WO2014090918A1

WO2014090918A1 - Process for the enantiomeric enrichment of diaryloxazoline derivatives

Info

Publication number: WO2014090918A1
Application number: PCT/EP2013/076321
Authority: WO
Inventors: Steve Nanchen
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2012-12-13
Filing date: 2013-12-12
Publication date: 2014-06-19
Anticipated expiration: 2015-06-13

Abstract

The present invention concerns a process for the manufacture of the S-enantiomer of a compound of formula (I) wherein the variables are as defined in the specification and claims, comprising the steps of (A) separating a racemic compound of formula (II) wherein R', R"and R'" and Y are as defined above and Z is Q; or is halogen, amino, carboxy (-COOH); into the enantiomers and collecting the S-enantiomer; (B) if Z is other than Q, converting the S-enantiomer of formula (II) from step (A) to a S- enantiomer of formula (I); (C) racemizing the R-enantiomer of formula (II) from step (A) in a reaction medium comprising a base and an aprotic organic solvent at a temperature of from 30°C to 150°C, and (D) subjecting the racemate from step (C) to a further manufacturing cycle comprising step (A) and optionally (B). Accordingly, a cyclic process is provided, wherein the undesired enantiomer of a first enantiomer separation step is racemized and then phased in a further enantiomer separation step.

Description

PROCESS FOR THE ENANTIOMERIC ENRICHMENT OF DIARYLOXAZOLINE

DERIVATIVES

The present invention relates to a process for the manufacture of pure diaryloxazoline enantiomers and their use for combating invertebrate pests in agriculture or in the veterinary field.

The chemical class of aryl isoxazoline compounds has attracted a lot of attention in the agrochemical and also veterinary field. For example, WO2005/085216 discloses the efficacy of said class of compounds as agrochemical pest control agents. As the active ingredients have at least one asymmetrical C-atom, they are in general present as a racemic mixture of two enantiomers. No separation of the enantiomers is usually performed.

It has now been found out that the antiparasiticidal activity of the two enantiomers of a given diarylisoxazoline is very different; in particular, the respective activity of the S- enantiomer in general exceeds that of the corresponding R-enantiomer by orders of magnitude, and the R-enantiomer often does not exhibit any antiparasiticidal activity at all when applied in a commonly used concentration. Therefore it would be desirable to develop a product containing only the active S-enantiomer and few or no R-enantiomer at all.

Manufacturing of pure enantiomers is usually expensive and time-consuming; following enantiomer separation only 50% or even less of the original product have the desired configuration and the other 50% or more product with the "wrong" configuration have to be discarded. Accordingly, there is a need for recovering the undesired R-enantiomer in order to make manufacturing feasible on an industrial scale. Surprisingly, a synthetic route now has been found to racemize diaryloxazoline enantiomers. This opens the opportunity for a cyclic process, wherein the undesired enantiomer of a first enantiomer separation step is racemized and then phased in a further enantiomer separation step.

The present invention therefore relates to a process for the manufacture of an enantiomer, preferably of the S-enantiomer, of a compound of formula

(I) or a veterinary acceptable salt thereof, wherein

R\ R" and R'" are each independently hydrogen, halogen, cyano, CrC₂-alkyl, halo-Ci-C₂- alkyl, CrC₂-alkoxy or CrC₂-haloalkoxy, subject to the proviso that at least one of R', R" and R'" is not hydrogen;

Y is phenylene, naphthylene, indanylene, 5- or 6-membered heteroarylene or 8-10- membered fused heterobicyclylene, which is each unsubstituted or substituted by Ci-C₂- alkyl, Ci-C₂-haloalkyl, halogen, nitro or cyano, and,

provided that Y is phenylene, naphthylene, heteroarylene or fused heterobicyclylene, Q is

(i) a 5- or 6-membered heteroaromatic ring comprising 1 to 3 same or different heteroatoms selected from the group consisting of O, S and N which is further unsubstituted or substituted; or is

(ii) a group -C(0)N(R₁)-T, wherein is H, C C₄-alkyl, C₂-C₄-alkylcarbonyl or C₂-C₄- alkoxycarbonyl and T is CrC₆-alkyl which is unsubstituted or substituted by C₃-C₆-cycloalkyl, halogen, cyano, nitro, amino, hydroxy, CrC₆-alkoxy, CrC₆-haloalkoxy, CrC₆-alkylthio, d- C₆-haloalkylthio, CrC₆-alkylsulfinyl, CrC₆-haloalkylsulfinyl, CrC₆-alkylsulfonyl, CrC₆- haloalkylsulfonyl, carboxy, carbamoyl, Ci-C₆-alkylcarbonylamino, CrC₆-haloalkyl- carbonylamino, CrC₆-alkoxycarbonyl, sulfonamido, N-mono- or N,N, di-CrC₄-alkylsulfon- amido, C₂-C₆-alkanoyl, unsubstituted or in the alkyl portion by halogen, cyano, ethenyl or ethynyl substituted N-Ci-C₆-alkylaminocarbonyl, or unsubstituted or halogen-, Ci-C₂-alkyl-, CrC₂-haloalkyl or cyano-substituted 4- to 6-membered heterocyclyl; or T is C₃-C₆-cycloalkyl or 4- to 6-membered heterocyclyl, which is each unsubstituted or substituted by halogen, Ci-C₂-alkyl, Ci-C₂-haloalkyl or cyano; or is

(iii) a radical -C(0)NH-CH=N-0-C C₂-alkyl, a radical -C(0)N=CH-N-di-C C₂-alkyl or a radical -C(0)N=C(NH₂)-0-C C₂-alkyl; or is

(iv) a group -CH(R₃)-N(R₄)-C(0)-T₁, wherein R₃ is H, C C₆-alkyl, CrC₆-haloalkyl, halogen or cyano, R₄ is H; CrC₄-alkyl C₂-C₄-alkylcarbonyl or C₂-C₄-alkoxycarbonyl, and Ti is

independently defined as T above; or,

provided that Y is indanylene, Q is a group -N(R₄)-C(0)-T₂, wherein T₂ independently has the meaning of T above and R₄ is as defined above;

comprising the steps of

(A) separating a racemic compound of formula

wherein R', R"and R'" and Y are as defined above and Z is Q; or is halogen, amino, carboxy

(-COOH) or a salt thereof; into the enantiomers and collecting the desired enantiomer, preferably the S-enantiomer;

(B) if Z is other than Q, converting the desired enantiomer, preferably the S-enantiomer, of formula (II) from step (A) to the desired enantiomer, preferably to the S-enantiomer, of formula (I);

(C) racemizing the undesired enantiomer, preferably the R-enantiomer, of formula (II) from step (A) in a reaction medium comprising a base and an aprotic organic solvent at a temperature of from 30°C to 150°C, and,

(D) subjecting the racemate from step (C) to a further manufacturing cycle comprising step (A) and optionally (B).

According to one embodiment of the present invention Z is Q, that is, a racemic compound of formula (I) is prepared and subjected to process steps (A), (C) and (D) in a repetitive cycle.

According to a further embodiment of the invention, Z is halogen, amino, carboxy (-COOH) or a salt or derivative thereof, in particular carboxy or a salt thereof, that is, a racemic intermediate compound of formula (II) is prepared and subjected to process steps (A), (B), (C) and (D) in a repetitive cycle.

A preferred embodiment of the invention comprises a cyclic batch process, wherein one or more batches of a racemic compound of formula (II) are subjected to process steps (A) and optionally (B), the undesired enantiomer, in particular the R-enantiomer, obtained from the enantiomer separation of the one or more batches is subjected to racemization step (C), and the racemate from step (C) is subjected to a further enantiomer separation step (D). Conveniently, the undesired enantiomer, in particular the R-enantiomer, obtained from step (A) of a first batch process is racemized according to step (C) above, and the racemate obtained is added to a subsequent batch of racemic compound of formula (II) to be separated into the enantiomers according to the present invention. No compound of formula (II) is thus lost, as the undesired enantiomer of an enantiomer separation step (A) is always recovered according to step (C), and the racemate from step (C) is phased in a subsequent enantiomer separation step (A).

Regarding the variables in formulae (I) and (II) the following preferences apply:

R', R" and R'" are each independently of the other preferably H, halogen, CF₃ or cyano, and in particular H, CI, F or CF₃, subject to the proviso that at least one of R', R" and R'" is not H. One preferred embodiment of the invention concerns compounds of formula (I), wherein R', R" and R'" are each independently of the other H, chlorine or fluorine, subject to the proviso that at least one of R', R" and R'" is not H. One especially preferred

embodiment concerns a compound of formula (I), wherein R' and R'" are each halogen, for example chlorine or fluorine, in particular chlorine, and R" is H, chlorine or fluorine, in particular H or chlorine and especially chlorine. Another preferred embodiment concerns a compound of formula (I), wherein one of R' and R'" is CF₃ and the other one is halogen, for example chlorine or fluorine, in particular chlorine, and R" is H.

A preferred phenylene radical Y is of formula

(Hi),

wherein R₂ is H, CrC₂-alkyl, CrC₂-haloalkyl, halogen, nitro or cyano, preferably H, methyl, chlorine, nitro, cyano or CF₃, more preferably H, methyl, chlorine CF₃ or cyano, in particular methyl, chlorine CF₃ or cyano, and especially methyl.

A preferred naphthylene radical Y is of formula

A preferred indanylene radical Y is of formula

wherein R₂' is H, methyl, chlorine, nitro, cyano or CF₃, in particular H.

A preferred heteroaryle

wherein for R₂ each the above given meanings and preferences apply, and A is O or S, in particular S.

A particularly preferred embodiment of the heteroarylene radical Y is a radical of formula (llld) above, wherein A is S, Q or Z is located in the 2-position, and R₂ is methyl and is located in the 3-position.

Further embodiments of the heteroarylene radical Y relate to

- a radical of formula (llld) wherein A is O, Q or Z is located in the 2-position, and R₂ is located in the 3-position;

- a compound of formula (llld) wherein A is S, Q or Z is located in the 3-position, and R₂ is located in the 2-position; or

- a compound of formula (llld) wherein A is O, Q or Z is located in the 3-position, and R₂ is located in the 2-position.

Embodiments of a fused heterobicyclylene emcompass, for example, a radical of formula

wherein B-i is CH, C(CH₃) or N, one of B₂ and B₃ is CH and the other one is CH or N. A suitable heterocyclic ring Q (embodiment (i)) is, for example, a 5- or 6-membered heteroaromatic ring having from 1 to 4, preferably from 1 to 3 same or different heteroatoms selected from the group consisting of N, O and S, which is further unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, CrC₄-alkyl, Ci-C₄-haloalkyl, hydroxy, Ci-C₄-alkoxy, Ci-C₄-haloalkoxy, Ci-C₄- alkylthio, Ci-C₄-haloalkylthio, CrC₄-alkylsulfinyl, CrC₄-haloalkylsulfinyl, CrC₄-alkylsulfonyl, CrC₄-haloalkylsulfonyl, -COOH, Ci-C₄-alkoxycarbonyl, sulfonamido, C₂-C₃-alkanoyl, aminocarbonyl, N-mono- or N,N-di-Ci-C₄-alkylaminocarbonyl and C(S)NH₂. The

heteroaromatic ring Q is preferably unsubstituted or substituted by 1 to 3, in particular 1 or 2, same or different substituents selected from the group consisting of halogen, cyano, nitro, CrC₂-alkyl, CrC₂-haloalkyl, Ci-C₂-alkoxy, Ci-C₂-haloalkoxy, Ci-C₂-haloalkylthio, d- C₄-alkoxycarbonyl, C₂-C₃-alkanoyl, aminocarbonyl, N-mono- or N,N-di-CrC₃- alkylaminocarbonyl and C(S)NH₂. The heteroaromatic ring Q is most preferably

unsubstituted or substituted by 1 substituent selected from the group consisting of halogen, cyano, CrC₂-alkoxycarbonyl, aminocarbonyl, N-mono- or N,N-di-Ci-C₂-alkylaminocarbonyl and C(S)NH₂.

Examples of a 5- or 6-membered heteroaromatic rings optionally substituted with from one or more substituents include the rings Q-1 through Q-60 illustrated in Exhibit 1 wherein R is any substituent as defined before including the preferences given, and r is an integer from 0 to 4, limited by the number of available positions on each Q group. As Q-28,- Q-29, Q-35, Q-36, Q-37, Q-38, Q-39, Q-40, Q-41 and Q-42 have only one available position, for these Q groups r is limited to the integers 0 or 1 , and r being 0 means that the Q group is

unsubstituted and a hydrogen is present at the position indicated by (R)_r.

Exhibit 1

Q-1 Q-2 Q-3 Q-4

Q-5 Q-6 Q-7 Q-8 Q-9 -7-

Q-60

A preferred heterocyclic ring Q is of formula

wherein r is an integer from 0 to 3 and R is independently selected from the group given before for the heteroaromatic ring including the preferences. Q is particularly preferred the unsubstituted radical Q-14, Q-24, Q-34, Q-43 or Q-47, wherein r is 0 in each case. Q is especially preferred a radical Q-14, Q-34 or Q-47, wherein r is 0.

If Q is a group -C(0)N(Ri)-T (embodiment (ii)), is preferably H, methyl, ethyl or acetyl and in particular H.

T as alkyl is preferably CrC₄-alkyl, more preferably CrC₂-alkyl and particularly preferably Ci-alkyl, which is each unsubstituted or substituted as defined above.

The alkyl radical T is preferably unsubstituted or substituted by halogen; CrC₄-alkoxy; C C₄-alkoxycarbonyl; N-Ci-C₆-alkylaminocarbonyl which is unsubstituted or substituted in the alkyl portion by halogen, cyano, ethenyl or ethynyl; or 5- to 6-membered heterocyclyl which is in turn unsubstituted or substituted by halogen-, CrC₂-alkyl- or CrC₂-haloalkyl.

A preferred N-alkylaminocarbonyl substituent of the alkyl radical T is N-Ci-C₂- alkylaminocarbonyl, which is unsubstituted or further substituted in the alkyl moiety by halogen, cyano, ethenyl or ethynyl. Especially preferred N-alkylaminocarbonyl substituents of the alkyl radical T are N-ethylaminocarbonyl or a radical -C(Q)NH-CH₂CF₃, -C(0)NH-CH₂CN, -C(0)NH-CH₂CH=CH₂ or -C(0)NH-CH₂C≡CH.

T as N-alkylaminocarbonyl-substituted alkyl is preferably N-ethylaminocarbonylmethyl, or a radical -CH₂-C(0)NH-CH₂CF₃, -CH₂-C(0)NH-CH₂CN or-CH₂-C(0)NH-CH₂C≡CH.

If T is heterocyclyl-substituted alkyl, preferred meanings of heterocyclyl include pyridyl, pyrimidinyl, thiazolyl, oxazolyl, tetrahydrofuranyl, thietanyl, thietanyl-1 ,1 -dioxide or oxetanyl. Preferred heterocyclyl-substituted alkyl radicals T are in particular 2-pyridylmethyl, 2- tetrahydrofuranylmethyl.

T as heterocyclyl preferably denotes as 4- to 6-membered ring comprising 1 to 3 same or different heteroatoms selected from the group consisting of O, S, S(O), S(0₂) and N, which is each unsubstituted or substituted by halogen, Ci-C₂-alkyl or Ci-C₂-haloalkyl.

If T is 4- to 6-membered heterocyclyl, preferred meanings of heterocyclyl include pyridyl, pyrimidyl, thiazolyl, oxazolyl, tetrahydrofuranyl, thietanyl, thietanyl-1 -oxide, thietanyl-1 ,1 - dioxide or oxetanyl and in particular 2- 3- or 4- pyridyl, 3- 4- or 5- pyrimidyl, 2- or 3- tetrahydrofuranyl, thietan-3-yl or oxetan-3-yl and even more preferred 5-CI-pyrimid-3-yl, 3- tetrahydrofuranyl, thietan-3-yl, thietan-3-yl-1 -oxide, thietan-3-yl-1 ,1 -dioxide or oxetan-3-yl.

If Q is a group -C(0)N(R₁)-T, is preferably H, methyl, ethyl or acetyl and T is Ci-C₂-alkyl; CrC₂-haloalkyl; Ci-C₂-alkoxycarbonyl-CrC₂-alkyl; Ci-C₂-alkyl which is substituted by pyridyl, pyrimidinyl, thiazolyl, oxazolyl or tetrahydrofuranyl; N-Ci-C₂-alkylaminocarbonyl-Cr C₂-alkyl which is unsubstituted or substituted in the N-alkyl moiety by halogen, cyano, ethenyl or ethynyl; or is pyridyl; pyrimidyl; thiazolyl; oxazolyl; tetrahydrofuranyl; thietanyl; thietanyl-1 -oxide; thietanyl-1 ,1 -dioxide; or oxetanyl.

If Q is a group -C(0)N(R₁)-T, is most preferably H, methyl or ethyl, and T is Ci-C₂-alkyl; CrC₂-haloalkyl; methyl which is substituted by pyridyl, pyrimidinyl, thiazolyl, oxazolyl or tetrahydrofuranyl; methyl which is substituted by N-Ci-C₂-alkylaminocarbonyl or by N-Ci-C₂- alkylaminocarbonyl substituted in the alkyl moiety by halogen, cyano, ethenyl or ethynyl; or is pyridyl; pyrimidyl; tetrahydrofuranyl; thietanyl; thietanyl-1 -oxide; thietanyl-1 ,1 -dioxide; or oxetanyl. If Q is a group -C(0)N(R₁)-T, is particularly preferably H, and T is CrC₂-alkyl; a radical -CH2CF_3; N-ethylaminocarbonylmethyl; a radical -CH2-C(0)NH-CH2CF_3!

-CH₂-C(0)NH-CH₂CN or -CH₂-C(0)NH-CH₂C≡CH; 2- pyridylmethyl; 5-CI-pyrimid-3-yl; 3- tetrahydrofuranyl; thietan-3-yl; thietan-3-yl-1 -oxide; thietan-3-yl-1 ,1 -dioxide; or oxetan-3-yl.

Preferred radicals Q of embodiment (iii) are a radical -C(0)NH-CH=N-0-CH₃, a radical -C(0)N=CH-N(CH₃)₂ or a radical -C(0)N=C(NH₂)-0-CH₃.

If Q is a group -CH(R₃)-N(R₄)-C(0)-T₁ (embodiment (iv)), R₃ is preferably H or C C₂-alkyl or cyano, more preferably H or methyl, and in particular H. R₄ is preferably H or CrC₂-alkyl, in particular H.

R₄ is preferably H or CrC₂-alkyl, in particular H.

T-i as optionally substituted alkyl is preferably straight-chain or branched CrC₄-alkyl, which is each unsubstituted or substituted by C₃-C₆-cycloalkyl, halogen, cyano, CrC₄-alkoxy, d- C₂-haloalkoxy, CrC₄-alkylthio, CrC₂-haloalkylthio, CrC₄-alkylsulfinyl, CrC₄-haloalkylsulfinyl, CrC₄-alkylsulfonyl, CrC₄-haloalkylsulfonyl, Ci-C₂-alkylcarbonylamino, CrC₂-haloalkyl- carbonylamino or 4- to 6-membered heterocyclyl. Especially preferred alkyl radicals ΤΊ are straight-chain or branched CrC₄-alkyl or CrC₄-alkyl which is substituted by cyclopropyl, halogen, cyano, CrC₂-alkoxy, CrC₂-haloalkoxy, CrC₂-alkylthio, CrC₂-alkylsulfinyl, CrC₂- alkylsulfonyl, Ci-C₂-haloalkylcarbonylamino, pyridyl, pyrimidyl, thiazolyl, oxazolyl, thietanyl, oxetanyl, dioxolanyl, methyldioxolanyl, dioxanyl or tetrahydrofuryl.

T-i as alkyl is especially preferred straight-chain or branched CrC₄-alkyl, Ci-C₃-haloalkyl, cyclopropylmethyl, cyano-CrC₂-alkyl, Ci-C2-alkoxy-Ci-C₂-alkyl, Ci-C₂-alkylthio-Ci-C₂-alkyl, Ci-C2-alkylsulfinyl-Ci-C₂-alkyl, Ci-C2-alkylsulfonyl-Ci-C₂-alkyl, or methyl which is substituted by 1 ,3-dioxolan-2-yl, 2-methyl-1 ,3-dioxolan-2-yl or tetrahydrofuran-2- or -3-yl.

Particularly preferred alkyl radicals ΤΊ are straight-chain or branched CrC₄-alkyl; CrC₂- alkyl which is substituted by halogen, cyano, CrC₂-alkoxy, CrC₂-alkylthio or CrC₂-alkylsulfonyl; or 2-methyl-1 ,3-dioxolan-2-yl-methyl. If Ti is C₃-C₆-cycloalkyl, said cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopropyl.

If T-i is 4- to 6-membered heterocyclyl, said heterocyclyl is, for example, a 4-6-membered heteroaromatic ring, preferably a thienyl, furyl, oxazolyl, thiazolyl, pyridyl or pyrimidinyl radical, which is each unsubstituted or substituted by CrC₂-alkyl, CrC₂-haloalkyl or Ci-C₄- alkoxycarbonyl. Especially preferred heteroaromatic radicals ΤΊ are 2-, 3- or 4-pyridyl, 2- or 4-pyrimidinyl, 2-thiazolyl, 2-furyl or 2-thienyl.

A further preferred heterocyclic radical ΤΊ is, for example, a 4- to 6-membered

heteroaliphatic ring selected from the group of thietanyl, for example thietan-3-yl, oxothietanyl, for example thietan-3-yl-1 -oxide or thiethan-3-yl-1 ,1 -dioxide, oxetanyl, for example oxetan-3-yl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl and thianyl which is each

unsubstituted or substituted by CrC₂-alkyl, CrC₂-haloalkyl or Ci-C₄-alkoxycarbonyl.

Especially preferred heteroaliphatic ring radicals ΤΊ include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, thietanyl, thietanyl oxide or thietanyl dioxide which are each unsubstituted or substituted by CrC₂-alkyl, Ci-C₂-haloalkyl or Ci-C₄-alkoxycarbonyl, and in particular pyrrolidine-1 -yl, tetrahydrofuran-2-yl,

tetrahydrofuran-3-yl, piperidine-1 -yl, morpholine-4-yl or thietan-3-yl, thietan-3-yl-1 -oxide or thiethan-3-yl-1 ,1 -dioxide.

Q as a group -CH(R3)-N(R4)-C(0)-Ti is most preferably a radical -CH₂-NH-C(0)-C C₂-alkyl, -CH₂-NH-C(0)-cyclopropyl, -CH₂-N H-C(0)-(CH₂)_1-2-0-Ci-C₂-alkyl,

-CH₂-N H-C(0)-(CH₂)_1-2-S-Ci-C₂-alkyl or -CH₂-N H-C(0)-(CH₂)_1-2-S(0)₂-Ci-C₂-alkyl.

If Q is a group -N(R₄)-C(0)-T₂, for R₄ each the above given meanings and preferences apply independently; in addition, for T₂ each the meanings and preferences given above for Ti apply.

Provided that Y is phenylene, naphthylene heteroarylene or fused heterobicyclylene, particular preferred meanings of Q are a radical

2) -C 0)NH-CH₂CF₃

-C(0)-N- (q6)

-C(0)-N-

S=0

7)

-C(0)-N-

-O

(q9)

(q10) -C(0)NH-CH₂-C(0)NH-CH₂CF₃ (q1 1 ) -C(0)NH-CH₂-C(0)NH-CH₂CN (q12) -C(0)NH-CH₂-C(0)NH-CH₂C≡CH (q13) -C(0)NH-C=N-0-CH₃

(q14) -C(0)N=C-N(CH₃)₂

(q15) -C(0)N=C(NH₂)-0-CH₃

(q16) -CH₂-NH-C(0)-CrC₃-alkyl (q17) -CH₂-NH-C(0)-cyclopropyl (q18) -CH₂-NH-C(0)-cyclobutyl (q19) -CH₂-NH-C(0)-CrC₂-haloalkyl (q20) -CH₂-NH-C(0)-(CH₂)_1-2-S-Ci-C₂-alkyl

(q21 ) -CH₂-NH-C(0)- )-(CH₂)_1-2-S(0)₂-Ci-C₂-alkyl

(q22) -CH₂-NH-C(0)-(CH₂)_1-2-0-Ci-C₂-alkyl

23) .-CH₂-NH-C(0)-(CH₂)_1-2-CN

Provided that Y is indanyl, particular preferred meanings of Q

(q26) -NH-C(0)-Ci-C₃-alkyl,

(q27) -NH-C(0)-cyclopropyl,

(q28) -NH-C(0)-cyclobutyl,

(q29) -NH-C(0)-CrC₂-haloalkyl,

(q30) -NH-C(O)-(CH₂)_1-2-S-Ci-C₂-alkyl,

(q31 ) -NH-C(0)-(CH₂)_1-2-S(0)₂-Ci-C₂-alkyl,

(q32) -NH-C(0)-Ci-C₃-alkyl-0-Ci-C₂-alkyl,

33) -NH-C(0)-(CH₂)_1-2-CN,

One embodiment of the invention relates to the manufacture of the S-enantiomer of a compound of the formula (I) above wherein R' and R'" are each independently of the other halogen, for example chlorine or fluorine, in particular chlorine, R" is H or halogen, preferably H or chlorine and in particular chlorine, Y is a radical of formula (llld) above, wherein A is S, Q is a radical (q2) to (q25) as mentioned above in the 2-position, and R₂ is methyl and is located in the 3-position. A further embodiment of the present invention comprises a process for the manufacture of the S-enantiomer

(la)

or a veterinary acceptable salt thereof, wherein for R', R", R'", Y and T each the above given meanings and preferences apply; comprising the steps of

(A) separating a racemic co

(II).

wherein R', R" and R'" and Y are as defined and Z carboxy (-COOH) or a salt thereof; into the enantiomers and collecting the S-enantiomer;

followed by steps (B), (C) and (D) as described above, and including the preferences given below.

Specific examples of preferred compounds of formula (I) are the S-enantiomers of the compounds:

5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2- carboxylic acid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide; or

5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene- 2-carboxylic acid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide;

4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N{-2-oxo-2- [(2,2,2-trifluoroethyl)amino]ethyl}-benzamide;

4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2- oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1 -naphthalenecarboxamide;

4-[5-[3,5-dichlorophenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2- trifluoroethyl)amino]ethyl]-1 -naphthalenecarboxamide; 4-[5-(3,5-dichlorophenyl)-5-trifluorom

yl)-benzamide;

4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N(thie 1 -oxo)-benzamide;

4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N(thie 1 ,1 -dioxo)-benzamide;

4- [5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-cyano-1 -(1 ,2,4-triazo

1 - yl)-phenyl.

Specific examples of preferred racemic compounds of formula (II), wherein Z is different from Q, are

5- [5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-

2- carboxylic acid;

5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2- carboxylic acid;

4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid; 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1 - naphthalenecarboxylic acid;

4-[5-[3,5-dichlorophenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1 -naphthalene- carboxylic acid.

Veterinary acceptable salts of the compounds of formula (I) as well as salts of the compounds of formula (II) include acid-addition salts with inorganic or organic acids; just by way of example, the following acids may be mentioned: hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acid.

Enantiomer separation of a compound of formula (II) according to step (A) may be performed in a manner known per se, for example by simple recrystallization, kinetic resolution, by means of biotechnological methods (whole cells, enzymes, etc.), by chromatographic methods, or by methods that are based on the difference of

physicochemical properties of diastereomers prepared by reversible addition of an optically pure reagent. For example, a compound of formula (II) may be separated into its enantiomers by chiral column chromatography, in particular by chromatography on chiral adsorbents using a Simulated Moving Bed (SMB) system. To this end, a liquid mobile phase carrying the racemic compound of formula (II) to be separated is contacted with a chiral stationary phase in a system that is constituted of a number of chromatographic columns in a circular flow arrangement, separated by ports where inlet and outlet streams can be fed or collected. A suitable chiral stationary phase is, for example, composed of a chiral polysaccharide (for example Chiralpak® AS-V, AD). The liquid mobile phase typically comprises one or more alcohols, for example methanol and/or ethanol , optionally in admixture with an organic acid, for example, formic acid. A suitable SMB system is described, for example, in

WO2006/050887.

According to a further embodiment, a racemic compound of formula (II) which is an acid or amine, is separated into the enantiomers by diastereomeric recrystallization. To this end, an optically pure reagent, which is an amine or acid, is reacted with a racemic compound of formula (II), wherein Z is amino, carboxy or a salt thereof, thereby forming pairs of diastereomeric salts, which can be separated by conventional techniques in physical chemistry, i.e. by crystallization.

In case of a racemic compound of formula (II) wherein Z is amino or a salt thereof, a typical optical pure reagent is an organic acid, for example, (+)-D-di-0-benzoyl-tartaric acid, (-)-L- di-O-benzoyltartaric acid, (-)-di-0,0'-p-tolyl-L-tartaric acid, (+)- di-0,0'-p-tolyi-D-tartaric acid, R(+)-malic acid, S-(-)-malic acid, (+)-camphanic acid, (-)-camphanic acid, R(-)-1 ,V- binaphthalene-2,2'-diyl hydrogen phosphate, S(+)-1 ,1 '-binaphthalene-2,2'-diyl hydrogen phosphate, (+)-camphoric acid, (-)-camphoric acid, S(+)-2-phenylpropionic acid, R(-)-2- phenylpropionic acid, D(-)- mandelic acid, L(+)-mandelic, acid, D-tartaric acid, L-tartaric acid, or a mixture thereof.

In case of a racemic compound of formula (II) which is an acid, a typical optical pure reagent is an optical pure amine, for example (R)-(+)-1 -(4-methylphenyl)ethylamine, (S )-(-)- 1 -(4-methylphenyl)ethylamine, (R)-(+)-a-methylbenzylamin, (S)-(-)-a-methylbenzylamin, (R)- (-)-aminoindane, (S)-(+)-aminoindane, (R)-(+)-N,a-dimethylbenzylamine, (S)-(-)-N,a- dimethylbenzylamine, (R)-(+)-N,N-dimethyl-1 -phenyletyhlamine, (S)-(-)-N,N-dimethyl-1 - phenyletyhlamine, (R)-(-)-1 -cyclohexylethylamine, (S)-(+)-1 -cyclohexylethylamine, (R)-(-)- 1 ,2,3,4-tetrahydro-l -naphthylamine, (S )-(+)- 1 ,2,3,4-tetrahydro-l -naphthylamine, (-)-bis[(S)- 1 -phenylethyl]amine, (+)-bis[(R)-1 -phenylethyl]amine. Upon the reaction of the racemic compound with the optical pure enantiomer, diasteriometric salts are formed which may be separated, for example, by crystallization.

According to a preferred embodiment, a racemic compound of formula (II), wherein Z is carboxy or a salt thereof, is separated into its enantiomers by reaction with an optical active amine, in particular (R)-(+)-1 -(4-methylphenyl)ethylamine.

The formation of the diastereomeric salt may be performed in a polar solvent or a solvent mixture comprising at least one polar solvent. Suitable solvents are for example, halogenated hydrocarbons, for example chlorobenzene, dichlorobenzene, bromobenzene, dichloromethane, trichloromethane, tetrachloromethane, dichloroethane, trichloroethene or tetrachloroethene; alcohols, such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol or tert. butanol; ethers, such as diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, tert. -butyl methyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, dimethoxydiethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone, methyl ethyl ketone or methyl isobutyl ketone; amides, such as N,N-dimethylformamide, Ν,Ν-diethylformamide, N,N-dimethylacetamide, N- methylpyrrolidone or hexamethylphosphoramide; esters, such as methyl acetate, ethylacetate; nitriles, such as acetonitrile or propionitrile; sulfoxides, such as dimethyl sulfoxide; or water. Preferred solvents for the formation and crystallization of the diastereomeric salts according to the invention are alcohols, in particular ethanol, isopropanol, n-, sec. or tert. -butanol, nitriles, in particular acetonitrile, ethers, in particular tert. - butyl methylether, esters, in particular methylacetate, or mixtures therof, or a mixture one of or more of the above mentioned solvents with water. A particularly preferred reaction medium for the formation of the diastereomeric salts is a mixture of water, a C₂-C₄-alcanol and a dipolar aprotic solvent such as acetonitrile or the like.

The formation of the diastereomeric salt may be performed at a temperatu re ranging from about 1 0° C to the reflux point of the solvent or solvent mixture. Salt formation is carried out preferably at a temperature ranging from room temperature to about 100°C. For example, the mixture of the racemate to be separated, the optical active reagent and the solvent(s) is heated to an elevated temperature, for example to 30 to 100°C or preferably to 50 to 80°C, kept at this temperature for some time and then cooled, for example, to room temperature in order to affect crystallization of one of the diastereomeric salts. The reaction time is not critical; in general, a time period of 0.5 minutes to 6 hours, preferably 1 to 4 hours, and in particular from 1 .5 to 3 hours at an elevated temperature is sufficient for the formation of the diastereomeric salts. Upon cooling of the reaction mixture, one of the diastereomeric salts, preferably the one covering the S-enantiomer, usually crystallizes and may be isolated by filtration.

Once the crystallized diastereomeric salt has been isolated, it may be purified to the desired diastereomeric purity, for example by recrystallization in a suitable solvent or solvent mixture. The purified diastereomeric salt is then dissociated in basic or acidic medium in a suitable solvent or solvent mixture, and the desired (S)-enantiomer is recovered from the racemic mixture of the compound of formula (II).

The desired S-enantiomer of the compound of formula (II) is collected and optionally further purified by processes known in the art, for example by recrystallization. The optical purity of the S-enantiomer as collected is for example≥90%, preferably≥95% and in particular ≥98%.

The S-enantiomer of formula (II), wherein Z is different from Q, is converted to a S- enantiomer of formula (I) according to step (B) in a manner known per se, for example from WO2010/070068 or WO201 1/157748.

For example, an S-enantiomer of formula

wherein R', R", R'" and Yare as defined above and Hal is halogen, for example, fluoro, chloro or bromo, may be reacted with a compound of formula

H - Q (IVa), wherein Q is a 5- or 6-membered heteroaromatic ring, in the presence of a catalyst, to yield the respective S-enantiomer of formula (I), wherein Q is a heteroaromatic radical. Typical catalysts are, for example copper iodide, a palladium catalyst or an inorganic base such as sodium or potassium carbonate.

Moreover, an S-enantiomer of formula

or a salt thereof, wherein R', R", R'" and Y are as defined above, may be first converted to the respective acid halide which is reacted with a compound of formula

wherein R-i and T are as defined above, optionally in the presence of a base, to yield the respective S-enantiomer of formula (I), wherein Q is a group -C(0)N(R₁)-T.

S-enantiomers of the formula (I), wherein Q is a radical -C(0)NH-CH=N-0-Ci-C₂-alkyl, -C(0)N=CH-N-di-C C₂-alkyl or -C(0)N=C(NH₂)-0-Ci-C₂-alkyl, may be obtained from a compound of formula (l ib) above via conversion to the respective amide.

An S-enantiomer of formula (l ib) above may also be first converted to the respective aldehyde, optionally via a respective ester, which is subjected to a triethylsilane-promoted reductive amination with a compound of formula

wherein R₄ and ΤΊ is as defined above, to yield the S-enantiomer of formula (I), wherein Q is a group -CH(R₃)-N(R₄)-C(0)-T₁.

An S-enantiomer of formula

or a salt thereof, wherein R', R", R'" and Y are as defined above, may be reacted with a compound of formula

Hal - C(0) - T₂ (IVd),

wherein T₂ and Hal is as defined above, optionally in the presence of a base, to yield the respective S-enantiomer of formula (I), wherein Q is a group -NR₄-C(0)T₂.

Suitable organic solvents in racemization step (C) are, for example aromatic, aliphatic (cyclic and alicyclic) and halogenated hydrocarbons, such as benzene, toluene, xylene, mesitylene, tetralin, chlorobenzene, dichlorobenzene, bromobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, trichloromethane, tetrachloromethane, dichloro- ethane, trichloroethene or tetrachloroethene; alcohols, such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol or tert. butanol; ethers, such as diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, tert. -butyl methyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, dimethoxydiethyl ether, tetrahydrofuran or dioxane; esters, such as methyl acetate, ethyl acetate or tert. -butyl acetate; ketones, such as acetone, methyl ethyl ketone or methyl isobutyl ketone; amides, such as N,N-dimethylformamide, Ν,Ν-diethylformamide, N,N-dimethylacetamide, N- methylpyrrolidone or hexamethylphosphoramide; nitriles, such as acetonitrile or propionitrile; and sulfoxides, such as dimethyl sulfoxide (DMSO).

Preferred groups of organic solvents applied in step (C) according to the process of the invention are aromatic hydrocarbons or halogenated aromatic hydrocarbons, preferably benzene, toluene, xylene, mesitylene, or tetralin, especially toluene or o-, m- oder p-xylene, and in particular toluene; alcohols, for example ethanol, nitriles, for example acetonitrile; or DMSO. The amount of organic solvent being present in step (C) may be, for example, from 30 to 90% (w/w), in particular from 50 to 90% (w/w) based on the entire reaction mixture. In addition, the reaction medium of step (C) may comprise water, in particular, if an alkali metal or alkaline earth metal hydroxide is used as the base. The amount of water being present in the reaction mixture, if present, may be, for example, from 1 to 20% (w/w), preferably from 1 .5 to 10% (w/w), based on the entire reaction mixture.

Suitable bases for racemization step (C) are, for example e.g. alkali metal or alkaline earth metal hydroxides, for example lithium, sodium or potassium hydroxide; ammonium hydroxide; alkali metal or alkaline earth metal hydrides, for example sodium hydride, calcium hydride; alkali metal or alkaline earth metal alkanolates, for example sodium methanolate sodium ethanolate, sodium butanolate, potassium tert.-butanolate; alkali metal carbonates, for example potassium carbonate or cesium carbonate; amines, for example triethylamine, N,N-diisopropylethylamine; carbocyclic amines, for example 2,2,6,6- tetramethylpiperidine, 1 ,5-diazabicyclo[5.4.0]undec-5-ene (DBU) or 1 ,5- diazabicyclo[5.4.0]undec-7-ene (DBA); lithium diisopropylamide (LDA); lithium N- isopropylcyclohexylamide (LICA); lithium or potassium hexamethyldisilazide (LHMDS, KHMDS); lithium 2,2,6, 6-tetramethylpiperidide (LTMP); guanidine; n-, sec- or tert- butyllithium; phosphazenes, for example tert.-butylimino-tris(dimethylamino)phosphorane.

A preferred base according to the present invention is an alkali metal hydroxide, in particular sodium hydroxide. The base is in general present in molar excess relative to the amount of enantiomer to be racemized.

A preferred reaction medium of step (C) comprises an aromatic hydrocarbon, in particular toluene, water and an alkali metal hydroxide, in particular sodium hydroxide.

In case of a reaction medium comprising an organic solvent with low water solubility and water it has proven as valuable to add a phase transfer catalyst to the reaction mixture. Suitable phase transfer catalysts are, for example, quaternary ammonium or phosphonium salts, preferably quaternary ammonium salts, in particular N-methyl-N,N-dioctyloctan-1 - ammonium chloride, benzyl trimethylammonium chloride, tetrabutylammonium bromide, or tributyl methylammonium chloride. The amount of phase transfer catalyst, if present in step (C) may be, for example, from 0.1 to 10% (w/w), preferably from 0.5 to 5% (w/w), and in particular from 1 to 4% (w/w) based on the entire reaction mixture. A further preferred reaction medium of step (C) according to the invention comprises an aromatic hydrocarbon, in particular toluene, water, a phase transfer catalyst, in particular a quaternary ammonium salt such as tributyl methylammonium chloride and an alkali metal hydroxide, in particular sodium hydroxide.

A suitable reaction mixture according to step (C) comprises

1 to 20 % (w/w) R-enantiomer of formula (II) to be racemized

1 to 20% (w/w) water

1 to 20% (w/w) base

0.1 to 10% (w/w) phase transfer catalyst, and

ad 100% (w/w) organic solvent.

A preferred reaction mixture according to step (C) comprises

1 to 20 % (w/w) R-enantiomer of formula (II) to be racemized, wherein the above

meanings and preferences apply;

1 to 10% (w/w) water

1 to 10% (w/w) alkali metal hydroxide

0.5 to 5% (w/w) quaternary ammonium salt as phase transfer catalyst, and

ad 100% (w/w) aromatic hydrocarbon as organic solvent.

A particularly preferred reaction mixture according to step (C) comprises

1 to 20 % (w/w) R-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-

3- methyl-thiophene-2-carboxylic acid;

1 to 10% (w/w) water;

1 to 10% (w/w) alkali metal hydroxide selected from sodium and potassium hydroxide; 0.5 to 5% (w/w) phase transfer catalyst selected from tetrabutyl ammonium bromide and tributyl methylammonium chloride; and

ad 100% (w/w) aromatic hydrocarbon selected from toluene or o-, m- oder p-xylene.

The racemization reaction according to step (C) advantageously takes place in a temperature range of about 50°C to about 120°C , preferably from ca. 50°C to ca. 100°C, and in particular from 60°C to 90°C. In a preferred embodiment, an R-enantiomer of formula (II) is racemized in a reaction medium comprising an aromatic hydrocarbon, preferably toluene, water, a phase transfer catalyst and a base which is an alkali metal hydroxide at a temperature from about 50°C to about 100°C, preferably from 60 to 90°C.

The reaction time may vary within wide limits, for example between 1 and 100 hours, preferably between 2 and 72 hours, more preferably between 2 and 24 hours and in particular between 3 and 12 hours. A particularly preferred reaction time is from 4 to 8 hours.

A preferred embodiment of the present invention comprises a process for the manufacture of the S-enantio

(la)

or a veterinary acceptable salt thereof, wherein R', R" and R'" are each independently of the other preferably H, CI, F or CF₃, subject to the proviso that at least one of R', R" and R' is not H; Y is a radical

and for T the above given meanings and preferences apply; comprising the steps of (A) separating a racemic co

(II).

wherein R', R" and R'" and Y are as defined above and Z carboxy (-COOH) or a salt thereof; into the enantiomers and collecting the S-enantiomer; (B) converting the S-enantiomer of formula (II) from step (A) to the S-enantiomer of formula

(I);

(C) racemizing the R-enantiomer of formula (II) from step (A) in a reaction medium comprising a base and an aprotic organic solvent at a temperature of from 50 to 120°C, and,

(D) subjecting the racemate from step (C) to a further manufacturing cycle comprising steps (A) and (B).

An especially preferred embodiment of the present invention comprises a process for the manufacture of the S-enantiomer of a compound of formula

or a veterinary acceptable salt thereof, wherein R' and R'" are each independently CI or CF₃, R" is H or CI; and Y is a radical (ΙΙΓ), (Ilia') or (llld') as shown above;

comprising the steps of

(A) separating a racemic compound of formula

wherein R', R" and R'" and Y are as defined above and Z is carboxy (-COOH) or a salt thereof; into the enantiomers, preferably by diastereomeric recrystallization, and collecting the S-enantiomer;

(B) converting the S-enantiomer of formula (II) from step (A) to the S-enantiomer of formula

(i);

(C) racemizing the R-enantiomer of formula (II) from step (A) in a reaction medium comprising an aromatic hydrocarbon, preferably toluene, water, a phase transfer catalyst and a base which is an alkali metal hydroxide at a temperature from about 50°C to about 100°C, preferably from 60 to 90°C; and (D) subjecting the racemate from step (C) to a further manufacturing cycle comprising steps (A) and (B).

While the above description concerns the collection of the S-enantiomer of a compound of formula (I), racemization of the R-enantiomer and the use of the resulting racemate in a further enantiomer separation step, the reverse process, that is collection of the R- enantiomer of a compound of formula (I), racemization of the S-enantiomer and use of the resulting racemate in a further enantiomer separation step, may be performed in the same manner including the above-given preferences and therefore constitutes a further object of the invention.

The Examples further illustrate the present invention.

Example 1 : Preparation of a racemic compound of formula (II)

(i) 89 kg 2-bromo-3-methyl-5-acetylthiophene and 1 13 kg trifluoro-3,4,5- trichloroacetophenone are heated in about 880 kg tert. -butyl methylether and 121 kg triethylamine for 2 hours at 57°C. The reaction mixture is then cooled to below 5°C, and 67 kg thionyl chloride are added slowly. The reaction mixture is then heated for 3 hours to 40°C and afterwards extracted with 10% sodium hydrogencarbonate solution and water, the combined aqueous phases are extracted twice with tert. -butyl methylether, and the combined organic phases are extracted again with water. Following the removal of the solvent (tert-butyl methylether) by distillation the product of formula

is crystallized from ethanol/water.

(ii) 90 kg of the butanone bromothiophene from step (i) and 1000 kg ethanol are cooled below 5°C, and 13 kg hydroxylammonium chloride are added to the reaction mixture.

Following the slow addition of 55 kg of 30% sodium hydroxide the suspension is stirred for 3 hours . 1650 kg water are then added, and the reaction mixture is stirred for additional 2 hours. The product of formula

is centrifuged, washed with water and dried in vacuum.

(iii) 18.5 kg of the isoxazolin bromothiophene from step (ii) are dissolved in 80 kg tetrahydrofuran (THF) at ambient temperature. 18.6 kg of ethyl magnesium chloride (25% in THF) are added slowly, followed by the slow addition of 5.8 kg of C0₂ below the surface. The reaction mixture is then stirred for approximately 30 minutes at ambient temperature. Thereafter a mixture of 8 kg NaCI, 64 kg water and 7.9 kg HCI 37% is added. Following phase separation the organic layer is distilled to a minimum and heptane is added.

Following the removal of the heptane by distillation, the residuwe is dissolved in about 10 kg ethyl acetate, and the product is precipitated by the slow addition of 240 kg heptane at 40°C. The prod nd the racemic product of formula

(II^*) is isolated.

Example 2: Enantiomer separation of racemic isoxazoline thiophene carboxylic acid of formula (II^*) and collection of the S-enantiomer

100 kg of of racemic isoxazoline thiophene carboxylic acid from Example 1 , 171 kg 2- butanol, 680 kg acetonitrile and 45 kg water are stirred at ambient temperature. To this reaction mixture a solution of 15 kg (R)-1 -(4-methylphenyl)ethylamine, 19 kg 2-butanol, 76 kg acetonitrile and 5 kg water are added, and the reaction mixture is then slowly heated to 60°C and kept for 2 hours at this temperature. Thereafter the reaction mixture is cooled slowly to room temperature; the (S)-isoxazoline thiophene carboxylic acid salt precipitates and is collected by filtration and washed with a mixture of acetonitrile/water (9:1 ). Chiral purity of the product >95%.

The chiral purity of the product may be further increased by a further recrystallization step with acetonitrile/water (9:1 ) at 60°C and subsequent cooling, (chiral purity >98%). Example 3: Racemization of (R)-isoxazoline thiophene carboxylic acid

3800 kg of the mother liquid from the racemic resolution of Example 2 are charged to a reactor and the solvent is removed under vacuum. 1750 kg of toluene are added and distilled off again. 54 kg of tributyl methylammonium chloride (as a 75% solution in water) 129 kg 50% aqueous sodium hydroxide solution and 1750 kg of toluene are added, and the mixture is then stirred for 6 hours at 75°C.The reaction mixture is then cooled to room temperature, followed by the addition of about 1600 kg of toluene. The organic layer is extracted three times with 1 molar HCI solution, and the toluene is then removed under vacuum. The residue is dissolved in about 1 10 kg of ethyl acetate at 40°C, and about 2600 kg of heptane are added slowly. Following cooling to ambient temperature, the product is isolated by centrifugation, washed with heptane and dried under vacuum. Yield: 80% racemic isoxazoline thiophene carboxylic acid of formula (II^*), S/R enantiomer ratio

49.9/50.1 .

Example 4: Preparation of an (S)-enantiomer of formula (I) from an(S)-isoxazoline thiophene carboxylic acid salt

(i) 15 kg of the (S)-isoxazoline thiophene carboxylic acid salt from Example 2 in 150 kg of toluene are heated to 60°C. the solution is extracted three times with 56 kg of 1 molar HCI solution. About 50% of the organic layer is then distilled off under vacuum. Following the addition of further 60 kg of toluene the mixture is heated to 1 10°C and 8 kg of thionyl chloride are dosed slowly to the reaction mixture. Following stirring for an additional hour 94 kg of toluene are removed under vacuum. The reaction mixture is cooled to ambient temperature, and 94 kg of dichloromethane are added.

(ii) The dichloromethane solution of step (i) is added to a mixture of 5.1 kg 2-amino-2',2',2'- trifluoroethyl-acetamide hydrochloride and 9.8 kg of triethylamine in 93 kg of dichloromethane at 5°C. The reaction mixture is stirred for additional 5 hours and is then extracted with 4% hydrochloric acid, 8% sodium hydrogen carbonate and water. Most of the organic layer is then removed under vacuum, and 50 kg of toluene are added. The reaction mixture is kept at 40°C, and 290 kg of heptane are added slowly to precipitate the product. The suspension obtained is cooled to below 5°C, and the crude product is isolated by filtration and is washed with 25 kg of heptane. Crystallization of the product may be performed as appropriate.

Claims

Claims:

1 . Process for the manufacture of an enantiomer of a compound of formula

(I)

or a veterinary acceptable salt thereof, wherein

provided that Y is phenylene, naphthylene, heteroarylene or fused heterobicycylene, Q is

(iii) a radical -C(0)NH-CH=N-0-C C₂-alkyl, a radical -C(0)N=CH-N-di-C C₂-alkyl or a radical -C(0)N=C(NH₂)-0-C C₂-alkyl; or is (iv) a group -CH(R₃)-N(R₄)-C(0)-T₁, wherein R₃ is H, CrC₆-alkyl, CrC₆-haloalkyl, halogen or cyano, R₄ is H; d-C₄-alkyl C₂-C₄-alkylcarbonyl or C₂-C₄-alkoxycarbonyl, and Ti is

independently defined as T above; or,

comprising the steps of

(A) separating a racemic compound of formula

(-COOH) or a salt or a derivative thereof; into the enantiomers and collecting the desired enantiomer;

(B) if Z is other than Q, converting the desired enantiomer of formula (II) from step (A) to the desired enantiomer of formula (I);

(C) racemizing the undesired enantiomer of formula (II) from step (A) in a reaction medium comprising a base and an aprotic organic solvent at a temperature of from 30°C to 150°C, and,

2. The process according to claim 1 , wherein the desired enantiomer is the S-enantiomer, and the undesired enantiomer is the R-enantiomer.

3. The process according to claim 1 or 2, wherein Z is Q.

4. The process according to claim 1 or 2, wherein Z is halogen, amino, carboxy (-COOH) or a salt thereof, in particular carboxy or a salt thereof.

5. The process according to claim 1 for the manufacture of the S-enantiomer of a compound of formula

(la)

or a veterinary acceptable salt thereof, wherein for R', R", R"\ Y and T are each as defined in claim 1 ; comprising the step

(A) separating a racemic co

(II).

wherein R', R" and R'" and Y are as defined and Z carboxy (-COOH) or a salt thereof; into the enantiomers and collecting the S-enantiomer.

6. The process according to claim 5, for the manufacture of the S-enantiomer of a compound of formula

(la) or a veterinary acceptable salt thereof, wherein R' and R'" are each independently CI or CF₃, R" is H or CI; and Y is a radical

comprising the step

(A) separating a racemic compound of formula

wherein R', R" and R'" and Y are as defined above and Z carboxy (-COOH) or a salt thereof; into the enantiomers, and collecting the S-enantiomer.

7. The process according to any one of claims 1 to 6, wherein separation of the racemic compound of formula (II) into the enantiomers according to step (A) is performed by chiral column chromatography or by diastereomeric recrystallization.

8. The process according to claim 7, wherein a compound of formula (II), which is an amine or acid or a salt thereof, is reacted with an optical pure reagent which is an acid or amine, thereby forming a pair of diastereomeric salts which are then separated.

9. The process according to any one of claims 1 to 8, wherein the reaction medium in step (C) comprises an aromatic hydrocarbon and water.

10. Process according to claim 9, wherein the reaction medium comprises, in addition, a phase transfer catalyst.

1 1 . The process according to claim 9 or 10, wherein in step (C) the R-enantiomer of formula (II) is racemized in a reaction medium comprising an aromatic hydrocarbon, water, a phase transfer catalyst and a base which is an alkali metal hydroxide at a temperature from 50°C to 100°C.

12. The process according to claim 1 for the manufacture of the S-enantiomer of a compound of formula

or a veterinary acceptable salt thereof, wherein R' and R'" are each independently CI or CF R" is H or CI; and Y is a radical

comprising the steps of

(A) separating a racemic compound of formula

wherein R', R" and R'" and Y are as defined above and Z carboxy (-COOH) or a salt thereof; into the enantiomers by diastereomeric recrystallization, and collecting the S- enantiomer;

(I);

(C) racemizing the R-enantiomer of formula (II) from step (A) in a reaction medium comprising an aromatic hydrocarbon, water, a phase transfer catalyst and a base which is an alkali metal hydroxide at a temperature from about 50°C to about 100°C; and

13. Process for the racemization of an enantiomer of a compound of formula

wherein R', R" and R'", Y and Z are as defined in claim 1 ,

comprising treating the enantiomer of formula (II) in a reaction medium comprising a base and an aprotic organic solvent at a temperature of from 30°C to 150°C.

14. The process according to claim 13, wherein the R-enantiomer of formula (II) is racemized in a reaction medium comprising an aromatic hydrocarbon, water, a phase transfer catalyst and a base which is an alkali metal hydroxide at a temperature from 50°C to 100°C.

15. The compound (S)-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3- yl]-3-methyl-thiophene-2-carboxylic acid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide.