The invention relates to a process for the preparation of optically enriched isoxazoline compounds of formula I wherein

R ¹ is halomethyl;

R ^2a is F, Cl, Br, or OCF ₃ , and

R ^2b and R ^2c are H, or as defined for R ^2a ;

G ¹ , G ² are each CR ³ ; each R ³ is independently selected from the meanings mentioned for R ⁴ or is C(=0)R ⁸ , or two R ³ bonded to adjacent carbon atoms may form a five- or sixmembered saturated, partially or fully unsaturated carbocyclic ring, or a dihydrofurane;

R ⁴ H, halogen, CN, N ₃ , NO2, SCN, SF ₅ , CrCe-alkyl, C ₃ -C ₈ -cycloalkyl, C2-Ce-alkenyl, C2- Ce-alkynyl, OR ⁹ , or S(0) _n R ⁹ ;

W is O or S;

R ⁵ is independently selected from the meanings mentioned for R ⁴ ;

R ⁶ is H, Ci-Cio-alkyl, GrCs-cycloalkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, which groups are unsubstituted, partially or fully halogenated and/or substituted with one or more same or different R ⁸ ; or CrC4-alkoxy, S(0) _n R ⁹ , or C(=0)R 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=0 and/or C=S as ring members, which heterocyclic ring is unsubstituted or partially or fully substituted with same or different halogen, CN, CrC ₆ -alkyl, CrC ₆ -haloalkyl, CrC ₆ -alkoxy, CrC ₆ -haloalkoxy, Ci-C ₆ -alkylthio, CrC ₆ -haloalkylthio, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -halocycloalkyl, C2-C6-alkenyl, C2-C6-halo- alkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, which groups are unsubstituted, or partially or fully substituted with same or different R ⁸ , or phenyl which may be partially or fully substituted with R ¹¹ ; each R ⁸ is independently CN, N ₃ , NO2, SCN, SF ₅ , C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -halocycloalkyl; Si(R ¹² ) ₃ , OR ⁹ , OSO2R ⁹ , S(0) _n R ⁹ , N(R ^10a )R ^10b , C(=O)N(R ^10a )R ^10b , C(=S)N(R ^10a )R ^10b , C(=0)0R ⁹ , CH=NOR ⁹ , phenyl, 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, or two R ⁸ present on the same carbon atom of an alkyl, alkenyl, alkynyl or cycloalkyl group together form a group =0, =C(R ¹³ ) ₂ ; =S; =S(0) _m (R ¹⁵ ) ₂ , =S(0) _m R ¹⁵ N(R ^14a )R ^14b , =NR ^10a , =NOR ⁹ ; or =NN(R ^10a )R ^10b ; or two radicals R 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 R ⁸ as a substituent on a cycloalkyl ring may additionally be CrC ₆ -alkyl, CrC ₆ -haloalkyl, C2-C6- alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, and C2-C6-haloalkynyl; and R ⁸ in the groups C(=0)R ⁸ and =C(R ⁸ )2 may additionally be H, halogen, CrC ₆ -alkyl, CrC ₆ -halo- alkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, or C2-C6-haloalkynyl; each R ⁹ is independently H, CrC ₆ -alkyl, or CrC ₆ -haloalkyl;

R ⁱ ° ^{a i} o ^b _are independently from one another H, CrC ₆ -alkyl, CrC ₆ -haloalkyl, C ₃ -C ₈ -cycloal- kyl, C3-C8-halocycloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalky- nyl;

Ci-C ₆ -alkyl-C(=0)0R ¹⁵ , CrC ₆ -alkyl-C(=0)N(R ^14a )R ^14b , CrC ₆ -alkyl-C(=S)N(R ^14a )R ^14b , Ci-C ₆ -alkyl-C(=NR ¹⁴ )N(R ^14a )R ^14b , CrCe-alkoxy, CrCe-haloalkoxy, CrCe-alkylthio, CrCe- haloalkylthio, S(0) _n R ¹⁵ , S(0) _n N(R ^14a )R ^14b , C(=0)R ¹³ , C(=0)OR ¹⁵ , C(=0)N(R ^14a )R ^14b , C(=S)R ¹³ , C(=S)SR ¹⁵ , C(=S)N(R ^14a )R ^14b , C(=NR ¹⁴ )R ¹³ ; phenyl; 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, preferably hetaryl; or R ^10a and R ^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; or _R ⁱ ° ^a _{and R} ⁱ o ^b together form a group =C(R ¹³ ) ₂ , =S(0) _m (R ¹⁵ ) ₂ , =S(0) _m R ¹⁵ N(R ^14a )R ^14b , =NR ¹⁴ , or =NOR ¹⁵ ;

R ^{1 1} is halogen, CN, N ₃ , NO ₂ , SCN, SF ₅ , Ci-Cio-alkyl, C ₃ -C8-cycloalkyl, C ₂ -Cio-alkenyl, C ₂ -C ₁₀ - alkynyl, or

OR ⁹ , NR ^10a R ^10b , S(0) _n R ⁹ , Si(R ¹² ) ₃ ; phenyl; 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; or two R ¹¹ present on the same ring carbon atom of an unsaturated or partially unsaturated heterocyclic ring may together form a group =0, =C(R ¹³ )2, =S, =S(0) _m (R ¹⁵ ) ₂ , =S(0)mR ¹⁵ N(R ^14a )R ^14b , =NR ¹⁴ , =NOR ¹⁵ , or =NN(R ^14a )R ^14b ; or two R 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 ¹⁴ , and/or 1 or 2 groups C=0, C=S, C=NR ¹⁴ as ring members; each R ¹² is independently CrC4-alkyl and phenyl; each R ¹³ is independently CN, NO2, OH, SH, SCN, SF ₅ , CrC ₆ -alkoxy, CrC ₆ -haloalkoxy, SO _n - CrCe-alkyl, SOn-CrCe-haloalkyl, Si(R ¹² ) ₃ , C(=0)N(R ^14a )R ^14b ,

OrCs-cycloalkyl; 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; or two R ¹³ present on the same carbon atom of an alkyl, alkenyl, alkynyl or cycloalkyl group may together be =0, =CH(Ci-C4-alkyl), =C(Ci-C4-alkyl)CrC4-alkyl, =N(CrC ₆ -alkyl) or =NO(Ci- C ₆ -alkyl); and

R ¹³ as a substituent of a cycloalkyl ring may additionally be CrC ₆ -alkyl, C2-C6-alkenyl or C2-C6- alkynyl, which groups are unsubstituted, partially or fully halogenated, or substituted with 1 or 2 CN, C ₃ -C4-cycloalkyl, CrC4-alkoxy, CrC4-haloalkoxy, and oxo; and R ¹³ in groups =C(R ¹³ )2, N=C(R ¹³ )2, C(=0)R ¹³ , C(=S)R ¹³ , and C(=NR ¹⁴ )R ¹³ may additionally be H, halogen, CrC ₆ -alkyl, C2-C6-alkenyl, or C2-C6-alkynyl, and oxo; each R ¹⁴ is independently H, CN, CrC ₆ -alkoxy, CrC ₆ -haloalkoxy, SO _n -CrC ₆ -alkyl, SO _n -Cr C ₆ -haloalkyl, Si(R ¹² ) ₃ ; CrC ₆ -alkyl, C2-C6-alkenyl, C2-C6-alkynyl; and oxo;

C ₃ -C ₈ -cycloalkyl; phenyl, benzyl, pyridyl, phenoxy; 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;

R ^14a and R ^14b independently of each other, have one of the meanings given for R ¹⁴ ; or R ^14a and R ^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; or R ^14a and R ¹⁴ or R ^14b and R ¹⁴ , together with the nitrogen atoms to which they are bound in the group C(=NR ¹⁴ )N(R ^14a )R ^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; each R ¹⁵ is independently H, CN, Si(R ¹² )3, Ci-C ₆ -alkyl, C2-C6-alkenyl, C2-C6-alkynyl; C3-C8- cycloalkyl; phenyl, benzyl, pyridyl, and phenoxy; each R ¹⁶ is independently halogen, NO2, CN, OH, SH, Ci-C ₆ -alkoxy, Ci-C ₆ -haloalkoxy, SO _n - Ci-C ₆ -alkyl, SO _n -Ci-C ₆ -haloalkyl, Ci-C4-alkylcarbonyl, Ci-C4-haloalkylcarbonyl, C1-C4- alkoxycarbonyl, Ci-C4-haloalkoxycarbonyl, aminocarbonyl, Ci-C4-alkylaminocarbonyl, di- (Ci-C4-alkyl)-aminocarbonyl, Si(R ¹² )3; CrCe-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl; C3-C8- cycloalkyl; or two R ¹⁶ present together on the same atom of an unsaturated or partially unsaturated ring may be =0, =S, =N(Ci-C ₆ -alkyl), =NO-Ci-C ₆ -alkyl, =CH(Ci-C4-alkyl), or =C(Ci-C ₄ -alkyl) ₂ ; or two R 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; each n is independently 0, 1 , or 2; and each m is independently 0, or 1 ; wherein the shown enantiomer has at least 75% ee; by oxo-Michael addition of hydroxyl amine or its salt to an enone of formula II, wherein the variables have the meanings given for formula I, in the presence of a catalyst of formula III wherein X is a counteranion, and R ^a ,R ^b are independently from each other halogen, CN, Ci-C3-alkyl, Ci-C3-alkoxy, Ci-C3-alkylthio, phenyl, benzyl, and phenoxy; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; and a base. The isoxazoline active compounds I and their pesticidal activity are generally known from W02007/105814.

W02009/063910 describes asymmetric syntheses of some isooxazoline compounds of for mula I by using cinchona alkaloid-based phase-transfer catalysts. The processes require rela tively high catalyst loadings and yield enantiomeric excesses of formula I compounds which still leave room for improvement.

Objective task for the invention therefore is providing an economical, industrially applicable manufacturing process for optically enriched compounds of formula I. This task is achieved by the process defined in the outset. The presence of a catalyst III as defined herein in the reaction of compound II ensures a quick and effective transformation at moderate temperatures.

The formula III catalysts are known from Eur. J. Org. Chem. 2002, 2087-2093.

In the invention this catalyst is used in asymmetric oxa-Michael addition of hydroxyl amine with an enone to enantioselectively form a C-0 bond. The process yields formula I compounds in good yield with at least 75% ee by using low catalyst loadings.

The reaction of an enone of formula II, wherein the variables have the meanings given in the outset, with hydroxyl amine or its salt is usually carried out at temperatures of from -30°C to 35°C, preferably from -10°C to 0°C, in an inert solvent, in the presence of a catalyst of formula III.

The enone of formula II is used preferably as E-isomer. It corresponds to formula II. E.

In another embodiment the enone of formula II is used as Z-isomer. It corresponds to formula II.Z.

Suitable solvents are preferably water immiscible solvents, such as aliphatic hydrocarbons such as pentane, hexane, cyclohexane, and petrol ether, aromatic hydrocarbons such as tolu ene, 0-, m-, and p-xylene, halogenated hydrocarbons such as methylene chloride, dichloro- ethane, and chloroform, ethers such as diethylether, diisopropylether, tert.-butylmethylether (MTBE), anisole, and ketones such as methyl ethyl ketone, diethyl ketone, and tert.-butyl methyl ketone, alcohols such as n-butanol, preferably halogenated hydrocarbons such as methylene chloride, dichloroethane, and chloroform. It is also possible to use mixtures of the solvents men tioned.

Suitable bases are in general, inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as LiOH, NaOH, KOH and Ca(OH)2, alkali metal and alkaline earth metal oxides, such as LhO, Na ₂ 0, CaO, and MgO, and alkaline earth metal carbonates, such as U2CO3, Na ₂ CC> ₃ , K2CO3 and CaCCh, and also alkali metal bicarbonates, such as NaHCCh, moreover organic bases, e.g. tertiary amines, such as trimethylamine, triethylamine (NEt3), diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines, such as DBU (1,8-Diazabicy- clo(5.4.0)undec-7-ene) and DBN (1,5-Diazabicyclo[4.3.0]non-5-ene). Particular preference is given to alkali metal and alkaline earth metal hydroxides, such as LiOH, NaOH, KOH, and Ca(OH)2, such as NaOH, and KOH.

The bases are generally employed in catalytic amounts; however, they can also be used in equimolar amounts or in excess. Under certain conditions an excess up to 10 mol equivalents of base to compound II may be advantageous.

For practical reasons hydroxylamine is preferably used in the form of an aqueous solution, al ternatively as acid addition salt, such as halogenide or sulfate, preferably halogenide, particu larly as HCI addition salt.

Hydroxylamine is generally employed in equimolar amounts; however, it can also be used in excess. Under certain conditions an excess up to 10 mol equivalents of hydroxylamine to com pound II may be advantageous.

The catalyst III is generally employed in catalytic amounts; such as in 0.005 to 0.05 mol equiv alents, or 0.01 to 0.5 mol eq., preferably 0.01 to 0.2, particularly about 0.02 to 0.1 mol equiva lents of compound II. The starting materials are generally reacted with one another in equimolar amounts. In terms of yield, it may be advantageous to employ an excess of hydroxyl amine, based on II. Compounds III can be prepared in accordance with the literature cited and US 9,126,995.

Compounds of formula II and their preparation are known from W02009/063910. These com pounds can be obtained by reaction of a ketone of formula IV with an acetyl compound of for mula V in the presence of a base [cf. W02009/063910]. This reaction is preferably carried out with the oxo-compound V to yield the oxo-enone II with W = O.

Starting materials of formulae IV and V for formula II required for preparing the compounds I are commercially available or known from the literature or can be prepared as outlined above, or in accordance with the literature cited.

Compounds of formula I', that is compounds of formula I wherein W is S, can be prepared by reacting the corresponding oxocompound (W is O) with Lawesson's reagent (CAS 19172-47-5), see, e.g. Jesberger et al. Synthesis, 2003, 1929-1958 and references therein.

The reaction mixtures are worked up in a customary manner, for example by mixing with wa ter, separating the phases and, if appropriate, chromatographic purification of the crude prod ucts. Some of the intermediates and end products are obtained in the form of colourless or slightly brownish viscous oils which are purified or freed from volatile components under reduced pressure and at moderately elevated temperature. If the intermediates and end prod ucts are obtained as solids, purification can also be carried out by recrystallization or digestion.

However, if the synthesis yields mixtures of isomers, a separation is generally not necessarily required since in some cases the individual isomers can be interconverted during work-up for use or during application (for example under the action of light, acids or bases). Such conver sions may also take place after use, e.g. in the treatment of plants in the treated plant.

The organic moieties mentioned in the above definitions of the variables are - like the term hal ogen - collective terms for individual listings of the individual group members. The prefix C _n -C _m indicates in each case the possible number of carbon atoms in the group.

The term “halogen” denotes in each case fluorine, bromine, chlorine, or iodine, in particular flu orine, chlorine, or bromine.

The term "alkyl" as used herein and in the alkyl moieties of alkylamino, alkylcarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl and alkoxyalkyl denotes in each case a straight-chain or branched al kyl group having usually from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, prefer ably 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms. Examples of an alkyl group are methyl (“Me”), ethyl (“Et”), n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl (“ ‘Bu”), n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl,

1 , 1 -dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, 1 , 1 -dimethylbutyl, 1 ,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-di- methylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethyl- propyl, 1 -ethyl-1 -methylpropyl, and 1-ethyl-2-methylpropyl.

The term "haloalkyl" as used herein and in the haloalkyl moieties of haloalkylcarbonyl, haloalk- oxycarbonyl, haloalkylthio, haloalkylsulfonyl, haloalkylsulfinyl, haloalkoxy and haloalkoxyalkyl, denotes in each case a straight-chain or branched alkyl group having usually from 1 to 10 car bon atoms, frequently from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms. Preferred haloalkyl moieties are selected from CrC4-haloalkyl, more preferably from CrC3-haloalkyl or CrC2-haloalkyl, in particular from Ci-C2-fluoroalkyl such as fluoromethyl, difluoromethyl, trifluo- romethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.

The term "alkoxy" as used herein denotes in each case a straight-chain or branched alkyl group which is bonded via an oxygen atom and has usually from 1 to 10 carbon atoms, fre quently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples of an alkoxy group are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert.-butyloxy, and the like.

The term "alkoxyalkyl" as used herein refers to alkyl usually comprising 1 to 10, frequently 1 to 4, preferably 1 to 2 carbon atoms, wherein 1 carbon atom carries an alkoxy radical usually com prising 1 to 4, preferably 1 or 2 carbon atoms as defined above. Examples are CH2OCH3, CH2- OC2H5, 2-(methoxy)ethyl, and 2-(ethoxy)ethyl.

The term "haloalkoxy" as used herein denotes in each case a straight-chain or branched alk oxy group having from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms, in particular fluorine atoms. Preferred haloalkoxy moieties include C1-C4- haloalkoxy, in particular Ci-C2-fluoroalkoxy, such as fluoromethoxy, difluoromethoxy, trifluoro- methoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-flu- oroethoxy, 2-chloro-2,2-difluoro-ethoxy, 2,2dichloro-2-fluorethoxy, 2,2,2-trichloroethoxy, penta- fluoroethoxy and the like. The term "alkylthio "(alkylsulfanyl: S-alkyl)" as used herein refers to a straight-chain or branched saturated alkyl group having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms (= Ci-C4-alkylthio), more preferably 1 to 3 carbon atoms, which is attached via a sulfur atom.

The term "alkylsulfinyl" (alkylsulfoxyl: S(=0)-Ci-C ₆ -alkyl), as used herein refers to a straight- chain or branched saturated alkyl group (as mentioned above) having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms (= Ci-C4-alkylsulfinyl), more preferably 1 to 3 carbon atoms bonded through the sulfur atom of the sulfinyl group at any position in the alkyl group.

The term "alkylsulfonyl" (S(=0) ₂ -alkyl) as used herein refers to a straight-chain or branched saturated alkyl group having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms (= CrC ₄ -al- kylsulfonyl), preferably 1 to 3 carbon atoms, which is bonded via the sulfur atom of the sulfonyl group at any position in the alkyl group.

The term "alkylcarbonyl" refers to an alkyl group as defined above, which is bonded via the carbon atom of a carbonyl group (C=0) to the remainder of the molecule.

The term "alkoxycarbonyl" refers to an alkylcarbonyl group as defined above, which is bonded via an oxygen atom to the remainder of the molecule.

The term "alkenyl" as used herein denotes in each case a singly unsaturated hydrocarbon rad ical having usually 2 to 10, frequently 2 to 6, preferably 2 to 4 carbon atoms, e.g. vinyl, allyl (2- propen-1-yl), 1 -propen-1 -yl, 2-propen-2-yl, methallyl (2-methylprop-2-en-1-yl), 2-buten-1-yl, 3- buten-1-yl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-en-1-yl, 2-ethylprop-2-en- 1 -yl and the like.

The term "haloalkenyl" as used herein refers to an alkenyl group as defined above, wherein the hydrogen atoms are partially or totally replaced with halogen atoms.

The term "alkynyl" as used herein denotes in each case a singly unsaturated hydrocarbon rad ical having usually 2 to 10, frequently 2 to 6, preferably 2 to 4 carbon atoms, e.g. ethynyl, pro- pargyl (2-propyn-1-yl), 1-propyn-1-yl, 1-methylprop-2-yn-1-yl), 2-butyn-1-yl, 3-butyn-1-yl, 1-pen- tyn-1-yl, 3-pentyn-1-yl, 4-pentyn-1-yl, 1 -methyl but-2-yn-1-yl, 1-ethylprop-2-yn-1-yl and the like.

The term "cycloalkyl" as used herein and in the cycloalkyl moieties of cycloalkoxy and cycloal- kylthio denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 or from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, cyclononyl, and cyclodecyl, or cyclopropyl (C-C ₃ H5), cyclobutyl (C-C4H7), cyclopentyl (C-C5H ₉ ), and cyclohexyl (c-CeHn).

The term "halocycloalkyl" as used herein and in the halocycloalkyl moieties of halocycloalkoxy and halocycloalkylthio denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 C atoms or 3 to 6 C atoms, wherein at least one, e.g. 1, 2, 3, 4 or 5 of the hydrogen atoms, are replaced by halogen, in particular by fluorine or chlorine. Examples are 1- and 2-fluo- rocyclopropyl, 1,2-, 2,2- and 2,3-difluorocyclopropyl, 1,2,2-trifluorocyclopropyl, 2,2,3,3-tetrafluo- rocyclpropyl, 1- and 2-chlorocyclopropyl, 1,2-, 2,2- and 2,3-dichlorocyclopropyl, 1,2,2-trichloro- cyclopropyl, 2,2,3,3-tetrachlorocyclpropyl, 1-,2- and 3-fluorocyclopentyl, 1,2-, 2,2-, 2,3-, 3,3-, 3,4-, 2,5-difluorocyclopentyl, 1-,2- and 3-chlorocyclopentyl, 1,2-, 2,2-, 2,3-, 3,3-, 3,4-, 2,5-dichlo- rocyclopentyl, and the like.

The term "cycloalkenyl" as used herein and in the cycloalkenyl moieties of cycloalkenyloxy and cycloalkenylthio denotes in each case a monocyclic singly unsaturated non-aromatic radical ha ving usually from 3 to 10, e.g. 3 or 4 or from 5 to 10 carbon atoms, preferably from 3- to 8 car bon atoms. Exemplary cycloalkenyl groups include cyclopropenyl, cycloheptenyl or cycloocte- nyl.

The term "cycloalkenylalkyl" refers to a cycloalkenyl group as defined above which is bonded via an alkylene group, such as a CrCs-alkyl group or a CrC4-alkyl group, in particular a meth ylene group (= cycloalkenylmethyl), to the remainder of the molecule. The term “carbocycle” or “carbocyclyl” includes in general a 3- to 12-membered, preferably a 3- to 8-membered or a 5- to 8-membered, more preferably a 5- or 6-membered mono-cyclic, non-aromatic ring comprising 3 to 12, preferably 3 to 8 or 5 to 8, more preferably 5 or 6 carbon atoms. Preferably, the term “carbocycle” covers cycloalkyl and cycloalkenyl groups as defined above.

The term “heterocycle” or "heterocyclyl" includes in general 3- to 12-membered, preferably 5- or 6-membered, in particular 6-membered monocyclic heterocyclic non-aromatic radicals. The heterocyclic non-aromatic radicals usually comprise 1, 2 or 3 heteroatoms selected from N, O and S as ring members, wherein S-atoms as ring members may be present as S, SO or SO2. Examples of heterocyclic radicals comprise saturated or unsaturated, non-aromatic heterocyclic rings, such as 2- and 3-azetidinyl, 2- and 3-oxetanyl, 2- and 3-thietanyl, 2- and 3-thietanyl-S- oxid (S-oxothietanyl), 2- and 3-thietanyl-S-dioxid (S-dioxothietanyl), 2- and 3-pyrrolidinyl, 2- and 3-tetrahydrofuranyl, 1,3-dioxolan-2-yl, thiolan-2-yl, S-oxothiolan-2-yl, S-dioxothiolan-2-yl, 4- and 5-oxazolidinyl, 1,3-dioxan-2-yl, 1- and 3-thiopyran-2-yl, S-oxothiopyranyl, and S-dioxothiopyra- nyl.

The term "hetaryl" includes monocyclic 5- or 6-membered heteroaromatic radicals comprising as ring members 1 , 2, or 3 heteroatoms selected from N, O and S. Examples of 5- or 6-mem- bered heteroaromatic radicals include pyridyl, i.e. 2-, 3-, and 4-pyridyl, pyrimidinyl, i.e. 2-, 4- and 5-pyrimidinyl, pyrazinyl, pyridazinyl, i.e. 3- and 4-pyridazinyl, thienyl, i.e. 2- and 3-thienyl, furyl, i.e. 2- and 3-furyl, pyrrolyl, i.e. 1-, 2- and 3-pyrrolyl, oxazolyl, i.e. 2-, 4- and 5-oxazolyl, isoxa- zolyl, i.e. 3-, 4- and 5-isoxazolyl, thiazolyl, i.e. 2-, 3- and 5-thiazolyl, isothiazolyl, i.e. 3-, 4- and 5-isothiazolyl, pyrazolyl, i.e. 1-, 3-, 4- and 5-pyrazolyl, imidazolyl, i.e. 1-, 2-, 4- and 5-imidazolyl, oxadiazolyl, e.g. 2- and 5-[1,3,4]oxadiazolyl, thiadiazolyl, e.g. 1,3,4-thiadiazol-5-yl, 1,2,4-thiadia- zol-3-yl, triazolyl, e.g. 1,3,4-triazol-2-yl, and 1,2,4-triazol-3-yl.

The terms "heterocyclyolalkyl" and "hetarylalkyl" refer to heterocyclyl or hetaryl, resp., as de fined above which are bound via a CrC4-alkyl group, in particular a methyl group (= heterocy- clylmethyl or hetarylmethyl, resp.), to the remainder of the molecule.

With respect to the variables, the particularly preferred embodiments of the intermediates cor respond to those of the compounds of the formula I.

In a particular embodiment, the variables of the compounds of the formula I have the following meanings, these meanings, both on their own and in combination with one another, being par ticular embodiments of the compounds of formula I.

In the compounds of the inventive process R ¹ is preferably fluoromethyl, in particular CF ₃ .

The phenyl ring in formula I and its sub formulae, is a group P

P wherein R ^2a is selected from

R ^2b and R ^2c are independently selected from H, F, Cl, Br, and OCF ₃ .

In a particularly preferred embodiment the substituents in group P, if not hydrogen, are se lected from halogen, such as Cl and F. Preferred embodiments of the invention are each one of the following combinations of R ^2a , R ^2b , and R ^2c wherein each line of Table A denotes a substitution pattern of the phenyl ring P bearing the R ^2a , R ^2b , and R ^2c moieties.

Table A

Groups A-8, A-9, and A-11 are more preferred patterns in formula I and its sub formulae com pounds. A-11 is particularly preferred.

In one embodiment R ³ is H, halogen, or CH ₃ .

In a preferred embodiment G ¹ and G ² represent each CR ³ , wherein R ³ is H, halogen, or C1-C4- alkyl, particularly G ¹ is CH and G ² is C-CI, or C-CH ₃ .

In a particularly preferred embodiment G ¹ and G ² represent each CR ³ , wherein the two R ³ form a five- or sixmembered saturated carbocyclic ring, or a dihydrofurane.

In a preferred embodiment W represents O.

Particularly preferred compounds of formula II correspond to formula II. A, wherein Q is CH or O; and the other variables are as defined and preferred for formula I.

The catalyst III is used preferably in an amount of 0.1-50 mol%, more preferred in 0.5-5 mol%, particularly in 1-5 mol% relative to formula II compounds.

The nature of the counteranion X in formula III catalyst is of minor importance. For practical reasons it is usually selected from halogen (preferably Cl, Br), BF4, PF ₆ , Ci-Cio-alkylsulfonate, benzenesulfonate, or methylbenzenesulfonate. Preferred III is used as bromide and chloride, mesylate, and tosylate. Particularly preferred are bromide and chloride. Preferably p and q are both 0. in another embodiment index p is 1 or 2, and q is 0 or 1.

Substituents R ^a and R ^b are preferably positioned in 2 and/or 7, or in 3 and/or 6 positions.

R ^a and R ^b are preferably halogen, CN, CrC ₃ -alkyl, or CrC ₃ -alkoxy, particularly CH ₃ , OCH ₃ , or halogen such as Cl or F.

Particularly preferred are catalysts of formula III wherein the substitution of the acridin group have the meanings as shown in Table III.1, wherein each compound corresponds to one line.

Table III.1; X is Cl or Br

The bromide (lll-1-Br) and chloride (III-1-CI) of 111-1 are preferred embodiments.

In the N-oxide of formula III catalyst the nitrogen atom in the acridin group is oxidized.

Another embodiment relates to the process for obtaining compounds I wherein R ⁵ is H or CH ₃ , and R ⁶ is H, CrC ₆ -alkyl, C2-C6-alkenyl, which groups are unsubstituted or substituted with one or more same or different R ⁸ , wherein R ⁸ is as defined and preferred above.

The process is particularly suitable for synthesis of following active compounds of formula I, which correspond to formulae I.A, and I.B, resp., wherein the variables are as defined and preferred above: wherein Q is CH or O; and the other variables are as defined and preferred for formula I, and wherein R ³ is preferably

The following examples illustrate the invention. In formulae I.A and I.B group R ⁵ is preferably H or CH ₃ , and R ⁶ is preferably H, CrC ₆ -alkyl, Ci- C2-alkoxy-CrC2-alkyl, or C2-C6-alkenyl.

Preference is given to the compounds of formula I compiled in the tables below. Each of the groups mentioned for a substituent in the tables is furthermore per se, independently of the combination in which it is mentioned, a particularly preferred aspect of the substituent in ques tion.

Table 1: Compounds of formula I.A in which R ^2a , R ^2b , and R ^2c correspond to A-8, R ⁵ is H and R ⁶ for a compound correspond in each case to one row of Table B Table 2: Compounds of formula I.A in which R ^2a , R ^2b , and R ^2c correspond to A-9, R ⁵ is H and R ⁶ for a compound correspond in each case to one row of Table B

Table 3: Compounds of formula I.A in which R ^2a , R ^2b , and R ^2c correspond to A-11, R ⁵ is H and R ⁶ for a compound correspond in each case to one row of Table B Table B

Preferably the process yields in formula I compounds which obtained from the raw reaction mixture have an ee of at least 80%, more preferably at least 85% ee. Further enrichment of the S-enantiomer can be achieved by following recrystallisation.

Examples

A. Preparation examples

With appropriate modification of the starting materials, the procedures given in the synthesis description were used to obtain further compounds I and II. The compounds obtained in this manner are listed in the tables that follow, together with physical data. Equivalents mentioned in the examples are mol-equivalents.

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

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

HPLC Method A (determination chemical purity of compounds): Shimadzu LC2010, Column: Waters XBridge C18, 150mm*4.6mm ID*5p; Mobile Phase: A: 0.1% trifluoroacetic acid (TFA) in water; B: 0.1% TFA in acetonitrile; Temperature: 40°C; Gradient: 10%B to 100%B in 5min; 100%B for 2mins; 10%B for 3min; Flow: 1 ,4ml/min; PDA detector MaxPlot (220nm to 400nm). Sample Preparation: In acetonitrile and water

HPLC Method B (determination of enantiomeric purity of compounds): Shimadzu LC2010; CHIRALPAK AD-RH ,150mm*4.6mm*5p. Mobile Phase: A: 0.1% TFA in Water; B: 0.1% TFA in acetonitrile; Temperature: 40°C; Gradient: 65%B for 12mins; 100%B for 1min; 35%B for 7mins; Flow: 1 ,4 ml/min; PDA detector at 265nm. Sample Preparation: In acetonitrile and water.

HPLC method C (determination chemical purity of compounds):

Agilent 1200 Series, Agilent XDB C18, 50mm*4.6mm*1.8pm. Mobile phase A: 0.1% H3PO4 in water; B: 0.1% H3PO4 in acetonitrile; Temperature: 20°C; Gradient: Start 50:50 A:B; 1min 38:62 A:B, 6min 32:68 A:B, 9min 0:100 A:B; Flow: 1.2ml_/min; PDA detector at 254nm. Sample prepa ration in acetonitrile.

HPLC method D (determination of enantiomeric purity of compounds):

Agilent 1290; Daicel Chiralcel OJ-3R 150mm*4.6mm*3pm. Elution: methanol / ethanol (1 :1v/v), isocratic; 10min run time; temperature: 23°C; detection at 215nm. Sample preparation in ethanol.

HPLC method E (LC/MS):

Phenomenex Kinetex 1 ,7pm XB-C18 100A; 50 x 2.1 mm. Elution: acetonitrile + 0.1% trifluoro- acetic acid (TFA) / water + 0.1 % trifluoroacetic acid (TFA) in a ratio of from 5:95 to 95:5 in 1.5min at 50°C

Preparation of formula II compounds

Example II. A: N-[[4-[(E )-3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-eno yl]-2,3-dihy- drobenzofuran-7-yl]methyl]thietane-3-carboxamide To a suspension of 2.2g N-[(4-acetyl-2,3-dihydrobenzofuran-7-yl)methyl]thietane-3-ca rbox- amide and 2.8g CS2CO3 in 16mL toluene and 16ml_ trifluorotoluene at 115°C was added 3.0g 1-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone dropwise over 2 hours. The reaction was then heated at 115°C for an additional 18 hours, then cooled to 20-25°C and concentrated in vacuo to afford a brown solid. The solid was slurried in water and stirred vigorously for 1 hour, cooled to 0°C, and filtered. The filtercake was then triturated with 25ml_ MTBE, filtered, and the filtercake then dried in a vacuum oven at 50°C to afford the title compound as a beige solid (2.77g, 69% yield).

LC/MS: [M] ⁺ 534; t _R =1.39 min (method E)

Preparation of formula I compounds

Example 1: N-[[4-[(5S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-is oxazol-3-yl]-2, 3-dihydro- benzofuran-7-yl]methyl]propanamide [I.A-1] A round bottom glass flask was charged with 1g (1eq) of N-[[4-[(E)-3-(3,5-dichlorophenyl)- 4,4,4-trifluoro-but-2-enoyl]-2,3-dihydrobenzofuran-7-yl]meth yl]propanamide in 20 ml of chloro form and the reaction mass was cooled to -10°C; then to this solution was added 0.127g (0.05eq) (R)-[1-(acridin-9-ylmethyl)-5-vinyl-quinuclidin-1-ium-2-yl]- (6-methoxy-4-quinolyl)metha- nol bromide, and the reaction mass was stirred at -10°C for 30min. To this reaction mass, a pre mixed solution of 0.7ml (5eq) 50% NH2OH solution in 2.56ml (6eq) of 20% NaOH was added dropwise, maintaining the reaction mass at 0°C, and after completion of addition the reaction mass was further stirred for 1 hr at 0°C. After HPLC control confirms complete conversion, the reaction mixture was warmed to 20 to 25°C and diluted with water and the organic phase was separated. The organic layer was washed with 6M HCI and water and evaporation of all vola tiles yielded 1.05g of the title compound (98% yield, 97.8% HPLC (method A) purity, 89.8:10.2 S:R HPLC method B).

Example 2: tert-butyl N-[[7-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromet hyl)-4H-isoxa- zol-3-yl]indan-4-yl]methyl]carbamate [I.A-2]

A round bottom glass flask was charged with 1.0g (1eq) of tert-butyl N-[[7-[(E)-3-(3,5-dichloro-

4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]indan-4-yl]m ethyl]carbamatein 10ml of dichloro- methane (DCM) and the reaction mass was cooled to -10°C. To this solution was added 0.056g (0.05eq) (R)-[1-(9-anthrylmethyl)-5-vinyl-quinuclidin-1-ium-2-yl]-(6- methoxy-4-quinolyl)methanol chloride, and the reaction mixture was stirred at -10°C for 30min. To this mixture, a premixed solution of 0.372g (3eq) 50% NH2OH solution and 1.50g (4 eq) of 20% aqueous NaOH was added dropwise over 30 min, and the reaction mixture was stirred at -10°C over night. The reac tion was diluted with water and the organic phase was separated. The organic layer was washed with 6M HCI and water and all volatiles were removed in vacuum to yield the title com pound (92% yield, 98.2% HPLC (method A) purity, 99:1 S:R (HPLC method B).

Example 3: N-[[4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromet hyl)-4H-isoxazol-3-yl]-

2.3-dihydrobenzofuran-7-yl]methyl]propanamide [I.A-3]

A round bottom glass flask was charged with 1g (1 eq) of N-[[4-[(E)-3-(3,5-dichloro-4-fluoro- phenyl)-4,4,4-trifluoro-but-2-enoyl]-2,3-dihydrobenzofuran-7 -yl]methyl]propanamide in 20ml of DCM and the reaction mass was cooled to 0°C; then to this solution was added 0.06g (0.05eq) (R)-[1-(acridin-9-ylmethyl)-5-vinyl-quinuclidin-1-ium-2-yl]- (6-methoxy-4-quinolyl)methanol bro mide, and the reaction mass was stirred at -10°C for 30min. To this reaction mass, a premixed solution of 0.67ml (5eq) 50% NH2OH solution in 2.45ml (6eq) of 20% NaOH was added drop- wise maintaining the reaction mass at 0°C, and after completion of addition reaction mass was further stirred for 1 hr at 0°C. After HPLC control confirms complete conversion, the reaction mixture was warmed to 20 to 25°C, diluted with water, and the organic phase was separated. The organic layer was washed with 6M HCI and water and evaporation of all volatiles yielded 0.98g of the title compound (96% yield, 98% HPLC (method A) purity, 96:4 S:R HPLC method B).

Example 4: N-[[4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromet hyl)-4H-isoxazol-3-yl]-

2.3-dihydrobenzofuran-7-yl]methyl]thietane-3-carboxamide [I.A-4]

Following the procedure described in Example 1 , N-[[4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-

5-(trifluoromethyl)-4H-isoxazol-3-yl]-2,3-dihydrobenzofur an-7-yl]methyl]thietane-3-carboxamide was synthesized using 1.2g (1eq) (E)-enone of Example II. A, and 0.05eq (R)-[1-(acridin-9-ylme- thyl)-5-vinyl-quinuclidin-1-ium-2-yl]-(6-methoxy-4-quinolyl) methanol bromide (lll-1-Br). 1.2g of the title compound were isolated as light yellow solid in 95% yield (98% HPLC (method C) purity, 95:5 S:R (HPLC method D)).

HPLC: 4.71 min (method C)

LC/MS: [M] ⁺ 549; t _R =1.38 min (method E)

Example 5: N-[[4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromet hyl)-4H-isoxazol-3-yl]-

2.3-dihydrobenzofuran-7-yl]methyl]-2-tetrahydrofuran-2-yl -acetamide [I.A-5]

Following the procedure described in Example 1, N-[[4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)- 5-(trifluoromethyl)-4H-isoxazol-3-yl]-2,3-dihydrobenzofuran- 7-yl]methyl]-2-tetrahydrofuran-2-yl- acetamide was synthesized using 2.0g (1eq) N-[[4-[(E)-3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4- trifluoro-but-2-enoyl]-2,3-dihydrobenzofuran-7-yl]methyl]-2- tetrahydrofuran-2-yl-acetamide, and 0.05eq lll-1-Br. 2.05g of the title compound were isolated as off-white solid in 98% yield (98% HPLC (method C) purity, 94:6 S:R (HPLC method D)).

HPLC: 3.25 min (method C)

LC/MS: [M] ⁺ 561; tR= 1.35 min (method E)

Example 6: N-[[4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromet hyl)-4H-isoxazol-3-yl]-

2.3-dihydrobenzofuran-7-yl]methyl]-3,3,3-trifluoro-propan amide [I.A-6]

Following the procedure described in Example 1, N-[[4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)- 5-(trifluoromethyl)-4H-isoxazol-3-yl]-2,3-dihydrobenzofuran- 7-yl]methyl]-3,3,3-trifluoro-propana- mide was synthesized using 1.2g (1eq) N-[[4-[(E)-3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro- but-2-enoyl]-2,3-dihydrobenzofuran-7-yl]methyl]-3,3,3-triflu oro-propanamide, and 0.05eq III-1- Br. 0.95g of the title compound were isolated as white solid in 62% yield (84 % HPLC (method C) purity, 93:7 S:R (HPLC method D)).

HPLC C: 4.63 min

LC/MS: [M] ⁺ 559; t _R =1.38 min (method E)

Example 7: N-[[4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromet hyl)-4H-isoxazol-3-yl]-

2.3-dihydrobenzofuran-7-yl]methyl]-3-methylsulfanyl-propa namide [I.A-7]

Following the procedure described in Example 1, N-[[4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)- 5-(trifluoromethyl)-4H-isoxazol-3-yl]-2,3-dihydrobenzofuran- 7-yl]methyl]-3-methylsulfanyl-propa- namide was synthesized using 1.1 g (1eq) N-[[4-[(E)-3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-triflu- oro-but-2-enoyl]-2,3-dihydrobenzofuran-7-yl]methyl]-3-methyl sulfanyl-propanamide, and 0.05eq lll-1-Br.

1.2g of the title compound were isolated as light yellow solid in 98% yield (93% HPLC (method C) purity, 95:5 S:R (HPLC method D)).

HPLC: 4.35 min (method C)

LC/MS: [M] ⁺ 551; t _R =1.43 min (method E)

Example 8: N-[[4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromet hyl)-4H-isoxazol-3-yl]-

2.3-dihydrobenzofuran-7-yl]methyl]-2,2,2-trifluoro-acetam ide [I.A-8]

Following the procedure described in Example 1, N-[[4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)- 5-(trifluoromethyl)-4H-isoxazol-3-yl]-2,3-dihydrobenzofuran- 7-yl]methyl]-2,2,2-trifluoro-aceta- mide was synthesized using 1.0g (1eq) N-[[4-[E-3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro- but-2-enoyl]-2,3-dihydrobenzofuran-7-yl]methyl]-2,2,2-triflu oro-acetamide, and 0.05eq lll-1-Br.

1.01 g of the title compound were isolated as light yellow solid in 98% yield (99% HPLC (method C) purity, 97:3 S:R (method D)).

HPLC. 5.37 min (method C) LC/MS: [M] ⁺ 545; t _R =1.42 min (method E)

Comparisons with other, known catalysts

Comparative Example C1: N-[[4-[(5S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-is oxazol-3- yl]-2,3-dihydrobenzofuran-7-yl]methyl]propanamide [I.A-1]

A round bottom glass flask was charged with 1.0 g (1 eq) of N-[[4-[(E)-3-(3,5-dichlorophenyl)- 4,4,4-trifluoro-but-2-enoyl]-2,3-dihydrobenzofuran-7-yl]meth yl]propanamide in 10 ml of dichloro- methane and the reaction mass was cooled to -10°C. To this solution was added (R)-[1-(9-an- thrylmethyl)-5-vinyl-quinuclidin-1-ium-2-yl]-(6-methoxy-4-qu inolyl)methanol chloride 0.063 g (0.05 eq) and the reaction mixture was stirred at -10°C for 30 min. To this mixture, a premixed solution of 0.42 g (3 eq) 50% NH2OH solution and 1.69 g (4 eq) of 20% aqueous NaOH was added dropwise over 30 min and the reaction mixture was stirred at -10°C over night. The reac tion mixture was diluted with water, and the organic phase was separated. The organic layer was washed with 6M HCI and water, and all volatiles were removed in vacuum to yield the title compound (95% yield, 96.7% HPLC (method A) purity, 78:22 (S:R) (HPLC method B)).

Comparative Example C2: N-[[4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromet hyl)-4H- isoxazol-3-yl]-2,3-dihydrobenzofuran-7-yl]methyl]propanamide [I.A-3]

A round bottom glass flask was charged with 1g (1 eq) of N-[[4-[(E)-3-(3,5-dichloro-4-fluoro- phenyl)-4,4,4-trifluoro-but-2-enoyl]-2,3-dihydrobenzofuran-7 -yl]methyl]propanamide in 20 ml of DCE and reaction mass was cooled to 0°C and then to this solution added (R)-[1-(9-anthrylme- thyl)-5-vinyl-quinuclidin-1-ium-2-yl]-(6-methoxy-4-quinolyl) methanol chloride 0.061 g (0.05 eq) and reaction mass was stirred at -10°C for 30min. To this reaction mass, a premixed solution of 0.7ml (5eq) 50% NH2OH solution in 2.5ml (6eq) of 20% NaOH was added dropwise in 90mins and the reaction mass was stirred at 0°C for 5-6hrs. After HPLC control confirms complete con sumption the reaction mixture was diluted with water and the organic phase was separated. The organic layer was washed with 6M HCI and water, and evaporation of the volatile contents yielded 0.75g of the title compound (72.8% yield, 99.8% HPLC (method A) purity, 84:16 S:R (HPLC method B)).

Comparisons with other catalysts III* not according to the invention

Bn = Benzyl