Enantioselective hydrogenation of 4-substituted 2-oxazolones in presence of a chiral palladium or nickel catalyst

Abstract

The present invention relates to a process for the enantioselective preparation of chiral 4-substituted 2-oxazolidinones of formula (la) or (lb) via asymmetric hydrogenation of the corresponding 4-substitued 2-oxazolones of formula (II) using a combination of palladium or nickel and a chiral bidentate P-ligand as catalyst. The oxazolidinones can then be converted to important chiral building blocks such as enantiopure chiral aminoalcohols and haloamines via decarboxylative ring opening reaction.

Description

[0001] BCS243003 FC KJ / Rak 2025-07-01 -1- Enantioselective hydrogenation of 4-substituted 2-xoazolones in presence of a chiral palladium or nickel catalyst The present invention relates to a process for en thaentioselective preparation of chiral 4-substditu 2te- oxazolidinones via asymmetric hydrogenation of the correspondingb 4s-tsituued 2-oxazolones using a combination of palladium or nickel and a chirale bnidtate P-ligand as catalyst. The oxazolidinones can then be converted to important chiral building bklsoc such as enantiopure chiral aminoalcohols or haloamines via decarboxylative ring opening reanc.tio Oxazolidinones are valuable as medicinally actoivmep counds (G.F.S. Fernandes et al., RSC Med. Chem., 2023, 14, 823-847) and as precursors for the ssyinsth oef crop protection agents, for example chiral oxadiazine compounds such as those disclosed in 20 W2O0 / 127780 A1. Several methods have been reported for the asymicm heytdrrogenation of oxazolones. In 2016, the group of Zhang reported the hydrogenation of 4-aryl siutubtsetd 2-oxazolones using rhodium / TangPhos as catalyst (Q. Wang et al., Tetrahedron Letters 205176, 6,58–662). The use of an expensive metal (urhmo)di in combination with an expensive ligand under hi cgahtalyst loading, in addition to the modestenantioselectivity makes this process inefficieonrt in fdustrial production. Furthermore, this methlod goywas limited to aryl-substituted oxazolones. In 2,0 t1h8e group of Frank Glorius reported a method th foer hydrogenation of N-benzylated oxazolidinones us riuntghenium and a chiral NHC ligand (W. Li et al., Chem. Sci., 2018, 9, 6260-6263). This processe dreelidv good overall yield and enantioselectivity, t bhuet use of a protecting group increases mass inte annsidty decreases efficiency. In 2020, the group ofn Zgha reported a method using Ni-catalysts in combina wtioitnh (S,S)-Ph-BPE as chiral phosphine ligand (Y. Liu et al., ACS Catal. 2020, 10, 11153−11161). T hhigeh catalyst loading, reaction temperature and hydrogen pressure make this process unfavourarb sleca fole up. Finally, a method using Pier’s boranithe w elevated temperature and pressure has also beoernte rdep (G. Cui et al., Org. Biomol. Chem., 2023, 21, 499-502). In view of the prior art described above, it is o abnject of the present invention to provide a prosc feosr preparing chiral 4-substituted 2-oxazolidinonesc whh pirocess has advantages over the processes p orifo trhe art. The process should allow the desired enantrio tom bee prepared in high yield and high enantiocmeri purity and be suitable for use on an industrialle s.caThe object described above was achieved by a psr foocre psreparing a compound of the formu (Ila ) or (Ib), (Ia) (Ib), BCS 243003 FC - 2 - wherein n is 0, 1, 2 or 3, and each substituent R, if present, is independentlleyct seed from the group consisting of halogen, hydroxy, C1-C6-alkyl, C1-C6-haloalkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylcarbonyl, C1- C6-alkoxycarbonyl and1C-C6-alkylcarbonyloxy,comprising enantioselective hydrogenation of a coumnpd of the formulaII ( ) wherein n and R are each as defined for the comdpo fu tnhe formulaI (a) or (Ib), in presence of a palladium or nickel catalyst coisminpgr a chiral bidentate P-ligand. Surprisingly, it has been found that chiral 4-siutubtsetd 2-oxazolidinones can be obtained in highld ysie and excellent enantioselectivity by asymmetric hoygdernation of the corresponding 4-substituted 2- oxazolones in presence of palladium or nickel an cdhir aal bidentate P-ligand as catalyst. This prsoc ises particularly efficient when the asymmetric hydroagteionn is conducted in presence of a fluorinatelvde snot and even more efficient when a combination of pdaiullma, Lewis acidic co-catalyst and fluorinated seonltv is used. Under these reaction conditions, thei roenact an be accelerated, the amount of catalystc reeddu and the service life of the catalyst extended. T ahlliosws the desired enantiomer to be obtained with complete conversion and 98% enantiomeric exces lesss in than a few hours using less than 0.1 mol% catalyst. It has also been found that a combina otifo pnalladium catalyst and Lewis acidic co-cataslyst allows for the use non-fluorinated solvents. Furrmthoere, the process generates very little wasteo aths b solvent and catalyst can be recycled. Without isolation the crude mixture can then berie cadr into a hydrolysis step with either aqueousiu smod hydroxide, hydrobromic acid or hydrochloric acid fu tornish the corresponding enantiopure aminoalcohol or haloamine respectively. Definitions In the definitions of the symbols given in the Muasrkh formulae used herein, collective terms are, u wsheidch are generally representative of the following siutubesntts: The term “halogen” as used herein refers to ai fnlueo,r chlorine, bromine or iodine atom. BCS 243003 FC - 3 - The term “C1-C6-alkyl” as used herein refers to a saturated, bhreadnc or straight hydrocarbon chain having1, 2, 3, 4, 5 or 6 carbon atoms. Particularly, shayid rocarbon chain has 1, 2, 3 or 4 carbon atomC1s-C (“4-alkyl”), e.g. methyl, ethyl, propyl, iso-propyl,t byul, sec-butyl, iso-butyl or tert-butyl, or the hryodcarbon chain has 3, 4, 5 or 6 carbon atoms3- (C“C6-alkyl”). The term “C1-C6-haloalkyl” as used herein refers to1a-C C6-alkyl group as defined above in which one or more hydrogen atoms are replaced with halogen a tthoamts may be the same or different. Examples1 o-f CC6-haloalkyl include but are not limited to1- C 4-haloalkyl such as chloromethyl, bromomethyl,dichloromethyl, trichloromethyl, fluoromethyl, duifolromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chlooerthyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethy 2l,,2- difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-foluroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichlor2o-- fluoroethyl, 2,2,2-trichloroethyl, pentafluoroeth aynld 1,1,1-trifluoroprop-2-yl. The term “C1-C6-hydroxyalkyl” as used herein refers to1a-C C6-alkyl group as defined above in which at least one hydrogen atom is replaced with a hydr gorxoyulp. Examples of1C-C6-hydroxyalkyl include but are not limited to C1-C4-hydroxyalkyls such as hydroxymethyl, 1-hydroxyel,thy 2-hydroxyethyl, 1,2- dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, -h 1ydroxypropyl, 1-hydroxypropan-2-yl, 2- hydroxypropan-2-yl, 2,3-dihydroxypropyl and 1,3-yddihroxypropan-2-yl. The term “C1-C6-alkoxy” as used herein refers to a group of foram (uCl1-C6-alkyl)-O-, in which the term"C1-C6-alkyl" is as defined herein. Examples o1f- C 6-alkoxy include but are not limited to1- C 4-alkoxygroups such as methoxy, ethoxy, n-propoxy, 1-methoylxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy and 1,1-dimethylethoxy.The term “C1-C6-alkylcarbonyl” as used herein refers to a linera brr oanched group of formula1 (-C 6-alkyl)-C(=O)-, in which the term "1C-C6-alkyl" is as defined herein.The term “C1-C6-alkylcarbonyloxy” as used herein refers to a lrin oera branched group of formula1 (-C 6-alkyl)-C(=O)-O-, in which the term "1C-C6-alkyl" is as defined herein.The term “C1-C6-alkoxycarbonyl” as used herein refers to a lin oera brranched group of formula 1 (-C 6-alkoxy)-C(=O)-, in which the term "1C-C6-alkoxy" is as defined herein. The term “di-(C1-C4-alkyl)amino” as used herein refers to an aminoic raald having two independently selected C1-C4-alkyl groups as defined herein. Examples of d1i--C(C4-alkyl)amino include but are not limited to N,N-dimethylamino, N,N-diethylamino, N,N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-N- n-propylamino, N-isopropyl-N-n-propylamino and N-tert-butyl-N-methylamino. The term “C3-C6-cycloalkyl” as used herein refers to a satura mteodn,ovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms. Exam opfle Cs3-C6-cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. BCS 243003 FC - 4 - The term “enantioselective” as used herein meaanst o thne of the two possible enantiomers of the hydrogenation product, namely the enantiomer of o thrmeula (Ia) or the enantiomer of the formulIab (), is preferably formed. The “enantiomeric ratio” oerr” “ indicates the relative ratio of the major enamnteior to the minor enantiomer in a mixture of both enantirosm. e Alternatively, the “enantiomeric excess” oere” “ can be used to indicate the degree of enanticotsiveitley : % ee = ^^^^^ ^^^^^^^^^^ ^^^^^ ^ ^^^^^ ^^^^^^^^^^ ^^^^^ ^^^^^ ^^^^^^^^^^ ^^^^^ ^ ^^^^^ ^^^^^^^^^^ ^^^^^ ^ 100% The major enantiomer can be controlled by thet sioelnec of the chiral ligand. Preferably, the process according to the inven istio unsed for preparing the compound of the form (Iual)a or (Ib), in particular (Ia), in an enantiomeric excess of at least 8 e0e%, more preferably at least 90 e%e, even more preferably at least 95 e%e, and in particular at least 98 e%e.Preferably, the substituents in the compoundse of o thrmulae (Ia), (Ib) and (II ) are defined as follows:n is 0, 1 or 2, and each substituent R, if present, is independenltelyct seed from the group consisting of halogen1-,C C6-alkyl, and C1-C6-haloalkyl. Preferably, the process according to the inven istio unsed for preparing the compound of the form (Iual’a’)or (Ib’’ ): (Ia’’) (Ib ’’)wherein the substituents are defined as follows: R1is chlorine or methyl, and R2is chlorine or methyl,and comprises enantioselective hydrogenation ofm ap cound of the formulaII (’’ ) BCS 243003 FC - 5 - (II’’ ),wherein R1 and R2 are each as defined for the compound of the foarm (Iau’l’ ) or (Ib’’ ).More preferably, the process according to the intiovenn is used for preparing the compound of the fuolarm(Ia’) or (Ib’ ): wherein the substituents are defined as follows: R1is chlorine, fluorine or methyl, and R2is methyl, ethyl, n-propyl or isopropyl,and comprises enantioselective hydrogenation ofm ap cound of the formulaII (’ ) (II’ ),wherein R1 and R2 are each as defined for the compound of the foarm (Iau’l ) or (Ib’ ).Likewise more preferably, the process accordin tghe to invention is used for preparing the compoun tdhe offormula (Ia’) or (Ib’ ): BCS 243003 FC - 6 - wherein the substituents are defined as follows: R1is hydrogen or chlorine, and R2is bromine, methyl or trifluoromethyl,and comprises enantioselective hydrogenation ofm ap cound of the formulaII (’ ) (II’ ),wherein R1 and R2 are each as defined for the compound of the foarm (Iau’l ) or (Ib’ ).Even more preferably, the substituents in the coumndpso of the formula (eIa’), (Ib’ ) and (II’ ) are defined asfollows: R1is chlorine or fluorine and2R is methyl, ethyl, n-propyl or isopropyl; and most preferably1, i Rs chlorine and R2is methyl.According to the invention, the enantioselectivder hoygenation of the compound of formuIlIa ), ( in particular(II’ ), is conducted in presence of a palladium or nlic aketalyst comprising a chiral bidentate P-liga Undse.of a palladium catalyst comprising a chiral bidetent Pa-ligand is particularly preferred. Preferably, the hydrogenation is conducted usindgro hgyen gas at a pressure of from 1 to 300 bare,r parbelfy 5 to 100 bar, and most preferably 10 to 60 bar. The hydrogenation is preferably conducted at ae teramtupre within the range of from 40°C to 100°C,e mor preferably 40°C to 80°C.Suitable solvents are fluorinated solvents suc 2h,2 a,s2,-trifluoroethanol, hexafluoroisopropanol (,1,13,3,3-hexafluoro-2-propanol), tetrafluoropropanol (2,32-,t3e,trafluoro-1-propanol) and trifluorotoluene ((trifluoromethyl)benzene), and non-fluorinatedv seonlts selected from the group consisting of an,is eothleyl BCS 243003 FC - 7 - acetate, isopropyl acetate, n-butyl acetate, moetl,h eatnhanol, n-propanol, iso-propanol, dimethylb coanrate, and mixtures thereof. The hydrogenation according to the invention matyio onpally be conducted in presence of a Lewis acidselected from the group consisting of of trifluboororane, aluminium trifluoromethanesulfonate, zrinifcla t eand titanium tetraisopropoxide. This is particuyla ardlvantageous when a palladium catalyst is used. If a nickel catalyst is used, the hydrogenatio pnre isferably conducted in presence of a fluorinatoelvde snt and in absence of any Lewis acid. In a preferred embodiment according to the invenn,t tiohe hydrogenation is conducted in presence of apalladium catalyst, a non-fluorinated solvent stel dec from the group consisting of anisole, ethylt a tcee,isopropyl acetate, n-butyl acetate, methanol, eotlh,a nn-propanol, iso-propanol, dimethyl carbonatned, a mixtures thereof, and in presence of a lewis asci sde ilected from the group consisting of trifluorroabnoe, aluminium trifluoromethanesulfonate and zinc trteifl.aIn another preferred embodiment according to thve n intion, the hydrogenation is conducted in prese onf cea fluorinated solvent selected from the group csotins gi of hexafluoroisopropanol, 2,2,2,-trifluoroaenthol,tetrafluoropropanol and trifluorotoluene, and mrixetsu thereof. Hexafluoroisopropanol, 2,2,2,- trifluoroethanol and mixtures thereof are particrluyla preferred. In this embodiment, the hydrogenna mtioay optionally be conducted in presence of a lewis asceildected from the group consisting of trifluoroabnoer, aluminium trifluoromethanesulfonate and zinc trteifl.aIn particularly preferred embodiment, the hydrogtieona is conducted in presence of a palladium csat ,aly(i) a fluorinated solvent selected from the group csotins gi of hexafluoroisopropanol, 2,2,2,-trifluoroethanol, tetrafluoropropanol, trifluoroutoelne and mixtures thereof, and (ii) a lewis acid selected from the group consisting t orif luoroborane, aluminiumtrifluoromethanesulfonate and zinc triflate.In an even more preferred embodiment, the hydrotigoenn ias conducted in presence of a palladium csat ,aly(i) a fluorinated solvent selected from hexafluoroisoopparnol, 2,2,2,-trifluoroethanol and mixtures thereof, and (ii) a lewis acid selected from the group consisting tr oiffluoroborane and aluminiumtrifluoromethanesulfonate. Trifluoroborane is particularly preferably used th aes Lewis Acid. BCS 243003 FC - 8 - Preferably, trifluoroborane is used in form ofif alu torroborane complex such as boron trifluorideth dyielether complex, trifluoroborane tetrahydrofuran complerxif,lu toroborane acetic acid complex, trifluoroborane acetonitrile complex or trifluoroborane hydrofludoeri etherate complex. If a Lewis acid is used, the amount of Lewis acsided u is preferably within the range of from 0.5 mo tol% 20 mol%, more preferably 1 mol% to 10 mol% and m poresfterably 2 mol% to 8 mol%, based on the amount of the compound of the formu (laII). The hydrogenation may optionally additionally bend cuocted in presence of a Brønsted acidic addi stiuvceh, as acetic acid, trifluoroacetic acid, camphorsuiclfo ancid, p-toluenesulfonic acid, phenol, pivalicid a,c benzoic acid, formic acid, butyric acid or oxalcicid a.According to the invention, the enantioselectivder hoygenation of the compound of formuIlIa ) ( is conductedin presence of a palladium or nickel catalyst coisminpgr a chiral bidentate P-ligand. Use of a paullamdi catalyst comprising a chiral bidentate P-ligan pda irsticularly preferred. Preferably, the palladium or nickel catalyst, inrti pcaular palladium catalyst, comprises a chiraaln ligd of theformula (IIIa ), (IIIb ), (IVa), (IVb ), (Va), (Vb), (VIa), (VIb ), (VIIa ), (VIIb ), (VIIIa ), (VIIIb ), (IXa),(IXb ), (Xa) or (Xb) BCS 243003 FC - 9 - wherein R3and R4are each independently selected from the grouspis ctoinng of phenyl, furan-2-yl, naphthalen-1-yl, C3-C6-cycloalkyl and C3-C6-alkyl, wherein the phenyl is unsubstituted or stiutubtsed with one to three substituents each independently selected fromr tohuep g consisting of C1-C4-haloalkyl, C1-C4-alkyl, and C1- C4-alkoxy, R5is C3-C6-alkyl or C3-C6-cycloalkyl, Q is N or CH, R6is phenyl, which is unsubstituted or substituteitdh w one to three substituents each independenletlyct seed from the group consisting of1- CC4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl and di-(C1-C4-alkyl)amino, or R6is C3-C6-cycloalkyl, C3-C6-alkyl or furan-2-yl, R7a, R7b, R8a, R8b, R9aand R9bare each independently selected from hydrog1e-nC,4- Calkoxy, C1-C4-alkyl and C1-C4-haloalkyl, where at least two of7aR, R7b, R8aand R8bare not hydrogen, or R7aand R8aform together a -O-(C2H)-O-, -O-(CH2)2-O-, -O-C(CH3)2-O-, -O-(CF2)-O- or -(CH)4- group, R7band R8bform together the same group (i.e. -O-(2C)-HO-, -O-(CH2)2-O-, -O-C(CH3)2-O-, -O-(CF2)-O- or -(CH)4-), and R9aand R9bare hydrogen, R10and R11are each independently selected from the grouspis ctoinng of phenyl, furan-2-yl, naphthalen-1- yl, C3-C6-cycloalkyl and C3-C6-alkyl, wherein the phenyl is unsubstituted or stiutubtsed with one to three BCS 243003 FC - 10 - substituents each independently selected fromr tohuep g consisting of C1-C4-haloalkyl, C1-C4-alkyl, and C1- C4-alkoxy, R12and R13are each independently selected from the grouspis ctoinng of phenyl, furan-2-yl, naphthalen-1- yl, C3-C6-cycloalkyl and C3-C6-alkyl, wherein the phenyl is unsubstituted or stiutubtsed with one to three substituents each independently selected fromr tohuep g consisting of C1-C4-haloalkyl, C1-C4-alkyl, and C1- C4-alkoxy, R14is phenyl or C1-C6-alkyl, R15and R16are each independently selected from the grouspis ctoinng of phenyl, furan-2-yl, naphthalen-1- yl, C3-C6-cycloalkyl and C3-C6-alkyl, wherein the phenyl is unsubstituted or stiutubtsed with one to three substituents each independently selected fromr tohuep g consisting of C1-C4-haloalkyl, C1-C4-alkyl, and C1- C4-alkoxy, and R17is C1-C6-alkyl.More preferably, Q and the substituen3ts to R R17 in formulaeI (IIa ), (IIIb ), (IVa), (IVb ), (Va), (Vb), (VIa),(VIb ), (VIIa ), (VIIb ), (VIIIa ), (VIIIb ), (IXa), (IXb ), (Xa) and (Xb) are defined as follows:R3is phenyl, which is unsubstituted or substituteitdh w one to three substituents each independenletlyct seed from the group consisting of trifluoromethyl, melth aynd methoxy, or3R is furan-2-yl, cyclohexyl, naphthalen-1-yl or tert-butyl, R4is cyclohexyl, tert-butyl or phenyl, wherein thhee pnyl is unsubstituted or substituted with oneh troee t substituents each independently selected fromr tohuep g consisting of trifluoromethyl, methyl and moexthy, R5is tert-butyl or cyclohexyl, Q is N or CH, R6is phenyl, which is unsubstituted or substituteitdh w one to three substituents each independenletlyct seed from the group consisting of1- CC4-alkyl, methoxy, dimethylamino and trifluorometh oylr, R6is furan-2-yl, cyclohexyl, tert-butyl or isopropyl, R7a, R7b, R8a, R8b, R9aand R9bare each independently selected from hydrogenh,o mxye,t methyl and trifluoromethyl, where at least two of7aR, R7b, R8aand R8bare not hydrogen, or R7aand R8aform together a -O-(C2H)-O-, -O-(CH2)2-O-, -O-C(CH3)2-O-, -O-(CF2)-O- or -(CH)4- group, R7band R8bform together the same group (i.e. -O-(2C)-HO-, -O-(CH2)2-O-, -O-C(CH3)2-O-, -O-(CF2)-O- or -(CH)4-), and R9aand R9bare hydrogen, R10and R11are each independently selected from tert-buhtyel,n pyl and cyclohexyl, BCS 243003 FC - 11 - R12and R13are each independently selected from pheny, ceycxylolh and tert-butyl, R14is phenyl or C1-C4-alkyl, R15and R16are each independently selected from the grouspis ctoinng of cyclohexyl, tert-butyl and phenyl, wherein the phenyl is unsubstituted or substitu wtiethd one to three substituents each independeenltelyct sed from the group consisting of trifluoromethyl, melth aynd methoxy, and R17is C1-C4-alkyl.Most preferably, Q and the substituen3ts to R R17 in formulaeI (IIa ), (IIIb ), (IVa), (IVb ), (Va), (Vb), (VIa),(VIb ), (VIIa ), (VIIb ), (VIIIa ), (VIIIb ), (IXa), (IXb ), (Xa) and (Xb) are defined as follows:R3is phenyl, which is unsubstituted or substituteitdh w one or two trifluoromethyl substituents, o3r is R furan-2-yl or naphthalen-1-yl, R4is cyclohexyl or tert-butyl, R5is tert-butyl, Q is N,R6 is phenyl, which is unsubstituted or substituteitdh w one to three substituents independently sedle fcrotemthe group consisting of methyl, tert-butyl and moextyh, R8aand R8bare methoxy and7Ra, R7b, R9aand R9bare hydrogen, or R7aand R8aform together a -O-(C2H)-O- or -O-(CH2)2-O-, R7band R8bform together the same -O-(C2)H- O- or -O-(CH2)2-O- group, and R9aand R9bare hydrogen, R10and R11are each independently selected from tert-butdyl p ahnenyl, R12is cyclohexyl or phenyl, R13is cyclohexyl or phenyl, R14is phenyl, R15is phenyl, which is unsubstituted or substituteitdh w one or two trifluoromethyl substituents, R16is cyclohexyl or tert-butyl, and R17is ethyl. BCS 243003 FC - 12 -Ligands of the formulaII (Ia ), (IIIb ), (IVa), (IVb ), (Va), (Vb), (VIa), (VIb ), (VIIa ), (VIIb ), (VIIIa ),(VIIIb ), (IXa), (IXb ), (Xa) and (Xb) are well known (G. Shang, W. Li, X. Zhang, Cattiacly AsymmetricSynthesis, 3rd Edition, Wiley, 2010, 344-349). Ma onfy them are commercially available. For example, the following ligands are commercial vlyailable and may particularly preferably be u isned the process according to the invention:IIIa-1 : Ligand of the formulaII (Ia ) with R3 = phenyl and R4 = cyclohexyl (CAS: 155806-35-2).IIIb-1 : Ligand of the formulaII (Ib ) with R3 = phenyl and R4 = cyclohexyl (CAS: 162291-02-3).IIIa-2 : Ligand of the formulaII (Ia ) with R3 = furan-2-yl and R4 = tert-butyl (CAS: 849924-41-0).IIIb-2 : Ligand of the formulaII (Ib ) with R3 = furan-2-yl and R4 = tert-butyl (CAS: 849924-42-1).IIIa-3 : Ligand of the formulaII (Ia ) with R3 = phenyl and R4 = tert-butyl (CAS: 155830-69-6).IIIb-3 : Ligand of the formulaII (Ib ) with R3 = phenyl and R4 = tert-butyl (CAS: 277306-29-3).IIIa-4 : Ligand of the formulaII (Ia ) with R3 =4-(trifluoromethyl)phenyl and4 R = tert-butyl (CAS: 246231-79-8).IIIb-4 : Ligand of the formulaII (Ib ) with R3 =4-(trifluoromethyl)phenyl and4 R = tert-butyl (CAS: 849924-37-4).IIIa-5 : Ligand of the formulaII (Ia ) with R3 = naphthalen-1-yl and4 R = tert-butyl (CAS: 849924-43-2).IIIb-5 : Ligand of the formulaII (Ib ) with R3 = naphthalen-1-yl and4 R = tert-butyl (CAS: 849924-44-3).IIIa-6 : Ligand of the formulaII (Ia ) with R3 = 3,5-di(trifluoromethyl)phenyl and4 R = cyclohexyl (CAS:292638-88-1).IIIb-6 : Ligand of the formulaII (Ib ) with R3 = 3,5-di(trifluoromethyl)phenyl and4 R = cyclohexyl (CAS:849923-15-5).IVa-1: Ligand of the formulaIV ( a ) with Q = N and R5 = tert-butyl (CAS: 866081-62-1).IVb-1 : Ligand of the formulaIV ( b ) with Q = N and R5 = tert-butyl (CAS: 1107608-80-9).Va-1: Ligand of the formulaV (a) with R6= phenyl, R7aand R8atogether form a -O-(C2H)-O- group, R7band R8btogether form a -O-(C2H)-O- group, and R9aand R9b= H (CAS: 244261-66-3). Vb-1: Ligand of the formulaV (b) with R6= phenyl, R7aand R8atogether form a -O-(C2H)-O- group, R7band R8btogether form a -O-(C2H)-O- group, and R9aand R9b= H (CAS: 210169-54-3). Va-2: Ligand of the formulaV (a) with R6= 3,5-di-tert-butyl-4-methoxyphenyl,7aR and R8atogether form a -O-(CH2)-O- group, R7band R8btogether form -O-(CH2)-O-, and R9aand R9b= H (CAS: 566940-03-2). Vb-2: Ligand of the formulaV (b) with R6= 3,5-di-tert-butyl-4-methoxyphenyl,7aR and R8atogether form a -O-(CH2)-O- group, R7band R8btogether form -O-(CH2)-O-, and R9aand R9b= H (CAS: 210169-40-7). BCS 243003 FC - 13 - Va-3: Ligand of the formulaV (a) with R6= phenyl, R8a, R8b= methoxy, R7a, R7b, R9aand R9b= H (CAS: 133545-16-1). Vb-3: Ligand of the formulaV (b) with R6= phenyl, R8a, R8b= methoxy, R7a, R7b, R9aand R9b= H (CAS: 133545-17-2). Va-4: Ligand of the formulaV (a) with R6= 3,5-dimethylphenyl,7Raand R8atogether form a -(CH)4- group, R7band R8btogether form a -(CH4-) group, and R9aand R9b= H (CAS: 137219-86-4). Vb-4: Ligand of the formulaV (b) with R6= 3,5-dimethylphenyl,7Raand R8atogether form a -(CH)4- group, R7band R8btogether form a -(CH4-) group, and R9aand R9b= H (CAS: 135139-00-)3. VIa-1: Ligand of the formulaV (Ia) with R10= phenyl and R11= tert-butyl (CAS: 1221746-56-0).VIb-1 : Ligand of the formulaV (Ib ) with R10 = phenyl and R11 = tert-butyl (CAS: 1221746-66-2).VIa-2: Ligand of the formulaV (Ia) with R10= tert-butyl and R11= phenyl (CAS: 1221745-90-)9.VIb-2 : Ligand of the formulaV (Ib ) with R10 = tert-butyl and R11 = phenyl (CAS: 1221746-31-)1.VIIa-1 : Ligand of the formulaV (IIa ) with R12 = cyclohexyl and R13 = cyclohexyl (CAS: 1156547-61-3.)VIIb-1 : Ligand of the formulaV (IIb ) with R12 = cyclohexyl and R13 = cyclohexyl (CAS: 914089-00-2.)VIIIa-1: Ligand of the formulaV (IIIa ) with R14 = phenyl (CAS: 528565-79-9).VIIIb -1: Ligand of the formulaV (IIIb ) with R14 = phenyl (CAS: 824395-67-7).IXa-1: Ligand of the formulaIX (a) with R15= 3,5-di(trifluoromethyl)phenyl and1R6= cyclohexyl (CAS: 821009-34-1.)IXb -1: Ligand of the formulaIX ( b ) with R15 = 3,5-di(trifluoromethyl)phenyl and1 R6 = cyclohexyl (CAS:849925-22-0.) Xa-1: Ligand of the formulaX (a) with R17= ethyl (CAS: 136705-64-1). Xb-1: Ligand of the formulaX (b) with R17= ethyl (CAS: 136779-28-7). The major enantiomer of the hydrogenated produnct b cea controlled by the selection of the chiraln lidg.a For example, the enantiomer of the formuIala) ( can be obtained by using a chiral ligand of tohrem fula(IIIa-1 ), (IIIa-2 ), (IIIa-3 ), (IIIa-4 ), (IIIa-5 ), (IIIa-6 ), (IVa-1), (Va-1), (Va-2), (Va-3), (Va-4), (VIa-1),(VIa-2), (VIIa-1 ), (VIIIb-1 ), (IXb-1) or (Xa-1), and accordingly, the enantiomer of the formuIbla) c (an beobtained by using the respective other enantiomf tehre ose ligands, i.e. a chiral ligand of the foram (uIIlIb-1), (IIIb-2 ), (IIIb-3 ), (IIIb-4 ), (IIIb-5 ), (IIIb-6 ), (IVb-1), (Vb-1), (Vb-2), (Vb-3), (Vb-4), (VIb-1), (VIb-2), (VIIb-1 ), (VIIIa-1 ), (IXa-1) or (Xb-1).Especially preferred in combination with palladiu amre ligands of the general formulaIIeIa ( ), (IIIb ), (IVa),(IVb ). (Va), (Vb), (VIa), (VIb ), (IXa) and (IXb ), where Q and the substituent3s t Ro R16 are as definedabove, such as the ligands of the formuIlaIIea- (1 ), (IIIb-1 ), (IIIa-2 ), (IIIb-2 ), (IIIa-3 ), (IIIb-3 ), (IIIa-4 ), BCS 243003 FC - 14 -(IIIb-4 ), (IIIa-5 ), (IIIb-5 ), (IIIa-6 ), (IIIb-6 ), (IVa-1), (IVb-1), (Va-1), (Vb-1), (Va-2), (Vb-2), (Va-3),(Vb-3), (Va-4), (Vb-4), (VIa-1), (VIb-1), (VIa-2), (VIb-2), (IXa-1) and (IXb-1) as defined herein.Especially preferred in combination with nickel aligreands of the general formulaIeIIa ( ), (IIIb ), (IVa) and(IVb ), where Q and the substituent3s to R R5 are as defined above, such as the ligands oof r thmeu flaeI (IIa-1), (IIIb-1 ), (IIIa-2 ), (IIIb-2 ), (IIIa-3 ), (IIIb-3 ), (IIIa-4 ), (IIIb-4 ), (IIIa-5 ), (IIIb-5 ), (IIIa-6 ), (IIIb-6 ),(IVa-1) and (IVb-1). The amount of the catalyst used is preferably wnith ei range of from 0.001 mol% to 5 mol%, based th oenamount of the compound of the formu (IlIa) . If palladium is used, the amount of palladiuma clyastt is morepreferably 0.005 mol% to 2 mol%, even more prefleyr 0a.b01 mol% to 0.9 mol%, and most preferably 0.01mol% to 0.5 mol%, based on the amount of the comndpou f the formula (II) .The chiral palladium or nickel catalyst can be parep d from a palladium (II) or nickel (II) cataly psrtecursor,such as palladium(II) trifluoroacetate, palladiuIm) (I acetylacetonate, nickel(II) acetate or nickel(II)acetylacetonate, and the chiral biden Pta-tleigand in presence of a suitable solvent. Parebfley,r the catalyst formation step is conducted under inemrto astphere using an ether or alcohol solvent. Suitable solvents for the preparation of the ch piraallladium catalyst are anisole, tetrahydrofura-mn,e 2thyl- tetrahydrofuran, 4-methyl-tetrahydrofuran, cyclotpyel n methyl ether, 2-butanol, tert-amyl alcohol (2- methylbutan-2-ol) and mixtures thereof. Suitablleve snots for the preparation of chiral nickel catatsly asre fluorinated solvents such as 2,2,2-trifluoroetha,n hoexlafluoroisopropanol and mixtures thereof.It is preferred to use a small excess of thel c bhi draentate P-ligand, e.g. 1.05 equivalents or e 1q.u1ivalents,relative to the palladium or nickel catalyst prescour.r Preferably, the solvent is removed, e.g. bstyill daition, before the chiral palladium or nickel catalysts ised u in the hydrogenation process according ton tvheen ition. Preferably, the hydrogenation reaction is condu ucntedder inert atmosphere, for example nitrogeng oorn a.r The reaction time is not critical and may, accogrd tion the batch size and the amount of catalyst, u bseedselected within a relatively wide range. Typicaalc rteion times are between 1 hour and 48 hours,rt inicu pla r2 to 24 hours.After the reaction has ended, the solvent maym beov re d from the reaction mixture by distillation a rnedusedin a new batch of the process according to then itniovne, i.e. the solvent can be recycled. Prefer,a ab hlyigher boiling second solvent is added prior to distiollanti of the solvent or between two or more stepshe of t distillation process to keep the reaction produiscsto dlved and to facilitate complete distillation th oef first solvent (the solvent used in the hydrogenationti roena)c. BCS 243003 FC - 15 - The remaining solution containing the product, c thaetalyst and the higher boiling solvent may diryec btel used in a further reaction step (e.g. the decarlabotivxey ring opening reaction described herein)h oer p troduct can be isolated by crystallization and optionaullryth fer purified by recrystallisation. The palladium or nickel catalyst may be recoverreodm f the mother liquor(s) of the crystallization and recrystallization steps. If the solution containg the product, the palladi ourm nickel catalyst and the higher boiling solv iesn utsed directly in a further reaction step, preferably d theecarboxylative ring opening reaction describerdei hne, thenthe palladium or nickel catalyst may be recoverfteedr a workup of the reaction mixture of this furth rer actionstep. For example, after aqueous workup of thetio renac mixture of the decarboxylative ring opening reaction, isolation of the product by crystallizoanti from the combined organic phases and optionally recrystallization of said product, the palladium ni ocrkel catalyst may be recovered from the mo ltiqhueorr(s) of the crystallization and optionally recrystaalltiizon steps. The starting material of the enantioselective hgydernoation according to the invention (the compoufnd oformula (II )) can be obtained by reacting a compound of thrmeu fola (XI )M+OCN- Bronstedt acid organic solvent (XI ) with an alkali metal cyanate salt, such as potamss ciyuanate or sodium cyanate, in presence of Brdøn asctied, such as acetic acid, and an organic solvent, parbelfye ar secondary alcoholic solvent such as secn-oblu otar isopropanol. This reaction can be performed acncogr tdoi literature procedures (see, for example L:iu Y. et al., ACS Catal.2020, 10, 11153−11161, Supportninfogrm I ation). In a particularly preferred embodiment of the prsosc aeccording to the invention, the process isr feopra pringa compound of the formulaIa (’ ) or (Ib’ ) wherein R1is chlorine, fluorine or methyl, preferably chlnoeri or fluorine, and BCS 243003 FC - 16 - R2is methyl, ethyl, n-propyl or isopropyl,and comprises enantioselective hydrogenation ofm ap cound of the formulaII (’ ) wherein R1 and R2 are each as defined for the compound of the foarm (Iau’l ) or (Ib’ ),wherein the hydrogenation is conducted in pres oenf c ae palladium catalyst comprising a chiral bidetent Pa-ligand of the formulaII (Ia ), (IIIb ), (IVa), (IVb ), (Va), (Vb), (VIa), (VIb ), (VIIa ), (VIIb ), (VIIIa ), (VIIIb ),(IXa), (IXb ), (Xa) or (Xb), a fluorinated solvent and a Lewis acid,wherein the fluorinated solvent is selected fromxa hfleuoroisopropanol, 2,2,2,-trifluoroethanol andxt muries thereof, the lewis acid is selected from trifluoroborane anludminium trifluoromethanesulfonate, the amount of the palladium catalyst used is with ein range of from 0.001 mol% to 5 mol%, basedh oen tamount of the compound of the formu (IlIa ), andwhich is conducted using hydrogen gas at a pres osfu fr oem 5 to 100 bar at a temperature within tahneg reof from 40°C to 100°C. In this particularly prefedrr embodiment, it is even more preferred to usheir a l cbidentate P-ligand of the formulIaIIa ( ), (IIIb ), (IVa), (IVb ), (Va), (Vb), (VIa), (VIb ), (IXa) or (IXb ), forexample the ligand of the formulIaIIa (-1 ), (IIIb-1 ), (IIIa-2 ), (IIIb-2 ), (IIIa-3 ), (IIIb-3 ), (IIIa-4 ), (IIIb-4 ),(IIIa-5 ), (IIIb-5 ), (IIIa-6 ), (IIIb-6 ), (IVa-1), (IVb-1), (Va-1), (Vb-1), (Va-2), (Vb-2), (Va-3), (Vb-3), (Va-4), (Vb-4), (VIa-1), (VIb-1), (VIa-2), (VIb-2), (IXa-1) or (IXb-1) as defined herein. In another embodiment of the process accordinghe to in tvention, the process is for preparing a comndpouof the formulaI (a’ ) or (Ib’ ) wherein BCS 243003 FC - 17 - R1is chlorine, fluorine or methyl, preferably chlnoeri or fluorine, and R2is methyl, ethyl, n-propyl or isopropyl,and comprises enantioselective hydrogenation ofm ap cound of the formulaII (’ ) (II’ ),wherein R1 and R2 are each as defined for the compound of the foarm (Iau’l ) or (Ib’ ),wherein the hydrogenation is conducted in prese onfc ae nickel catalyst comprising a chiral bident Pat-eligand of the formulaII (Ia ), (IIIb ), (IVa), (IVb ), (Va), (Vb), (VIIIa ), (VIIIb ), (Xa) or (Xb) and afluorinated solvent, wherein the fluorinated solvent is selected fromxa hfleuoroisopropanol, 2,2,2,-trifluoroethanol andxt muries thereof, wherein the amount of nickel used is within theg rean of from 0.1 mol% to 5 mol%, based on the amou f ntthe compound of the formu (laII’ ), andwhich is conducted using hydrogen gas at a pres osfu fr oem 5 to 100 bar at a temperature within tahneg reof from 40°C to 100°C. In this embodiment, it ise env more preferred to use 1 mol% to 5 mol% nickelcatalyst and a chiral bidentate P-ligand of them fuolra (IIIa ), (IIIb ), (IVa) or (IVb ), for example the ligandof the formulaI (IIa-1 ), (IIIb-1 ), (IIIa-2 ), (IIIb-2 ), (IIIa-3 ), (IIIb-3 ), (IIIa-4 ), (IIIb-4 ), (IIIa-5 ), (IIIb-5 ),(IIIa-6 ), (IIIb-6 ), (IVa-1) or (IVb-1) as defined herein.In another embodiment of the process accordinghe to in tvention, the process is for preparing a comndpouof the formulaI (a’’ ) or (Ib’’ ) (Ia’’) (Ib ’’)wherein the substituents are defined as follows: R1is chlorine or methyl, and BCS 243003 FC - 18 - R2is chlorine or methyl,and comprises enantioselective hydrogenation ofm ap cound of the formulaII (’’ ) (II’’ ),wherein R1 and R2 are each as defined for the compound of the foarm (Iau’l’ ) or (Ib’’ ).wherein the hydrogenation is conducted in prese onfc ae nickel catalyst comprising a chiral bident Pat-eligand of the formulaII (Ia ), (IIIb ), (IVa), (IVb ), (Va), (Vb), (VIIIa ), (VIIIb ), (Xa) or (Xb) and afluorinated solvent, wherein the fluorinated solvent is selected fromxa hfleuoroisopropanol, 2,2,2,-trifluoroethanol andxt muries thereof, wherein the amount of nickel used is within theg rean of from 0.1 mol% to 5 mol%, based on the amou f ntthe compound of the formu (laII’’ ), andwhich is conducted using hydrogen gas at a pres osfu fr oem 5 to 100 bar at a temperature within tahneg reof from 40°C to 100°C. In this embodiment, it ise env more preferred to use 1 mol% to 5 mol% nickelcatalyst and a chiral bidentate P-ligand of them fuolra (IIIa ), (IIIb ), (IVa) or (IVb ), for example the ligandof the formulaI (IIa-1 ), (IIIb-1 ), (IIIa-2 ), (IIIb-2 ), (IIIa-3 ), (IIIb-3 ), (IIIa-4 ), (IIIb-4 ), (IIIa-5 ), (IIIb-5 ),(IIIa-6 ), (IIIb-6 ), (IVa-1) or (IVb-1) as defined herein.The nickel catalzed hydrogenation according to in thve ntion may be conducted in presence of a Lecwidis asuch as trifluoroborane, aluminium trifluoromethsaunlefonate or zinc triflate. It has however beenn fdou thatin case of the nickel catalysed hydrogenationi roena,c tthe addition of a Lewis acidic co-catalyst m hay ve adisadvantageous effect on the reaction outcom pea,r itnicular the enantioselectivity. Accordingly, t nhieckel catalzed hydrogenation is more preferably condu icnte absence of any Lewis acid co-catalyst.The present invention also relates to a compoun thde of ormulaI (a’ ) or (Ib’ ) BCS 243003 FC - 19 - (Ia’ ) (Ib’ ),wherein R1is chlorine, fluorine or methyl, preferably chlnoeri or fluorine, and R2is methyl, ethyl, n-propyl or isopropyl.The present invention also relates to a compoun thde of ormulaI (a’ ) or (Ib’ ) wherein R1is hydrogen or chlorine, and R2is bromine, methyl or trifluoromethyl.The present invention also relates to a compoun thde of ormulaI (a’’ ) or (Ib’’ ) (Ia’’) (Ib ’’)wherein R1is chlorine or methyl, and R2is chlorine or methyl,Especially preferred are compounds of the formIual’a ) ( or (Ib’ ), wherein R1 is chlorine and R2 is methyl.The compound of formulaIa () or (Ib), in particularI (a’ ) or (Ib’ ), obtained by the process according to theinvention can be converted to important chirald binugi blocks such as enantiopure chiral aminoallcsoho and haloamines by subsequent decarboxylative rpinegnin og reaction. BCS 243003 FC - 20 -Accordingly, the present invention also relate as t porocess for preparing a compound of the formula(XIIa) or (XIIb) , wherein n is 0, 1, 2 or 3, each substituent R, if present, is independenltelyct seed from the group consisting of halogen, hydroxy, C1-C6-alkyl, C1-C6-haloalkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy and C1-C6- alkylcarbonyl, and X is hydroxy, chlorine or bromine, comprising the process for preparing the compoufn thde o formula (Ia) or (Ib) according to the invention, wherein n and R are each defined as in the comdpo fu tnhe formulaX (IIa ) or (XIIb ),and further comprising decarboxylative ring open oinfg the compound of the formulIaa () to the compoundof the formula X ( IIa ) or ring opening of the compound of the formuIlba) ( to the compound of therespectively X (IIb ) using aqueous sodium hydroxide, aqueous pomtas hsyiudroxide solution, hydrogenchloride, aqueous hydrochloric acid, hydrogen bdroem oir aqueous hydrobromic acid.Accordingly, the present invention also prefera rbely ates to a process for preparing a compounde of thformula (XIIa) or (XIIb) , (XIIa ) (XIIb ),wherein n is 1 or 2, BCS 243003 FC - 21 - each substituent R, if present, is independenltelyct seed from the group consisting of fluorine, chlorine, bromine, methyl, ethyl and trifluoromelth aynd X is hydroxy, chlorine or bromine, comprising the process for preparing the compoufn thde o formula (Ia) or (Ib) according to the invention, wherein n and R are each defined as in the comdpo fu tnhe formulaX (IIa ) or (XIIb ),and further comprising decarboxylative ring open oinfg the compound of the formulIaa () to the compoundof the formula X ( IIa ) or ring opening of the compound of the formuIlba) ( to the compound of therespectively X (IIb ) using aqueous sodium hydroxide, aqueous pomtas hsyiudroxide solution, hydrogenchloride, aqueous hydrochloric acid, hydrogen bdroem oir aqueous hydrobromic acid. The decarboxylative ring opening reaction may bned cuocted according to literature procedures (US 2,617,825, J.R. Piper et al. J. Med. Chem. 197,5, 80138-812; M. Viard, P. Piganio Ql,uelques nouveaux dérivés de l’éthylèn,e XXIIIe Congrès International de Chimie Industlreie,l Milan, 17-23 Septembre 1950),for example by heating the compound of formuIala) ( respectivelyI (b) in presence of the aqueous sodiumhydroxide, aqueous potassium hydroxide, hydrogelonri cdhe, hydrochloric acid, hydrogen bromide or hydrobromic acid solution and optionally an organ soiclvent, such as chlorobenzene. Preferably, the decarboxylative ring opening reaction is conduc atetd a temperature within the range of from 60 °C to 130 °C, in particular 80 °C to 120 °C.Compounds of the formulaXI (Ia ) or (XIIb ) with X = OH are obtained when aqueous sodiumo hxyidr e oraqueous potassium hydroxide solution is used in d tehcearboxylative ring opening reaction, whereascompounds of the formulaXI (Ia ) or (XIIb ) with X = Cl can be obtained by using hydrogeno crihdle oraqueous hydrochloric acid and compounds of theu folarm (XIIa ) or (XIIb ) with X = Br can be obtained byusing hydrogen bromide or aqueous hydrobromic acid.In the two-step process according to the inven (tcion mprising the inventive enantioselective hydroagtieonand the decarboxylative ring opening reaction), c tohme pounds of the formulaXI (Ia) and (XIIb) arepreferably compounds of the formulXaII (a’) and (XIIb’) BCS 243003 FC - 22 - (XIIa’ ) (XIIb’ ),wherein R1is chlorine, fluorine or methyl, R2is methyl, ethyl, n-propyl or isopropyl, and X is hydroxyl, chlorine or bromine.In the two-step process according to the inven (tcion mprising the inventive enantioselective hydroagtieonand the decarboxylative ring opening reaction), c tohmepounds of the formulaXI (Ia) and (XIIb) are likewisepreferably compounds of the formulXaII (a’) and (XIIb’) wherein R1is chlorine, fluorine or methyl, R2is methyl, ethyl, n-propyl, isopropyl or trifluoromethyl, and X is hydroxyl, chlorine or bromine.More preferably, the substituents in the compou onfd thse formulaX ( IIa’ ) or (XIIb’ ) are defined as follows:R1is chlorine, R2is methyl and X is hydroxyl, chlorine or bromine.The present invention also relates to a compoun thde of ormulaX ( IIa’ ) or (XIIb’ ) wherein R1is chlorine or fluorine, R2is methyl, ethyl, n-propyl or isopropyl, and BCS 243003 FC - 23 - X is hydroxyl, chlorine or bromine.Preferred are compounds of the formulXaeIIa (’ ) and (XIIb’ ), wherein R1 is chlorine or fluorine, R2 isbromine, methyl or trifluoromethyl, and X is hydxryol, chlorine or bromine.More preferred are compounds of the formulXaIeIa (’ ) and (XIIb’ ), wherein R1 is chlorine, R2 is methyland X is hydroxyl, chlorine or bromine.Even more preferred are compounds of the formuXlaIIea’ ( ) and (XIIb’ ), wherein R1 is chlorine, R2 ismethyl and X is hydroxyl or bromine.Still even more preferred are compounds of theu folarme (XIIa’ ) and (XIIb’ ), wherein R1 is chlorine, R2is methyl and X is hydroxyl.The present invention also relates to compound thse o fformula (XIIa) or (XIIb) , (XIIa ) (XIIb ),wherein n is 1 or 2, each substituent R, if present, is independenltelyct seed from the group consisting of halogen1-,C C4- alkyl and C1-C4-haloalkyl, X is hydroxy, chlorine or bromine, prepared by the process according to the invention.Preferred are compounds of the formuXlaIIa (’ ) or (XIIb’ ) wherein R1is chlorine or fluorine, BCS 243003 FC - 24 - R2is methyl, ethyl, n-propyl or isopropyl, and X is hydroxyl, chlorine or bromine, prepared by the process according to the invention.More preferred are compounds of the formulXaIeIa (’ ) and (XIIb’ ), wherein R1 is chlorine, R2 is methyland X is hydroxyl, chlorine or bromine prepared th bey process according to the invention.Even more preferred are compounds of the formuXlaIIea’ ( ) and (XIIb’ ), wherein R1 is chlorine, R2 ismethyl and X is hydroxyl or bromine prepared by p throecess according to the invention.Still even more preferred are compounds of theu folarme (XIIa’ ) and (XIIb’ ), wherein R1 is chlorine, R2is methyl and X is hydroxyl prepared by the proc aecscsording to the invention. The present invention is further illustrated inf tohlelowing examples.

[0002] BCS 243003 FC - 25 - Examples Abbreviations: AcOH acetic acid Al(OTf)3 aluminium trifluoromethanesulfonate BF3.Et2O boron trifluoride diethyl etherate CSA camphorsulfonic acid ee enantiomeric excess er enantiomeric ratio EtOH ethanol EtOAc ethyl acetate h hour(s) HPLC high-performance liquid chromatography iPrOAc isopropyl acetate LCMS liquid chromatography-mass spectrometry MeCN acetonitrile Me2CO3dimethyl carbonate 2-Me-THF 2-methyl-tetrahydrofuran Ni(OAc)2.4H2O nickel(II)acetate tetrahydrate NMR nuclear magnetic resonance spectroscopy Pd(TFA)2palladium(II) trifluoroacetate PhCF3trifluorotoluene TFA trifluoroacetic acid TFE 2,2,2,-trifluoroethanol THF tetrahydrofuran Ti(OiPr)4: titanium tetraisopropoxide Zn(OTf)2 zinc triflate Methods: The compounds were characterized by LCMS, NMR, H aPnLdC on a chiral stationary phase. Method A: LCMS was performed on a Waters UPLC smys wteith SQD2 detector; column: Agilent Zorbax Eclipse Plus C18, 2.1 x 50mm; injection volume:l; 1 fl µow rate 1 ml / min; column temperature: 55 °C;Detection: Single Quad MS and Diode Array dete 2ct1o0r – 450nm, with 210 nm observation wavelength;eluent A: acetonitrile + 0.1% formic acid; eluen:t H B2O + 0.1% formic acid; gradient program: BCS 243003 FC - 26 - Time (%) Pump A (%) Pump B 0 10 90 0.2 10 90 1.8 95 5 2.6 95 5 2.65 10 90 2.7 10 90 NMR spectra were aquired at room temperature (2)2 on °C a Bruker Avance III HD 600 MHz spectrometer operating at 600 MHz for proton nuclei and and M 15H0z for carbon nuclei, or on a Bruker Avance III HD 400 MHz spectrometer operating at 400 MHz for pnro ntouclei and and 100 MHz for carbon nuclei. Proton chemical shifts are expressed in parts pilleiorn m (ppm, δ scale) and are referenced to residual protium in the NMR solvent. Carbon chemical shifts are esxsperd in parts per million (ppm δ, scale) and are referenced to the carbon resonance of the NMRn sto.l 1vHe NMR spectroscopic data are reported asw fosl:lo Chemical shift in ppm (multiplicity, coupling conasntts J (Hz), integration intensity). The multiptliiecsi are abbreviated with s (singlet), d (doublet), t (teritp),l q (quartet), app (apparent), combinationse tohfe,r and m (multiplet). In case of combined multiplicities,e th multiplicity with the larger coupling constant s itsated first. Except for complex and overlapping multipsl,e wt here a resonance range is given, the chemhiicftal s of all other symmetric signals is reported as tehnete cr of the resonance range.13C NMR spectrosc doaptaic are reported as follows: Chemical shift in ppm. N 2DMR techniques such as homonuclear correlation spectroscopy (COSY), heteronuclear single quantouhmer cence (HSQC) and heteronuclear multiple bond coherence (HMBC) were used to assist signal asseingtn.m Purity of substances was determined by quantita NtMiveR using an internal standard (methyl-3,5-din-itro benzoate, trimethoxybenzene or dimethylcarbonaft ken)o own and certified purity and by employing a relaxation delay (D1) of 60 s. Method B: HPLC on chiral stationary phase was prmerefod on an Agilent Chemstation 1100 system; Column: Phenomex Lux Amylose-2, 5 µm, 250 x 4.6 ( mLHmS6245); Solvent: isocratic elution with 60% Water containing 0.1%3 HPO4 and 40% MeCN containing 0.1%3P HO4; Flow: 0.7 mL / min; Runtime: 30 min; Detection: UV at 210 nm; Oven temperature:C 2;5 S°ample preparation: crude product dissolved in 1 mL MeCN; Injection volume: 2 μL; Method C: HPLC on chiral stationary phase was prmerefod on an Agilent Chemstation 1260 system; Column: Phenomex Lux Amylose-2, 5 µm, 250 x 4.6 ( mLHmS6245); Solvent: isocratic elution with 90% n-hexane and 10% Ethanol containing 0.2% ethanonleam byi Volume; Flow rate 1.0 mL / min; Runtime: 20 min; Detection: UV at 220 nm; Oven temperatureC 2;5 S °ample preparation: dissolve approc.10 mg product in 10 mL of isopropanol; Injection volum 1e0: μL; BCS 243003 FC - 27 - Method D: HPLC on chiral stationary phase was prmerefod on an Agilent 1260 system; Column: Chiralpak AZ-RH 5 µm, 150 x 4.6 mm; Injection volume: μ 3L; Flow rate: 1.2 mL / min; Column temperature: 40°C;Detection: DAD at 210 nm; Eluent A: 0.1 % (w / w) aeqou s phosphoric acid, eluent B: acetonitrile;Sample preparation: prepare a solution of approtxeilmya 1 mg / mL in acetonitrile / 0.1 % (w / w) aqueous phosphoric acid with a ratio of 80 / 20. Sonicat nee icfessary. Gradient program: Time (min) (%) Pump A (%) Pump B 0.00 90 10 15.00 40 60 16.00 40 60 16.01 90 10 Method E: HPLC on chiral stationary phase was prmerefod on an Agilent 1260 system; Column: Chiralpak AZ-RH 5 µm, 150 x 4.6 mm; Injection volume μ:L 3; flow rate: 1.0 mL / min; Column temperature: amnbtie (not controlled); Detection: DAD at 210 nm; Elue An:t 0.1 % (w / w) aqueous phosphoric acid, eluent B: acetonitrile; Sample preparation: prepare a solution of approtxeilmya 1 mg / mL in acetonitrile / 0.1 % (w / w) aqueous phosphoric acid with a ratio of 80 / 20. Sonicat nee icfessary. Gradient program: Time (min) (%) Pump A (%) Pump B 0 90 10 16.00 62 38 18.00 62 38 18.01 90 10 Method F: HPLC on chiral stationary phase was prmerefod on an Agilent 1260 system; Column: Chiralpak AY-RH 5 µm, 150 x 4.6 mm; Injection volume: 1 μ.5L; flow rate: 1.5 mL / min; Column temperature: ambient (not controlled); Detection: DAD at 210 n Emlu;ent A: sodium phosphate buffer pH: 6.5, elu Be:nt acetonitrile; Sample preparation: prepare a sonlu otifo approximately 1 mg / mL in acetonitrile / 0.1 % / w (w) aqueous phosphoric acid with a ratio of 80 / 20.c Saotnei if necessary. BCS 243003 FC - 28 - Gradient program: Time (min) (%) Pump A (%) Pump B 0 95 5 1.00 95 5 16.00 15 85 19.00 15 85 20.00 95 5 23.00 95 5 Method G: HPLC on chiral stationary phase was prmerefod on an Agilent 1260 system; Column: Chiralpak AZ-RH 5 µm, 150 x 4.6 mm; Injection volume μ:L 3; flow rate: 0.75 mL / min; Column temperature: amenbti (not controlled); Detection: DAD at 210 nm; Elue An:t 0.1 % (w / w) aqueous phosphoric acid, eluent B: acetonitrile; Sample preparation: prepare a solution of approtxeilmya 1 mg / mL in acetonitrile / 0.1 % (w / w) aqueous phosphoric acid with a ratio of 80 / 20. Sonicat nee icfessary. Gradient program: Time (min) (%) Pump A (%) Pump B 0.00 70 30 10.00 70 30 25.00 25 75 26.00 70 30 Method H: HPLC on chiral stationary phase was premrefod on an Agilent 1260 system; column: Chiralpak AZ-RH 5 µm, 150 x 4.6 mm; injection volume μ:L 3; flow rate: 0.75 mL / min; column temperature: amenbti (not controlled); detection: DAD at 210 nm; elue An:t 0.1 % (w / w) aqueous phosphoric acid, eluent B: acetonitrile; sample preparation: prepare a solution of approtxeilmya 1 mg / mL in acetonitrile / 0.1 % (w / w) aqueous phosphoric acid with a ratio of 80 / 20. Sonicat nee icfessary. BCS 243003 FC - 29 - Gradient program: Time (min) (%) Pump A (%) Pump B 0 78 22 15.00 62 38 17.00 62 38 17.20 78 22 Conversion is based on HPLC Area % and is calcdula ste follows; 100 Selectivity is based on HPLC Area % and is calceudlat s follows: 100 Solvent and Ligand peaks are ignored in the catlicounlsa. Chiral ligands: The following ligands were used in the examples:IIIa-1 : Ligand of the formulaII (Ia ) with R3 = phenyl and R4 = cyclohexyl.IIIa-2 : Ligand of the formulaII (Ia ) with R3 = furan-2-yl and R4 = tert-butyl.IIIa-3 : Ligand of the formulaII (Ia ) with R3 = phenyl and R4 = tert-butyl.IIIb-3 : Ligand of the formulaII (Ib ) with R3 = phenyl and R4 = tert-butyl.IIIa-4 : Ligand of the formulaII (Ia ) with R3 =4-(trifluoromethyl)phenyl and4 R = tert-butyl.IIIa-5 : Ligand of the formulaII (Ia ) with R3 = naphthalen-1-yl and4 R = tert-butyl.IIIa-6 : Ligand of the formulaII (Ia ) with R3 = 3,5-di(trifluoromethyl)phenyl and4 R = cyclohexyl.IVa-1: Ligand of the formulaIV ( a) with Q = N and R5= tert-butyl. Va-1: Ligand of the formulaV (a) with R6= phenyl, R7aand R8atogether form a -O-(C2H)-O- group, R7band R8btogether form a -O-(C2H)-O- group, and R9aand R9b= H. Va-2: Ligand of the formulaV (a) with R6= 3,5-di-tert-butyl-4-methoxyphenyl,7aR and R8atogether form a -O-(CH2)-O- group, R7band R8btogether form -O-(CH2)-O-, and R9aand R9b= H. Vb-3: Ligand of the formulaV (b) with R6= phenyl, R8a, R8b= methoxy, R7a, R7b, R9aand R9b= H. Va-4: Ligand of the formulaV (a) with R6= 3,5-dimethylphenyl,7Raand R8atogether form a -(CH)4- group, R7band R8btogether form a -(CH4-) group, and R9aand R9b= H. BCS 243003 FC - 30 - VIa-1: Ligand of the formulaV (Ia) with R10= phenyl and R11= tert-butyl. VIa-2: Ligand of the formulaV (Ia) with R10= tert-butyl and R11= phenyl.VIIa-1 : Ligand of the formulaV (IIa ) with R12 = cyclohexyl and R13 = cyclohexyl.VIIIa -1: Ligand of the formulaV (IIIa ) with R14 = phenyl.IXa-1: Ligand of the formulaIX (a) with R15= 3,5-di(trifluoromethyl)phenyl and1R6= cyclohexyl. Xa-1: Ligand of the formulaX (a) with R17= ethyl.

[0003] BCS 243003 FC - 31 - Example 1: Preparation of (S)-4-(2-chloro-4-metheynlzbyl)oxazolidine-2-one 1.1 Preparation of 4-(2-chloro-4-methylbenzyl)oxla-2z(o3H)-one: A 30-L triple jacketed reactor equipped with oveardhe stirrer under inert atmosphere at 22 °C wasg cehdar with 2-butanol (15.7 L, 170.8 mol), 1-(2-chloro-4e-mthylphenyl)-3-hydroxypropan-2-one (1.983 kg, 9.8 mol), potassium cyanate (1.245 kg, 14.7 mol) anedtic ac acid (1.180 kg, 19.6 mol). The reaction was heated to 60 °C internal temperature and stirrerd 12 fo0 min. The reaction was then cooled to room temperature and washed with water (10 L). The oicrga pnhase was concentrated to dryness and resuspended in cyclopentyl methyl ether (7 L). T mhiexture was heated to 75 °C until the material dissolved. After dissolution of the solids the rteioanc was cooled naturally to room temperature beefor being stirred at 5 °C for 1.5 hour Tsh.e product was then collected by filtration o ave larrge, fritted funnel. The solid was washed with cyclopentyl methyl et (h0e.5r L). The product was then suspended in water (9 L) and then collected over a por. 3 fritted feuln.n The solids were washed with water (1.0 L). The material was then dried to afford 4-(2-chloro-4-hmyelbtenzyl)oxazol-2(3H)-one in form of a light pink solid (1.687 kg, 76% yield, 99% purity as determdin bey quantitative NMR).1H NMR (600 MHz, CDC3l) δ 9.36 (br s, 1H), 7.24 – 7.19 (m, 1H), 7.16 J (d =, 7.8 Hz, 1H), 7.05 (ddd J, =7.8, 1.7, 0.8 Hz, 1H), 6.48 ( Jq, = 1.2 Hz, 1H), 3.74 (d J, = 1.4 Hz, 2H), 2.31 (s, 3H).13C NMR (150 MHz, CDC3l) δ 157.66, 139.31, 133.76, 130.52, 130.44, 130.28.,2182, 125.39, 125.34, 27.97, 20.92. LCMS (ESI) for C11H11ClNO2+ [M+H]+ calculated: 224.05; found: 224.0; Retention Time (LCMS, Method A): 1.04 min. Retention time (HPLC on chiral stationary Phaset,h Mode B): 16.8 min. BCS 243003 FC - 32 - General procedure for the preparation of additio 2n-oaxlazolones in laboratory scale (typical sca0le-:401 mmol of hydroketone) In a round-bottom flask equipped with a magnetiircre srt, hydroxyketone (1.0 eq) and sodium cyanate (1.2 eq) added to isopropanol (10 mL solvent every 1f h gyd oroxyketone). Then, acetic acid (2.2 eq) wadse add and the reaction mixture was stirred overnight h ()17 at 60°C. The suspension was diluted with EtO (6A0c mL) and washed with water (50 mL). The aqueousr la wyaes extracted with EtOAc (20 mL). All organic phases were combined, washed with saturated Na3H soCluOtion (30 mL), saturated NaCl solution (30 mL), dried over Na2SO4, and filtered. The bulk of tohleve snt was removed under reduced pressure to a tfhfoerd crude reaction product which was further purifieladsh f colum chromatography (S2i,O gradient of cyclohexane / ethyl acetate). For further purificna,tio the product was recrystallised from tert-butyelth myl ether and cyclohexane to afford a white solid. Example 7.1: Preparation of 4-[4-(trifluoromethyl)benzyl]-1,3-aozxol-2(3H)-one The target compound was obtained in 53% yield; g 1 (.67,99 mmol) were prepared.1H NMR (600 MHz, CDC3l) δ 9.84 (s, 1H), 7.59 (d J, = 8.0 Hz, 2H), 7.36 (d J, = 8.0 Hz, 2H), 6.52 (s, 1H), 3.71 (s, 2H).13C NMR (151 MHz, CDC3l) δ 157.95, 139.56, 139.55, 129.89 J (q =, 32.5 Hz), 129.19, 125.98 ( Jq, = 3.8Hz), 124.15 (q J, = 271.9 Hz); 30.43.LCMS (ESI) for C11H9F3NO2+ [M+H] + calculated: 244.1; found: 244.4;Retention Time (LCMS, Method A 0):.96 min. Example 7.2: Preparation of 4-(3,5-dichlorobenzyl)-1,3-oxazo3l-H2()-one The target compound was obtained in 66% yield; g 3 (.189.03 mmol) were prepared.1H NMR (600 MHz, CDC3l) δ 9.56 (s, 1H), 7.28 (d J, = 3.8 Hz, 1H), 7.13 (d J, = 1.9 Hz, 2H), 6.55 (s, 1H), 3.62 (d, J = 1.4 Hz, 2H).13C NMR (151 MHz, CDCl3) δ 157.66, 138.75, 135.55, 127.88, 127.30, 125.55.,3102, 29.97.LCMS (ESI) for C10H8Cl2NO2+ [M+H] + calculated: 244.0; found: 244.2;Retention Time (LCMS, Method A 1):.01 min. Example 7.3: Preparation of 4-(4-bromo-2-chlorobenzyl)-1,3-oxla-2z(o3H)-one The target compound was obtained in 48% yield; g 3 (.162.48 mmol) were prepared. BCS 243003 FC - 33 -1H NMR (600 MHz, CDC3l) δ 9.20 (s, 1H), 7.57 (d J, = 2.0 Hz, 1H), 7.39 (dd J, = 8.2, 2.0 Hz, 1H), 7.16(d, J = 8.2 Hz, 1H), 6.52 (d J, = 1.5 Hz, 1H), 3.76 – 3.72 (m, 2H).13C NMR (150 MHz, CDC3l) δ 157.43, 135.05, 132.65, 132.54, 131.81, 130.758.,6162, 124.41, 121.94, 27.97.LCMS (ESI) for C10H8BrClNO2+ [M+H] + calculated: 288.0 ; found: 288.1;Retention Time (LCMS, Method A): 1.03 min. Example 7.4: Preparation of 4-(4-methylbenzyl)-1,3-oxazol-2(3oHn)e- The target compound was obtained in 51% yield; g 3 (.169.03 mmol) were prepared.1H NMR (600 MHz, CDC3l) δ 9.35 (s, 1H), 7.16 – 7.09 (m, 4H), 6.47 (s, 1H.6),03 (s, 2H), 2.33 (s, 3H).13C NMR (150 MHz, CDC3l) δ 157.82, 137.13, 132.32, 129.70, 128.67, 127.045.,8152, 30.22, 21.18.LCMS (ESI) for C11H12NO2+ [M+H] + calculated: 190.1 ; found: 190.3;Retention Time (LCMS, Method A): 0.86 min. Example 7.5: Preparation of 4-(2,4-dimethylbenzyl)-1,3-oxazo3l-H2)(-one The target compound was obtained in 51% yield; g 3 (.178.19 mmol) were prepared.1H NMR (600 MHz, CDC3l) δ 8.89 (s, 1H), 7.07 – 6.95 (m, 3H), 6.36 J (q =, 1.5 Hz, 1H), 3.61 (d J, = 1.6Hz, 2H), 2.30 (s, 3H), 2.26 (s, 3H).13C NMR (150 MHz, CDC3l) 157.52, 137.45, 136.34, 131.67, 130.27, 129.2571.,216, 126.17, 125.11, 27.92, 21.09, 19.23.LCMS (ESI) for C12H14NO2+ [M+H] + calculated: 204.1 ; found: 204.4;Retention Time (LCMS, Method A): 0.96 min. 1.2 Preparation of (S)-4-(2-chloro-4-methylbenzxyal)zoolidine-2-one BCS 243003 FC - 34 - A 100 ml Schlenk-tube equipped with teflon-coatteirdrin sg bar was charged with Pd(TF2A ()0.369 g, 1.1mmol) and ligand IIIa-4 (0.828 g, 1.2 mmol). The tube was connected toch ale Snk line, and it wasevacuated and refilled 3 times with arg boenfore the addition of anisole (56 ml). A 8 L autoclave was rendered inert by applying anr (g5o bar) followed by slow release of pressure th veia exhaust pipe. A 10 L vacuum glass bottle was chdar wgieth 4-(2-chloro-4-methylbenzyl)oxazol-2(3H)-one (500 g, 2.22 mol). Next, hexafluoroisopropa (n5o.0l L) from the drum was transferred into the vuamcuglass bottle that contained the starting materyia alp bplying a slight overpressure of argon (0.12 - b 0a.r) while carefully shaking the bottle. The homogene sooulsution was bubbled with argon for 5 min. Argon was connected directly to the 10 L vacuum flask a tnhde solution of starting material in hexafluoroisopropanol was transferred from the s gla bsottle into the autoclave applying a slight overpressure of argon (0.1 - 0.2 bar). Afterwar thdes, autoclave was charged with3B•OFEt2(8.22 ml, 0.067 mol) followed by the catalyst stock solution under agh stli argon counter flow. The 8 L autoclave was made inert by applying argon (5 bar) followeyd s blow release of the pressure through the exhaust pipe. The stirrer was switched on and the autoc wlaavse pressurized to 15 ba2r. H The temperature was set to 80°C (60°C / h heating ramp). The reaction warsre sdti at 80 °C for 14 h. The autoclave was coolewdn do to 25 °C and then the pressure was carefully redle vaisa the exhaust pipe. The autoclave was flus whitehdargon (3 minutes stirring) and pressure carefuelly ea rsed via the exhaust pipe (repeated 3 timese). Threaction mixture was then transferred into a 10o Lub dle jacketed reactor equipped with a distillation apparatus and ice-cooled distillate receiving f.la Tshke first batch of hexafluoroisopropanol wasil dleisdtat ambient pressure with a jacket temperature f 9r0om – 120 °C (vapor temperature of 58 °C). The purresswas then reduced to 175 mbar, and the hexafluoprrooispoanol distillation was continued at 120 °C (vrapo temperature of 35 °C). Chlorobenzene (0.5 L) wdadsed a, and the distillation was continued (60 mbnadr a 120 °C). Chlorobenzene (0.5 L) was added and tmheai rneing hexafluoroisopropanol was distilled (20mbar, 120 °C). The second batch of hexafluoroispoapnro l was distilled under vacuum at a pressure of175 mbar with a jacket temperature of 120 °C. Tihsetill dation was continued until 680 g of solution remained. At this point chlorobenzene (0.5 L) wdadse ad and the remaining hexafluoroisopropanol was distilled at 60 mbar, 120 °C jacket temperature. th Teo reaction mixture was added chlorobenzene L ()0.5 and the distillation was continued at a pressur 2e0 o mf bar, 120 °C jacket temperatu Treh.e mixture wasdiluted to 37 wt% with chlorobenzene (0.675 L). t Theo reaction mixture was then added aqueous sodiumbisulfite solution (20 wt% aqueous solution, 0.6 a Ln)d the mixture was stirred at 60 °C internal temperature for 2 hours. Then water (0.1 L) wase add. Tdhe phases were separated, and the organiec phas was then washed with water (0.4 L). The organics peh waas then filtered through celite (61 g) and the filter cake was washed with chlorobenzene. Theti roenac mixture can be carried to the next step withou further purification (cf. example 6). Alternatively, the oxazolidinone can be isolated a a ssolid. To the reaction mixture was added hep (t1a.n0e L) at 80 °C, and then the mixture was slowly coo tloed -20 °C overnight. The product was collected by BCS 243003 FC - 35 - filtration, washed with three portions of heptan0e.25 (0 L) and dried to afford (S)-4-(2-chloro-4- methylbenzyl)oxazolidine-2-one as a tan solid (14481 g., 96.3 % yield, 99.6 % purity, 98 e%e).1H NMR (400 MHz, CDC3l) δ 7.25 – 7.19 (m, 1H), 7.10 (d J, = 7.7 Hz, 1H), 7.04 (ddd J, = 7.7, 1.7, 0.8 Hz, 1H), 5.30 (br s, 1H), 5.29 (s, 1H), 4.52 – 4 (.m41, 1H), 4.24 – 4.12 (m, 2H), 3.08 – 2.98 (m, 12H.9),2 (dd, J = 13.6, 7.4 Hz, 1H), 2.32 (s, 3H).13C NMR (150 MHz, CDC3l) δ 159.36, 139.25, 133.87, 131.24, 130.63, 130.589.,212 , 69.67, 52.13, 38.80,20.89. LCMS (ESI) for C11H13ClNO2+ [M+H]+ calculated: 226.06; found: 226.0; Retention Time (LCMS, Method A): 0.96 min. Retention time (HPLC on chiral stationary Phaset,h Mode B): (R)-enantiomer: 13.2 min, (S)-enantiomer: 14.0 min. Example 2: Preparation of (S)-4-(2-chloro-4-metheynlzbyl)oxazolidine-2-one using various reaction conditions General procedure for the preparation of cataloylsutti sons: Pd(TFA)2and ligand in a molar ratio of 1 to 1.25 were ad tdoe ad Schlenk flask equipped with a stirring bar and dry, degassed THF. The resulting solutions w steirrreed for 30 minutes at room temperature andn the aliquoted into the appropriate reaction wells. Ni(OAc)2x 4 H2O and ligand in a molar ratio of 1 to 1.25 weree addd to a Schlenk flask equipped with a stirring bar and dry, degassed TFE. The resultoinlugti sons were stirred for 16 hours at room tempuerrea atnd then aliquoted into the appropriate reaction wells. General procedure for hydrogenation reactions: Under an inert gas atmosphere, a well of a 96 p wlaetlle- autoclave was charged with 4-(2-chloro-4- methylbenzyl)oxazol-2(3H)-one (9.66 mg, 41 μ.m6ol, 1.0 equiv), solvent or solvent mixture (0.5, m sLee Table 1), followed by previously prepared cataliygsat / nd solution (0.04 equiv.). The autoclave ase cdlo, evacuated, backfilled with hydrogen gas (3x), purreizsesd to 60 bar pressure, heated to 40 °C ande snh aatk that temperature for 16 h.Chromatographic analysis of the cooled and de-upr iezsesd reaction mixture by HPLC on chiral statioynarphase was used to determine conversion, selec,t aivnitdy enantiomeric ratio. The metal precursors, chiral ligands and solvesnetsd u as well as the results are summarized in T 1a:ble BCS 243003 FC - 36 - Table 1: No. Metal precursor Ligand Solven1t Conversion (%) Selectivity e.r. (4 mol%) (%) (R) / (S) 2.12Pd(TFA)2 IIIb-3 TFE 64 90 86:134 2.2 Pd(TFA2) IIIa-3 TFE 86 96 31:692.3 Pd(TFA2) IIIa-2 TFE 68 90 11:892.4 Pd(TFA2) IIIa-1 TFE 64 94 10:902.5 Pd(TFA2) IVa-1 TFE 79 97 1:99 2.6 Pd(TFA2) IVa-1 TFE / toluene (1:1) 57 91 1:99 2.7 Pd(TFA2) VIa-1 TFE 33 61 3:97 2.8 Pd(TFA2) VIa-1 TFE / toluene (1:1) 19 25 4:96 2.9 Pd(TFA2) VIIa-1 TFE 18 54 2:982.10 Pd(TFA)2 Va-2 TFE 36 80 5:95 2.11 Pd(TFA)2Va-1 TFE 23 59 5:95 2.12 Pd(TFA)2 VIIIa-1 TFE 48 92 82:1382.13 Ni(OAc)2.4H2O VIIIa-1 TFE 55 90 85:1532.14 Ni(OAc)2.4H2O Xa-1 TFE 48 8314:862.15 Ni(OAc)2.4H2O IVa-1 TFE 53 80 6:94 2.16 Ni(OAc)2.4H2O Va-2 TFE 41 80 8:92 2.17 Ni(OAc)2.4H2O IIIa-3 TFE 55 73 14:861: Solvent used in the hydrogenation reaction.e In c tahtalyst preformation step, tetrahydrofuran wsaesd u to prepare palladium catalysts and 2,2,2,-trifluoraoneothl was used to prepare nickel catalysts.2:The reaction time was 21 h.3: (R)-4-(2-chloro-4-methylbenzyl)oxazolidine-2-one w thaes major enantiomer. BCS 243003 FC - 37 - The results summarized in Table 1 demonstrate c thhiraatl 4-substituted 2-oxazolidinones can be obetdain with medium to good conversion rates and high eionsaenltectivity by asymmetric hydrogenation of the corresponding 4-substituted 2-oxazolones in thsee pnrcee of a fluorinated solvent and a palladiumic okre nl catalyst comprising a chiral bidentate P-ligand. Example 3: Preparation of (S)-4-(2-chloro-4-metheynlzbyl)oxazolidine-2-one using various reaction conditions Pd(TFA)2 and ligand in a molar ratio of 1 to 1.25 were ad tdoe ad Schlenk flask equipped with a stirring bar and dry, degassed THF. The resulting solutions w steirrreed for 30 minutes at room temperature andn the aliquoted into the appropriate reaction wells. Ni(OAc)2x 4 H2O and ligand in a molar ratio of 1 to 1.25 weree addd to a Schlenk flask equipped with a stirring bar and dry, degassed TFE. The resultoinlugti sons were stirred for 16 hours at room tempuerrea atnd then aliquoted into the appropriate reaction wells. General procedure for hydrogenation reactions: Under an inert gas atmosphere, a well of a 96 p wlaetlle- autoclave was charged with 4-(2-chloro-4- methylbenzyl)oxazol-2(3H)-one (9,66 mg, 41 μ,m6ol, 1.0 equiv), solvent or solvent mixture (0.5, m sLee Table 2), followed by previously prepared cataliygsat / nd solution (0.04 eq) and B3.F Et2O (0.08 eq,). The autoclave as closed, evacuated, backfilled withro hgyedn gas (3x), pressurized to 60 bar pressurete,d he toa 80 °C and shaken at that temperature for 16 h.Chromatographic analysis of the cooled and de-upr iezsesd reaction mixture by HPLC on chiral statioynarphase was used to determine conversion, selec,t aivnitdy enantiomeric ratio.The metal precursors, ligands, solvents and adedsit uivsed as well as the results are summarizedb ilne T 2:aTable 2: No. Metal precursor Ligand Solven1t Additive Conversion Selectivity e.r. (4 mol%) (%) (%) (R) / (S) 3.1 Pd(TFA2) IIIa-1 TFE - 57 92 9:913.2 Pd(TFA2) IVa-1 TFE - 99 92 1:99 3.3 Pd(TFA2) IVa-1 TFE BF3.Et2O 99 93 1:99 3.4 Pd(TFA2) IVa-1 EtOH BF3.Et2O 99 90 1:99 3.5 Pd(TFA2) Va-1 TFE - 29 76 6:94 3.6 Pd(TFA2) Va-1 TFE BF3.Et2O 99 98 5:95 BCS 243003 FC - 38 - No. Metal precursor Ligand Solven1t Additive Conversion Selectivity e.r. (4 mol%) (%) (%) (R) / (S) 3.7 Pd(TFA2) Va-2 TFE - 98 98 9:91 3.8 Pd(TFA2) Va-2 TFE BF3.Et2O 99 99 5:95 3.9 Pd(TFA2) Va-2 EtOH BF3.Et2O 62 83 26:74 3.10 Pd(TFA)2 Va-4 TFE - 44 90 19:81 3.11 Pd(TFA)2 Va-4 TFE BF3.Et2O 100 100 18:823.12 Pd(TFA)2 VIIa-1 TFE - 11 22 15:853.13 Pd(TFA)2 VIIa-1 TFE BF3 . Et2O 42 85 3:973.14 Pd(TFA)2 Vb-3 TFE - 42 85 93:27 3.15 Pd(TFA)2Vb-3 TFE BF3.Et2O 99 99 94:623.16 Pd(TFA)2 VIa-2 TFE - 27 75 4:96 3.17 Pd(TFA)2VIa-2 TFE BF3.Et2O 91 99 2:98 3.18 Pd(TFA)2 VIa-2 EtOH BF3.Et2O 15 11 28:723.19 Pd(TFA)2 IIIa-4 TFE - 98 99 4:963.20 Pd(TFA)2 IIIa-4 TFE BF3 . Et2O 99 99 5:953.21 Pd(TFA)2 IIIa-4 THF BF3 . Et2O 12 5 n.d.3.22 Pd(TFA)2 IXa-1 TFE BF3.Et2O 89 98 93:723.23 Ni(OAc)2.4H2O IVa-1 TFE - 99 95 2:98 3.24 Ni(OAc)2.4H2O IVa-1 TFE BF3.Et2O 99 96 13:873.25 Ni(OAc)2.4H2O IIIa-1 TFE - 99 98 12:883.26 Ni(OAc)2.4H2O IIIa-1 TFE BF3 . Et2O 99 94 25:753.27 Ni(OAc)2.4H2O IIIa-4 TFE - 89 91 4:963.28 Ni(OAc)2.4H2O IIIa-4 TFE BF3 . Et2O 35 86 16:843.29 Ni(OAc)2.4H2O IIIa-4 THF BF3 . Et2O 29 40 9:913.30 Ni(OAc)2.4H2O IIIa-5 TFE - 20 68 3:973.31 Ni(OAc)2.4H2O IIIa-5 TFE BF3 . Et2O 17 81 11:893.32 Ni(OAc)2.4H2O IIIa-6 TFE - 19 73 9:91 BCS 243003 FC - 39 - No. Metal precursor Ligand Solven1t Additive Conversion Selectivity e.r. (4 mol%) (%) (%) (R) / (S) 3.33 Ni(OAc)2.4H2O IIIa-6 TFE BF3.Et2O 88 99 17:83 3.34 Ni(OAc)2.4H2O Va-2 TFE - 44 88 7:931: Solvent used in the hydrogenation reaction.e In c tahtalyst preformation step, tetrahydrofuran wsaesd u to prepare palladium catalysts and 2,2,2,-trifluoraoneothl was used to prepare nickel catalysts.2: (R)-4-(2-chloro-4-methylbenzyl)oxazolidine-2-one w thaes major enantiomer.The results summarized in Table 2 demonstrate t trhiflautoroborane as Lewis acidic co-catalyst can accelerate the palladium catalyzed reaction anrdea insce its enantioselectivity. By using a combinna otifo afluorinated solvent, a Lewis acidic co-catalyst an pdalladium catalyst comprising a ligand of tyIpIIea / (b ),(IVa / b), (Va / b), (VIa / b) or (IXa / b), the desired chiral 4-substituted 2-oxazolidin wonaes obtained with high conversion rate, high chemoselectivity and excet ellennantioselectivity. The best results were acehdie wvithligands (IIIa-4 ) and (IVa-1). The results further show that the beneficiael c etff of the Lewis Acid evenallows the reaction to be to carried out in a nlouno-rfinated solvent such as ethanol. When using a chiral nickel catalyst, the presenfc terifl ouoroborane also had an accelerating effeuctt w basdetrimental to the enantioselectivity. Moderate hi tgoh conversion rates, high chemoselectivity anodd g toexcellent enantioselectivity could be achievedb inse ance of any Lewis acid using a combination of afluorinated solvent and a nickel catalyst compgris ain ligand of typeII (Ia / b ) or (IVa / b), in particular ligand(IVa-1). Example 4: Preparation of (S)-4-(2-chloro-4-metheynlzbyl)oxazolidine-2-one using various reaction conditions General procedure for catalyst solution prepara:tionA Schlenk tube was charged with a stirring bar,T PFdA()2 (6.65 mg) and ligan IdIIa-4 (14.9 mg). The tubewas connected to the Schlenk-line and it was evteadcu aand refilled 3 times with Argon before additi oofn 1.8 mL of dry THF. The solution was stirred at roo temmperature for 30 minutes. Then the THF was evaporated with the aid of the Schlenk-line and re thseulting solid was under high-vacuum for 30 meinsu.t The solid was redissolved in 5 mL of dry, degas ssoelvdent (HFIP or TFE, respectively). General procedure for hydrogenation reactions: A 12 mL Schlenk-tube was charged with a stirringr a bnad 4-(2-chloro-4-methylbenzyl)oxazol-2(3H)-one (0.917 g, 4.0 mmol, 1.0 equiv.). The tube was coctnende to the Schlenk-line and it was evacuatede afnildle rd 3 times with Argon before addition of dry HFIP oFrE T, respectively (9.0 mL) and B3.F Et2O (40.0 μL, 0.320mmol, 8.0 mol%). The solution was stirred at rooem p terature for 10 minutes. BCS 243003 FC - 40 - A 50 ml autoclave was sealed and rendered ine thrtre ine cycles (pressurized with argon to 8 bar aenledas re of pressure). Next, the substrate solution andliq auno at of the catalyst stock solution were tranrsefder in this order into the autoclave under an argon countewr. f Tlohe vessel containing the substrate was rinsitehd 2 w.5 mL of solvent. The autoclave was set under hydro (g3e cnycles at 5.0 bar), pressurized to 30 bar aenadte hd to 80 °C and heated for the time shown in Table 3.The conversion, chemoselectivity and enantiomeartic o r were determined by chiral HPLC after withdral waof a 20 μL aliquot of the reaction mixture (solvent was eovrap ted and residue was redissolved in 1.0 mLMeCN prior to HPLC analysis) The metal precursors, ligands, solvents and adedsit uivsed as well as the results are summarizebdle in 3 t:a Table 3: No. Metal Ligand Solvent Additive Time (h) Conversion Selectivity e.r. precursor (8 mol%) (%) (%) (R) / (S) 4.1 Pd(TFA)2IIIa-4 TFEBF3.Et2O 2 99 99 1:99 (0.5 mol%) (0.08 M) 4.2 Pd(TFA)2IIIa-4 TFEBF3.Et2O 3.5 99 89 1:99 (0.1 mol%) (0.33 M) 4.3 Pd(TFA)2 IIIa-4 HFIPBF3.Et2O 2 99 99 1:99 (0.1 mol%) (0.33 M) 4.4 Pd(TFA)2 IIIa-4 TFEBF3.Et2O 2 86 69 2:98 (0.05 mol%) (0.33 M) 4.5 Pd(TFA)2IIIa-4 TFEBF3.Et2O 4 97 75 2:98 (0.05 mol%) (0.33 M) 4.6 Pd(TFA)2 IIIa-4 HFIP BF3.Et2O 2 92 73 1:99 (0.05 mol%) (0.33 M) 4.7 Pd(TFA)2 IIIa-4 HFIP BF3.Et2O 4 99 75 1:99 (0.05 mol%) (0.33 M) It becomes evident from table 3 that by using ab cionmation of palladium, Lewis acidic co-catalyst,fluorinated solvent and ligandIII (a-4 ), the desired enantiomer could be obtained wit%h 9 c9onversion andan enantiomeric ratio of 1:99 in only 2-4 hoursn ugs oinly 0.1 mol% or 0.05 mol% of catalyst. Example 5: Preparation of (S)-4-(2-chloro-4-metheynlzbyl)oxazolidine-2-one using various reaction conditions General procedure for the preparation of catalnydst a additive / acid stock solutions: BCS 243003 FC - 41 -Pd(TFA)2 and ligand IIIa-4 (molar ratio of 1 to 1.1) were added to a Schl felanskk equipped with a stirringbar and dry, degassed THF (for 100 mg of Pd(T2F 1A1.)6 mL of THF were used). The resulting solutioans w stirred for 30 minutes at room temperature anda thlieqnuoted into the reaction wells. Additives and Brønsted acids were weighed andl dviesdso in 2-Me-THF to afford stock solutions, whicher wedispensed as solutions (5 μL0 for Additives, 25 μL for Brønsted acids, concentration adjusted tope rcetsivemolecular weight) to the reaction wells. General procedure for hydrogenation reactions: Under an inert gas atmosphere, a well of a 96 p wlaetlle- autoclave was charged with 4-(2-chloro-4- methylbenzyl)oxazol-2(3H)-one (14.29 mg, 63 μm.9ol, 1.0 equiv), solvent or solvent mixture (0.5, m sLee Table 4), additive stock solution (0.08 equiv. T seabele 4), Brønsted acid stock solution (2.0 eq sueive. Table 4, added where required), followed by previousleyp parred catalyst / ligand solution (0.01 eq). Thec alauvtoeas closed, evacuated, backfilled with hydrogen (3 gxa)s, pressurized to 80 bar pressure, heated ° toC 4 a0ndshaken at that temperature for 16 h.Chromatographic analysis of the cooled and de-upr iezsesd reaction mixture by HPLC on chiral statioynarphase was used to determine conversion, selec,t aivnitdy enantiomeric ratio. The metal precursors, chiral ligands, solvents,iti avdeds and Brønsted acids used as well as thets re asruel summarized in table 4: Table 4: No. Metal Ligand Solven1t Additive2Brønsted Conversion Selectivity e.r. precursor acid2(%) (%) (R) / (S) (8 mol%) (2 equiv.) 5.1 Pd(TFA)2IIIa-4 TFE:HFIP BF3.Et2O - 100 100 1:99 (1.0 mol%) (10:1) 5.2 Pd(TFA)2IIIa-4 TFE BF3 . Et2O - 100 100 1:99(1.0 mol%) 5.3 Pd(TFA)2 IIIa-4 HFIP BF3.Et2O - 100 99 4:96 (1.0 mol%) 5.4 Pd(TFA)2 IIIa-4 TFE BF3 . Et2O AcOH 100 100 1:99(1.0 mol%) 5.5 Pd(TFA)2IIIa-4 TFE BF3 . Et2O CSA 100 100 1:99(1.0 mol%) 5.6 Pd(TFA)2 IIIa-4 TFE BF3 . Et2O phenol 100 100 1:99(1.0 mol%) BCS 243003 FC - 42 - No. Metal Ligand Solven1t Additive2Brønsted Conversion Selectivity e.r. precursor acid2(%) (%) (R) / (S) (8 mol%) (2 equiv.) 5.7 Pd(TFA)2IIIa-4 TFE BF3 . Et2O TFA 100 100 1:99(1.0 mol%) 5.8 Pd(TFA)2IIIa-4 TFE Al(OTf)3 - 100 100 1:99(1.0 mol%) 5.9 Pd(TFA)2 IIIa-4 TFE Ti(OiPr)4 - 32 81 5:95(1.0 mol%) 5.10 Pd(TFA)2IIIa-4 TFE Zn(OTf)2 - 83 99 7:93(1.0 mol%) 5.11 Pd(TFA)2IIIa-4 PhCF3:HFIP BF3.Et2O - 77 95 1:99 (1.0 mol%) (10:1) 5.12 Pd(TFA)2 IIIa-4 PhCF3:TFE BF3.Et2O - 93 99 1:99 (1.0 mol%) (10:1) 5.13 Pd(TFA)2IIIa-4 PhCF3BF3.Et2O CSA 94 96 4:96 (1.0 mol%) 5.14 Pd(TFA)2 IIIa-4 PhCF3 Al(OTf)3 - 69 91 8:92 (1.0 mol%) 5.15 Pd(TFA)2IIIa-4 anisole:TFE BF3.Et2O - 98 95 2:98 (1.0 mol%) (10:1) 5.16 Pd(TFA)2 IIIa-4 anisole BF3.Et2O CSA 84 93 2:98 (1.0 mol%) 5.17 Pd(TFA)2IIIa-4 anisole Al(OTf)3- 70 93 2:98 (1.0 mol%) 5.18 Pd(TFA)2IIIa-4 iPrOAc:HFIP BF3.Et2O - 46 80 2:98 (1.0 mol%) (10:1) 5.19 Pd(TFA)2 IIIa-4 iPrOAc:TFE BF3.Et2O - 66 91 2:98 (1.0 mol%) (10:1) 5.20 Pd(TFA)2IIIa-4 iPrOAc BF3.Et2O CSA 76 89 2:98 (1.0 mol%) 5.21 Pd(TFA)2 IIIa-4 iPrOAc Al(OTf)3 - 67 91 3:97 (1.0 mol%) 5.22 Pd(TFA)2IIIa-4 MeCO3:TFE BF3.Et2O - 81 96 2:98 (1.0 mol%) (10:1) 5.23 Pd(TFA)2 IIIa-4 MeCO3:HFIP BF3.Et2O - 54 86 2:98 (1.0 mol%) (10:1) BCS 243003 FC - 43 - No. Metal Ligand Solven1t Additive2Brønsted Conversion Selectivity e.r. precursor acid2(%) (%) (R) / (S) (8 mol%) (2 equiv.) 5.24 Pd(TFA)2 IIIa-4 MeCO3 BF3.Et2O CSA 89 87 2:98 (1.0 mol%) 5.25 Pd(TFA)2 IIIa-4 MeCO3 Al(OTf)3 - 57 86 2:98 (1.0 mol%)1: Solvent used in the hydrogenation reaction.e In c tahtalyst preformation step, tetrahydrofuran wsaesd. u2: Dispensed as solution in 2-Me-THF. It becomes evident from table 4 that it is alsos piboles to carry out the reaction in non-fluorina steodlvents, such as anisole, isopropyl acetate or dimethylo cnaartbe, or mixtures of fluorinated and non-fluoreindat solvents. It further becomes evident that alumini turimfluoromethanesulfonate and zinc triflate areso al suitable co-catalysts. The results in table 4 feurrt dhemonstrate that the reaction may be performned i presence of a Brønsted acidic additive, such atsic a acceid, trifluoroacetic acid, camphorsulfonicd ac oir phenol. General procedure for the enantioselective hydraotgioenn of additional 2-oxazolones (reaction scal ge: o 1f the respective 2-oxazolone, catalyst loading 1 m)ol% A Schlenk tube with a stirring bar was charged w Pidth(TFA)2 (0.01 eq.) and ligand IIIa-4 (0.011. e Tq.h)e tube was connected to the Schlenk line and evadcu aantde refilled 3 times with Argon before the adodniti of 2-butanol (8 eq.). The resulting solution was e sdtirr for 30 min and transferred to a an Argon-flushed autoclave. (Buchi Parallel Pressure Reactor Sys 1te0m0, mL Hastelloy) A Schlenk flask with a stirring bar was chargedh w Oitxazolone (1.0 g) and HFIP (20 eq.). Then, BF3.OEt2 (0.03 eq.) was added dropwise and the reactiotnirr iesd s for 10 min. Once homogenous, mixture wase addd to the autoclave containing the Pd catalyst stoclukti son. The autoclave was sealed, set under hydrogen (le3s c ayct 3.0 bar), pressurized to 30 bar, and he taoted 80 °C for 24h. Afterwards, the autoclave was coo tole 2d5 °C and the pressure was released via thhaeu estx pipe. The autoclave was flushed with Ar (3 cyclte 3s.0 a bar) and the reaction mixture was transfe orruetd ofthe autoclave via cannula, flushing the autoclaivthe M weCN (20 g). The bulk of the solvent was remdoveunder reduced pressure to afford the crude rea pctrio dnuct. The yield of the reaction was determi bnyedquantitative NMR against an external standardr (a rfeteconstituting in MeCN to obtain a homogeneous solution). The enantiomeric ratio was determined H bPyLC on chiral stationary Phase. An analyticaullyre p sample of the hydrogenated products was obtaine pdur bifyication an aliquot of the reaction mixture f blaysh colum chromatography (S2iO, gradient of cyclohexane / ethyl acetate). Example 8.1: (S)-4-(2-chloro-4-methylbenzyl)-1,3a-zooxlidin-2-one BCS 243003 FC - 44 - The target compound was obtained in 94.06% yiedld 9 a8n.51 / 1.49 e.r. favoring the S-enantiomer. Retention time (HPLC on chiral stationary Phaset,h Mode D): (R)-enantiomer: 11.50 min, (S)-enantiomer: 12.57 min. All other analytical data match the data repornte Edx iample 1 Example 8.2: Preparation of-4-[4-(trifluoromethyel)nbzyl]-1,3-oxazolidin-2-one The target compound was obtained in 96.7% yield 9 a9n.5d0 / 0.50 e.r. favoring th Se-enantiomer.1H NMR (600 MHz, CDCl3) δ 7.61 (d, J = 8.0 Hz, 2H), 7.31 (d J, = 8.0 Hz, 2H), 5.72 (s, 1H), 4.51 – 4.43 (m, 1H), 4.17 – 4.08 (m, 2H), 2.99 – 2.91 (m, 2H).13C NMR (150 MHz, CDC3l) δ 159.29, 140.11 (d J, = 1.4 Hz), 129.79 (q J, = 32.5 Hz), 129.56, 126.12 (q, J = 3.8 Hz), 125.03, 124.13 ( Jq, = 272.3 Hz), 123.22, 69.57, 53.57, 41.38. LCMS (ESI) for C11H11F3NO2+[M+H]+calculated: 246.2; found: 246.4; Retention Time (LCMS, Method A): 0.92 min. Example 8.3: Preparation of (S)-4-(3,5-dichlorobyeln)-z1,3-oxazolidin-2-one The target compound was obtained in 99.8% yield 9 a5n.8d2 / 4.18 e.r. favoring th Se-enantiomer.1H NMR (600 MHz, CDC3l) δ 7.30 (t, J = 1.9 Hz, 1H), 7.08 (d J, = 1.9 Hz, 2H), 5.64 (s, 1H), 4.49 J (t =, 8.2 Hz, 1H), 4.15 – 4.05 (m, 2H), 2.88 – 2.79 (mH),.213C NMR (150 MHz, CDC3l) δ 159.13, 139.34, 135.72, 127.85, 127.66, 69.504,25,34.1.02.LCMS (ESI) for C10H10Cl2NO2 [M+H] + calculated: 247.1; found: 248.0;Retention Time (LCMS, Method A): 1.03 min. Retention time (HPLC on chiral stationary Phaset,h Mode F): (R)-enantiomer: 10.53 min, (S)-enantiomer: 12.34 min. Example 8.4: Preparation of (S)-4-(4-bromo-2-chlboeronzyl)-1,3-oxazolidin-2-one The target compound was obtained in 77.8% yield 9 a7n.9d2 / 2.08 e.r. favoring th Se-enantiomer.1H NMR (600 MHz, CDC3l) δ 7.57 (d, J = 2.0 Hz, 1H), 7.38 (dd J, = 8.2, 2.0 Hz, 1H), 7.11 (d J, = 8.1 Hz,1H), 5.77 (s, 1H), 4.50 – 4.42 (m, 1H), 4.22 – 4 (.m12, 2H), 3.01 (dd J, = 13.7, 5.7 Hz, 1H), 2.94 (d Jd, =13.8, 7.2 Hz, 1H). BCS 243003 FC - 45 -13C NMR (151 MHz, CDC3l) δ 159.38, 135.16, 132.93, 132.74, 132.60, 130.617.,8132, 69.55, 51.86, 38.74.LCMS (ESI) for C10H10BrClNO2+ [M+H] + calculated: 290.0; found: 290.1;Retention Time (LCMS, Method A): 1.03 min. Retention time (HPLC on chiral stationary Phaset,h Mode G): (R)-enantiomer: 21.59 min, (S)-enantiomer: 24.10 min. Example 8.5: Preparation of (S)-4-(4-methylbenz1y,3l)--oxazolidin-2-one The target compound was obtained in 99.6% yield 9 a9n.3d1 / 0.69 e.r. favoring th Se-enantiomer.1H NMR (600 MHz, CDC3l) δ 7.15 – 7.08 (m, 2H), 7.08 – 7.03 (m, 2H), 6.101 (Hs),, 4.40 (t, J = 8.4 Hz, 1H), 4.12 (dd, J = 8.6, 5.6 Hz, 1H), 4.06 (dtd Jd, = 7.9, 6.7, 5.5, 1.0 Hz, 1H), 2.86 (d Jd =, 13.6, 7.0 Hz, 1H), 2.80 (dd, J = 13.6, 6.7 Hz, 1H), 2.32 (s, 2H).13C NMR (150 MHz, CDC3l) δ 159.77, 136.89, 132.88, 129.69, 128.99, 69.649,25,34.0.99, 21.10. LCMS (ESI) for C11H14NO2+[M+H]+calculated: 192.1; found: 192.5; Retention Time (LCMS, Method A): 0.81 min. Retention time (HPLC on chiral stationary Phaset,h Mode H): (R)-enantiomer: 13.71 min, (S)-enantiomer: 14.68 min. Example 8.6: Preparation of (S)-4-(2,4-dimethylbyel)n-1z,3-oxazolidin-2-one The target compound was obtained in 92.6% yield 9 a9n.2d8 / 0.72 e.r. favoring th Se-enantiomer.1H NMR (600 MHz, CDC3l) δ 7.02 – 6.95 (m, 3H), 5.59 (s, 1H), 4.48 – 4.421 (mH),, 4.14 (dd, J = 8.6, 5.5Hz, 1H), 4.06 (tddd J, = 7.7, 6.4, 5.4, 1.0 Hz, 1H), 2.90 – 2.81 (m, 22H.2),9 (d, J = 8.2 Hz, 6H).13C NMR (150 MHz, CDC3l) δ 159.49, 137.08, 136.13, 131.76, 131.28, 129.671.,1192, 69.95, 52.77, 38.37, 21.01, 19.58. LCMS (ESI) for C12H16NO2+[M+H]+calculated: 206.3; found: 206.6; Retention Time (LCMS, Method A): 0.93 min. Retention time (HPLC on chiral stationary Phaset,h Mode D): (R)-enantiomer: 10.74 min, (S)-enantiomer: 11.67 min. Example 6: Preparation of (S)-2-amino-3-(2-chlor-om-4ethylphenyl)propan-1-ol BCS 243003 FC - 46 - A 5 L alloy-reactor was charged withS)- (2-amino-3-(2-chloro-4-methylphenyl)propan-1-ol0 (3wt% solution in chlorobenzene, 1750 g, 2326 mnodl) a dditional chlorobenzene (0.75 T Lo). the stirringreaction mixture was then added aqeuous sodiumo hxiydder solution (20 wt% solution in water, 1400 g, 6979 mol) in portions T.he reaction mixture was then heated to 100 °Ce jta tcekmperature (90 – 95 °C internal temperature) and stirred vigorously for h 1o7urs. The reaction was then cooled to 1 °C inatlerntemperature and stirred for 2 hours. The produeccti p irtated out of the reaction mixture was colledc bteyfiltration over a large, sintered funnel (Por.3 T)h.e residue was washed with chlorobenzene (0.6 a5nd L) water (18 L), and dried to to afforSd) (-2-amino-3-(2-chloro-4-methylphenyl)propan-1-ol a a lsight yellow crystalline solid (367 g, 75.1 % yield, 96.1 % ptyu,ri 99% ee). Note: As a result of washing the filter cake wiothpi cous amount of water, 15% of product was deteermdin to reside in the wash liquor.1H NMR (400 MHz, d-DMSO) δ 7.68 (d, J = 8.7 Hz, 1H), 7.23 – 7.16 (m, 2H), 7.05 (dd Jd =, 7.7, 1.8,0.8 Hz, 1H), 4.79 (t J, = 5.6 Hz, 1H), 3.97 (tq J, = 10.1, 5.2 Hz, 1H), 3.41 – 3.25 (m, 2H), 2.96, ( Jdd =13.9, 5.0 Hz, 1H), 2.59 (dd J, = 14.0, 9.3 Hz, 1H), 2.25 (s, 3H), 1.71 (s, 3H).13C NMR (150 MHz, DMSO) δ 137.29, 134.27, 132.94, 131.56, 129.36, 127.5.91,26,653.04, 37.41, 20.17. LCMS (ESI) for C10H15ClNO2+ [M+H]+ calculated: 200.08; found: 200.0; Retention Time (LCMS, Method A): 0.44 min Retention time (HPLC on chiral stationary Phaset,h Mode C): (R)-enantiomer: 7.97 min, (S)-enantiomer: 9.23 min.

Claims

BCS243003 FC KJ / Rak 2025-07-01 -47- Claims:

1. A process for preparing a compound of the foarm (Iual) or (Ib),(Ia) (Ib), wherein n is 0, 1, 2 or 3, and each substituent R, if present, is independenltelyct seed from the group consisting of halogen, hydroxy, C1-C6-alkyl, C1-C6-haloalkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy, C1-C6- alkylcarbonyl, C1-C6-alkoxycarbonyl and1 C-C6-alkylcarbonyloxy, comprising enantioselective hydrogenation of a coumnpd of the formulaII ( )(II ),wherein n and R are each as defined for the comdpo fu tnhe formulaI (a) or (Ib), in presence of a palladium or nickel catalyst coisminpgr a chiral bidentate P-ligand.

2. The process according to claim 1, character iinze thdat the hydrogenation is conducted (a) in presence of a palladium or nickel catal ays fltu,orinated solvent and optionally a Lewis ac oird, (b) in presence of a palladium catalyst, a nonr-ifnluaoted solvent and a Lewis acid, wherein the fluorinated solvent is selected froem g trhoup consisting of hexafluoroisopropanol, 2-,2,2, trifluoroethanol, tetrafluoropropanol and trifluotoroluene, and mixtures thereof, wherein the lewis acid is selected from the grouopns cisting of trifluoroborane, aluminium trifluoromethanesulfonate and zinc triflate, andBCS 243003 FC - 48 - wherein the non-fluorinated solvent is selectedm fr tohe group consisting of anisole, methanol, ethanol, n-propanol, iso-propanol, ethyl acetasteo,pr iopyl acetate, n-butyl acetate and dimethyl carbonate.

3. The process according to claim 1 or 2, chariazcetder in that the catalyst used is a palladiumy csatt.al 4. The process according to claim 3, character iinze tdhat the hydrogenation is further conducted in presence of a lewis acid selected from the grounpsis ctoing of trifluoroborane, aluminium trifluoromethanesulfonate and zinc triflate.

5. The process according to any of the precedianigm csl, characterized in that the hydrogenation is conducted in presence of a fluorinated solvent c steedle from the group consisting of hexafluoroisopropanol, 2,2,2,-trifluoroethanolr,a tefltuoropropanol and trifluorotoluene, and mixtures thereof.

6. The process according to claim 5, wherein thueori fnlated solvent is selected from hexafluoroisopropanol, 2,2,2,-trifluoroethanol a mnidxtures thereof.

7. The process according to any of the precedianigm csl, wherein the hydrogenation is conducted at a temperature within the range of from 40°C to 100°C.

8. The process according to any of the precedianigm csl, wherein the hydrogenation is conducted using hydrogen gas at a pressure of from 5 to 100 bar.

9. The process according to any of the precedianigm csl, wherein the amount of catalyst used is within the range of from 0.001 mol% to 5 mol%, based oen a tmhount of the compound of the form (uIlIa).

10. The process according to any of the precedlainimgs c, wherein the chiral bidentate P-ligand haes th general formulaII (Ia ), (IIIb ), (IVa), (IVb ), (Va), (Vb), (VIa), (VIb ), (VIIa ), (VIIb ), (VIIIa ),(VIIIb ), (IXa), (IXb ), (Xa) or (Xb)(IIIa ) (IIIb ) (IVa) (IVb )BCS 243003 FC - 49 -wherein R3and R4are each independently selected from the groupsis ctoinng of phenyl, furan-2-yl, naphthalen-1-yl, C3-C6-cycloalkyl and C3-C6-alkyl, wherein the phenyl is unsubstituted or stiutubtsed with one to three substituents each independenetlleyct sed from the group consisting o1f- C 4-haloalkyl, C1-C4-alkyl and C1-C4-alkoxy, R5is C3-C6-alkyl or C3-C6-cycloalkyl, Q is N or CH, R6is selected from the group consisting of phenuyrla,n f-2-yl, C3-C6-cycloalkyl and C3-C6-alkyl, wherein the phenyl is unsubstituted or substitu wteithd one to three substituents each independentlyBCS 243003 FC - 50 - selected from the group consisting o1f- C 4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl and di-(C1-C4-alkyl)amino, R7a, R7b, R8a, R8b, R9aand R9bare each independently selected from hydroge1-nC,4- Calkoxy, C1-C4- alkyl and C1-C4-haloalkyl, where at least two of7aR, R7b, R8aand R8bare not hydrogen, or R7aand R8aform together a -O-(C2H)-O-, -O-(CH2)2-O-, -O-C(CH3)2-O-, -O-(CF2)-O- or -(CH)4- group, R7band R8bform together the same -O-(C2)H-O-, -O-(CH2)2-O-, -O-C(CH3)2-O-, -O-(CF2)-O- or -(CH)4- group, and R9aand R9bare hydrogen, R10and R11are each independently selected from the groupsis ctoinng of phenyl, furan-2-yl, naphthalen-1-yl, C3-C6-cycloalkyl and C3-C6-alkyl, wherein the phenyl is unsubstituted or stiutubtsed with one to three substituents each independenetlleyct sed from the group consisting o1f- C 4-haloalkyl, C1-C4-alkyl, and C1-C4-alkoxy, R12and R13are each independently selected from the groupsis ctoinng of phenyl, furan-2-yl, naphthalen-1-yl, C3-C6-cycloalkyl and C3-C6-alkyl, wherein the phenyl is unsubstituted or stiutubtsed with one to three substituents each independenetlleyct sed from the group consisting o1f- C 4-haloalkyl, C1-C4-alkyl, and C1-C4-alkoxy, R14is phenyl or C1-C6-alkyl, R15and R16are each independently selected from the groupsis ctoinng of phenyl, furan-2-yl, naphthalen-1-yl, C3-C6-cycloalkyl and C3-C6-alkyl, wherein the phenyl is unsubstituted or stiutubtsed with one to three substituents each independenetlleyct sed from the group consisting o1f- C 4-haloalkyl, C1-C4-alkyl, and C1-C4-alkoxy, and R17is C1-C6-alkyl.

11. The process according to claim 10, whereind Q th aen substituents3 R to R17 in formulaeI (IIa ), (IIIb ),(IVa), (IVb ), (Va), (Vb), (VIa), (VIb ), (VIIa ), (VIIb ), (VIIIa ), (VIIIb ), (IXa), (IXb ), (Xa) and (Xb)are defined as follows: R3is phenyl, which is unsubstituted or substituteitdh w one to three substituents each independently selected from the group consisting of trifluoromyel,th methyl and methoxy, or3R is furan-2-yl, cyclohexyl, naphthalen-1-yl or tert-butyl, R4is cyclohexyl, tert-butyl or phenyl, wherein thhee pnyl is unsubstituted or substituted with one to three substituents each independently selected t fhroem group consisting of trifluoromethyl, methyl and methoxy, R5is tert-butyl or cyclohexyl,BCS 243003 FC - 51 - Q is N or CH, R6is phenyl, which is unsubstituted or substituteitdh w one to three substituents each independently selected from the group consisting o1f- C 4-alkyl, methoxy, dimethylamino and trifluoromethy olr,R6is furan-2-yl, cyclohexyl, tert-butyl or isoprop,yl R7a, R7b, R8a, R8b, R9aand R9bare each independently selected from hydrogenh,o mxye,t methyl and trifluoromethyl, where at least two of7aR, R7b, R8aand R8bare not hydrogen, or R7aand R8aform together a -O-(C2H)-O-, -O-(CH2)2-O-, -O-C(CH3)2-O-, -O-(CF2)-O- or -(CH)4- group, R7band R8bform together the same -O-(C2)H-O-, -O-(CH2)2-O-, -O-C(CH3)2-O-, -O-(CF2)-O- or -(CH)4- group, and R9aand R9bare hydrogen, R10and R11are each independently selected from tert-buhtyel,n pyl and cyclohexyl, R12and R13are each independently selected from cyclohexhyeln, pyl and tert-butyl, R14is phenyl or C1-C4-alkyl, R15and R16are each independently selected from the grouspis ctoinng of cyclohexyl, tert-butyl and phenyl, wherein the phenyl is unsubstituted or t situb tesd with one to three substituents eachindependently selected from the group consistin tgrif oluforomethyl, methyl and methoxy, and R17is C1-C4-alkyl.

12. The process according to any of the precedlianigms c, which is for preparing a compound of the formula (Ia’ ) or (Ib’ )wherein R1is chlorine, fluorine or methyl, and R2is methyl, ethyl, n-propyl or isopropyl.

13. The process according to claim 11, which is p froerparing a compound of the formuIla ’ () or (Ib’ )BCS 243003 FC - 52 -wherein R1is chlorine, fluorine or methyl, and R2is methyl, ethyl, n-propyl or isopropyl,and comprises enantioselective hydrogenation ofm ap cound of the formulaII (’ )(II’ ),wherein R1 and R2 are each as defined for the compound of the foarm (Iau’l ) or (Ib’ ),wherein the hydrogenation is conducted in prese onfc ae palladium catalyst comprising a chiralbidentate P-ligand of the formulaIIIa ( ), (IIIb ), (IVa), (IVb ), (Va), (Vb), (VIa), (VIb ), (IXa) or(IXb ),a fluorinated solvent and a Lewis acid, wherein the fluorinated solvent is selected froemxa hfluoroisopropanol, 2,2,2,-trifluoroethanol and mixtures thereof, the lewis acid selected from trifluoroborane anudm ainlium trifluoromethanesulfonate, wherein the amount of palladium catalyst used itshin wi the range of from 0.001 mol% to 5 mol%,based on the amount of the compound of the form (IIu )l,a andwhich is conducted using hydrogen gas at a pres osfu fr oem 5 to 100 bar at a temperature within therange of from 40°C to 100°C.BCS 243003 FC - 53 - 14. The process according to any of the precedlainimgs c, wherein the catalyst used is a palladiumaly csatt which is formed prior to the hydrogenation reacti fornom palladium(II) trifluoroacetate or palladium(II) acetylacetonate and the chiral bidaetent P-ligand.

15. A compound of the formul (aIa’) or (Ib’) ,wherein R1is chlorine, fluorine or methyl, and R2is methyl, ethyl, n-propyl or isopropyl.

16. A process for preparing a compound of the folarm (XuIIa) or (XIIb) ,(XIIa ) (XIIb ),wherein n is 0, 1, 2 or 3, each substituent R, if present, is independenltelyct seed from the group consisting of halogen, hydroxy, C1-C6-alkyl, C1-C6-haloalkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy and C1-C6- alkylcarbonyl, and X is hydroxy, chlorine or bromine, comprising the process according to any of claim tos 114 for preparing the compound of the formula (Ia) or (Ib),(Ia) (Ib),BCS 243003 FC - 54 - wherein n and R are each defined as in the comdpo fu tnhe formulaX (IIa ) or (XIIb ),and further comprising decarboxylative ring open oinfg the compound of the formulaIa () to the compound of the formulaX (IIa ) or ring opening of the compound of the formuIlba) ( to thecompound of the formulaX (IIb ), respectively, using aqueous sodium hydroxidqeu,e aous potassiumhydroxide solution, aqueous hydrochloric acid oure aoqus hydrobromic acid.

17. A compound of the formul (aXIIa) or (XIIb) ,(XIIa ) (XIIb ),wherein n is 1 or 2, each substituent R, if present, is independenltelyct seed from the group consisting of halogen, C1-C4-alkyl and C1-C4-haloalkyl, X is hydroxy, chlorine or bromine, prepared by the process according to claim 16.

18. A compound of the formul (aXIIa’) or (XIIb’) ,wherein R1is chlorine or fluorine, R2is methyl, ethyl, n-propyl or isopropyl, and X is hydroxyl, chlorine or bromine, prepared by the process according to claim 16.BCS 243003 FC - 55 -19. A compound o (fXIIa’) or (XIIb’) ,wherein R1is chlorine or fluorine, R2is bromine, methyl or trifluoromethyl, and X is hydroxyl, chlorine or bromine.

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