Method for preparing an enantiomerically enriched form of 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one

Abstract

Process for preparing an enantiomerically enriched form of 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy- ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one (compound (I)) or a tautomer thereof which comprises reducing 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5- phenyl-pyrimidin-4-one (compound (II)) with a silane compound in the presence of a chiral zinc compound.

Description

[0001] Method for preparing an enantiomerically enriched form of 2-[2-(2-chlorothiazol-5-yl)-2- hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one

[0002] The present invention relates to a method for preparing 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy- ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of the formula (I) as depicted below or a tautomer thereof or enantiomerically enriched forms thereof.

[0003] Technical background

[0004] 2-[2-(2-Chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one (I) (or its tautomer) has been found to be a valuable intermediate in the preparation of 2,3- dihydrothiazolo[3,2-a]pyrimidinium compounds, and more specifically of 3-(2-chlorothiazol-5-yl)- 8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate and enantiomerically enriched forms thereof if 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one is used in an enantiomerically enriched form. Said pyriminidium compounds have insecticidal properties and are known, for example, from WO 2018 / 177970 or WO 2014 / 167084.

[0005] The methods thus far known for the preparation of these pyriminidium compounds are cumbersome and not yet satisfactory.

[0006] In WO 2018 / 177970, WO 2018 / 197541 and WO 2018 / 202654, non-racemic 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds are prepared by reaction of a non-racemic 4- heteroaryl-substituted thiazolidin-2-imine with a 2-substituted malonic acid derivative. In WO 2018 / 177970 and WO 2018 / 197541, the non-racemic 4-heteroaryl-substituted thiazolidin-2- imine is in turn prepared by catalytic asymmetric hydrogenation of a 1-heteroaryl-substituted ethanimine carrying in 2-position a leaving group. The resulting amine is then reacted with an isothiocyanate to the thiazolidin-2-imine. The reaction sequence is described in WO 2018 / 197541 as follows:

[0007]

[0008] RAis a sulfanyl or sulfinyl, phosphoroxy, alkoxy or benzyl group; Het is optionally substituted pyridin-3-yl, thiazol-5-yl or pyrimidin-5-yl, W and LG are leaving groups, R1is a (cyclo)aliphatic group and R2is 5- or 6-membered carbo- or heterocyclic ring.

[0009] In WO 2018 / 177970 the amine VII is obtained via another reaction path from the corresponding sulfinylimine.

[0010] WO 2018 / 177970 and WO 2018 / 202654 describe a further access to the non-racemic 4- heteroaryl-substituted thiazolidin-2-imine. This is here prepared starting from a heteroaryl methyl ketone, where the methyl group carries a leaving group, conversion of this leaving group into an alkylcarbonyloxy group, hydrolysis of the latter to a hydroxyl group, reaction of the resulting heteroarylhydroxymethyl ketone with a sulfamoyl halide to a 4-heteroaryl-5H-oxathiazole 2,2- dioxide, submission of the latter to a catalytic asymmetric hydrogenation to yield a non-racemic 4-heteroaryloxathiazolidine 2,2-dioxide and reaction thereof with an isothiocyanate to the thiazolidin-2-imine. The reaction sequence is described in WO 2018 / 202654 as follows: Het is optionally substituted pyridin-3-yl, thiazol-5-yl or pyrimidin-5-yl, W and LG are leaving groups, M2is Li, Na, K, Al, Ba, Cs, Ca or Mg, RACis alkylcarbonyl, X1is halogen, R1is a (cyclo)aliphatic group and R2is 5- or 6-membered carbo- or heterocyclic ring.

[0011] WO 2022 / 200594 and WO 2022 / 157316 disclose processes for the reduction of compound II using formiates or hydrogen.

[0012] These methods are however not very economic. Some reagents are expensive, recycling of some of the reagents which are not or not entireyl consumed is difficult, the overall yield is not satisfactory and too many reaction steps are involved.

[0013] Summary of the invention

[0014] The present invention is directed to new processes for the preparation of 2-[2-(2-chlorothiazol-5- yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one and especially a process for the preparation of an enantiomerically enriched form thereof which yields the S or R enantiomer with high selectivity.

[0015] The problem is solved by a method for preparing an enantiomerically enriched form of 2-[2-(2- chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of the formula (I): where the asterisk * shows the stereogenic center; or a tautomer thereof; which method comprises reducing 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3- methyl-5-phenyl-pyrimidin-4-one of the formula (II) or a tautomer thereof with a silane in the presence of a chiral zinc catalyst; to obtain an enantiomerically enriched form of the pyrimidinone of the formula (I) or of a tautomer thereof.

[0016] The compound according to formula (I) and its tautomers are herein referred to as “compound

[0017] (I)” or “compound I” or “PAL”.

[0018] The compound according to formula (II) and its tautomers are herein referred to as “compound

[0019] (II)” or “compound II” or “PKET”.

[0020] Detailed description of the invention

[0021] Definitions

[0022] “Enantiomerically enriched form” of compound (I) or the compound (I) “in enantiomerically enriched form” and similar terms denote a non-racemic compound (I) in which either the S enantiomer or the R enantiomer predominates or is even present as only stereoisomer. The compound (I) has one stereogenic center which is at the aliphatic carbon atom carrying the OH group and marked with an asterisk.

[0023] The organic moieties mentioned below are - like the term halogen - collective terms for individual listings of the individual group members. The prefix Cn-Cmindicates in each case the possible number of carbon atoms in the group.

[0024] The term halogen denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine or bromine.

[0025] The term "alkyl" as used herein and in the alkyl moieties of alkoxy refers to saturated straight-chain (linear) or branched hydrocarbon radicals having 1 to 3 ("Ci-C3-alkyl "), 1 to 4 ("Ci-C4-alkyl "), 1 to 6 ("Ci-C6-alkyl”), 3 to 4 ("C3-C4-alkyl ") or 3 to 6 ("C3- Ce-alkyl”) carbon atoms. Ci-C3-Alkyl denotes a saturated linear or branched aliphatic radical with 1 to 3 carbon atoms. Examples are methyl, ethyl, n-propyl or isopropyl. Ci-C4-Alkyl denotes a saturated linear or branched aliphatic radical with 1 to 4 carbon atoms. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. Ci-Ce-Alkyl denotes a saturated linear or branched aliphatic radical with 1 to 6 carbon atoms. Examples are, in addition to those mentioned for Ci-C4-alkyl, pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dime- thylpropyl, 1-ethylpropyl, 1 , 1-dimethylpropyl, 1 ,2-dimethylpropyl, hexyl, 1 -methylpentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1 -dimethylbutyl, 1 ,2-dimethylbutyl, 1,3-dimethyl- butyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1 ,2-tri- methylpropyl, 1 ,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl. C3-C4-AI- kyl denotes a saturated linear or branched aliphatic radical with 3 or 4 carbon atoms. Examples are n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. Ca-Ce-Alkyl denotes a saturated linear or branched aliphatic radical with 3 to 6 carbon atoms. Examples are, in addition to those mentioned for C3-C4-alkyl, pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dime- thylpropyl, 1-ethylpropyl, 1 , 1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1 -methylpentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 , 1-dimethylbutyl, 1 ,2-dimethylbutyl, 1,3-dimethyl- butyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1 ,2-tri- methylpropyl, 1 ,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl.

[0026] The term " Ci-C4-haloalkyl" as used herein, which can also be expressed as "alkyl” which is partially or fully halogenated", refers to straight-chain or branched alkyl groups having 1 to 4 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above. Examples are chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1 -chloroethyl, 1-bromoethyl, 1 -fluoroethyl, 2-fluoro- ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2- dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl. Ci-Cs-haloalkyl is additionally, for example, 1 -fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1 , 1-difluoropropyl, 2,2-difluoropropyl, 1 ,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 1 , 1 , 1 -trifluoroprop- 2-yl, 3-chloropropyl, 4-chlorobutyl and the like.

[0027] The term "Ci-C4-alkoxy" refers to a Ci-C4-alkyl group, as defined above, attached via an oxygen atom to the remainder of the molecule. Examples are methoxy, ethoxy, n-propoxy, 1- methylethoxy (isopropoxy), n-butoxy, 1 -methylpropoxy (sec-butoxy), 2-methylpropoxy (isobutoxy) or 1 ,1 -dimethylethoxy (tert- butoxy).

[0028] If not specified otherwise, amino is NH2.

[0029] Ci-C4-Alkylamino is a group -NHR, where R is a Ci-C4-alkyl group, as defined above.

[0030] Di-(Ci-C4-alkyl)-amino is a group -NRR’, where R and R’, independently of each other, are a Ci-C4-alkyl group, as defined above.

[0031] Imino is a group containing a C=N double bond. The C=N bond can also be part of a heterocycle.

[0032] In chiral ligands which comprise just one phosphino group and additionally at least one of a phosphine oxide group, an amino group or an imino group, the amino and imino groups are nitrogen-containing groups in which the nitrogen atom can coordinate to a central metal in a complex. In this context, unlike defined above, the amino group is not limited to NH2, but is a group -NRR’, where R and R’, independently of each other, are hydrogen or an organic radical. Moreover, the amino or imino group can also be part of a heterocyclic ring, as is for example the case in ligand L.5 (depicted below). A phosphino group in this context is a group -PRR’, where R and R’, independently of each other, are hydrogen or an organic radical; and a phosphine oxide group is a group -P(=O)RR’, where R and R’, independently of each other, are hydrogen or an organic radical.

[0033] The 5- or 6-membered heteroaromatic ring having 1 , 2 or 3 heteroatoms selected from O, N and S are ring members may be attached to the remainder of the molecule via a carbon ring member or via a nitrogen ring member. As a matter of course, the heteroaromatic ring contains at least two carbon ring atoms. The heteroaromatic ring contains 1 , 2 or 3 nitrogen atoms as ring members, or contains 1 oxygen atom and optionally one or two nitrogen atoms as ring members, or contains one sulfur atom and optionally one or two nitrogen atoms as ring members. Examples are 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-1- pyrazolyl, 3_,-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1 ,3,4-triazol-1-yl, 1 ,3,4-triazol- 2-yl, 1 ,3,4-triazol-3-yl, 1 ,2,3-triazol-1-yl, 1 ,2,3-triazol-2-yl, 1 ,2,3-triazol-4-yl, 1 ,2,5-oxadiazol-3-yl, 1 ,2,3-oxadiazol-4-yl, 1 ,2,3-oxadiazol-5-yl, 1 ,3,4-oxadiazol-2-yl, 1 ,2,5-thiadiazol-3-yl, 1 ,2,3- thiadiazol-4-yl, 1 ,2,3-thiadiazol-5-yl, 1 ,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3- pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1 ,3,5-triazin-2- yl, 1 ,2,4-triazin-3-yl, 1 ,2,4-triazin-5-yl, and the like.

[0034] If R3and R4, together with the nitrogen atom to which they are bonded, form a 5- or 6- membered saturated heterocyclic ring (see below definition), the NR3R4group is 1 -pyrrolidinyl or 1-piperidinyl.

[0035] Compound (I) can be present as a tautomer thereof or as a mixture of different tautomeric forms. An example for a tautomeric form of the compound of the formula (I) as depicted above is the following formula:

[0036] Mixtures of different tautomeric forms are for example mixtures of this tautomer and the tautomer depicted above as formula (I).

[0037] Also compound II can be present as a tautomer thereof or as a mixture of different tautomeric forms. An example for a tautomeric form of the compound of the formula 1 as depicted above is the following formula:

[0038] Mixtures of different tautomeric forms are for example mixtures of this tautomer and the tautomer depicted above as formula (II). For the sake of simplicity, reference is made herein normally only to compounds (I) and (II) are mentioned. Nevertheless, all embodiments also relate to their tautomers and mixtures of different tautomeric forms thereof.

[0039] The reaction sequence of the method of the invention can be depicted as follows:

[0040] According to the inventive process, the keto group in alpha position to the thiazolyl ring is reduced to give an alcohol group. This is done by through the use of a reducing agent. Typically, said reducing agent used in inventive processes is a silane.

[0041] Preferred reducing agents are phenyl silane, diphenyl silane, triethoxysilane or diethyl silane.

[0042] Typically, such reducing agents are used in an excess relative to compound (II). Typically, when the silane is a monosilane, silanes are used in an amount of 1.0 to 20.0 mol per mol of compound (II), preferably 1.1 to 10 mol or 1.5 to 8 mol per mol of compound (II).

[0043] Processes of the invention are carried out in the presence of a chiral metal compound, typically a zinc compound.

[0044] Typically, such zinc compound is present in the inventive processes in substoichiometric amounts, based on the molar amount of Zn ions and of compound (II). Thus, such zinc compounds are typically present in catalytic amounts and such zinc compounds act as a catalyst for the reduction reaction. Said zinc compound is herein also referred to as the “zinc catalyst”.

[0045] Preferably, the chiral zinc catalyst, calculated on the basis of the zinc content, is used in an amount of 0.01 to 10 mol%, more preferably from 0.05 to 5 mol-%, even more preferably from 0.1 to 5 mol-%, and in particular from 1 to 5 mol-%, relative to 1 mol of compound (II)

[0046] According to the invention, the reduction reaction is carried in the presence of a chiral zinc compound that can also be referred to as a zinc complex. The term “zinc compound” as used herein includes zinc complexes. Typically, such chiral zinc compound comprises one or more chiral ligands L coordinated to zinc.

[0047] In one embodiment, said zinc compound, in addition to the chiral ligands L as defined below, contains one or more further ligands. Such further ligands may be coordinated to the zinc center, or may be present as counterions.

[0048] In one embodiment, such further ligands are selected from halides (e.g. Cl, Br or I; among which Cl is preferred), sulfonate (e.g. triflate, mesylate, tosylate or nonaflate; among which tri- flate is preferred), carboxylate (e.g. acetate, trifluoroacetate, benzoate). Such chiral zinc compound is typically prepared from an achiral zinc precursor (also referred to as the “zinc source” or the “catalyst precursor”).

[0049] Said zinc precursor is typically an achiral salt of zinc. Typically, said zinc precursor is a salt of zinc in an oxidation state of +11. It is also possible to use mixtures of more that one zinc salts as the zinc precursor.

[0050] In one embodiment, said zinc precursor is selected from Zn(OAc)2, Zn(acac)2, Zn(OTf)2, ZnCI2, ZnBr2, Znl2,ZnSC>4, Zn(NO2)2 or mixtures thereof.

[0051] (OAc means acetate, acac means acetylacetonate, OTf means triflate).

[0052] In one embodiment, such chiral zinc compound is preformed prior to its use in processes of the invention and is added to the reaction mixture as such.

[0053] In one embodiment, said chiral zinc compound is prepared in situ from a zinc precursor and one or more chiral ligands L.

[0054] Preformed catalysts are typically prepared by mixing the catalyst precursor with the chiral ligand L (herein also referred to as the “chiral ligand” or “ligand L”). The reaction is generally carried out in a solvent. The catalyst precursor and the chiral ligand L are generally mixed in a molar ratio of from 2:1 to 1 :2, preferably 1.5:1 to 1 :1.5, in particular 1.3:1 to 1 :1.3 and specifically 1 :1 to 1 :1.3, where the molar ratio is based on the amount of transition metal (in mol) in the catalyst precursor. The formed catalyst can either be isolated before being used in the reaction or the obtained reaction mixture can be used without isolation of the complex.

[0055] If the catalyst is formed in situ, catalyst precursor and chiral ligand L come into contact with each other in the presence of at least one of the reactants, e.g. of starting compound (II) and / or silane. In this case, too, the catalyst precursor and the chiral ligand L are generally used in a molar ratio of from 2:1 to 1 :2, preferably from 1.5:1 to 1 :1.5, in particular from 1.3:1 to 1 :1.3 and specifically from 1 :1 to 1 :1.3, where the molar ratio is based on the molar amount of zinc in the catalyst precursor.

[0056] In one embodiment, the catalyst is preformed. In a particular embodiment, catalyst precursor and the chiral ligand are reacted with each other, and the obtained reaction mixture is used, i.e. it is brought into contact with compound (II), without isolation of the preformed catalyst. In another particular embodiment, catalyst precursor and the chiral ligand L are reacted with each other, and the obtained complex is isolated and if desired purified before being used in the reduction method of the present invention. Isolation can be carried out by usual means, such as simply removing the solvent, optionally after aqueous workup, or extracting the reaction mixture and then removing the solvent. Further purification can for example be carried out by (recrystallization.

[0057] Specifically, the catalyst is obtainable by reacting one of the aforementioned chiral ligands L with Zn(OAc)2, Zn(acac)2, Zn(OTf)2, ZnCI2, ZnBr2, Znl2,ZnSC>4, Zn(NO2)2 or mixtures thereof in a molar ratio of from 2:1 to 1 :2, preferably from 1.5:1 to 1 :1.5, in particular from 1.3:1 to 1 :1.3 and specifically from 1 :1 to 1 :1.3, where the molar ratio is based on the amount of transition metal (in mol) in the catalyst precursor.

[0058] In one embodiment said chiral ligand L contains nitrogen atoms. In one embodiment, said chiral ligand contains amine groups. In one embodiment, said chiral ligand contains imine groups.

[0059] In one embodiment, said chiral ligand is a diamine.

[0060] In one embodiment, said chiral ligand is a diamine and contains a1 ,2-diaryl-ethane-1 ,2-diamine moiety.

[0061] In one embodiment, said chiral ligand is a diamine and contains a1 ,2-diphenyl-ethane-1 ,2-dia- mine moiety, where said phenyl substituents can in one embodiment carry substituents like alkyl, halo, haloalkyl or alkoxy groups.

[0062] In one embodiment, said chiral ligand is a diamine and contains a1 ,2-dinaphthyl-ethane-1 ,2-dia- mine moiety, where said naphthyl substituents can in one embodiment carry substituents like alkyl, halo, haloalkyl or alkoxy groups.

[0063] In one embodiment, said chiral ligand contains a 1 ,2-cyclohexyl diamine moiety.

[0064] The amino groups in chiral ligands L can be either primary amino groups or secondary amino groups.

[0065] In one embodiment, the chiral transition metal catalyst contains one bidentate diamine ligand. When reference is made herein to an “aryl”, “phenyl”, “naphthyl” or “anthracenyl” groups, this shall be understood to include the unsubstituted aryl, phenyl, naphthyl or anthracenyl groups, as well as aryl, phenyl, naphthyl or anthracenyl groups that bear one or more substituents.

[0066] In one embodiment, said chiral ligand is selected from the group consisting of the chiral forms of the ligands of formulae L.1

[0067] L.1 , wherein

[0068] Ar is an aryl group that is optionally further substituted with one or more groups such as alkyl, halo, haloalkyl, alkoxy groups; and

[0069] R is selected from H, alkyl, cycloalkyl, aryl that may optionally bear further substituents, aralkyl that may optionally bear further substituents.

[0070] In one embodiment Ar is selected from phenyl and naphthyl that may each optionally be substituted with one or more groups such as aralkyl, halo, haloalkyl, alkoxy groups; and

[0071] R is selected from H, C1-4 alkyl, methylene phenyl, methylene naphthyl or methylene anthracenyl that may optionally be substituted with one or more groups such aralkyl, halo, haloalkyl, alkoxy groups. In one embodiment, said chiral ligand is selected from the group consisting of the chiral forms of the ligands of formula L.1.1

[0072] L.1.1 , wherein

[0073] R is selected from H, alkyl, cycloalkyl, aryl, aralkyl that may optionally bear further substituents, R being preferably selected from H, C1-4 alkyl, methylene phenyl, methylene naphthyl or methylene anthracenyl that may in each case optionally be substituted on the aromatic system with one or more groups such aralkyl, halo, haloalkyl, alkoxy groups;

[0074] R1is selected from alkyl, especially C1-4 alkyl, particularly, methyl, tert.-butyl; halo, especially Cl, Br, I; hydroxy, alkoxy, especially Ci-4-alkoxy, particularly methoxy; n = 0-3, especially 0, 1 , 2 or 3.

[0075] In one embodiment n is 0.

[0076] In one embodiment n is 1.

[0077] In one embodiment n is 2.

[0078] In one embodiment n is 3.

[0079] In one embodiment in L.1.1 , R1is selected from methyl, trifluormethyl, hydroxy and methoxy. In one embodiment in L.1.1 , R1is methyl. In one embodiment in L.1.1 , R1is trifluormethyl. In one embodiment in L.1.1 , R1is methoxy. In one embodiment in L.1.1 , R1is hydroxy.

[0080] In one embodiment in L.1.1 , R is selected from H, C1-4 alkyl, especially methyl; methylene anthracenyl, methylene naphthyl, benzyl that may optionally be further substituted; bisphenyl or dibenzo cycloheptenyl. In one embodiment in L.1.1 , R is H. In one embodiment in L.1.1 , R is C1-4 alkyl, especially methyl. In one embodiment in L.1.1 , R is methylene anthracenyl. In one embodiment in L.1.1 , R is methylene naphthyl. In one embodiment in L.1.1 , R is benzyl that may optionally be further substituted. In one embodiment in L.1.1 , R is bisphenyl. In one em- bodiment in L.1.1 , R is dibenzo cycloheptenyl.

[0081] “dibenzo cycloheptenyl” as used herein i

[0082] In one embodiment in L.1.1 , n = 0 and R is selected from H, C14 alkyl, especially methyl; methylene anthracenyl, methylene naphthyl, benzyl that may optionally be further substituted; bisphenyl, . In one embodiment in L.1.1 , n = 1 and R1is selected from methyl, trifluormethyl and methoxy. In one embodiment in L.1.1 , n = 1 , R1is selected from o-methyl me-methyl, p-methyl, m-trifluor- methyl, o-trifluormethyl, o-methoxy, m-methoxy, p-methoxy. In one embodiment in L.1.1 , n = 1 , R1is selected from methyl, trifluormethyl and methoxy; and R is selected from H, C1-4 alkyl, especially methyl; methylene anthracenyl, methylene naphthyl, benzyl that may optionally be further substituted; bisphenyl.

[0083] In one embodiment in L.1.1 , n = 2 and R1is selected from methyl, trifluormethyl and methoxy, preferably methyl; In one embodiment in L.1.1 , n = 2, R1is selected from methyl, trifluormethyl and methoxy, preferably methyl; and R is selected from H, C1-4 alkyl, especially methyl; methylene anthracenyl, methylene naphthyl, benzyl that may optionally be further substituted; bisphenyl.

[0084] In one embodiment in L.1.1 , n = 2 and R1is selected from 2,6-dimethyl, 3,5 dimethyl, 2,6.-di- methoxy, 3,5-dmethoxy. In one embodiment in L.1.1 , n = 2, R1is selected from from 2,6-dime- thyl, 3,5 dimethyl, 2, 6. -dimethoxy, 3,5-dmethoxy; and R is selected from H, CM alkyl, especially methyl; methylene anthracenyl, methylene naphthyl, benzyl that may optionally be further substituted; bisphenyl.

[0085] In one embodiment, said chiral ligand is selected from the group consisting of the chiral forms of the ligands of formula L.1.1 a

[0086] L.1.1a, wherein R, R1 and n have the same meaning as in L.1.1.

[0087] In one embodiment, said chiral ligand is selected from the group consisting of the chiral forms of the ligands of formula L.1.1 b

[0088] L.1.1 b, wherein R, R1and n have the same meaning as in L.1.1 . In one embodiment, said chiral ligand is selected from the group consisting of the chiral forms of the ligands of formula L.1.2

[0089] L.1.2, wherein R is selected from H, alkyl, cycloalkyl, aryl that may optionally bear further substituents, aralkyl that may optionally bear further substituents; R being preferably selected from H, C1-4 alkyl, methylene phenyl, methylene naphthyl or methylene anthracenyl that may in each case optionally be substituted on the aromatic system with one or more groups such aralkyl, halo, haloalkyl, alkoxy groups; and

[0090] R4is situated at any of the aromatic rings of the naphthyl moiety and is selected from alkyl, especially C1-4 alkyl, particularly, methyl, tert.-butyl; halo, especially Cl, Br, I; hydroxy, alkoxy, especially Ci-4-alkoxy, particularly methoxy; o = 0-6, especially 0, 1 , 2 or 3.

[0091] In one embodiment o is 0.

[0092] In one embodiment o is 1 .

[0093] In one embodiment o is 2.

[0094] In one embodiment o is 3.

[0095] In one embodiment in L.1.2, R4is selected from methyl, trifluormethyl, hydroxy and methoxy. In one embodiment in L.1.2, R4is methyl. In one embodiment in L.1.2, R4is trifluormethyl. In one embodiment in L.1.2, R4is methoxy. In one embodiment in L.1.2, R4is hydroxy.

[0096] In one embodiment in L.1.2, R is H. In one embodiment in L.1.2, R is alkyl, especially C1-4 alkyl, especially methyl. In one embodiment in L.1.2, R is aryl. In one embodiment in L.1.2, R is methylene anthracenyl. In one embodiment in L.1.2, R is methylene naphthyl. In one embodiment in L.1.2, R is benzyl that may optionally be further substituted. In one embodiment in L.1.2, R is bisphenyl.

[0097] In one embodiment in L.1.2, R4is selected from methyl, trifluormethyl, hydroxy and methoxy. In one embodiment in L.1.2, R4is methyl. In one embodiment in L.1.2, R4is trifluormethyl. In one embodiment in L.1.2, R4is methoxy. In one embodiment in L.1.2, R4is hydroxy.

[0098] In one embodiment in L.1.2, o = 0 and R is H. In one embodiment in L.1.2, o = 0 and R is alkyl, especially C14 alkyl, especially methyl. In one embodiment in L.1.2, o = 0 and R is aryl. In one embodiment in L.1.2, o = 0 and R is methylene anthracenyl. In one embodiment in L.1.2, o = 0 and R is methylene naphthyl. In one embodiment in L.1.2, o = 0 and R is benzyl that may optionally be further substituted. In one embodiment in L.1.2, o = 0 and R is bisphenyl. In one embodiment, said chiral ligand is selected from the group consisting of the chiral forms of the ligands of formulae L.2

[0099] L.2, wherein

[0100] R2is selected from H, alkyl, especially C1-4 alkyl, especially methyl; benzyl that may optionally bear further substituents; n = 0-4, preferably 0;

[0101] R3is selected from alkyl, cycloalkyl, aryl that may optionally bear further substituents, aralkyl that may optionally bear further substituents.

[0102] In one embodiment, said chiral ligand is selected from the group consisting of the chiral forms of the ligands of formula L.2a

[0103] L.2a , wherein R2, R3and n have the same meaning as in L.2.

[0104] In one embodiment, said chiral ligand is selected from the group consisting of the chiral forms of the ligands of formula L.2b wherein R2, R3and n have the same meaning as in L.2.

[0105] In one embodiment, ligand ,

[0106] In one embodiment, ligand L is

[0107] In one embodiment, ligand L is In one embodiment, ligand L is

[0108] In one embodiment, ligand L is

[0109] In one embodiment, ligand L is

[0110] In one embodiment, ligand L is

[0111] In one embodiment, ligand

[0112] , , In one embodiment, ligand L is

[0113] In one embodiment, ligand L is

[0114] In one embodiment, ligand L is

[0115] In one embodiment, ligand L is

[0116] In one embodiment, ligand L is

[0117] In one embodiment, ligand L is

[0118] In one embodiment, ligand L is

[0119] In one embodiment, ligand L is

[0120] In one embodiment, ligand L is ,

[0121] In one embodiment, ligand L is In one embodiment, ligand L is

[0122] Typically, the chiral ligand is used in the inventive processes in an amount of 1.0 to 3.0 mol per mol of Zn, preferably 1.0 to 2.0 mol per mol of Zn or 1 .0 to 1.3 mol per mol of Zn.

[0123] The reaction time depends on various factors, such as the reaction temperature, the concentration of the reactants in the reaction mixture and the like. Typically, it is in the range of from about 0 to 48 h, preferably from 1 to 24 h, in particular from 1 to 18 h, specifically from 10 to 18 h. A reaction time of “0 h” in this context means that after complete addition of all components, the reaction can be sufficiently complete to continue with the isolation of the desired compound (I). This can for example be the case if the addition of the reactants has lasted rather long or if it is intended to recycle the non-reacted starting material.

[0124] The reaction is preferably carried out in the presence of a solvent. The solvent is preferably selected from the group consisting of polar aprotic solvents, polar protic solvents, Ci-C4-alkyl acetates, chlorinated alkanes, open-chained ethers, aromatic solvents and mixtures thereof.

[0125] In principle many solvents are suitable for carrying out processes of the invention. Typically, said solvent dissolves the silane under the reaction conditions. The zinc precursor is typically not well soluble in such solvent. Typically, such solvent is chosen such that preformed zinc catalyst, compound-l, compound II silane and ligand are at least partially soluble in solvent under the reaction conditions. In one embodiment, such solvent is chosen such that preformed zinc catalyst, compound-l, silane and ligand are completely dissolved in the solvent under the reaction conditions.

[0126] The reaction is preferably carried out in the presence of a solvent. The solvent is preferably selected from the group consisting of polar aprotic solvents or polar protic solvents. In one embodiment the solvent is selected from Ci-C4-alkyl acetates, chlorinated alkanes, open-chained ethers, aromatic solvents and mixtures thereof. Polar aprotic solvents are polar solvents without a functional group from which a proton can dissociate. Examples for suitable polar aprotic solvents are amides, such as dimethylformamide (DMF), diethylformamide, dibutylformamide, and dimethylacetamide; cyclic ethers, such as tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,3-dioxane and 1 ,4-dioxane; sulfoxides, such as dimethylsulfoxide (DMSO); nitriles, such as acetonitrile; lactams, such as N-methylpyrrolidone (NMP), N-(n-butyl)-pyrrolidone or N-(tert-butyl)-pyrrolidone; sulfones, such as sulfolane; carbonic acid esters, such as dimethylcarbonate, ethylenecarbonate or propylene carbonate; lactones, such as y-butyrolactone or y-valerolactone; ureas, such as N,N,N’,N’-tetramethyl urea, N,N,N’,N’-tetrabutyl urea, dimethylpropylene urea (DMPLI) or 1 ,3-dimethyl-2-imidazolinone (DMEll; DMI); and nitro compounds, such as nitromethane.

[0127] Polar protic solvents are solvents with a functional group from which a proton can easily dissociate. Examples of suitable polar protic solvents are Ci-C4-alkanols, fluorinated Ci-C4-alkanols, glycols and mixtures thereof. Ci-C4-Alkanols are for example methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol and tert-butanol. Fluorinated Ci-C4-alkanols are for example 2-fluoroethanol, 3-fluoropropanol, 1-fluoropropan-2-ol, 4-fluorobutanol, 1 , 1 -difluoro- ethanol, 2,2-difluoroethanol, 2,2-difluoropropanol, 3,3-difluoropropanol, 1 ,1-difluoropropan-2-ol,

[0128] 2.2.2-trifluoroethanol, 3,3,3-trifluoropropanol, 4,4,4-trifluorobutanol and the like. Examples for glycols are ethylene glycol, diethylene glycol and triethylene glycol.

[0129] Examples for suitable Ci-C4-alkyl acetates are methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate.

[0130] Examples for suitable chlorinated alkanes are dichloromethane, trichloromethane or dichloroethane.

[0131] Open-chained ethers are compounds of formula R-O-R’, where R and R’, independently of each other, are an aliphatic, cycloaliphatic or aromatic group. In contrast to cyclic ethers, R and R’ do not form together a bridging group; i.e. the ether oxygen atom is not a ring member of a cyclic ring system. Examples are di-(Ci-C4-alkyl)-ethers, such as diethyl ether, dipropylether, diisopropylether, dibutylether or methyl-tert-butyl ether; and anisole (methoxybenzene).

[0132] Examples for suitable aromatic solvents are benzene, toluene, trifluorotoluene, the xylenes (i.e.

[0133] 1.2-xylene, 1 ,3-xylene or 1 ,4-xylene), chlorobenzene, dichlorobenzene or anisole.

[0134] In one embodiment, said solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,3- dioxane, 1 ,4-dioxane, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dime- thylacetamide (DMAC), C1-C4-alkanols, fluorinated C1-C4-alkanols, C1-C4-alkyl acetates, chlorinated C1-C2-alkanes, di-(C1-C4-alkyl)-ethers, benzene, toluene, trifluorotoluene, the xylenes, chlorobenzene, dichlorobenzene, anisole and mixtures of the aforementioned solvents.

[0135] In one embodiment, said solvent is selected from 2-methyltetrahydrofuran, 1 ,4-dioxane, DMSO, DMF, Ci-Cs-alkanols, 2,2,2-trifluoroethanol, ethyl acetate, chlorinated Ci-C2-alkanes, di-(C1-C4- alkyl)-ethers, toluene, anisole, dimethoxy ethane, monochloro benzene, cyclopentyl methyl ether, N,N-dimethyl acetamide and mixtures of the aforementioned solvents.

[0136] In one embodiment, said solvent is selected from toluene, xylene, dioxane, 2-methyltetrahydro- furan, monochloro benzene, dimethoxy ethane, cyclopentyl methyl ether, N,N-dimethyl acetamide, or mixtures thereof.

[0137] Typically, the inventive processes are carried out at a temperature from -5 to 120°C.

[0138] In one embodiment, the inventive processes are carried out at a temperature of from 10 to 80°C.

[0139] In one embodiment, the inventive processes are carried out at a temperature of from 30 to 60°C.

[0140] The inventive process can typically be carried under acidic, neutral or basic conditions. However, strongly acidic , e.g. a pH below 5, or strongly basic conditions, e.g. pH above 8, are normally avoided.

[0141] The reaction is generally carried out by mixing the starting compound II, the chiral catalyst (either in preformed form or in form of a catalyst precursor and a chiral ligand), optionally the solvent, the silane and optionally any further additives at the desired reaction, or mixing the components, and bringing then the temperature to the desired range. The order of addition is normally not particularly critical.

[0142] For instance,

[0143] (i) the starting compound (II) is dissolved in a solvent, the catalyst (or catalyst precursor and ligand, if the catalyst is to be prepared in situ), optionally dissolved in a solvent, is added, and silane is added; or

[0144] (ii) the starting compound (II), optionally dissolved in a solvent, is added to the catalyst (or a mixture of catalyst precursor and ligand, if the catalyst is to be prepared in situ) dissolved in a solvent, and silane is added.

[0145] After completion of the reaction, the pyrimidinone of the formula (I) in enantiomerically enriched form can be isolated from the reaction mixture. When the inventive processes are carried out on a commercial scale, workup of compound (I) is not always necessary. Rather Compound (I) can be used in the next synthesis step without further purification.

[0146] If compound (I) is to be isolated and purified, isolation typically comprises adding water to the reaction mixture, isolating and optionally purifying the pyrimidinone of the formula (I) precipitated upon addition of water. Alternatively, isolation comprises setting the pH of the reaction mixture acidic; removing at least a part of the solvent, if any, to obtain a concentrate; adding water and a solvent which has low or no miscibility with water to the concentrate; extracting the pyrimidinone of the formula (I) into the solvent which has low or no miscibility with water; and isolating the pyrimidinone of the formula (I) from the extract. The solvent which has low or no miscibility with water is preferably selected from the group consisting of 2-methyltetrahydrofuran, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methylisopropyl ketone, and chlorobenzene. In one embodiment, processes of the invention allow the preparation of enantiomerically enriched compound (I) with S configuration (compound (l-S) with an enantiomeric excess (EE) of at least 55 %ee, preferably at least 60 %ee, more preferably at least 70 %ee, even more preferably at least 80%ee, or at least 90 %ee or at least 95%ee.

[0147] In one embodiment, processes of the invention allow the preparation of enantiomerically enriched compound (I) with R configuration (compound (l-R) with an enantiomeric excess (EE) of at least 55 %ee, preferably at least 60 %ee, more preferably at least 70 %ee, even more preferably at least 80%ee, or at least 90 %ee or at least 95%ee.

[0148] The starting compound (II) is obtainable by reaction of N-methylthiourea with an alkyl 2-phe- nylmalonate to 6-hydroxy-3-methyl-5-phenyl-2-sulfanyl-pyrimidin-4-one or the corresponding thiolate and reaction thereof with 2-chloro-1-(2-chlorothiazol-5-yl)ethanone to the compound (II). These reactions are known.

[0149] N-methylthiourea and alkyl 2-phenylmalonates are commercially available. 2-Chloro-1-(2-chloro- thiazol-5-yl)ethanone can be prepared, for example, as described in WO 2018 / 197541 or WO 2018 / 202654 by reaction of 2-chlorothiazole with a Grignard reagent to the corresponding chloro-(2-chlorothiazol-5-yl) magnesium species and reaction thereof with 2-chloro-N-methoxy- N-metyl-acetamide. Alternatively, the compound 3 can be prepared from thiourea according the method described by T. Chalopin et al. in Org. Biomol. Chem., 2016, 14, 3913-3925.

[0150] The present method leads to the compound (I) in high yields and stereoselectivity.

[0151] The compound (I) can be converted in just one further step into 3-(2-chlorothiazol-5-yl)-8-me- thyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate, and especially into enantiomerically enriched forms thereof. For this purpose, the compound (I) is subjected to an internal cyclization by a nucleophilic attack of the unsubstituted nitrogen atom of the pyrimidine ring on the carbon atom carrying the aliphatic OH group. This reaction is described under separate cover, e.g. in PCT / EP2022 / 051368.

[0152] While the compound (I) can be converted in just one step into 3-(2-chlorothiazol-5-yl)-8-methyl- 7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate and enantiomerically enriched forms thereof, it can also be first subjected to some modifications, such as etherification of the hydroxyl group on the pyrimidine ring, substitution of the Cl atom on the thiazole ring or introduction of substituents on the phenyl ring, so as to allow formation of 2,3-dihydrothiazolo[3,2- a]pyrimidinium compounds other than 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5- olate.

[0153] The present invention inter alia offers the following advantages: Processes of the invention are easy and economical to carry out. Processes of the invention are environmentally friendly.

[0154] Processes of the invention yield compound (I) in high yields. Processes of the invention yield compound (I) with high purity.

[0155] Processes of the invention allow the preparation of enantiomerically enriched compound (I) with an enantiomeric excess (EE) of at least 55 %ee, preferably at least 60 %ee, more preferably at least 70 %ee, even more preferably at least 80%ee, or at least 90 %ee or at least 95%ee.

[0156] The present invention is further illustrated in the following examples.

[0157] Examples

[0158] Abbreviations:

[0159] THF tetra hydrofuran

[0160] MCB monochloro benzene

[0161] DCM dichloromethane

[0162] 2-MeTHF 2-methyltetrahydrofuran

[0163] MeOH methanol

[0164] EtOAc ethyl acetate iPrOH isopropanol

[0165] TFA trifluoroacetic acid t time min minute(s) h hour(s) rc.t. reaction time r.t. room temperature rt retention time

[0166] Methods:

[0167] The compounds were characterized by coupled High Performance Liquid Chromatography.

[0168] Achiral HPLC for conversion and chemoselectivity:

[0169] Software: Agilent Series 1100

[0170] Column: Dr. Maisch Retrospher 100 C18, 4.6x75 mm, 3.0 pm

[0171] Eluent: -A: H2O with 0.1 vol% TFA

[0172] -B: MeCN with 0.1 vol % TFA

[0173] Detector: UV detector = 220 nm, band width = 4 nm

[0174] Inject, vol.: 2 pL

[0175] Temperature: 30°C Analysis time: 15 min

[0176] Chiral HPLC for %ee:

[0177] Software: Agilent Series 1260

[0178] Column: Chiralpak AD-RH 5 pm 150*4.6 mm from Daicel

[0179] Eluent: - A: H2O with 0.1 vol% H3PO4

[0180] - B: MeCN / 2-Propanol (1 :1)

[0181] Detector: UV detector = 216 nm, band width = 4 nm

[0182] Inject, vol.: 3 pL

[0183] Temperature: 40°C

[0184] Analysis time: 22 min

[0185] Pressure: ca. 95 bar

[0186] Examples 1 to 4: Screening of ligands L

[0187] Compound (II) (50 mg, 0.127 mmol), Zn(OAc)2 (30 mol%., 0.04 mmol) and separately chiral amine ligand (30 mol%, 0.04 mmol) were suspended in toluene (0.13M) under ambient atmosphere. After 10 min of stirring PhSiHa (2.5 eq, 0.32 mmol) was added, and the reactions were stirred at 25 °C for 1 to 3 hours. Reaction sampling was done by taking 20 pL and dissolving it in MeOH (1 mL). All reactions were monitored by HPLC (“PAL A %” denotes the yield of compound (I)).

[0188]

[0189] Experiments 5 to 7: Screening of Silane Sources

[0190] Compound (II) (50 mg, 0.127 mmol), Zn(OAc)2(30 mol%., 0.04 mmol) and separately chiral amine ligand(30 mol%, 0.04 mmol) were suspended in toluene (0.13M) under ambient atmosphere. After 10 min of stirring the silane (2.5 eq, 0.32 mmol) was added, and the reactions were stirred at 40 °C for 1 to 3 hours. Reaction sampling was done by taking 20 pL and dissolving it in MeOH (1 mL). All reactions were monitored by HPLC (“PAL A %” denotes the yield of compound (I)).

[0191] Experiments 8 to 12: Screening of Zn sources Compound (II) (50 mg, 0.127 mmol), zinc salt (30 mol%., 0.04 mmol) and separately chiral amine ligand (30 mol%, 0.04 mmol) were suspended in toluene (0.13M) under ambient atmosphere. After 10 min of stirring phenylsilane (2.5 eq, 0.32 mmol) was added, and the reactions were stirred at 40 °C for 1 to 3 hours. Reaction sampling was done by taking 20 pL and dissolving it in MeOH (1 mL). All reactions were monitored by HPLC (“PAL A %” denotes the yield of compound (I)). Experiments 13 to 24: Screening of temperature

[0192] Compound (II) (50 mg, 0.127 mmol), Zn(OAc) (30 mol%., 0.04 mmol) and separately chiral amine ligand(30 mol%, 0.04 mmol) were suspended in the solvent given in the below table (0.13M) under ambient atmosphere. After 10 min of stirring phenylsilane (2.5 eq, 0.32 mmol) was added, and the reactions were stirred at the temperature given in the below table for 1 to 3 hours. Reaction sampling was done by taking 20 pL and dissolving it in MeOH (1 mL). All reactions were monitored by HPLC (“PAL A %” denotes the yield of compound (I)).

[0193] Experiments 25 to 41 : Screening of solvents

[0194] Compound (II) (50 mg, 0.127 mmol), Zn(OAc) (30 mol%., 0.04 mmol) and separately chiral amine ligand (30 mol%, 0.04 mmol) were suspended in the solvent given in the below table (0.13M) under ambient atmosphere. After 10 min of stirring phenylsilane (2.5 eq, 0.32 mmol) was added, and the reactions were stirred at 40 °C for 1 to 3 hours. Reaction sampling was done by taking 20 pL and dissolving it in MeOH (1 mL). All reactions were monitored by HPLC (“PAL A %” denotes the yield of compound (I)).

[0195]

Claims

Claims1. Process for preparing an enantiomerically enriched form of 2-[2-(2-chlorothiazol-5-yl)-2- hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one (compound (I)) or a tautomer thereof which comprises reducing 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl- 6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one (compound (II)) with a silane compound in the presence of a chiral zinc compound.

2. Process according to claim 1 , where said zinc compound is used in substoichiometric amount relative to compound (II).

3. Process according to any of claims 1 to 2 where said silane is selected from phenyl silane, diphenyl silane, triethoxysilane and diethyl silane.

4. Process according to any of claims 1 to 3, where the chiral zinc compound is prepared from an achiral zinc precursor and a chiral ligand.

5. Process according to claim 4, where said zinc precursor is selected from salts of Zn(ll).

6. Process according to any of claims 4 to 5, where said zinc precursor is selected from Zn(OAc)2, Zn(acac)2, Zn(OTf)2, ZnCh, ZnBr2, Znl2,ZnSO4, Zn(NOa)2 or mixtures thereof.

7. Process according to any of claims 4 to 6, where said chiral ligand is a nitrogen containing ligand.

8. Process according to any of claims 4 to 7, where said chiral ligand contains amino groups or imino groups.

9. Process according to any of claims 4 to 8, where said chiral ligand is a diamine.

10. Process according to any of claims 4 to 9, where said chiral ligand contains a1 ,2-diaryl- ethane-1 ,2-diamine moiety or a 1 ,2-cyclohexyl diamine moiety.

11. Process according to any of claims 4 to 10, where said chiral ligand is selected from the group consisting of the chiral forms of the ligands of formulae L.1 or L.2L.1 , L.2 wherein in L.1Ar is an aryl group that is optionally further substituted with one or more groups such as alkyl, halo, haloalkyl, alkoxy groups; andR is selected from H, alkyl, cycloalkyl, aryl that may optionally bear further substituents, aralkyl that may optionally bear further substituents; wherein in L.2R2is selected from H, alkyl, especially C1-4 alkyl, especially methyl, benzyl that may optionally bear further substituents; n = 0-4, preferably 0;R3is selected from alkyl, cycloalkyl, aryl that may optionally bear further substituents, aralkyl that may optionally bear further substituents.

12. Process according to any of claims 4 to 11 , where said chiral ligand is selected from the group consisting of the chiral forms of the ligands of formula L.1.1 or L.1.2L.1.1 , L.1.2, wherein in L.1.1R is selected from H, alkyl, cycloalkyl, aryl, aralkyl that may optionally bear further substituents, R being preferably selected from H, CM alkyl, methylene phenyl, methylene naphthyl or methylene anthracenyl that may in each case optionally be substituted on the aromatic system with one or more groups such aralkyl, halo, haloalkyl, alkoxy groups;R1 is selected from alkyl, especially C1-4 alkyl, particularly, methyl, tert.-butyl; halo, especially Cl, Br, I; hydroxy, alkoxy, especially C1-4-alkoxy, particularly methoxy; n = 0-3, especially 0,1 2 or 3; wherein in L.1.2R is selected from H, alkyl, cycloalkyl, aryl that may optionally bear further substituents, aralkyl that may optionally bear further substituents; R being preferably selected from H, C1-4 alkyl, methylene phenyl, methylene naphthyl or methylene anthracenyl that may in each case optionally be substituted on the aromatic system with one or more groups such aralkyl, halo, haloalkyl, alkoxy groups;R4is situated at any of the aromatic rings of the naphthyl moiety and is selected from alkyl, especially CM alkyl, particularly, methyl, tert.-butyl; halo, especially Cl, Br, I; hydroxy, alkoxy, especially Ci-4-alkoxy, particularly methoxy; o = 0-6, especially 0,1 , 2 or 3.

13. Process according to any of claims 4 to 12, where said chiral ligand is selected from the group consisting of14. Process according to any of claims 4 to 11 , where the chiral zinc compound, calculated on the basis of the zinc content, is used in an amount of from 0.1 to 5 mol-%, preferably from10 1 to 5 mol-%, relative to 1 mol of compound II.

Images