⁹F NMR, and GCMS analyses as the amide product (0.53 g, 73%). Example 4

Reaction sequence

(VI M)

A 50ml three neck round bottom flask was fitted with a magnetic flea, thermometer, oil bath, condenser, and Dean & Stark apparatus filled with 3A molecular sieves 8-12 mesh (with 10ml xylene). The system was purged with nitrogen and vented to atmosphere.

DF-Pyrazole acid (compound IV) (0.4Ig), aniline (compound VII) (0.56g), xylene (15ml) and boric acid catalyst (14.2mg) were charged to the flask. The mixture was heated to reflux (-144 deg C) and held on temperature for 8hrs. Reaction was monitored via GCMS.

Conversion = 94% conversion based on compound (IV) by GCMS = 54% conversion based on compound (VII) by GCMS = 55% conversion by NMR

GC/MS Details: The product had the same retention time, molecular ion (M⁺ 331) and fragmentation pattern as found with the authentic compound. NMR: NMR spectrum of product was consistent with that for authentic material.

Example 5

Reaction sequence

(VI M)

A selection of catalysts (10mol%) were screened. The procedure in Example 4 was repeated varying the catalyst employed.

Conversions were determined by GCMS analysis. The results presented in the table are based on consumption of the aniline component. Conversions based on carboxylic acid consumption are different, presumably due to response factor differences. NMR analysis has shown that monitoring aniline consumption gives the best measure of reaction conversion. Desired product was formed in all cases, but reaction rate was very slow without catalyst present. Reasonably good rates were achieved with both of the boron-based catalysts tried. Interestingly, a synthetically advantageous rate was achieved with cheap boric acid catalyst (55% conversion in 8hr), The product was isolated and its structure confirmed by NMR analysis.

Example 6

Reaction Sequence

A 50 ml three neck round bottom flask was fitted with a magnetic flea, thermometer, oil bath, condenser, and Dean & Stark apparatus filled with 3 A molecular sieves 8-12 mesh (with 10 ml xylene). The system was purged with nitrogen and vented to the atmosphere.

DF-pyrazole acid X (0.5 g), BiCP-aniline XI (0.94 g), xylene (20 ml) and 2-(N,N- dimethyl aminomethyl) phenylboronic acid catalyst (47 mg) were charged to the flask. The mixture was heated to reflux (-143 ⁰C) and held at this temperature for 10 hours. The reaction was monitored via HPLC; 45 % conversion being achieved after 5 hours, and 58 % after 10 hours.

Product identity was confirmed by HPLC and GCMS comparison with authentic material.

Example 7

Reaction Sequence

The procedure of Example 6 was repeated varying the catalyst employed.

These results show that in the absence of catalysts, virtually no reaction occurred after 5 hours at 140 ⁰C. Addition of catalyst, however, had a dramatic effect on reaction rate - 45 % conversion being achieved after 5 hours with 10 % of 2-(N,N-dimethylaminomethyl) phenylboronic acid. Boric acid catalyst was less effective, but still generated a useful reaction rate (25 % conversion after 5 hours). Product identity was confirmed by GCMS comparison with authentic material.

Claims

1. A process for (a) the preparation of compounds of the formula (I)

(I) wherein

Het is pyrrolyl or pyrazolyl, either being substituted by groups R8, R9 and RlO;

X is a single bond; Y is (CR12R13)(CR14R15)m(CR16R17)n or C=C(A)Z in which A and Z are independently Ci_₆ alkyl or halogen; m is 0 or 1 ; n is 0 or 1 ;

Rl is hydrogen; R2 and R3 are each, independently, hydrogen, halogen, Ci_4 alkyl, Ci_4 alkoxy or

Ci_4 haloalkoxy;

R4, R5, R6 and R7 are each, independently, hydrogen, halogen, Ci_₄ alkyl,

Ci_4 haloalkyl, Ci_4 alkoxy, Ci_4 haloalkoxy, Ci_4 alkylthio, Ci_4 halo alky It hio, hydroxymethyl, Ci_₄ alkoxymethyl, C(O)CH₃ or C(O)OCH₃; R8, R9 and RlO are each, independently, hydrogen, halogen, cyano, nitro, Ci_4 alkyl,

R12 and R13 are each, independently, hydrogen, halogen, Ci_5 alkyl, Ci_₃ alkoxy,

CH₂OH, CH(O), C₃_6 cycloalkyl, CH₂O-C(=O)CH₃, CH₂-C_3-6 cycloalkyl or benzyl; or R12 and R13 together with the carbon atom to which they are attached form the group C=O or a 3-5 membered carbocyclic ring; or R12 and R13 together form Ci_5 alkylidene or C₃_₆ cycloalkylidene; and

R14, R15, R16 and R17 are each, independently, H or CH₃; comprising the step of reacting a carboxylic acid of formula (II)

Het' OH

(H) wherein Het is as defined above with an aniline of the formula (III)

wherein Rl, R2, R3, R4, R5, R6, R7, X and Y are as defined above; in the presence of a boronic acid catalyst or an antimony catalyst;

or (b) the preparation of compounds of the formula (IA)

(IA) wherein

Heta is pyrrolyl, pyrazolyl or thiazolyl, each being substituted by groups R4a, R5a, R6a;

RIa is hydrogen, fluoro, chloro or bromo; R2a is hydrogen, fluoro, chloro or bromo; R3a is optionally substituted C_2-12 alkyl, wherein, when present, each optional substituent is, independently, selected from fluoro, chloro, bromo, hydroxy, cyano, Ci_4 alkoxyC(=O), formyl, nitro, Ci_4 alkoxy, Ci_4 haloalkoxy, Ci_4 alkylthio, Ci_4 haloalkylthio, HC(OR')=N and R'R"NN=C(H); optionally substituted C2-12 alkenyl, wherein, when present, each optional substituent is, independently, selected from fluoro, chloro, bromo, hydroxy, cyano, Ci_4 alkoxyC(=O), formyl, nitro, Ci_4-alkoxy, Ci_4 haloalkoxy, Ci_-4 alkylthio, Ci_-4 haloalkylthio, HC(OR')=N and R'R"NN=C(H); optionally substituted C_2-12 alkynyl, wherein, when present, each optional substituent is, independently, selected from fluoro, chloro, bromo, hydroxy, cyano, Cl-4alkoxyC(=O), formyl, nitro, Ci_4 alkoxy, Ci_4 haloalkoxy, Ci_4 alkylthio, Ci_4 haloalkylthio,

HC(OR')=N and R'R"NN=C(H); optionally substituted C₃-₁₂ cycloalkyl, wherein, when present, each optional substituent is, independently, selected from Ci .₃ alkyl, fluoro, chloro, bromo, hydroxy, cyano, Ci_4 alkoxyC(=O), formyl, nitro, Ci_4 alkoxy, C_M haloalkoxy, Ci_-4 alkylthio, Ci_-4 haloalkylthio, HC(OR')=N and R'R"NN=C(H); optionally substituted phenyl, wherein, when present, each optional substituent is, independently, selected from Ci_6 alkyl, fluoro, chloro, bromo, hydroxy, cyano, Ci_4 alkoxyC(=O), formyl, nitro, Ci_4 alkoxy, Ci_4 haloalkoxy, Ci_4 alkylthio, Ci_4 haloalkylthio, HC(OR')=N and R'R"NN=C(H); or optionally substituted heterocyclyl, wherein, when present, each optional substituent is, independently, selected from Ci_₆ alkyl, fluoro, chloro, bromo, hydroxy, cyano, Ci_4 alkoxyC(=O), formyl, nitro, Ci_4 alkoxy, Ci_₄ haloalkoxy, Ci_₄ alkylthio, Ci_₄ haloalkylthio, HC(OR')=N; R' and R" are, independently, hydrogen or Ci_₄ alkyl; and

R4a, R5a, and R6a are, independently, selected from hydrogen, fluoro, chloro, bromo, cyano, nitro, Ci_4 alkyl, Ci_4 halo alkyl, Ci_4 alkoxy(Ci_4)alkyl and Ci_4 haloalkoxy(C_1-4)alkyl, provided that at least one of R4a, R5a, and R6a is not hydrogen.

comprising reacting a carboxylic acid of formula (HA)

o

Het OH (IIA) with an aniline of the formula (IIIA)

(IIIA) in the presence of a boronic acid catalyst or an antimony catalyst.

2. The process according to claim 1 wherein the boronic acid catalyst is an aryl boronic acid.

3. The process according to claim 1 wherein the boronic acid catalyst is 2-(N ,N- dimethylaminomethyl)phenylboronic acid, boric acid or 3,5- trifluoromethylphenyl boronic acid.

4. The process according to claim 1 wherein the antimony catalyst is Sb(OEt)₃.

5. The process according to any preceding claim wherein the catalyst is employed in an amount of between 1 and 15 mol % based on the amount of carboxylic acid (II) or (HA).

6. The process according to any preceding claim wherein the catalyst is employed in an amount of between 1 and 15 mol % based on the amount of aniline (III) or

(IIIA).

7. The process according to any preceding claim wherein the molar ratio of acid (II) or (IIA): aniline (III) or (IIIA) is in the range of from 2: 1 to 1 :2.

8. The process according to any preceding claim wherein Het is a group of formula (VIIA)

(VIIA) in which R7a is selected from CF3 and CHF₂;

and/or wherein Y is CHCH(CH₃)CH₃ or C=CCl₂;

and/or wherein R2, R3, R4, R5, R6, R7 are independently selected from hydrogen.

9. The process according to any one of the preceding claims wherein Y is CHCH(CH₃)CH₃.

10. The process according to any one of the preceding claims wherein Y is C=CCl₂.

11. A process according to any preceding claim for the preparation of a compound of formula (VI)

comprising reacting a carboxylic acid of formula (IV)

(IV) with an aniline of formula (V)

(V)

in the presence of a boronic acid catalyst or an antimony catalyst.

12. A process according to anyone of claims 1 to 10 for the preparation of a compound of formula (VIII)

(VIII) comprising reacting a carboxylic acid of formula (IV)

(IV) with an aniline of formula (VII)

(VII) in the presence of a boronic acid catalyst or an antimony catalyst.

13. The process according to any one of claims 1 to 7, wherein Heta is a group of formula (VIIA)

(VIIA)

in which R7a is selected from CF3 and CHF?

and/or wherein R3a is a group of the formula (VIIIA)

(VIIIA)

in which R8 is H or C 1-6 alkyl.

14. A process according to any one of claims 1 to 7 and 13 for the preparation of a compound of formula (IXA)

(IXA)

comprising reacting a carboxylic acid of formula (IV)

(IV)

with an aniline of formula (XIA)

(XIA) in the presence of a boronic acid catalyst or an antimony catalyst.