PROCESS FOR PREPARATION OF OPTICALLY ENRICHED ALDOL COMPOUNDS

Abstract

The present invention relates to a process for preparing benzylic amides of formula (I) wherein the variables are as defined in the specification, and the shown enantiomer has at least 50% ee; by condensation of a ketone o formula (II) with an acetyl compound of formula (III) in the presence of a catalyst of formula (IV) wherein the variables are as defined in the specification.

##STR00001##

Claims

1. A process for preparing compounds a compound of formula I ##STR00044## wherein R.sup.1 is halomethyl; each R.sup.2 is independently H, halogen, CN, N.sub.3, NO.sub.2, SCN, SF.sub.5, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, which groups are unsubstituted, partially or fully halogenated and/or substituted with one or more same or different R.sup.8, Si(R.sup.12).sub.3, OR.sup.9, S(O).sub.nR.sup.9, NR.sup.10aR.sup.10b, phenyl which is unsubstituted or partially or fully substituted with R.sup.11, and a 3- to 10-membered saturated, partially or fully unsaturated heteromonocyclic or heterobicyclic ring containing 1, 2, 3 or 4 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or substituted with one or more same or different R.sup.11, preferably the unsubstituted or substituted HET; n is 0, 1, or 2; G.sup.1, G.sup.2 are each CR.sup.3, or together form a sulfur atom; each R.sup.3 is independently selected from the meanings mentioned for R.sup.2, or two R.sup.3 bonded to adjacent carbon atoms may form a five- or six-membered saturated, partially or fully unsaturated carbocyclic ring, or a dihydrofurane, or R.sup.3 bonded to carbon atom in position G.sup.1 form a bond to the chain *-Q-Z— in group A.sup.2; A is a group A.sup.1, A.sup.2, A.sup.3, or A.sup.4; wherein A.sup.1 is C(═W)Y; W is O, or S; Y is N(R.sup.5)R.sup.6, or OR.sup.9; A.sup.2 is ##STR00045## wherein # denotes the bond of group A, and % denotes the bond to G.sup.1; Q-Z is %-CH.sub.2—O—*, ′%-CH.sub.2—S(O).sub.n—*, or %-C(═O)—O—*, wherein % marks the bond of Q to phenyl, and * the bond of Z to azetidin; and R.sup.A4 is H or C(═O)R.sup.4A, wherein R.sup.4A is H, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.2-C.sub.6-haloalkynyl, C.sub.1-C.sub.4-alkylcarbonyl, which aliphatic groups are unsubstituted or substituted with one or more radicals R.sup.41; C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halocycloalkyl which cyclic groups are unsubstituted or substituted with one or more R.sup.42; C(═O)N(R.sup.43)R.sup.44, N(R.sup.43)R.sup.45, CH═NOR.sup.46; phenyl, heterocycle, or hetaryl HET which rings are unsubstituted or partially or fully substituted with R.sup.A; R.sup.41 is independently OH, CN, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, S(O).sub.n—C.sub.1-C.sub.6-alkyl, S(O).sub.n—C.sub.1-C.sub.6-haloalkyl, C(═O)N(R.sup.43)R.sup.44, C.sub.3-C.sub.6-cycloalkyl, or C.sub.3-C.sub.6-halocycloalkyl which cycles are unsubstituted or substituted with one or more R.sup.411; or phenyl, heterocycle or hetaryl HET which rings are unsubstituted or partially or fully substituted with R.sup.A; R.sup.411 is independently OH, CN, C.sub.1-C.sub.2-alkyl, or C.sub.1-C.sub.2-haloalkyl; R.sup.43 is H, or C.sub.1-C.sub.6-alkyl, R.sup.44 is H, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.2-C.sub.6-haloalkynyl, or C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halocycloalkyl, C.sub.3-C.sub.6-cycloalkylmethyl, or C.sub.3-C.sub.6-halocycloalkylmethyl which rings are unsubstituted or substituted with a cyano; R.sup.45 H, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, CH.sub.2—CN, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halocycloalkyl, C.sub.3-C.sub.6-cycloalkylmethyl, C.sub.3-C.sub.6-halocycloalkylmethyl, phenyl and hetaryl HET which aromatic rings are unsubstituted or partially or fully substituted with R.sup.A; R.sup.42 C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, or a group as defined for R.sup.41; R.sup.46 is independently H, C.sub.1-C.sub.6-alkyl, or C.sub.1-C.sub.6-haloalkyl; R.sup.A is independently selected from halogen, CN, NO.sub.2, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.2-C.sub.4-haloalkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halocycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, S(O).sub.n—C.sub.1-C.sub.4-alkyl, S(O).sub.n—C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkylcarbonyl, C.sub.1-C.sub.4-haloalkylcarbonyl, C(═O)N(R.sup.43)R.sup.44; or two R.sup.A present on the same carbon atom of a saturated or partially saturated ring may form together ═O or ═S; or two R.sup.A present on the same S or SO ring member of a heterocyclic ring may together form a group ═N(C.sub.1-C.sub.6-alkyl), ═NO(C.sub.1-C.sub.6-alkyl), ═NN(H)(C.sub.1-C.sub.6-alkyl) or ═NN(C.sub.1-C.sub.6-alkyl).sub.2; A.sup.3 is CH.sub.2—NR.sup.5C(═W)R.sup.6; A.sup.4 is cyano; R.sup.5 is independently selected from the meanings mentioned for R.sup.2; R.sup.6 is H, CN, C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkynyl, which groups are unsubstituted, partially or fully halogenated and/or substituted with one or more same or different R.sup.8; or S(O).sub.nR.sup.9, or C(═O)R.sup.8; or a 3- to 8-membered saturated, partially or fully unsaturated heterocyclic ring, which ring may contain 1, 2, 3, or 4 heteroatoms O, S, N, C═O and/or C═S as ring members, which heterocyclic ring is unsubstituted or partially or fully substituted with same or different halogen, CN, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-haloalkylthio, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.2-C.sub.6-haloalkynyl, which groups are unsubstituted, or partially or fully substituted with same or different R.sup.8, or phenyl which may be partially or fully substituted with R.sup.11; or R.sup.5 and R.sup.6 together form a group ═C(R.sup.8).sub.2, ═S(O).sub.m(R.sup.9).sub.2, ═NR.sup.10a, or ═NOR.sup.9; R.sup.7a, R.sup.7b are each independently H, halogen, CN, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.2-C.sub.6-alkenyl, or C.sub.2-C.sub.6-alkynyl, which groups are unsubstituted, partially or fully halogenated and/or substituted with same or different R.sup.8; each R.sup.8 is independently CN, N.sub.3, NO.sub.2, SCN, SF.sub.5, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl, wherein the carbon chains may be substituted with one or more R.sup.13; Si(R.sup.12).sub.3, OR.sup.9, OSO.sub.2R.sup.9, S(O).sub.nR.sup.9, N(R.sup.10a)R.sup.10b, C(═O)N(R.sup.10a)R.sup.10b, C(═S)N(R.sup.10a)R.sup.10b, C(═O)OR.sup.9, CH═NOR.sup.9, phenyl, which is unsubstituted or partially or fully substituted with same or different R.sup.16, or a 3-, 4-, 5-, 6- or 7-membered saturated, partially or fully unsaturated heterocyclic ring comprising 1, 2 or 3 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted or partially or fully substituted with same or different R.sup.16, or two R.sup.8 present on the same carbon atom of an alkyl, alkenyl, alkynyl or cycloalkyl group together form a group ═O, ═C(R.sup.13).sub.2; ═S; ═S(O).sub.m(R.sup.15).sub.2, ═S(O).sub.mR.sup.15N(R.sup.14a)R.sup.14b, ═NR.sup.10a, ═NOR.sup.9; or ═NN(R.sup.10a)R.sup.10b; or two radicals R.sup.8, together with the carbon atoms of the alkyl, alkenyl, alkynyl or cycloalkyl group which they are bonded to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated or partially unsaturated carbocyclic or heterocyclic ring, which heterocyclic ring comprises 1, 2, 3 or 4 heteroatoms N, O, and/or S as ring members, and which ring is unsubstituted, or partially or fully substituted with same or different R.sup.16; and R.sup.8 as a substituent on a cycloalkyl ring may additionally be C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, and C.sub.2-C.sub.6-haloalkynyl, which groups are unsubstituted, or partially or fully substituted with same or different R.sup.13; and R.sup.8 in the groups C(═O)R.sup.8 and ═C(R.sup.8).sub.2 may additionally be H, halogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, or C.sub.2-C.sub.6-haloalkynyl, which groups are unsubstituted, or partially or fully substituted with same or different R.sup.13; each R.sup.9 is independently H, CN, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl-, C.sub.3-C.sub.8-halocycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, or C.sub.2-C.sub.6-haloalkynyl, which groups are unsubstituted, or partially or fully substituted with same or different R.sup.13, or C.sub.1-C.sub.6-alkyl-C(═O)OR.sup.15, C.sub.1-C.sub.6-alkyl-C(═O)N(R.sup.14a)R.sup.14b, C.sub.1-C.sub.6-alkyl-C(═S)N(R.sup.14a)R.sup.14b, C.sub.1-C.sub.6-alkyl-C(═NR.sup.14)N(R.sup.14a)R.sup.14b, Si(R.sup.12).sub.3, S(O).sub.nR.sup.15, S(O).sub.nN(R.sup.14a)R.sup.14b, N(R.sup.10a)R.sup.10b, N═C(R.sup.13).sub.2, C(═O)R.sup.13, C(═O)N(R.sup.14a)R.sup.14b, C(═S)N(R.sup.14a)R.sup.14b, C(═O)OR.sup.15, or phenyl, which is unsubstituted, or partially or fully substituted with R.sup.16; and a 3- to 7-membered saturated, partially or fully unsaturated heterocyclic ring comprising 1, 2 or 3 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different R.sup.16; and R.sup.9 in the groups S(O).sub.nR.sup.9 and OSO.sub.2R.sup.9 may additionally be C.sub.1-C.sub.6-alkoxy, or C.sub.1-C.sub.6-haloalkoxy; R.sup.10a, R.sup.10b are independently from one another H, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2—C.sub.6-alkynyl, C.sub.2-C.sub.6-haloalkynyl, which groups are unsubstituted, or partially or fully substituted with same or different R.sup.13; C.sub.1-C.sub.6-alkyl-C(═O)OR.sup.15, C.sub.1-C.sub.6-alkyl-C(═O)N(R.sup.14a)R.sup.14b, C.sub.1-C.sub.6-alkyl-C(═S)N(R.sup.14a)R.sup.14b, C.sub.1-C.sub.6-alkyl-C(═NR.sup.14)N(R.sup.14a)R.sup.14b, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-haloalkylthio, S(O).sub.nR.sup.15, S(O).sub.nN(R.sup.14a)R.sup.14b, C(═O)R.sup.13, C(═O)OR.sup.15, C(═O)N(R.sup.14a)R.sup.14b, C(═S)R.sup.13, C(═S)SR.sup.15, C(═S)N(R.sup.14a)R.sup.14b, C(═NR.sup.14)R.sup.13; phenyl, which is unsubstituted, or partially or fully substituted with same or different R.sup.16; and a 3-, 4-, 5-, 6- or 7-membered saturated, partially or fully unsaturated heterocyclic ring comprising 1, 2, 3 or 4 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different R.sup.16, preferably unsubstituted or substituted HET; or R.sup.10a and R.sup.10b together with the nitrogen atom they are bonded to form a 3- to 8-membered saturated, partially or fully unsaturated heterocyclic ring, which ring may additionally contain one or two heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different halogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-haloalkylthio, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.2-C.sub.6-haloalkynyl, phenyl which may be partially or fully substituted with R.sup.16, and a 3-, 4-, 5-, 6,- or 7-membered saturated, partially or fully unsaturated heterocyclic ring comprising 1, 2 or 3 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different R.sup.16; or R.sup.10a and R.sup.10b together form a group ═C(R.sup.13).sub.2, ═S(O).sub.m(R.sup.15).sub.2, ═S(O).sub.mR.sup.15N(R.sup.14a)R.sup.14b, ═NR.sup.14, or ═NOR.sup.15; R.sup.11 is halogen, CN, N.sub.3, NO.sub.2, SCN, SF.sub.5, C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkynyl, which groups are unsubstituted, partially or fully halogenated, and/or may be substituted with same or different R.sup.8, or OR.sup.9, NR.sup.10aR.sup.10b, S(O)nR9, Si(R.sup.12).sub.3; phenyl, which is unsubstituted, or partially or fully substituted with same or different R.sup.16; and a 3- to 7-membered saturated, partially or fully unsaturated aromatic heterocyclic ring comprising 1, 2, 3, or 4 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different R.sup.16; or two R.sup.11 present on the same ring carbon atom of an unsaturated or partially unsaturated heterocyclic ring may together form a group ═O, ═C(R.sup.13).sub.2, ═S, ═S(O).sub.m(R.sup.15).sub.2, ═S(O).sub.mR.sup.15N(R.sup.14a)R.sup.14b, ═NR.sup.14, ═NOR.sup.15, or ═NN(R.sup.14a)R.sup.14b; or two R.sup.11 bound on adjacent ring atoms form together with the ring atoms to which they are bound a saturated 3- to 9-membered ring, which ring may contain 1 or 2 heteroatoms O, S, N, and/or NR.sup.14, and/or 1 or 2 groups C═O, C═S, C═NR.sup.14 as ring members, and which ring is unsubstituted, or partially or fully substituted with same or different halogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-haloalkylthio, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.2-C.sub.6-haloalkynyl, phenyl which may be partially or fully substituted with same or different R.sup.16, and a 3- to 7-membered saturated, partially or fully unsaturated heterocyclic ring containing 1, 2, or 3 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different R.sup.16; each R.sup.12 is independently C.sub.1-C.sub.4-alkyl and phenyl, which is unsubstituted, or partially or fully substituted with same or different C.sub.1-C.sub.4-alkyl; each R.sup.13 is independently CN, NO.sub.2, OH, SH, SCN, SF.sub.5, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, SO.sub.n—C.sub.1-C.sub.6-alkyl, SO.sub.n—C.sub.1-C.sub.6-haloalkyl, Si(R.sup.12).sub.3, —C(═O)N(R.sup.14a)R.sup.14b, C.sub.3-C.sub.8-cycloalkyl which is unsubstituted, partially or fully halogenated or substituted with 1 or 2 same or different C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy and/or oxo; phenyl, benzyl, phenoxy, where the phenyl moiety may be substituted with one or more same or different R.sup.16; and a 3- to 7-membered saturated, partially or fully unsaturated heterocyclic ring containing 1, 2, or 3 heteroatoms N, O, and/or S, as ring members, which ring is unsubstituted, or partially or fully substituted with same or different R.sup.16; or two R.sup.13 present on the same carbon atom of an alkyl, alkenyl, alkynyl or cycloalkyl group may together be ═O, ═CH(C.sub.1-C.sub.4-alkyl), ═C(C.sub.1-C.sub.4-alkyl)C.sub.1-C.sub.4-alkyl, ═N(C.sub.1-C.sub.6-alkyl) or ═NO(C.sub.1-C.sub.6-alkyl); and R.sup.13 as a substituent of a cycloalkyl ring may additionally be C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl or C.sub.2-C.sub.6-alkynyl, which groups are unsubstituted, partially or fully halogenated, or substituted with 1 or 2 CN, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, and oxo; and R.sup.13 in groups ═C(R.sup.13).sub.2, N═C(R.sup.13).sub.2, C(═O)R.sup.13, C(═S)R.sup.13, and C(═NR.sup.14)R.sup.13 may additionally be H, halogen, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, or C.sub.2-C.sub.6-alkynyl, which groups are unsubstituted, partially or fully halogenated, or substituted with 1 or 2 CN, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, and oxo; each R.sup.14 is independently H, CN, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, SO.sub.n—C.sub.1-C.sub.6-alkyl, SO.sub.n—C.sub.1-C.sub.6-haloalkyl, Si(R.sup.12).sub.3; C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, which groups are unsubstituted, partially or fully halogenated, or substituted with 1 or 2 CN, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, SO.sub.n—C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl which is unsubstituted or substituted with 1 or 2 substituents halogen and CN; and oxo; C.sub.3-C.sub.8-cycloalkyl which is unsubstituted, or partially or fully halogenated or substituted with 1 or 2 CN, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, SO.sub.n—C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.4-cycloalkyl, C.sub.3-C.sub.4-cycloalkyl-C.sub.1-C.sub.4-alkyl-, which groups are unsubstituted, or substituted with 1 or 2 substituents selected from halogen and CN; phenyl, benzyl, pyridyl, phenoxy, which cyclic moieties are unsubstituted, or substituted with one or more same or different halogen, CN, NO.sub.2, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-haloalkylthio, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.2-C.sub.4-haloalkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halocycloalkyl, and C.sub.1-C.sub.6-alkoxycarbonyl; and a 3-, 4-, 5- or 6-membered saturated, partially or fully unsaturated heterocyclic ring comprising 1, 2 or 3 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different R.sup.16; R.sup.14a and R.sup.14b independently of each other, have one of the meanings given for R.sup.14; or R.sup.14a and R.sup.14b, together with the nitrogen atom to which they are bound, form a 3- to 7-membered saturated, partially, or fully unsaturated heterocyclic ring, wherein the ring may additionally contain 1 or 2 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, or C.sub.1-C.sub.4-haloalkoxy; or R.sup.14a and R.sup.14 or R.sup.14b and R.sup.14, together with the nitrogen atoms to which they are bound in the group C(═NR.sup.14)N(R.sup.14a)R.sup.14b, form a 3- to 7-membered partially, or fully unsaturated heterocyclic ring, wherein the ring may additionally contain 1 or 2 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different halogen, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, or C.sub.1-C.sub.4-haloalkoxy; each R.sup.15 is independently H, CN, Si(R.sup.12).sub.3 C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, which groups are unsubstituted, partially or fully halogenated, or substituted with 1 or 2 radicals C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, SO.sub.n—C.sub.1-C.sub.6-alkyl, or oxo; C.sub.3-C.sub.8-cycloalkyl which is unsubstituted, partially or fully halogenated or substituted with 1 or 2 radicals C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, SO.sub.n—C.sub.1-C.sub.6-alkyl, or oxo; phenyl, benzyl, pyridyl, and phenoxy, which rings are unsubstituted, partially or fully halogenated, or substituted with 1, 2 or 3 substituents C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, or (C.sub.1-C.sub.6-alkoxy)carbonyl; each R.sup.16 is independently halogen, NO.sub.2, CN, OH, SH, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, SO.sub.n—C.sub.1-C.sub.6-alkyl, SO.sub.n—C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.4-alkylcarbonyl, C.sub.1-C.sub.4-haloalkylcarbonyl, C.sub.1-C.sub.4-alkoxycarbonyl, C.sub.1-C.sub.4-haloalkoxycarbonyl, aminocarbonyl, C.sub.1-C.sub.4-alkylaminocarbonyl, di-(C.sub.1-C.sub.4-alkyl)-aminocarbonyl, Si(R.sup.12).sub.3; C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, which groups are unsubstituted, partially or fully halogenated, or substituted with 1 or 2 radicals CN, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, or oxo; C.sub.3-C.sub.8-cycloalkyl which is unsubstituted, partially or fully halogenated or substituted with 1 or 2 radicals CN, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, or oxo; phenyl, benzyl, pyridyl and phenoxy, which rings are unsubstituted, partially or fully halogenated, or substituted with 1, 2 or 3 substituents C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, or (C.sub.1-C.sub.6-alkoxy)carbonyl; or two R.sup.16 present together on the same atom of an unsaturated or partially unsaturated ring may be ═O, ═S, ═N(C.sub.1-C.sub.6-alkyl), ═NO—C.sub.1-C.sub.6-alkyl, ═CH(C.sub.1-C.sub.4-alkyl), or ═C(C.sub.1-C.sub.4-alkyl).sub.2; or two R.sup.16 on two adjacent carbon atoms form together with the carbon atoms they are bonded to a 4- to 8-membered saturated, partially or fully unsaturated ring, wherein the ring may contain 1 or 2 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, or C.sub.1-C.sub.4-haloalkoxy; each n is independently 0, 1, or 2; and each m is independently 0, or 1; wherein the shown enantiomer has at least 50% ee; by condensation of a ketone of formula II with an acetyl compound of formula III, ##STR00046## wherein the variables have the meanings given for formula I, in the presence of a catalyst of formula IV ##STR00047## wherein the variables have following meanings: in case IVa: R.sup.91a to R.sup.91e are independently from one another selected from H, CN, NO.sub.2, and C.sub.1-C.sub.6-alkoxycarbonyl; R.sup.92 and R.sup.93 together with the carbon atoms they are bound to form a cyclohexyl ring; R.sup.94a, R.sup.94b are selected from C.sub.1-C.sub.3-alkyl; in case IVb: R.sup.91a to R.sup.91e are independently from one another selected from H, CN, NO.sub.2, and C.sub.1-C.sub.6-alkoxycarbonyl; R.sup.92 is selected from 6-methoxy-4-quinolyl, and 4-quinolyl; R.sup.93, R.sup.94a and R.sup.94b together with the bridging nitrogen atom form a bridged ring system containing 5 to 10 ring members which is unsubstituted or substituted with one or more halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-haloalkyl, or C.sub.2-C.sub.4-alkenyl, wherein two substitutents bound to the same C-atom may form a ═CH.sub.2 group.

2. The process according to claim 1, which further comprises reacting I with hydroxylamine VII
NH.sub.2—OH  VI or its salt, to yield a Z-oxime of formula VI ##STR00048##

3. The process according to claim 2, wherein the solvent comprises predominantly of pyridine, 2,6-lutidine, 2,3-lutidine, 2,5-lutidine, or 2-methyl pyridine, neat or as mixture with one another.

4. The process according to claim 2, which further comprises cyclisation of formula VI compounds under basic conditions to yield a compound of formula Va ##STR00049##

5. The process according to claim 4, which further comprises reacting Va wherein A is COOR.sup.9 with an amine HNR.sup.5R.sup.6 to yield a compound V wherein A is C(═O)NR.sup.5R.sup.6.

6. The process according to claim 5, wherein the compound of formula V is compound V.2 ##STR00050##

7. The process according to claim 1, wherein the catalyst of formula IV is compound IVa-1 ##STR00051##

8. The process according to claim 1, wherein the catalyst of formula IV is compound IVb-1 ##STR00052##

9. The process according to claim 1, wherein the catalyst of formula IV is selected from compound IVb-2, IVb-3, and IVb-4 ##STR00053##

10. The process according to claim 1, wherein the phenyl ring in formula I and II, bearing the R.sup.2.sub.n substitution is preferably a group P ##STR00054## wherein R.sup.2a is F, Cl, Br, CF.sub.3, or OCF.sub.3, and R.sup.2b and R.sup.2c are H, or as defined for R.sup.2a.

11. The process according to claim 1, wherein G.sup.1 is C—CH.sub.3, or C—Cl, and G.sup.2 is CH.

12. The process according to claim 1, wherein in formulae I and III, is COOR.sup.9, wherein R.sup.9 is C.sub.1-C.sub.4-alkyl.

13. The process according to claim 1, wherein the catalyst of formula IV is applied in 0.01 to 0.5 mol equivalents of compound II.

14. A Z-oxime of formula VI which corresponds to formula Via ##STR00055## wherein R.sup.1 is CF.sub.3; R.sup.2a is F, Cl, Br, CF.sub.3, or OCF.sub.3; R.sup.2b and R.sup.2c are independently from each other FI, F, Cl, Br, CF.sub.3, or OCF.sub.3; A is A.sup.1, A.sup.2, or A.sup.3; wherein A.sup.1 is C(═O)N(R.sup.5)R.sup.6, C(═O)OR.sup.9, wherein A.sup.2 is ##STR00056## wherein # denotes the bond of group A, and % denotes the bond to G.sup.1; Q-Z is %-CH.sub.2—O—*, wherein % marks the bond of Q to phenyl, and * the bond of Z to azetidin; and R.sup.A4 is H, or C(═O)R.sup.4A, wherein R.sup.4A is H, C.sub.1-C.sub.4-alkylcarbonyl, which is unsubstituted or substituted with S(O).sub.n—C.sub.1-C.sub.6-alkyl; A.sup.3 is CH.sub.2—NR.sup.5C(═O)R.sup.6; G.sup.1, and G.sup.2 are each CR.sup.3, or together form a sulfur atom; R.sup.3 is H or C.sub.1-C.sub.4-alkyl, or two R.sup.3 bonded to adjacent carbon atoms may form a five- or six-membered saturated or aromatic carbocyclic ring, or a dihydrofurane, or R.sup.3 bonded to a carbon atom in position G.sup.1 form a bond to the chain *-Q-Z— in group A.sup.2; R.sup.5 is H; R.sup.6 is H, or C.sub.1-C.sub.6-alkyl which is unsubstituted, or substituted with one or two R.sup.8; or R.sup.5 and R.sup.6, together with the nitrogen atom to which they are bound, form a 5- or 6-membered saturated, heterocyclic ring, which ring contain 1 or 2 groups selected from O, S, N, and C═O as ring members, which heterocyclic ring is unsubstituted or partially substituted with same or different C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-haloalkylthio, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.2-C.sub.6-haloalkynyl; each R.sup.8 is C(═O)N(R.sup.10a)R.sup.10b, or two R.sup.8 present on the same carbon atom of an alkyl group together form ═NOR.sup.9; R.sup.9 being C.sub.1-C.sub.4-alkyl; R.sup.10a, R.sup.10b are independently from one another H, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.2-C.sub.6-haloalkynyl.

15. A compound of formula VI according to claim 14 wherein R.sup.1 is CF.sub.3, R.sup.2 is as defined in claim 14, G.sup.1 is C—CH.sub.3 or C—Cl, G.sup.2 is CH, or G.sup.1 and G.sup.2 are both C—R.sup.3, wherein two R.sup.3 bonded to adjacent carbon atoms form a five- or six-membered saturated carbocyclic ring or a dihydrofurane, and A is C(═O)Y, wherein Y is NHCH.sub.3, or C.sub.1-C.sub.4-alkoxy.

Description

A. PREPARATION EXAMPLES

[0232] With appropriate modification of the starting materials, the procedures given in the synthesis description were used to obtain further compounds I. The compounds obtained in this manner are listed in the table that follows, together with physical data.

[0233] The products shown below were characterized by melting point determination, by NMR spectroscopy or by the masses ([m/z]) or retention time (RT; [min.]) determined by HPLC-MS or HPLC spectrometry.

[0234] HPLC-MS=high performance liquid chromatography-coupled mass spectrometry;

[0235] HPLC method A: HPLC method: Phenomenex Kinetex 1.7 μm XB—C18 100A; 50×2.1 mm; mobile phase: A: water+0.1% trifluoroacetic acid (TFA); B: acetonitrile; gradient: 5-100% B in 1.50 minutes; 100% B 0.25 min; flow: 0.8-1.0 ml/min in 1.51 minutes at 60° C. MS: ESI positive, m/z 100-1400.

[0236] HPLC method B: HPLC Phenomenex Kinetex 1.7 μm XB—C18 100A, 50×2.1 mm″, Mobile Phase: A: water+0.1% TFA; B:Acetonitrile; Temperature: 60° C.; Gradient: 5% B to 100% B in 1.50 min; 100% B 0.25 min; Flow: 0.8 ml/min to 1.0 ml/min in 1.51 min; MS method: ESI positive; Mass range (m/z): 100-700″.

[0237] HPLC method C: Daicel Chiralpak AD-RH 5 μm 150×4.6 mm, mobile phase A: water+0.1% v/v H.sub.3PO.sub.4, B: acetonitrile/2-propanol (1:1) Temperature 50° C., Gradient: 50% B 0 min, 50% B 10 min, 70% B 25 min, 100% B 30 min100% B 35 min, 50% B 35.5 min, total runtime 40 min; flow 1.2 mL/min. UV-detector lambda=216 nm; BW 4 nm; pressure 130 bar.

Example 1: Preparation of S-fluralaner

Step 1: preparation of methyl 4-[(3S)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxy-butanoyl]-2-methyl-benzoate

[0238] To a solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoro-ethanone (preparation known from WO 2010125130, 13.15 g, 54.11 mmol, 1.30 equiv.) in toluene (70 mL) was added R,R-TUC (344 mg, 0.832 mmol, 0.02 equiv.) and methyl 4-acetyl-2-methyl-benzoate (cf. WO 2013/025425, 8.00 g, 41.6 mmol, 1.00 equiv.) and the mixture was stirred at 20 to 25° C. overnight. After completed reaction, all volatiles were removed under reduced pressure and the residue was taken up in petrol ether at 45° C. After 1 h at 20 to 25° C., the precipitate was removed by filtration which contained the racemate of the title compound (5.4 g). The mother liquid was concentrated in vacuum and purified via flash chromatography on silica gel to yield 11.3 g of the title compound (enantiomeric ratio 99.7:0.3).

[0239] .sup.1H NMR: (400 MHz, CDCl.sub.3): δ 2.66 (s, 3H), 3.69 (d, 1H), 3.88 (d, 1H), 3.94 (s, 3H), 5.63 (s, 1H), 7.35 (m, 1H), 7.51 (s, 2H), 7.79 (m, 2H), 8.00 (m, 1H) ppm.

[0240] Racemate: HPLC Method C: Rt=8.032 min and 8.708 min

[0241] Title compound S-isomer: HPLC Method C: Rt=8.094 min

Step 2: preparation of methyl 4-[(Z)—C-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxy-propyl]-N-hydroxy-carbonimidoyl]-2-methyl-benzoate

[0242] To a mixture of methyl 4-[(3S)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxy-butanoyl]-2-methyl-benzoate (54.4 g, 125 mmol, 1.00 equiv.) and 2,6-lutidine (300 mL) was added solid hydroxylamine hydrochloride (69.49 g, 250 mmol, 2.00 equiv) in several portions at 20 to 25° C. After stirring overnight, the reaction mixture was poured on ice-water (1 L) and extracted with dichloromethane. Combined organic layers were washed with aqueous hydrochloric acid (6N) and water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was triturated with TBME to remove residual lutidine hydrochloride. The filtrate was concentrated and filtered through a plug of silica gel to obtain 46.7 g of the title compound (83% yield).

[0243] .sup.1H NMR: (400 MHz, Acetone-d.sub.6): δ 2.49 (s, 3H), 3.39 (d, 1H), 3.70 (d, 1H), 3.88 (s, 3H), 6.04 (s, 1H), 7.10 (s, 1H), 7.15 (d, 1H), 7.36 (s, 1H), 7.48 (s, 2H), 7.76 (d, 1H), 10.38 (s, 1H) ppm.

Step 3: preparation of methyl 4-[(5S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoate

[0244] To a suspension of methyl 4-[(Z)—C-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxy-propyl]-N-hydroxy-carbonimidoyl]-2-methyl-benzoate (5.90 g, 13.1 mmol, 1.00 equiv.) in toluene (30 mL) was added a solution of lithium bis(trimethylsilyl)amide (LiHMDS; 15.7 mL of a 1 M solution in THF, 15.7 mmol, 1.2 equiv.) at 0° C. After 30 min at this temperature, methane sulfonylchloride (3.75 g, 32.8 mmol, 2.5 equiv.) was added slowly and the mixture was allowed to reach 20 to 25° C. After completion of the reaction, water and TBME were added under ice-cooling. The layers were separated, and the organic layer was washed with 1N HCl and water. After drying over Na.sub.2SO.sub.4, the solids were removed by filtration and the filtrate was concentrated in vacuum. The obtained residue was purified via silica gel chromatography to yield 4.20 g of the title compound (74% yield).

[0245] .sup.1H NMR: (400 MHz, CDCl.sub.3): δ 2.62 (s, 3H), 3.73 (d, 1H), 3.93 (s, 3H), 4.11 (d, 1H), 7.45 (s, 1H), 7.51-7.58 (m, 3H), 7.96 (d, 1H) ppm.

[0246] Racemate: HPLC Method C: Rt=9.544 min and 10.309 min

[0247] Title compound S-isomer: HPLC Method C: Rt=9.540 min

Step 4: preparation of 4-[(5S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid

[0248] To a solution of methyl 4-[(5S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoate (21.90 g, 50.67 mmol, 1.00 equiv.) in THF (100 mL) was added an aqueous solution of LiOH (101 mL of a 2 M solution, 101 mmol, 2.0 equiv.) and the mixture was stirred at 40° C. overnight. After complete conversion, the mixture was cooled and aqueous hydrochloric acid (2N) was added to acidify. After extraction with ethyl acetate, the combined organic layers were washed with brine and dried over Na.sub.2SO.sub.4. After filtration and removal of the solvents under reduced pressure, 21.1 g of the title compound (100%) were obtained and used in the next step without purification.

[0249] .sup.1H NMR: (400 MHz, CDCl.sub.3): δ 2.69 (s, 3H), 3.73 (d, 1H), 4.12 (d, 1H), 7.44 (s, 1H), 7.52 (s, 2H), 7.65 (m, 2H), 8.12 (d, 1H) ppm.

Step 5: preparation of 4-[(5S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]benzamide (S-fluralaner)

[0250] To a mixture of 4-[(5S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid (200 mg, 478 mmol, 1.00 equiv.), [2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]ammonium chloride (111 mg, 574 mmol, 1.20 equiv.) and bromotripyrrolidinophosphonium hexafluoro-phosphate (PyBroP®; 267 mg, 574 mmol, 1.00 equiv.) in dichloromethane (10 mL) was added diisopropylethylamine (0.34 mL, 0.26 g, 2.0 mmol, 4.2 euqiv.) at 0-5° C. and the mixture was allowed to reach 20 to 25° C. After completion of the reaction, all volatiles were removed in vacuum and the residue was taken up in ethyl acetate. This solution was washed with 2N HCLI and water before being dried over Na.sub.2SO.sub.4. After filtration, the solvents were removed in vacuum and the residue was purified via flash chromatography on silica gel to obtain 154 mg S-fluralaner (55%) as a colorless solid.

[0251] LC-MS: Mass calculated for C.sub.22H.sub.17Cl.sub.2F.sub.6N.sub.3O.sub.3.sup.+ [(M+H).sup.+)] 556.3, found 556.1; RT=1.311 min (Method A).

[0252] .sup.1H NMR: (400 MHz, CDCl.sub.3): δ 2.49 (s, 3H), 3.73 (d, 1H), 3.95 (m, 2H), 4.09 (d, 1H), 4.21 (d, 2H), 6.68 (m, 1H), 6.86 (m, 1H), 7.39-7.61 (m, 6H) ppm.

Example 2: Preparation of S-isocycloseram

Step 1: preparation of methyl 4-[(3S)-3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxy-butanoyl]-2-methyl-benzoate

[0253] The reaction was performed analogously to Example 1, step 1. Crystallization of the crude mixture from petrol ether gave the title compound in the mother liquor with enantiomeric ratio (S:R) of 98:2 in isolated yield of 61%.

[0254] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=2.67 (s, 3H), 3.71 (d, 1H), 3.85 (d, 1H), 3.96 (s, 3H), 5.69 (s, 1H), 7.58 (d, 2H), 7.78 (m, 2H), 8.00 (d, 1H)

Step 2: preparation of methyl 4-[(Z)—C-[(2S)-2-(3,5-dichloro-4-fluoro-phenyl)-3,3,3-trifluoro-2-hydroxy-propyl]-N-hydroxy-carbonimidoyl]-2-methyl-benzoate

[0255] To a 2 L four necked flask with propeller stirring, 2,6-lutidine (1250 mL) and hydroxylammonium chloride (69.00 g, 3 equiv.) were added. After 1 h at 20-25° C., methyl 4-[(3S)-3-(3,5-di-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxy-butanoyl]-2-methyl-benzoate (150 g, 1 equiv.) in 2,6-luditine (250 mL) were added. After the starting material was consumed, the reaction mixture was added to ice water (1.5 L) and ethyl acetate (1 L) and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2×500 mL) and combined organic layers were washed with ice-cold 6N HCl (1.7 L). After washing with water (2×1.5 L), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The resulting residue was triturated with n-pentane (150 mL) to yield the title compound (154 g, 99%).

[0256] .sup.1H-NMR (400 MHz, acetone-d.sub.6): δ=2.49 (s, 3H), 3.36 (d, 1H), 3.71 (d, 1H), 3.87 (s, 3H), 6.10 (s, 1H), 7.09 (s, 1H), 7.16 (d, 1H), 7.56 (d, 2H), 7.77 (d, 1H), 10.36 (s, 1H).

Step 3: preparation of methyl 4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoate

[0257] To a solution of methyl 4-[(Z)—C-[(2S)-2-(3,5-dichloro-4-fluoro-phenyl)-3,3,3-trifluoro-2-hydroxy-propyl]-N-hydroxy-carbonimidoyl]-2-methyl-benzoate (120.6 g, 1.0 equiv.) in THF (600 mL) was added a solution of LiHMDS (566 mL of a 1M solution in THF, 2.2 equiv.) at −5° C. After 30 min at that temperature, a solution of mesyl chloride (42.3 mL, 62.5 g, 2.12 equiv. in 100 mL THF) was added slowly, whereupon the temperature rose to 0° C. After 2 h at 0° C., the cooling bath was removed, and the mixture was stirred at 20-25° C. overnight. Water (200 mL) and 2N HCl (200 mL) were added at 0-5° C., and the volatiles were removed in vacuum. The remaining aqueous mixture was extracted with ethyl acetate. Combined organic layers were washed with water and dried over Na.sub.2SO.sub.4. After removal of the solvents, the residue was purified via flash chromatography on silica gel to yield the title compound (90.0 g, 78%).

[0258] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=2.63 (s, 3H), 3.69 (d, 1H), 3.89 (s, 3H), 4.11 (d, 1H), 7.52 (m, 2H), 7.60 (m, 2H), 7.96 (d, 1H)

Step 4: preparation of 4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid

[0259] To a solution of methyl 4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoate (150 g, 333 mmol, 1.00 equiv.) in THF (1500 mL) was added aq. 1M LiOH (666 mL) at 20-25° C. The reaction mixture was stirred at 40° C. over night, cooled to 0° C. and 2M HCl was added until pH 1 was reached. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×500 mL). Combined organic layers were washed with brine and dried over Na.sub.2SO.sub.4. Removal of the solvents in vacuum yielded the title compound (145 g, 100%).

[0260] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=2.71 (s, 3H), 3.72 (d, 1H), 4.11 (d, 1H), 7.54-7.63 (m, 4H), 8.10 (m, 1H).

Step 5: preparation of 4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoyl chloride

[0261] To a solution of 4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid (160 g, 366 mmol, 1.00 equiv.) in dichloromethane (1700 mL) was added DMF (1 mL), followed by oxalyl chloride (94 mL, 1.10 mol, 3 equiv.) in dichloromethane (300 mL) at 20-25° C. within 3 h. After completion of the reaction, all volatiles were removed in vacuum to yield the title compound (166 g, 100%).

[0262] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=2.60 (s, 3H), 3.71 (d, 1H), 4.11 (d, 1H), 7.54-7.70 (m, 4H), 8.27 (m, 1H).

Step 6: preparation of 4-[(5S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]benzamide (S-isocycloseram)

[0263] A suspension of [(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]ammoniumchloride (67.12 g, 403.3 mmol (1.100 equiv.) in THF (1500 mL) was added DMAP (2.24 g, 0.018 mol, 0.05 equiv.), followed by diisopropyl ethylamine (251 mL, 1.83 mol, 5 equiv.) at 0-5° C. within 60 min. After 30 min at 0-5° C., a solution of 4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoyl chloride (166 g, 366 mmol, 1.00 equiv.) in THF (400 mL) was added at 0°−5° C. within 120 min. The cooling bath was removed, and the mixture was stirred overnight whereupon the product has formed and no starting material could be observed. To this mixture, 2M HCl was added until pH 1 was reached. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×). Combined organic layers were washed with water and brine, then dried over Na.sub.2SO.sub.4. After removal of the solvents, the residue was triturated with diisopropyl ether to yield the title compound (166.6 g, 83%) as a colorless solid (mp. 141° C.).

[0264] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=1.25 (t, 3H), 2.49 (s, 3H), 3.56-3.77 (m, 3H), 4.01-4.12 (m, 2H), 4.85 (m, 1H), 4.99 (m, 1H), 6.47 (m, 1H), 7.46-7.62 (m, 5H).

Example 3: Preparation of S-sarolaner

Step 1: Synthesis of (3S)-3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxy-1-[1′-(2-me-thylsulfonylacetyl)spiro[3H-isobenzofuran-1,3′-azetidine]-5-yl]butan-1-one

[0265] The reaction was performed analogously to Example 1, step 1. Crystallization of the crude mixture from petrol ether gave the title compound in the mother liquor with enantiomeric ratio of 99:1.

[0266] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=3.20 (s, 3H), 3.71 (d, 1H), 3.82 (d, 1H), 3.85 (s, 2H), 4.36 (d, 1H), 4.47 (d, 1H), 5.19 (s, 1H), 5.70 (d, 1H), 7.55 (d, 2H), 7.70 (d, 1H), 7.79 (s, 1H), 8.00 (d, 1H).

Step 2: Synthesis of 1-[6-[(Z)—C-[(2S)-2-(3,5-dichloro-4-fluoro-phenyl)-3,3,3-trifluoro-2-hydroxy-propyl]-N-hydroxy-carbonimidoyl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methylsulfonyl-ethanone

[0267] To a mixture of hydroxylamine hydrochloride (95 mg) and 2,6-lutidine (10 mL) was added a solution of 3S)-3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxy-1-[1′-(2-methylsulfonylacetyl)spiro[3H-isobenzofuran-1,3′-azetidine]-5-yl]butan-1-one (160 mg) in 2,6-lutidine (5 mL). After the starting material was consumed, the reaction mixture was added to ethyl acetate and washed with 1M HCl (3×), water (2×), before the organic layer was dried over Na.sub.2SO.sub.4. After removal of all volatiles in vacuum the title compound (160 mg) was obtained as a colorless solid. that was used in the next stage without further purification.

Step 3: Synthesis of 1-[6-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methylsulfonyl-ethanone (S-sarolaner)

[0268] To a solution of 1-[6-[(Z)—C-[(2S)-2-(3,5-dichloro-4-fluoro-phenyl)-3,3,3-trifluoro-2-hydroxy-propyl]-N-hydroxy-carbonimidoyl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methylsulfonyl-ethanone (160 mg, 267 mmol) in THF (10 mL) was added LiHMDS (0.59 mL of a 1 M solution, 587 mmol, 2.2 equiv.) at 0° C. The mixture was stirred at 0° C. for 60 min, then mesyl chloride (61 mg, 534 mmol, 2.0 equiv.) was added drop wise. The mixture was allowed to reach 20-25° C. and stirred for 12 h. TLC showed completion of the reaction, and ethyl acetate and aqueous NH.sub.4Cl solution were added. The layers were separated and the organic layer was washed with water (3×). After removal of the solvents, the residue was purified via flash chromatography on silica gel to obtain the title compound (101 mg, 65%).

[0269] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=3.13 (s, 3H), 4.19-4.24 (m, 4H), 4.30-4.42 (m, 2H), 4.59 (s, 2H), 5.17 (s, 2H), 7.64-7.83 (m, 5H).

Example 4: Preparation of 4-[(5S)-5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]naphthalene-1-carboxamide (S-afoxolaner)

Step 1: Preparation of methyl 4-[(3S)-3-[3-chloro-5-(trifluoromethyl)phenyl]-4,4,4-trifluoro-3-hydroxy-butanoyl]naphthalene-1-carboxylate

[0270] The reaction was performed analogously to Example 1, step 1. Crystallization of the crude mixture from petrol ether gave the title compound in the mother liquor with enantiomeric ratio of 96:4.

[0271] The subsequent steps 2 to 5 were performed in analogy to Example 3.

[0272] .sup.1H-NMR of 4-[(5S)-5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]naphthalene-1-carboxamide (S-afoxolaner) (500 MHz, CDCl.sub.3): δ=3.85-3.99 (m, 3H), 4.23-4.36 (m, 3H), 7.29-7.64 (m, 6H), 7.71 (s, 1H), 7.83 (s, 1H), 7.89 (s, 1H), 8.20 (m, 1H), 8.81 (m, 1H).