Method for preparing the enantiomerized concentrated form of 3-(2-chlorothiazole-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-A]pyrimidine-4-ium-5-oleate.

Abstract

The present invention relates to a process for preparing enantiomerically enriched forms of 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate.

Description

[Technical Field]

[0001] The present invention relates to a method for preparing an enantiomerized form of 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate. The present invention further relates to the use of 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula 2 shown below or its enantiomerized form, as well as 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds, particularly 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate and its enantiomerized form as intermediates in the preparation of these compounds. [Background technology]

[0002] 3-(2-chlorothiazole-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate and its enantiomerized forms possess insecticidal properties and are known, for example, from International Publication No. 2018 / 177970 or International Publication No. 2014 / 167084.

[0003] The methods known to date for preparing this pyriminidium compound are cumbersome and still unsatisfactory.

[0004] In International Publication Nos. 2018 / 177970, 2018 / 197541, and 2018 / 202654, non-racemic 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds are prepared by the reaction of non-racemic 4-heteroaryl-substituted thiazolidinedion-2-imines with 2-substituted malonic acid derivatives. In International Publication Nos. 2018 / 177970 and 2018 / 197541, non-racemic 4-heteroaryl-substituted thiazolidinedion-2-imines are prepared by catalytic asymmetric hydrogenation of 1-heteroaryl-substituted ethaneimines having a leaving group at the 2-position. The resulting amine is then reacted with an isothiocyanate to obtain the thiazolidinedion-2-imine. The reaction sequence is described in International Publication No. 2018 / 197541 as follows: [ka] R A is a sulfanyl group or sulfinyl group, a phosphoroxy group, an alkoxy group or a benzyl group, Het is optionally substituted pyridine-3-yl, thiazole-5-yl or pyrimidine-5-yl, W and LG are leaving groups, R 1 is a (cyclo)aliphatic group, R 2 It is a 5- or 6-membered carbon or heterocycle. In International Publication No. 2018 / 177970, amine VII is obtained from the corresponding sulfinylimine via an alternative reaction pathway.

[0005] International Publication Nos. 2018 / 177970 and 2018 / 202654 describe further access to non-racemic 4-heteroaryl-substituted thiazolidinedion-2-imines. These are prepared starting from a heteroarylmethyl ketone, where the methyl group has a leaving group, and involve the conversion of this leaving group to an alkylcarbonyloxy group, hydrolysis of the latter to a hydroxyl group, reaction of the resulting heteroarylhydroxymethyl ketone with sulfamoyl halide to 4-heteroaryl-5H-oxathiazole 2,2-dioxide, catalytic asymmetric hydrogenation of the latter to obtain non-racemic 4-heteroaryloxathiazolidine 2,2-dioxide, and reaction of its isothiocyanate with thiazolidinedion-2-imine. The reaction sequence is described in International Publication Nos. 2018 / 202654 as follows: [ka]

[0006] Het is optionally substituted pyridine-3-yl, thiazole-5-yl, or pyrimidine-5-yl, W and LG are leaving groups, and M 2 is Li, Na, K, Al, Ba, Cs, Ca, or Mg, and R AC is an alkylcarbonyl, X 1 It is a halogen, and R 1 is a (cyclo)aliphatic group, R 2 It is a 5- or 6-membered carbon or heterocycle.

[0007] However, these methods are not very economical. Some reagents are expensive, recycling of some reagents that are not consumed or not consumed at all is difficult, the overall yield is not satisfactory, and too many reaction steps are involved. [Overview of the project] [Problems that the invention aims to solve]

[0008] The object of the present invention was to provide an economical process for the preparation of 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate, in particular a process for the preparation of its enantiomer-enriched form which gives rise to the S or R enantiomer with high selectivity.

Means for solving the problems

[0009] This problem is solved by a method for preparing an enantiomer-enriched form of formula (I):

Chemical formula

Chemical formula

Chemical formula

[0010] The present invention further relates to 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one 2 or its tautomers or mixtures of different tautomers thereof, and enantiomerized forms thereof.

[0011] The present invention also relates to the use of 2-[2-(2-chlorothiazolo[3,2-a]pyrimidinium compounds, particularly 3-(2-chlorothiazolo[3,2-a]pyrimidine-4-ium-5-oleate(I)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate(I) and its enantiomerized forms, as intermediates in the preparation of these compounds. [Modes for carrying out the invention]

[0012] definition The terms “enantiomerized form” and similar terms for compound (I) of formula (I) 3-(2-chlorothiazole-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate or enantiomerized form indicate a non-racemic compound (I) in which either the S enantiomer or the R enantiomer is dominant, or exists simply as a stereoisomer. Compound (I) has a single stereocenter marked with an asterisk at the ring carbon atom having a thiazole ring.

[0013] The terms "enantiomerized form" and similar terms in formula 2, 2-[2-(2-chlorothiazole-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidine-4-one or enantiomerized form of compound 2, indicate a non-racemic compound 2 in which either the S enantiomer or the R enantiomer is dominant, or exists simply as a stereoisomer. Compound 2 has a single stereocenter marked with an asterisk at an aliphatic carbon atom having an OH group.

[0014] M + This is the cation equivalent. This represents a metal cation or an ammonium cation (in this case, ammonium is the ammonium cation NH4 in the appropriate sense). + This represents a substituted ammonium cation, but also represents a substituted ammonium cation). In the case of a cation with a double or triple charge, the cation equivalent is (M n+ ) 1 / n It can be expressed as follows, where n is the number of charges.

[0015] In connection with the present invention, holmate is a salt of formic acid (HC(=O)O - M + (In the formula, M + This term refers to the cation equivalent of the formic acid anion (HC(=O)O). - ) can also represent ester. However, in relation to the present invention, this term does not mean ester unless otherwise specified.

[0016] The organic part mentioned below, like the term halogen, is a general term for the individual enumeration of each group member. Prefix C n ~C m This represents the number of carbon atoms that can be present in the base in each case.

[0017] The term halogen refers to fluorine, bromine, chlorine, or iodine in each case, and more specifically to fluorine, chlorine, or bromine.

[0018] As used herein and in the alkyl portion of alkoxys, the term "alkyl" refers to a saturated linear (linear) or branched hydrocarbon group having 1 to 3 ("C1-C3 alkyl"), 1 to 4 ("C1-C4 alkyl"), or 1 to 6 ("C1-C6 alkyl") carbon atoms. C1-C3 alkyl represents a saturated linear or branched aliphatic group having 1 to 3 carbon atoms. Examples include methyl, ethyl, n-propyl, and isopropyl. C1-C4 alkyl represents a saturated linear or branched aliphatic group having 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. C1-C6 alkyl represents a saturated linear or branched aliphatic group having 1 to 6 carbon atoms. Examples include those stated for C1-C4 alkyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 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-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl.

[0019] The term "C1-C4 haloalkyl" as used herein, which can also be expressed as "partially or completely halogenated alkyl," refers to a linear or branched alkyl group having 1 to 4 carbon atoms (as described above), in which some or all of the hydrogen atoms of these groups are replaced by halogen atoms as described above. Examples include chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 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. C1-C3 haloalkyls include, 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-trifluoropropane-2-yl, 3-chloropropyl, and 4-chlorobutyl.

[0020] As used herein, the term "C3-C6 cycloalkyl" refers to a monocyclic saturated hydrocarbon group having 3 to 6 carbon atoms as its (sole) ring member. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0021] C6~C 10 The term bicycloalkyl refers to a bicyclic, bridged saturated hydrocarbon group containing 6 to 10 carbon atoms as the (sole) ring member. Examples include bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, and bicyclo[3.2.1]octyl. These are C6-C substituted with alkyl and / or oxo. 10Examples of bicycloalkyls are 7,7-dimethyl-bicyclo[2.2.1]hepta-1-yl and 7,7-dimethyl-2-oxo-bicyclo[2.2.1]hepta-1-yl.

[0022] C6~C 10 The term bicycloalkyl-C1~C3 alkyl refers to a group where one hydrogen atom is defined on top of C6~C3 alkyl. 10 This refers to a linear or branched alkyl group having 1 to 3 carbon atoms as defined above, which is replaced by a bicycloalkyl group.

[0023] The term "C1-C4 alkoxy" refers to the C1-C4 alkyl groups defined above, which are bonded to the remainder of the molecule via an oxygen atom. Examples include methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, 1-methylpropoxy (sec-butoxy), 2-methylpropoxy (isobutoxy), or 1,1-dimethylethoxy (tert-butoxy).

[0024] The term "C1-C4-alkoxy-C1-C4-alkyl" refers to a linear or branched alkyl group having 1 to 4 carbon atoms, where one hydrogen atom is replaced by the C1-C4-alkoxy group defined above. Examples include methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, n-butoxymethyl, sec-butoxymethyl, isobutoxymethyl, tert-butoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 1-propoxyethyl, 1-isopropoxyethyl, 1-n-butoxyethyl, 1-sec-butoxyethyl, 1-isobutoxyethyl, 1-tert-butoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 2-n-butoxyethyl, 2-sec-butoxyethyl, 2-isobutoxyethyl, 2-tert-butoxyethyl, 1-methoxypropyl, 1-ethoxypropyl Examples include pyrus, 1-propoxypropyl, 1-isopropoxypropyl, 1-n-butoxypropyl, 1-sec-butoxypropyl, 1-isobutoxypropyl, 1-tert-butoxypropyl, 2-methoxypropyl, 2-ethoxypropyl, 2-propoxypropyl, 2-isopropoxypropyl, 2-n-butoxypropyl, 2-sec-butoxypropyl, 2-isobutoxypropyl, 2-tert-butoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 3-isopropoxypropyl, 3-n-butoxypropyl, 3-sec-butoxypropyl, 3-isobutoxypropyl, 3-tert-butoxypropyl, etc.

[0025] "Phenyl-C1~C3-alkyl" refers to a linear or branched alkyl group having 1 to 3 carbon atoms (as described above), in which one hydrogen atom is replaced by a phenyl ring (in other words, a phenyl group bonded to the rest of the molecule via a C1~C3-alkylene linker).

[0026] Alkylenes are linear or branched divalent alkanediyl groups. C1-C3 alkylenes are linear or branched divalent alkyl groups having one, two, or three carbon atoms. Examples include: -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, and -C(CH3)2-. C2-C6 alkylenes are linear or branched divalent alkyl groups having two, three, four, five, or six carbon atoms. Examples include -CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2-, -CH2CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -(CH2)5-, -(CH2)6- and their positional isomers.

[0027] Straight-chain C3-C6 alkylenes are -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-.

[0028] Examples of 5- or 6-membered saturated heterocycles containing one nitrogen atom as a ring member and optionally one further heteroatom selected from N and O as a ring member are pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, isoxazolidine, piperidine, piperazine, or morpholine.

[0029] Oxo is =O, meaning that the substituent "oxo" replaces the CH2 group with a C(=O) group.

[0030] Group VIII metal catalysts refer to catalysts that have a metal from Group VIII of the periodic system as their central metal. Group VIII corresponds to current IUPAC group designations 8, 9, and 10, with respect to IUPAC group definitions valid before 1985.

[0031] Compound 1 can exist as its tautomers or as mixtures of different tautomer forms. An example of a tautomer of the compound of formula 1 above is given by the following formula. [ka]

[0032] A mixture of different tautomers is, for example, this tautomer, a mixture of tautomers shown above as formula 1.

[0033] Compound 2 may also exist as its tautomers or mixtures of different tautomer forms. An example of a tautomer of the compound of formula 2 above is given by the following formula. [ka]

[0034] A mixture of different tautomers is, for example, this tautomer, a mixture of the tautomers shown above as formula 2.

[0035] For simplicity, only compounds 1 and 2 will be mentioned below. Nevertheless, all embodiments also relate to their tautomers and mixtures of their different tautomer forms.

[0036] The condensed zwitterionic ring of the compound of formula (I) is stabilized mesomerially. The mesomelic form of the condensed ring can be represented by different isoelectronic formulas in which the positive and negative charges are distributed to different atoms, for example, as shown below. [ka]

[0037] Embodiment of the Invention (Ex) General and preferred embodiments Ex are summarized in the following non-exclusive list. Further preferred embodiments will become apparent in the paragraphs following this list. E.1. Enantiomer-enriched form, formula (I): [ka] (In the formula, an asterisk * indicates the center of the solid.) A method for preparing 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate, (a) Formula 1 [ka] 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one is converted to formic acid HC(=O)OH, formula HC(=O)O, in the presence of a chiral transition metal catalyst and optionally a base. - M + Formate and formic acid HC(=O)OH and formula HC(=O)O - M + A mixture of one or more formates (wherein M + The process involves reduction with a reducing agent selected from the group consisting of (where is the cation equivalent), and when formic acid is used as the reducing agent, the reaction is carried out in the presence of a base, reducing the enantiomerized form, Equation 2 [ka] Obtain a reaction containing 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one, (b) The reaction mixture obtained in step (a) is reacted (without isolating it from compound 2) with an activator that enhances the electrophilicity of the asterisked carbon atom in the compound of formula 1 without promoting racemization at the carbon atom, thereby obtaining the enantiomerized form of the compound of formula (I). A method that includes this. E.2.M + This is an alkali metal cation, formula [NHR 1 R 2 R 3 ] + (In the formula, R 1 , R 2 and R 3These are ammonium cations (selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, and C1-C4-alkoxy-C1-C4-alkyl), formula NR, independently of each other. 1 R 2 -A-NR 3 R 4 (In the formula, R 1 , R 2 , R 3 and R 4 These are, independently of each other, hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, and C1-C4-alkoxy-C1-C 4- The method according to Embodiment E.1, a protonated 5 or 6-membered saturated heterocycle selected from the group consisting of alkyl groups, where A is a protonated diamine (CH2)2 or (CH2)3) and one nitrogen atom as a ring member, and optionally one further heteroatom selected from N and O as a ring member, wherein the protonated 5 or 6-membered saturated heterocycle may have 1 to 6 C1-C4 alkyl groups and / or 1 or 2 OH groups. E.3.M + Li + na + , K + , Cs + NH4 + [NH2(C2H5)2] + [NH(C2H5)3] + [NH(CH2CH2CH2CH3)3] + [NH(C2H5)(CH(CH3)2] + [NH(CH3)2(CH(CH3)] + [NH2(C2H5)(C(CH3)3] + [NH2(CH(CH3)2)(C(CH3)3] + [NH2(C2H4OCH3)(CH3)] + [NH(cyclohexyl)2(CH3)] + [NH(cyclohexyl)(CH3)2] +The method according to Embodiment E.2, selected from the group consisting of protonated N,N,N',N'-tetramethylethylenediamine, protonated N,N,N',N'-tetramethylpropylene-1,3-diamine, protonated piperidine, protonated N-methylpiperidine, protonated 2,2,6,6-tetramethylpiperidine, protonated N-methyl-2,6,6-tetramethylpiperidine, protonated N-methyl-4-hydroxy-2,2,6,6-tetramethylpiperidine, protonated morpholine, and protonated N-methylmorpholine. E.4.M + is, formula [NHR 1 R 2 R 3 ] + (In the formula, R 1 , R 2 and R 3 These are independently selected from the group consisting of hydrogen and C1-C6 alkyl, preferably R 1 , R 2 and R 3 The method according to Embodiment E.2, wherein at least one, preferably at least two, of the alkali metal cations (which are C1-C6 alkyl) and ammonium cations are selected from the group. E.5.M + is [NH(C2H5)3] + [NH(CH2CH2CH2CH3)3] + and [NH(C2H5)(CH(CH3)2] + A method according to either embodiment E.3 or E.4, selected from the group consisting of the following. E.6. The base used optionally or required in step (a) is an alkali metal hydroxide, formula NR 1 R 2 R 3 (In the formula, R 1 , R 2 and R 3 R is independently selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, and C1-C4-alkoxy-C1-C4-alkyl. 1 , R 2 and R 3at least one of which is an amine other than hydrogen), of the formula NR 1 R 2 -A-NR 3 R 4 (wherein R 1 、R 2 、R 3 and R 4 are each independently selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy and C1-C4-alkoxy-C1-C4-alkyl, and A is (CH2)2 or (CH2)3), a diamine and a 5- or 6-membered saturated heterocyclic ring containing one nitrogen atom as a ring member and optionally one further heteroatom selected from N and O as a ring member, a 5- or 6-membered saturated heterocyclic ring which may have 1 to 6 C1-C4-alkyl groups and / or 1 or 2 OH groups, a method according to any of embodiments E.1 to E.5. E.7. The base is selected from the group consisting of LiOH, NaOH, KOH, diethylamine, triethylamine, tributylamine, diisopropylethylamine, dimethylisopropylamine, ethyl-tert-butylamine, isopropyl-tert-butylamine, (2-methoxyethyl)methylamine, N,N-dicyclohexylmethylamine, N-cyclohexyldimethylamine, N,N,N',N'-tetramethylethylenediamine, N,N,N',N'-tetramethylpropylene-1,3-diamine, piperidine, N-methylpiperidine, 2,2,6,6-tetramethylpiperidine, N-methyl-2,6,6-tetramethylpiperidine, N-methyl-4-hydroxy-2,2,6,6-tetramethylpiperidine, morpholine and N-methylmorpholine, and the base can be used in supported form (i.e. on a support material), a method according to embodiment E.6. E.8. The base is of the formula NR 1 R 2 R 3 (wherein R 1 、R 2 and R 3 are each independently selected from the group consisting of hydrogen and C1-C6-alkyl, R 1 、R 2 and R3 The method according to Embodiment E.6, wherein at least one of is selected from the group consisting of amines (which are C1-C6 alkyl). E.9. The base is selected from the group consisting of triethylamine, tributylamine, and diisopropylethylamine, as described in either embodiment E.7 or E.8. E.10. The method according to any one of Embodiments E.1 to E.9, wherein formic acid is used as a reducing agent step (a), and formic acid and the base are used in a molar ratio of 100:1 to 1:10. E.11. The method according to Embodiment E.10, wherein formic acid and a base are used in a molar ratio of 10:1 to 1:5. E.12. The method according to Embodiment E.11, wherein formic acid and a base are used in a molar ratio of 10:1 to 1:2. E.13. The method according to Embodiment E.12, wherein formic acid and a base are used in a molar ratio of 5:1 to 1:1. E.14. The method according to any one of Embodiments E.1 to E.13, wherein Compound 1 and the reducing agent are used in a molar ratio of 1:1 to 1:10. E.15. The method according to Embodiment E.14, wherein compound 1 and the reducing agent are used in a molar ratio of 1:1 to 1:5. E.16. The method according to any one of Embodiments E.1 to E.15, wherein one or more chiral ligands are coordinately bonded to a central transition metal in a chiral transition metal catalyst. E.17. The chiral transition metal catalyst used in step (a) is selected from group VIII metal catalysts, as described in any of embodiments E.1 to E.16. E.18. The method according to Embodiment E.17, wherein the chiral transition metal catalyst is selected from Group 8 and Group 9 metal catalysts. E.19. The method according to Embodiment E.18, wherein the chiral transition metal catalyst is selected from Ru catalysts, Rh catalysts, and Ir catalysts. E.20. The chiral transition metal catalyst is selected from Rh catalysts and Ir catalysts as described in Embodiment E.19. E.21. The method according to any one of Embodiments E.1 to E.20, wherein the chiral transition metal catalyst is used in an amount of 0.01 to 10 mol% per mole of compound 1, calculated based on the transition metal content. E.22. The method according to Embodiment E.21, wherein the chiral transition metal catalyst is used in an amount of 0.05 to 5 mol% per mole of compound 1, calculated based on the transition metal content. E.23. The method according to Embodiment E.22, wherein the chiral transition metal catalyst is used in an amount of 0.1 to 5 mol%, for example 0.1 to 2 mol%, per mole of compound 1, calculated based on the transition metal content. E.24. The method according to Embodiments E.1 to E.23, wherein the chiral transition metal catalyst comprises one or more chiral ligands that are pre-formed and coordinated to the transition metal, or is formed in situ by a reaction between a transition metal precursor compound and one or more chiral ligands. E.25. The method according to Embodiment E.24, wherein the chiral ligand is selected from the group consisting of bidentate amine chiral ligands. E.26. The method according to Embodiment E.25, wherein the chiral ligand is selected from the group consisting of chiral 1,2-diphenyl-ethylene-1,2-diamine, 1,2-cyclohexanediamine, and 1,2-bis(methylamino)cyclohexane. E.27. The method according to Embodiment E.26, wherein the chiral ligand is selected from the group consisting of chiral 1,2-diphenyl-ethylene-1,2-diamine. E.28. Chiral ligands are chiral forms of equation (II) [ka] (In the formula, The asterisk indicates the center of the stereochemistry. R 5 and R 6 These are independently selected from the group consisting of OH, halogens, C1-C4-alkyl and C1-C4-alkoxy elements. R 7 and R 8are, independently of one another, hydrogen, C1-C4-alkyl, -L-phenyl (where the phenyl ring may have 1, 2, 3, 4 or 5 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy) and SO2R 9 selected from the group consisting of L is a linker selected from the group consisting of C2-C6-alkylene, C1-C3-alkylene-O-(CH2) p (where p is 0, 1 or 2) and C1-C3-alkylene-(1,2-phenylene)-(CH2) r (where r is 0, 1 or 2) R 9 is C1-C4-alkyl, C1-C4-haloalkyl, phenyl, phenyl-C1-C3-alkyl (where the phenyl in two of the aforementioned groups may have 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy), naphthyl, C6-C 10 -bicycloalkyl-C1-C3-alkyl (where the bicycloalkyl ring may be substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of C1-C4-alkyl and oxo) and NR 10 R 11 selected from the group consisting of R 10 is hydrogen or C1-C4-alkyl, R 11 is phenyl-C1-C3-alkyl, the phenyl ring of which may have 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, and m and n are, independently of one another, 0, 1, 2, 3, 4 or 5) selected from the group consisting of 1,2-diphenyl-ethylene-1,2-diamine as described in embodiment E.27 E.29. In compound (II), R 5 and R 6 are C1-C4-alkoxy R 7 and R 8 One of them is selected from the group consisting of hydrogen, C1-C4-alkyl and -L-phenyl, and phenyl may have 1, 2, 3, 4 or 5 substituents selected from the group consisting of C1-C 4- alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, and R 7 and R 8 The other is selected from the group consisting of hydrogen and SO2R 9 and L is a linker selected from the group consisting of linear C3-C6-alkylene, (CH2) o -O-(CH2) p (where p and o are independently 1 or 2) and (CH2) q -(1,2-phenylene)-(CH2) r (where q and r are independently 0, 1 or 2, and at least one of q and r is not 0), R 9 is phenyl which may have 1, 2, 3, 4 or 5 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl, halogen, C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, C7-bicycloalkyl-methyl (where the bicycloalkyl ring may be substituted by 1, 2 or 3 substituents selected from the group consisting of C1-C4-alkyl and oxo) and NR 10 R 11 and is selected from the group consisting of R 10 is hydrogen or C1-C4-alkyl, R 11 is phenyl-(CH2) s -alkyl, s is 2 or 3, the phenyl ring may have 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, and[[ID=​​E.30. Chiral ligands include DPEN, TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, TripsMesitylDPEN, CsDPEN, MesitylDPEN, RsDPEN, TsDiOMeDPEN, and formula (II) (wherein R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8 The method according to either Embodiment E.28 or E.29, wherein is -(CH2)3-phenyl or -(CH2)4-phenyl, and the phenyl in the two last mentioned groups may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, and m and n are 0). E.31. Chiral ligands include TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, MesitylDPEN, RsDPEN, TsDiOMeDPEN, and formula (II) (wherein R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8 The method according to Embodiment E.30, wherein is selected from the group consisting of compounds of -(CH2)3-phenyl or -(CH2)4-phenyl, and m and n are 0. E.32. The method according to Embodiment E.31, wherein the chiral ligand is selected from the group consisting of TsDPEN, MsDPEN, and CsDPEN in (1R,2R) or (1S,2S) form. E.33. Chiral transition metal catalysts include Ru, Rh or Ir as the central metal, and DPEN, TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, TripsMesitylDPEN, CsDPEN, MesitylDPEN, RsDPEN, TsDiOMeDPEN, and formula (II) (wherein R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8 The method according to Embodiment E.30, wherein the catalyst comprises a ligand selected from the group consisting of compounds of the following types: -(CH2)3-phenyl or -(CH2)4-phenyl, where the phenyl in the two last mentioned groups may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, and m and n are 0. E.34. Chiral transition metal catalysts include Ru, Rh or Ir as the central metal, and TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, MesitylDPEN, RsDPEN, TsDiOMeDPEN, and formula (II) (wherein R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8 The method according to Embodiments E.31 and E.33, wherein the catalyst comprises at least one ligand selected from the group consisting of compounds of -(CH2)3-phenyl or -(CH2)4-phenyl, where m and n are 0. E.35. Chiral transition metal catalysts include a catalyst comprising Ru, Rh, or Ir as a central metal and at least one ligand selected from the group consisting of DPEN, TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, TripsMesitylDPEN, CsDPEN, MesitylDPEN, RsDPEN, and TsDiOMeDPEN in (1R,2R) or (1S,2S) form, and a catalyst comprising Ru as a central metal and formula (II) (wherein R) in (1R,2R) or (1S,2S) form. 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8 The method according to Embodiment E.33, wherein the catalyst comprises a ligand selected from compounds of the following types: -(CH2)3-phenyl or -(CH2)4-phenyl, where the phenyl in the two last mentioned groups may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, and m and n are 0. E.36. Chiral transition metal catalysts include a catalyst comprising Ru, Rh or Ir as a central metal and at least one ligand selected from the group consisting of TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, MesitylDPEN, RsDPEN and TsDiOMeDPEN in (1R,2R) or (1S,2S) form, and a catalyst comprising Ru as a central metal and formula (II) (wherein R) in (1R,2R) or (1S,2S) form. 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8The method according to Embodiment E.35, wherein the catalyst comprises a catalyst with at least one ligand selected from compounds of -(CH2)3-phenyl or -(CH2)4-phenyl, where m and n are 0. E.37. Chiral transition metal catalysts are catalysts comprising Ru, Rh, or Ir as a central metal and at least one chiral ligand selected from the group consisting of TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, MesitylDPEN, RsDPEN, and TsDiOMeDPEN in (1R,2R) or (1S,2S) form, or the following formula [ka] The method according to Embodiment E.36, which is a catalyst. E.38. The method according to Embodiment E.37, wherein the chiral transition metal catalyst is a catalyst comprising Ru, Rh, or Ir as a central metal and a chiral ligand selected from the group consisting of TsDPEN, MeMsDPEN, and CsDPEN in (1R,2R) or (1S,2S) form. E.39.R 7 and R 8 Both are -L-phenyl or SO2R 9 Instead, ❖R 9 is phenyl-C1~C3-alkyl or NR 10 R 11 If so, the catalyst further comprises a ligand selected from an aromatic ring, as described in any of embodiments E.28 to E.31 and E.33 to E.37. E.40. The method according to Embodiment E.39, wherein the aromatic ring is selected from the group consisting of Cp, Cp*, benzene, p-cymene, mesitylene, and hexamethylbenzene. E.41. The method according to Embodiment E.40, wherein the aromatic ring is selected from the group consisting of Cp*, benzene, p-cymene, mesitylene, and hexamethylbenzene. E.42. The method according to Embodiment E.41, wherein the aromatic ring is selected from the group consisting of Cp*, p-cymene, and mesitylene. E.43. The method according to Embodiment E.42, wherein the central metal is Rh or Ir and the aromatic ring is Cp*, or the central metal is Ru and the aromatic ring is p-cymene or mesitylene. E.44. The chiral transition metal catalyst further comprises one or two halogen or sulfonate ligands, as described in any of Embodiments E.1 to E.43. E.45. The method according to Embodiment E.44, wherein the chiral transition metal catalyst further comprises one or two halogen ligands. E.46. The method according to Embodiment E.45, wherein the chiral transition metal catalyst further comprises one or two, preferably one Cl ligand. E.47. The chiral transition metal catalyst is a catalyst comprising Ru, Rh or Ir as a central metal, a chiral ligand selected from the group consisting of TsDPEN, MeMsDPEN and CsDPEN in (1R,2R) or (1S,2S) form, a ligand selected from the group consisting of Cp*, p-cymene and mesitylene, and a halogen or sulfonate ligand, preferably a Cl ligand, according to any one of Embodiments E.38 to E.46. E.48. In step (a), Equation 2-S [ka] A method according to any one of Embodiments E.1 to E.47 for preparing 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one in an enantiomer excess of at least 55%ee. E.49. The method according to Embodiment E.48 for preparing 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula 2-S in an enantiomer excess of at least 60%ee. E.50. The method according to Embodiment E.49 for preparing 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula 2-S in an enantiomer excess of at least 70%ee. E.51. The method according to Embodiment E.50 for preparing 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula 2-S in an enantiomer excess of at least 80%ee. E.52. The method according to Embodiment E.51 for preparing 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula 2-S in an enantiomer excess of at least 90%ee. E.53. Chiral transition metal catalysts include (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-FsDPEN, (1S,2S)-TripsMesitylDPEN, (1S,2S)-CsDPEN, (1S,2S)-MesitylDPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and formula (II) in the form of (1S,2S) (wherein R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4 haloalkyl compounds, 8(wherein R is -(CH2)3-phenyl or -(CH2)4-phenyl, and the phenyl in the two last mentioned groups may have 1, 2, or 3 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, and m and n are 0) and comprises a chiral ligand selected from the group consisting of compounds of the form (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)-MesitylDPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN and formula (II) in the form of (1S,2S) 7 SO2R 9 And R 9 It may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl, R 8 The method according to any one of Embodiments E.48 to E.52, selected from the group consisting of compounds of -(CH2)3-phenyl or -(CH2)4-phenyl, where m and n are 0. E.54. The method according to Embodiment E.53, wherein the chiral ligand is selected from the group consisting of (1S,2S)-TsDPEN, (1S,2S)-MsDPEN, and (1S,2S)-CsDPEN. E.55. Chiral transition metal catalysts include Ru, Rh or Ir as the central metal and a chiral ligand selected from the group consisting of (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-FsDPEN, (1S,2S)-TripsMesitylDPEN, (1S,2S)-CsDPEN, (1S,2S)-MesitylDPEN, (1S,2S)-RsDPEN, and (1S,2S)-TsDiOMeDPEN, and formula (II) in (1S,2S) form (wherein R 7 SO2R 9 And R9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8 The catalyst comprises a compound of -(CH2)3-phenyl or -(CH2)4-phenyl (where the phenyl in the two last mentioned groups may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl, and C1-C4-alkoxy), and m and n are 0), or preferably the catalyst comprises Ru, Rh, or Ir as the central metal. Furthermore, (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)-MesitylDPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN and formula (II) of the form (1S,2S) (wherein R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8 The method according to any one of Embodiments E.48 to E.54, comprising a chiral ligand selected from the group consisting of compounds of -(CH2)3-phenyl or -(CH2)4-phenyl, wherein m and n are 0. E.56. Chiral transition metal catalysts are catalysts containing Ru, Rh or Ir as a central metal and a chiral ligand selected from the group consisting of (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-FsDPEN, (1S,2S)-TripsMesitylDPEN, (1S,2S)-CsDPEN, (1S,2S)-MesitylDPEN, (1S,2S)-RsDPEN, and (1S,2S)-TsDiOMeDPEN, or a catalyst containing Ru as a central metal and a chiral ligand of formula (II) in (1S,2S) form (wherein R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4 haloalkyl compounds, 8 The catalyst comprises a catalyst with at least one ligand selected from compounds of the following types: (where the phenyl in the two last mentioned groups may have 1, 2, or 3 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl, and C1-C4-alkoxy, and m and n are 0), wherein the chiral ligand preferably contains Ru, Rh, or Ir as the central metal and (1S,2S)- A catalyst comprising a chiral ligand selected from the group consisting of TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)-MesitylDPEN, (1S,2S)-RsDPEN, and (1S,2S)-TsDiOMeDPEN, or a catalyst comprising Ru as the central metal and a (1S,2S) form of formula (II) (wherein R 7 SO2R 9 And R 9 It may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl, R 8The method according to any one of Embodiments E.48 to E.55, wherein the catalyst comprises a catalyst with at least one ligand selected from compounds of -(CH2)3-phenyl or -(CH2)4-phenyl (where m and n are 0). E.57. Chiral transition metal catalysts contain Ru, Rh, or Ir as the central metal and include a chiral ligand selected from the group consisting of (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)-MesitylDPEN, (1S,2S)-RsDPEN, and (1S,2S)-TsDiOMeDPEN, or the following formula [ka] The method according to Embodiment E.56, which is a catalyst. E.58. The method according to Embodiment E.57, wherein the catalyst comprises Ru, Rh, or Ir as a central metal and a chiral ligand selected from the group consisting of (1S,2S)-TsDPEN, (1S,2S)-MsDPEN, and (1S,2S)-CsDPEN. E.59. In step (a), Equation 2-R [ka] A method according to any one of Embodiments E.1 to E.47 for preparing 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one with an enantiomer excess of at least 55%ee. E.60. The method according to Embodiment E.59 for preparing 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula 2R in an enantiomer excess of at least 60%ee. E.61. The method according to Embodiment E.60 for preparing 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula 2R in an enantiomer excess of at least 70%ee. E.62. The method according to Embodiment E.61 for preparing 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula 2R in an enantiomer excess of at least 80%ee. E.63. The method according to Embodiment E.62 for preparing 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula 2R in an enantiomer excess of at least 90%ee. E.64. Chiral transition metal catalysts include (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-FsDPEN, (1R,2R)-TripsMesitylDPEN, (1R,2R)-CsDPEN, (1R,2R)-MesitylDPEN, (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN, and formula (II) in the form of (1R,2R) (wherein R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4 haloalkyl compounds, 8(wherein R is -(CH2)3-phenyl or -(CH2)4-phenyl, and the phenyl in the two last mentioned groups may have 1, 2, or 3 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, and m and n are 0) and comprises a chiral ligand selected from the group consisting of compounds of the form (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)-MesitylDPEN, (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN and formula (II) in the form of (1R,2R) 7 SO2R 9 And R 9 It may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl, R 8 The method according to any one of Embodiments E.59 to E.63, selected from the group consisting of compounds of -(CH2)3-phenyl or -(CH2)4-phenyl, where m and n are 0. E.65. The method according to Embodiment E.64, wherein the chiral ligand is selected from the group consisting of (1R,2R)-TsDPEN, (1R,2R)-MsDPEN, and (1R,2R)-CsDPEN. E.66. Chiral transition metal catalysts include Ru, Rh or Ir as the central metal and are composed of a chiral ligand selected from the group consisting of (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-FsDPEN, (1R,2R)-TripsMesitylDPEN, (1R,2R)-CsDPEN, (1R,2R)-MesitylDPEN, (1R,2R)-RsDPEN, and (1R,2R)-TsDiOMeDPEN, and a chiral ligand of formula (II) in (1R,2R) form (wherein R 7 SO2R 9 And R9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8 The catalyst comprises a compound of (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)-MesitylDPEN, (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN, and formula (II) in the form of (1R,2R) (wherein R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8 The method according to any one of Embodiments E.59 to E.64, comprising a chiral ligand selected from the group consisting of compounds of -(CH2)3-phenyl or -(CH2)4-phenyl, wherein m and n are 0. E.67. Chiral transition metal catalysts are catalysts containing Ru, Rh or Ir as a central metal and a chiral ligand selected from the group consisting of (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-FsDPEN, (1R,2R)-TripsMesitylDPEN, (1R,2R)-CsDPEN, (1R,2R)-MesitylDPEN, (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN, or a catalyst containing Ru as a central metal and a chiral ligand of formula (II) in (1R,2R) form (wherein R7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4 haloalkyl compounds, 8 The catalyst comprises a catalyst with at least one ligand selected from the compounds (where m and n are 0), wherein the phenyl in the two last mentioned groups may have 1, 2, or 3 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl, and C1-C4-alkoxy, and m and n are 0), and the chiral ligand preferably contains Ru, Rh, or Ir as the central metal, and (1R,2R)- A catalyst comprising a chiral ligand selected from the group consisting of TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)-MesitylDPEN, (1R,2R)-RsDPEN, and (1R,2R)-TsDiOMeDPEN, or a catalyst comprising Ru as the central metal and formula (II) in (1R,2R) form (wherein R 7 SO2R 9 And R 9 It may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl, R 8 The method according to any one of Embodiments E.59 to E.66, wherein the catalyst comprises at least one ligand selected from compounds of -(CH2)3-phenyl or -(CH2)4-phenyl, where m and n are 0. E.68. The chiral transition metal catalyst contains Ru, Rh or Ir as the central metal and contains a chiral ligand selected from the group consisting of (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)-MesitylDPEN, (1R,2R)-RsDPEN and (1R,2R)-TsDiOMeDPEN, or the following formula [Chemical formula] The method according to embodiment E.67, which is the catalyst of E.69. The catalyst contains Ru, Rh or Ir as the central metal and contains a chiral ligand selected from the group consisting of (1R,2R)-TsDPEN, (1R,2R)-MsDPEN and (1R,2R)-CsDPEN, the method according to embodiment E.68. E.70. The reaction in step (a) is carried out at a temperature of -20 to 120 °C, the method according to any one of embodiments E.1 to E69. E.71. The reaction in step (a) is carried out at a temperature of -15 to 25 °C, the method according to embodiment E.70. E.72. The reaction in step (a) is carried out at a temperature of 30 to 100 °C, the method according to embodiment E.70. E.73. The reaction in step (a) is carried out at a temperature of 50 to 90 °C, the method according to embodiment E.72. [[ID=]] E.74. The reactions in steps (a) and (b) are carried out in the presence of a solvent, the method according to any one of embodiments E.1 to E73. E.75. The solvent is selected from the group consisting of polar aprotic solvents, C1-C4-alkyl acetates, chlorinated alkanes, aromatic solvents, heterocyclic solvents, mixtures of the aforementioned solvents, and mixtures of the aforementioned solvents and water. When formic acid and / or a base that is liquid at the reaction temperature is used, at least the reaction in step (a) can be carried out undiluted instead, the method according to embodiment E.74. E.76. Solvents include dimethylformamide, diethylformamide, dibutylformamide, dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, N-methylpyrrolidone, N-(n-butyl)-pyrrolidone, N-(tert-butyl)-pyrrolidone, sulfolane, dimethylcarbonate, diethylcarbonate, propylenecarbonate, γ-valerolactone, N,N,N',N'-tetrabutylurea, 1,3-dimethyl-2-imidazolinone, ethyl acetate, isopropyl acetate, The method according to Embodiment E.75, selected from the group consisting of dichloromethane, trichloromethane, dichloroethane, benzene, toluene, α,α,α-trifluorotoluene (benzotrifluoride), xylene, fluorobenzene, chlorobenzene, dichlorobenzene, anisole (methoxybenzene), 4-formylmorpholine, dihydrolevoglucocenone (cyrene®), mixtures of the aforementioned solvents, and mixtures of the aforementioned solvents with water in an amount of up to 15% by weight, preferably up to 10% by weight, particularly up to 5% by weight, specifically up to 3% by weight, relative to the total weight of the solvent. E.77. The solvent is selected from the group consisting of dimethylformamide, dimethylacetamide, dichloromethane, trichloromethane, dichloroethane, α,α,α-trifluorotoluene (benzotrifluoride), fluorobenzene, chlorobenzene, dichlorobenzene, anisole (methoxybenzene), and mixtures thereof, particularly dimethylformamide, dimethylacetamide, and mixtures thereof, according to Embodiment E.76. E.78. The method according to any of Embodiments E.1 to E.77, wherein during the reaction in step (a), an inert gas other than CO2 is sparged through the reaction mixture, or alternatively or additionally, the reaction is carried out under reduced pressure. The method according to Embodiment E.78, wherein the gas different from CO2 is selected from the group consisting of argon, nitrogen, and a mixture of oxygen and nitrogen, the mixture containing 1 to 8 volume percent of oxygen relative to the total amount of the oxygen / nitrogen mixture. E.80. The gas different from CO2 is nitrogen, according to the method of embodiment E.79. E.81. The reaction in steps (a) and (b) is carried out in the presence of an additive selected from the group consisting of diethyl phosphite, borate esters, and zinc salts, wherein the zinc salt is preferably selected from the group consisting of zinc halides, zinc acetate, and zinc trifluoromethanesulfonate, according to any one of Embodiments E.1 to E.80. E.82. The method according to Embodiment E.81, wherein the additive is diethyl phosphite or a zinc salt. E.83. The method according to either Embodiment E.81 or E.82, wherein the additive is used in an amount such that the molar ratio of the additive to compound 1 is in the range of 1:10000 to 10:1. E.84. The method according to Embodiment E.83, wherein the molar ratio of the additive to compound 1 is in the range of 1:10000 to 5:1. E.85. The method according to Embodiment E.84, wherein the molar ratio of the additive to compound 1 is in the range of 1:10000 to 2:1. E.86. The activator used in step (b) is P(OR 1 )2Cl, P(OR 1 )Cl2, P(=O)(OR 1 )2Cl, P(=O)(OR 1 )Cl2(where each R in the four compounds 1 These are independently C1-C4 alkyl groups, PCl3, P(=O)Cl3, polyphosphate, P4O 10 The method according to any one of Embodiments E.1 to E.85, selected from the group consisting of a Mitsunobu-type reagent, triphenylphosphine in combination with a halogenating agent, an amine, a carboxamide, and a Lewis base selected from heteroaromatic compounds containing one, two or three basic nitrogen ring atoms, an SO3 complex with a Lewis base, (O)Cl2, CH3S(O)2Cl, carbonyldiimidazole (CDI), Vilsmeyer reagent, a complex of N,N-dimethylformamide and / or N,N-dimethylacetamide with a Lewis acid, and a mixture of two or more of the above activators. E.87. The activator used in step (b) is P(OR 1 )2Cl, P(OR 1 )Cl2, P(=O)(OR 1)2Cl(where each R in the three compounds 1 (These are independently selected from the group consisting of C1-C4-alkyl, PCl3, P(O)Cl3, SO3 / dimethylformamide complex, SOCl2, CH3S(=O)2Cl, CDI, and Mitsunobu-type reagents), particularly P(OR 1 )2Cl (in the formula, each R 1 The method according to Embodiment E.86, wherein is independently selected from the group consisting of C1-C4 alkyl and PCl3. E.88. The activator used in step (b) is selected from the group consisting of dimethylchlorophosphite (P(OCH3)2Cl), diethylchlorophosphite (P(OCH2CH3)2Cl), methyldichlorophosphite (P(OCH3)Cl2), ethyldichlorophosphite (P(OCH2CH3)Cl2), PCl3, P(O)Cl3, SOCl2, CH3S(=O)2Cl, CDI, and Mitsunobu-type reagent, preferably dimethylchlorophosphite (P(OCH3)2Cl), diethylchlorophosphite (P(OCH3)2Cl), methyldichlorophosphite (P(OCH3)Cl2), ethyldichlorophosphite (P(OCH2CH3)Cl2), PCl3, P(O)Cl3, CH3S(=O)2Cl, and CDI, as described in Embodiment E.87. The method according to Embodiment E.88, wherein the activator used in step (b) is selected from the group consisting of dimethylchlorophosphite (P(OCH3)2Cl), diethylchlorophosphite (P(OCH2CH3)2Cl), methyldichlorophosphite (P(OCH3)Cl2), ethyldichlorophosphite (P(OCH2CH3)Cl2), PCl3, P(O)Cl3, and especially dimethylchlorophosphite (P(OCH3)2Cl), diethylchlorophosphite (P(OCH2CH3)2Cl), and PCl3. The method according to Embodiment E.89, wherein the activator used in step (b) E.90 is selected from the group consisting of dimethylchlorophosphite (P(OCH3)2Cl) and diethylchlorophosphite (P(OCH2CH3)2Cl). E.91. The method according to any one of Embodiments E.1 to E.90, wherein the activator is used in an amount such that the molar ratio of the compound of Formula 1 to the activator is in the range of 10:1 to 1:10. E.92. The method according to Embodiment E.91, wherein the activator is used in an amount such that the molar ratio of the compound of Formula 1 to the activator is in the range of 2:1 to 1:5, preferably 1:1 to 1:4. E.93. The method according to Embodiment E.92, wherein the activator is used in an amount such that the molar ratio of the compound of Formula 1 to the activator is in the range of 1:1 to 1:3. E.94. The method according to Embodiment E.93, wherein the activator is used in an amount such that the molar ratio of the compound of Formula 1 to the activator is in the range of 1:1 to 1:2. E.95. The reaction in step (b) is carried out at a temperature of -80 to 120°C, according to any of Embodiments E.1 to E.94. E.96. The reaction in step (b) is carried out at a temperature of -20 to 100°C, as described in Embodiment E.95. E.97. The reaction in step (b) is carried out at a temperature of -10 to 90°C, as described in Embodiment E.96. E.98. Formula (IR) [ka] This is for preparing (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate with an enantiomer excess of at least 55% ee. (a.1) At an enantiomer excess of at least 55%ee, Equation 2-S [ka] The compound of formula 1 is reduced so that a reaction mixture containing 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one is formed, (b.1) The reaction mixture obtained in step (a.1) is reacted with an activator as defined in Embodiment E.1 or E.86 to E.94. The method according to any one of embodiments E.1 to E.97, including the method described above. E.99. This is for preparing (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate of formula (IR) with an enantiomer excess of at least 60% ee. (a.1) Reducing the compound of formula 1 such that a reaction mixture containing 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula 2-S is formed at an enantiomer excess of at least 60% ee, (b.1) The reaction mixture obtained in step (a.1) is reacted with an activator as defined in any of embodiments E.86 to E.94. The method according to Embodiment E.98, including the method described above. E.100. is for preparing (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate of formula (IR) with an enantiomer excess of at least 70%ee. (a.1) Reducing the compound of formula 1 such that a reaction mixture containing 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidine-4-one of formula 2-S is formed at an enantiomer excess of at least 70%ee, (b.1) The reaction mixture obtained in step (a.1) is reacted with an activator as defined in any of embodiments E.86 to E.94. The method according to Embodiment E.99, including the method described in Embodiment E.99. E.101. This is for preparing (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate of formula (IR) with an enantiomer excess of at least 80% ee. (a.1) Reducing the compound of formula 1 such that a reaction mixture containing 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidine-4-one of formula 2-S is formed at an enantiomer excess of at least 80%ee, (b.1) The reaction mixture obtained in step (a.1) is reacted with an activator as defined in any of embodiments E.86 to E.94. The method according to Embodiment E.100, including the method described above. E.102. This is for preparing (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate of formula (IR) with an enantiomer excess of at least 90% ee. (a.1) Reducing the compound of formula 1 such that a reaction mixture containing 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula 2-S is formed at an enantiomer excess of at least 90%ee, (b.1) The reaction mixture obtained in step (a.1) is reacted with an activator as defined in any of embodiments E.86 to E.94. The method according to Embodiment E.101, including the method described above. E.103. Formula (IS) [ka] This is for preparing (3S)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate with an enantiomer excess of at least 55% ee. (a.2) At an enantiomer excess of at least 55%ee, Equation 2-R [ka] The compound of formula 1 is reduced so as to form a reaction mixture containing 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one, (b.2) The reaction mixture obtained in step (a.1) is reacted with an activator as defined in either Embodiment E.1 or E.86 to E.94. The method according to any one of embodiments E.1 to E.97, including the method described above. E.104. This is for preparing (3S)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate of formula (IS) with an enantiomer excess of at least 60% ee. (a.2) Reducing the compound of formula 1 such that a reaction mixture containing 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula 2-R is formed at an enantiomer excess of at least 60%ee, (b.2) The reaction mixture obtained in step (a.1) is reacted with an activator as defined in any of embodiments E.86 to E.94. The method according to Embodiment E.103, including the method described in Embodiment E.103. E.105. This is for preparing (3S)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate of formula (IS) with an enantiomer excess of at least 70%ee. (a.2) Reducing the compound of formula 1 such that a reaction mixture containing 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula 2-R is formed at an enantiomer excess of at least 70%ee, (b.2) The reaction mixture obtained in step (a.1) is reacted with an activator as defined in any of embodiments E.86 to E.94. The method according to Embodiment E.104, including the method described in Embodiment E.104. E.106. A method for preparing (3S)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate of formula (IS) with an enantiomer excess of at least 80% ee, (a.2) Reducing the compound of formula 1 such that a reaction mixture containing 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula 2-R is formed at an enantiomer excess of at least 80%ee, (b.2) The reaction mixture obtained in step (a.1) is reacted with an activator as defined in any of embodiments E.86 to E.94. The method according to Embodiment E.105, including the method described in Embodiment E.105. E.107. A method for preparing (3S)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate of formula (IS) with an enantiomer excess of at least 90%ee, (a.2) Reducing the compound of formula 1 such that a reaction mixture containing 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula 2-R is formed at an enantiomer excess of at least 90%ee, (b.2) The reaction mixture obtained in step (a.1) is reacted with an activator as defined in any of embodiments E.86 to E.94. The method according to Embodiment E.106, including the method described above.

[0038] The reaction sequence can be expressed as follows: [ka]

[0039] Here, only formate is shown as the reducing agent, but formic acid (in the presence of a base) or a mixture of formic acid and formate (optionally in the presence of a base) can be used as alternatives.

[0040] The reaction in step (a) can be classified as asymmetric transfer hydrogenation. The reaction in step (b) is intramolecular S N It can be classified into reactions.

[0041] M + Preferably, alkali metal cations, formula [NHR 1 R 2 R 3 ] + (In the formula, R 1 , R 2 and R 3 These are ammonium cations (selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, and C1-C4-alkoxy-C1-C4-alkyl), formula NR, independently of each other. 1 R 2 -A-NR 3 R 4 (In the formula, R 1 , R 2 , R3 and R 4 A is independently selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy and C1-C4-alkoxy-C1-C4-alkyl, and A is selected from the group consisting of protonated 5 or 6-membered saturated heterocycles comprising a protonated diamine (which is (CH2)2 or (CH2)3) and one nitrogen atom as a ring member, and optionally one further heteroatom selected from N and O as a ring member, and which may have 1 to 6 C1-C4-alkyl groups and / or 1 or 2 OH groups.

[0042] Formula derived from monoamines [NHR 1 R 2 R 3 ] + In the ammonium cation, preferably R 1 , R 2 and R 3 At most one of the elements is hydrogen, and the other two or all three are independently selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, and C1-C4-alkoxy-C1-C4-alkyl. Such ammonium cations correspond to the amine NR 1 R 2 R 3 This is the protonated form of diamine NR. 1 R 2 -A-NR 3 R 4 In R 1 , R 2 , R 3 and R 4 Preferably, at least one of them is not hydrogen. More preferably, R 1 , R 2 , R 3 and R 4 None of them are hydrogen. Preferably, R 1 , R 2 , R 3 and R 4 These are C1-C4 alkyl groups, independently of each other.

[0043] Protonated diamine NR 1 R 2 -A-NR 3 R 4 is monoprotonation ([NHR 1 R 2 -A-NR 3 R 4 ] + ) or bisprotonation ([NHR 1 R 2 -A-NHR 3 R 4 ] 2+ ) can be done. In the latter case, M + is, (M 2+ ) 1 / 2 or ([NHR 1 R 2 -A-NHR 3 R 4 ] 2+ ) 1 / 2 It is shown more accurately as follows.

[0044] Protonated 5- or 6-membered saturated heterocycles are preferably derived from pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, isoxazolidine, piperidine, piperazine, or morpholine. In the case of two nitrogen ring atoms, such as pyrazolidine, imidazolidine, or piperazine, the ring can also be bisprotonated. Protonated 5- or 6-membered saturated heterocycles may have 1 to 6 C1-C4-alkyl and / or 1 or 2 hydroxyl groups on the nitrogen and / or carbocyclic atoms. In particular, protonated saturated heterocyclic rings are 6-membered and therefore preferably derived from piperidine, piperazine, or morpholine, which may have 1 to 6 C1-C4-alkyl and / or 1 or 2 hydroxyl groups on the nitrogen and / or carbocyclic atoms.

[0045] In particular, M + Li + na + , K + , Cs + NH4 + [NH2(C2H5)2] + [NH(C2H5)3] + [NH(CH2CH2CH2CH3)3]+ [NH(C2H5)(CH(CH3)2] + [NH(CH3)2(CH(CH3)] + [NH2(C2H5)(C(CH3)3] + [NH2(CH(CH3)2)(C(CH3)3] + [NH2(C2H4OCH3)(CH3)] + [NH(cyclohexyl)2(CH3)] + [NH(cyclohexyl)(CH3)2] + The following are selected from the group consisting of protonated N,N,N',N'-tetramethylethylenediamine, protonated N,N,N',N'-tetramethylpropylene-1,3-diamine, protonated piperidine, protonated N-methylpiperidine, protonated 2,2,6,6-tetramethylpiperidine, protonated N-methyl-2,6,6-tetramethylpiperidine, protonated N-methyl-4-hydroxy-2,2,6,6-tetramethylpiperidine, protonated morpholine, and protonated N-methylmorpholine. More specifically, M + These are alkali metal cations (for example, Li + na + , K + or Cs + ) and formula [NHR 1 R 2 R 3 ] + (In the formula, R 1 , R 2 and R 3 These are independently selected from the group consisting of hydrogen and C1-C6 alkyl, preferably R 1 , R 2 and R 3 At least one, preferably at least two, of these is C1-C6 alkyl (e.g., NH2(C2H5)2) + [NH(C2H5)3] + [NH(CH2CH2CH2CH3)3] + [NH(C2H5)(CH(CH3)2] + [NH(CH3)2(CH(CH3)] + [NH2(C2H5)(C(CH3)3] +or [NH2(CH(CH3)2)(C(CH3)3] + Selected from the group consisting of ammonium cations of ) ). Specifically, M + is, Na + , K + [NH(C2H5)3] + [NH(CH2CH2CH2CH3)3] + and [NH(C2H5)(CH(CH3)2] + Selected from the group consisting of, more specifically, Na + , K + [NH(C2H5)3] + [NH(CH2CH2CH2CH3)3] + and [NH(C2H5)(CH(CH3)2] + Selected from, more specifically, [NH(C2H5)3] + [NH(CH2CH2CH2CH3)3] + and [NH(C2H5)(CH(CH3)2] + Selected from.

[0046] The reducing agent is formic acid HC(=O)OH, formula HC(=O)O - M + Formate and formic acid HC(=O)OH and formula HC(=O)O - M + A mixture of one or more of the following formates (wherein M + The group is selected from the group consisting of (where is the cation equivalent). When formic acid is used as a reducing agent, the reaction is forced to proceed in the presence of a base. Depending on the amount of base, formic acid can be partially or completely converted in situ to the corresponding formate.

[0047] Formula HC(=O)O - M + Formate and formic acid HC(=O)OH and formula HC(=O)O - M + A mixture of one or more holmates can be used in the reaction in a pre-formed form, or it can be formed in situ by mixing formic acid with the corresponding base in an appropriate molar ratio. +In order to obtain a formate or a mixture of formates, which is a metal cation, such as an alkali metal cation, formic acid is mixed with, for example, a metal hydroxide, such as an alkali metal hydroxide, or a metal carbonate, such as an alkali metal carbonate. As described above, M + To obtain a formate or a mixture of formates where the formate is an ammonium cation or a protonated diamine or a protonated heterocycle, formic acid is used to obtain the corresponding monoamine NR as defined above. 1 R 2 R 3 , diamine NR 1 R 2 -A-NR 3 R 4 Alternatively, it can be appropriately mixed with a 5- or 6-membered saturated heterocycle.

[0048] In connection with the present invention, the base used optionally or compulsorily is holmate HC(=O)O - M + It is different from that.

[0049] Depending on the reducing agent, the base used optionally or compulsorily is preferably an alkali metal hydroxide, formula NR 1 R 2 R 3 (In the formula, R 1 , R 2 and R 3 R is independently selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, and C1-C4-alkoxy-C1-C4-alkyl. 1 , R 2 and R 3 At least one of them is an amine (not hydrogen), formula NR 1 R 2 -A-NR 3 R 4 (In the formula, R 1 , R 2 , R 3 and R 4A is independently selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy and C1-C4-alkoxy-C1-C4-alkyl, and A is selected from the group consisting of 5 or 6-membered saturated heterocycles comprising a diamine (which is (CH2)2 or (CH2)3) and one nitrogen atom as a ring member, and optionally one further heteroatom selected from N and O as a ring member, and which may have 1 to 6 C1-C4-alkyl groups and / or 1 or 2 OH groups.

[0050] When formate or a mixture of formic acid and formate is used as a reducing agent, especially M + is monoamine NR 1 R 2 R 3 , diamine NR 1 R 2 -A-NR 3 R 4 Alternatively, if derived from the aforementioned 5- or 6-membered saturated heterocyclic ring, the base is preferably a cation M in formate. + It corresponds to.

[0051] More preferably, the base is selected from the group consisting of LiOH, NaOH, KOH, diethylamine, triethylamine, tributylamine, diisopropylethylamine, dimethylisopropylamine, ethyl-tert-butylamine, isopropyl-tert-butylamine, (2-methoxyethyl)methylamine, N,N-dicyclohexylmethylamine, N-cyclohexyldimethylamine, N,N,N',N'-tetramethylethylenediamine, N,N,N',N'-tetramethylpropylene-1,3-diamine, piperidine, N-methylpiperidine, 2,2,6,6-tetramethylpiperidine, N-methyl-2,6,6-tetramethylpiperidine, N-methyl-4-hydroxy-2,2,6,6-tetramethylpiperidine, morpholine, and N-methylmorpholine, where the base may be used in a supported form (i.e., on a supporting material). Among these, amine NR 1 R 2 R 3 (In the formula, R1 , R 2 and R 3 These are independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, R 1 , R 2 and R 3 At least one of the bases is preferably a C1-C6 alkyl group, such as diethylamine, triethylamine, tributylamine, diisopropylethylamine, dimethylisopropylamine, ethyl-tert-butylamine, or isopropyl-tert-butylamine. Specifically, the base is selected from triethylamine, tributylamine, and diisopropylethylamine.

[0052] Suitable support materials for bases / supported bases include, for example, silica (SiO2) and organic polymers, such as polystyrene or acrylic ester-based supports, such as polymers typically used in ion exchange resins, such as styrene(co)polymers containing sulfonic acid groups, and especially styrene-divinylbenzene copolymers containing sulfonic acid groups. Examples of commercially available ion exchange support materials include those sold under the brands Lewatit® (Lanxess), Purolite® (The Purolite Company), Dowex® (Dow Chemical Company), Amberlite® (Rohm and Haas Company), or Amberlyst® (Rohm and Haas Company).

[0053] Holmath HC(=O)O - M + When used solely as a reducing agent, it is convenient to use it mixed with water.

[0054] Formic acid HC(=O)OH and formula HC(=O)O - M +When using a mixture of formate with one or more of the above as a reducing agent, formic acid and formate can be used in any mixing ratio. However, if formic acid is substantially dominant in the mixture (i.e., present in an amount of at least 90 mol%), it is advantageous to carry out the reaction in the presence of a base. Conversely, if formate is substantially dominant in the mixture (i.e., present in an amount of at least 90 mol%), it is advantageous to carry out the reaction in the presence of water.

[0055] Preferably, formic acid is used as the reducing agent. Therefore, it is essential to carry out the reaction in the presence of a base.

[0056] Formic acid and the base are preferably used in a molar ratio of 100:1 to 1:10, preferably 10:1 to 1:5, particularly 10:1 to 1:2, and particularly 5:1 to 1:1.

[0057] Compound 1 and the reducing agent are preferably used in a molar ratio of 1:1 to 1:10, more preferably 1:1 to 1:5.

[0058] Chiral transition metal catalysts are preferably selected from Group VIII metal catalysts. Group VIII metal catalysts refer to catalysts having a metal from Group VIII of the periodic system as the central metal. Group VIII corresponds to the current IUPAC Group designations 8, 9, and 10 with respect to the IUPAC group definitions that were in effect before 1985. Group 8 includes Fe, Ru, and Os; Group 9 includes Co, Rh, and Ir; and Group 10 includes Ni, Pd, and Pt. Group 8 and Group 9 metal catalysts are preferred. Among these, Ru, Rh, and Ir catalysts are preferred. Specifically, chiral transition metal catalysts have Rh or Ir as the central atom.

[0059] Preferably, the chiral transition metal catalyst is used in an amount of 0.01 to 10 mol%, more preferably 0.05 to 5 mol%, particularly 0.1 to 5 mol%, for example 0.1 to 2 mol%, calculated based on the transition metal content, per mole of compound 1.

[0060] The chirality of a chiral transition metal catalyst is preferably based on the presence of one or more chiral ligands coordinately bonded to the central transition metal.

[0061] Chiral transition metal catalysts can be used in a pre-formed form. In pre-formed catalysts, the central metal is coordinately bonded to one or more chiral ligands. Alternatively, chiral transition metal catalysts are formed in situ by the reaction of a transition metal precursor compound with one or more chiral ligands.

[0062] The chiral ligand is preferably selected from bidentate amine chiral ligands. A suitable bidentate amine chiral ligand is based on 1,2-ethylenediamine, i.e., a stereocenter, in which at least one of the carbon atoms having the amino group is substituted asymmetrically. Preferably, one or both carbon atoms of the 1,2-ethylenediamine ligand have a phenyl, naphthyl, or cyclohexyl ring, or two carbon atoms are part of a ring system that confers chirality. More preferably, the chiral ligand is selected from the group consisting of chiral 1,2-diphenyl-ethylene-1,2-diamine, 1,2-cyclohexanediamine, and 1,2-bis(methylamino)cyclohexane.

[0063] More preferably, the chiral ligand is selected from the group consisting of chiral 1,2-diphenyl-ethylene-1,2-diamines, particularly formula (II) [ka] (In the formula, The asterisk indicates the center of the stereochemistry. R 5 and R 6 These are independently selected from the group consisting of OH, halogens, C1-C4-alkyl and C1-C4-alkoxy elements. R 7 and R 8These are, independently of each other, hydrogen, C1-C4-alkyl, -L-phenyl (where the phenyl ring may have 1, 2, 3, 4, or 5 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl, and C1-C4-alkoxy) and SO2R 9 Selected from the group consisting of, L represents C2-C6-alkylene and C1-C3-alkylene-O-(CH2). p (wherein p is 0, 1, or 2) and C1~C3-alkylene-(1,2-phenylene)-(CH2) r A linker selected from the group consisting of (wherein r is 0, 1, or 2), R 9 C1-C4-alkyl, C1-C4-haloalkyl, phenyl, phenyl-C1-C3-alkyl (wherein the two aforementioned groups, the phenyl may have 1, 2, 3, 4, or 5 substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, and C1-C4-alkoxy), naphthyl, C6-C 10 -Bicycloalkyl-C1~C3-alkyl (where the bicycloalkyl ring may be substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of C1~C4-alkyl and oxo) and NR 10 R 11 Selected from the group consisting of, R 10 is hydrogen or C1-C4 alkyl, R 11 It is a phenyl-C1~C3-alkyl group, and the phenyl ring may have 1, 2, 3, 4, or 5 substituents selected from the group consisting of halogens, C1~C4-alkyl groups, C1~C4-haloalkyl groups, and C1~C4-alkoxy groups. (m and n are 0, 1, 2, 3, 4, or 5, independently of each other.) Selected from the chiral forms of 1,2-diphenylethylene-1,2-diamine.

[0064] Preferably, in compound (II), R 5 and R 6These are C1-C4 alkoxy compounds, R 7 and R 8 One of the atoms is selected from the group consisting of hydrogen, C1-C4-alkyl and -L-phenyl, where phenyl may have 1, 2, 3, 4 or 5 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, R 7 and R 8 The other is hydrogen and SO2R 9 Selected from the group consisting of, L is a linear C3-C6 alkylene, (CH2) o -O-(CH2) p (wherein p and o are independently 1 or 2) and (CH2) q -(1,2-phenylene)-(CH2) r A linker selected from the group consisting of (wherein q and r are independently 0, 1, or 2, and at least one of q and r is not 0), R 9 These are phenyl, C7-bicycloalkyl-methyl (where the bicycloalkyl ring may be substituted with 1, 2, or 3 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl, halogen, C1-C4-alkyl, C1-C4-haloalkyl, and C1-C4-alkoxy) and NR, which may have 1, 2, 3, 4, or 5 substituents selected from the group consisting of C1-C4-alkyl and oxo. 10 R 11 Selected from the group consisting of, R 10 is hydrogen or C1-C4 alkyl, R 11 is phenyl-(CH2) s -It is alkyl, s is 2 or 3, and the phenyl ring may have 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogens, C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy. m and n are both 0 or both 1, preferably both are 0.

[0065] For a molecule to be chiral, both stereocenters (i.e., the carbon atoms indicated by asterisks in Equation II) must be in the R configuration, or both must be in the S configuration. When one is S and the other is R, an achiral meso system is formed.

[0066] Such ligands are known from Noyori-type asymmetric transfer hydrogenation and are generally commercially available. Preferred ligands of formula (II) are DPEN, TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, TripsMesitylDPEN, CsDPEN, MesitylDPEN, RsDPEN, TsDiOMeDPEN, and the chiral form (i.e., (1S,2S) or (1R,2R) form) of the compound of formula (II); the 1st and 2nd positions are a phenyl ring and an amino group having an asterisk (wherein R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8 is -(CH2)3-phenyl or -(CH2)4-phenyl, where the phenyl in the two last mentioned groups may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, and m and n are 0) with respect to the two carbon atoms represented by . The acronym corresponds to the following formula: [ka] [ka]

[0067] In addition to the phenyl ring and the two carbon atoms marked with an asterisk in formula II, CsDPEN has two further stereocenters (positions 1 and 4; position 1: a carbocyclic atom bonded to the -CH2-SO2-NH-...) on the camphor moiety (more precisely, on the norbornanone ring), i.e., on the carbon atoms that form the bridging points. However, since the stereochemistry of the camphor moiety does not significantly affect the stereoselectivity of the hydrogenation reaction, CsDPEN can be derived from racemic camphor or any camphor enantiomer (1S,4R or 1R,4S) or a non-racemic mixture of enantiomers. However, in certain embodiments, CsDPEN is derived from the 1S,4R enantiomer, specifically N-[(1S,2S)-2-amino-1,2-diphenyl-ethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonamide as (1S,2S)-CsDPEN and N-[(1R,2R)-2-amino-1,2-diphenyl-ethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonamide as (1R,2R)-CsDPEN.

[0068] Chiral transition metal catalysts include, in particular, Ru, Rh or Ir as the central metal, and DPEN, TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, TripsMesitylDPEN, CsDPEN, MesitylDPEN, RsDPEN, TsDiOMeDPEN, and formula (II) (wherein R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8The catalyst is selected from a catalyst comprising Ru, Rh or Ir as the central metal and at least one ligand selected from the group consisting of compounds of formula (1R,2R) or (1S,2S) form, where the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, and m and n are 0). More specifically, chiral transition metal catalysts include Ru, Rh or Ir as the central metal and TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, MesitylDPEN, RsDPEN, TsDiOMeDPEN, and formula (II) (wherein R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8 The catalyst is selected from a group comprising -(CH2)3-phenyl or -(CH2)4-phenyl, where the phenyl in the two last mentioned groups may have 1, 2, or 3 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy compounds, and m and n are 0) and at least one ligand selected from the group consisting of compounds.

[0069] Specifically, the chiral transition metal catalyst comprises Ru, Rh, or Ir as the central metal, and at least one ligand selected from the group consisting of DPEN, TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, TripsMesitylDPEN, CsDPEN, MesitylDPEN, RsDPEN, and TsDiOMeDPEN in (1R,2R) or (1S,2S) form, and Ru as the central metal, and formula (II) (wherein R) in (1R,2R) or (1S,2S) form. 7 SO2R 9 And R 9R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8 A catalyst comprising a compound of (1R,2R) or (1S,2S) form of formula (II) (wherein R, R, R, Ir) as a central metal and at least one ligand selected from the group consisting of TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, MesitylDPEN, RsDPEN and TsDiOMeDPEN, and where R, R, Ir) as a central metal and at least one ligand selected from the group consisting of TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, MesitylDPEN, RsDPEN and TsDiOMeDPEN, and where R, R, Ir) as a central metal and at least one ligand selected from the group consisting of TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, MesitylDPEN, RsDPEN and TsDiOMeDPEN 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-haloalkyl and C1-C4-haloalkyl compounds, 8 The catalyst is selected from a catalyst comprising a ligand selected from compounds of the following types: (where is -(CH2)3-phenyl or -(CH2)4-phenyl, and the phenyl in the two last mentioned groups may have 1, 2, or 3 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, and m and n are 0).

[0070] More specifically, a chiral transition metal catalyst is a catalyst comprising Ru, Rh, or Ir as a central metal, and at least one ligand selected from the group consisting of TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, MesitylDPEN, RsDPEN, and TsDiOMeDPEN in (1R,2R) or (1S,2S) form, and the following formula [ka] Selected from the catalysts.

[0071] More specifically, the chiral transition metal catalyst is selected from catalysts comprising Ru, Rh, or Ir as the central metal and at least one ligand selected from the group consisting of TsDPEN, MsDPEN, and CsDPEN in (1R,2R) or (1S,2S) form.

[0072] Chiral transition metal catalysts generally contain only one of the bidentate amine ligands mentioned above.

[0073] R 7 or R 8 In the sense of -L-phenyl, an optionally substituted phenyl ring, and an optionally substituted phenyl ring in phenyl-C1~C3-alkyl, R 9 It is in the sense of R 11 In the sense of phenyl-C1~C3-alkyl, an optionally substituted phenyl ring generally acts as an additional (tethered) ligand to the central metal. Such complexes, containing aromatic ligands linked to ethylenediamine ligands, are commonly known as Will catalysts.

[0074] R 7 and R 8 Both are -L-phenyl or SO2R 9 Instead, ❖R 9 is phenyl-C1~C3-alkyl or NR 10 R 11 In this case, the catalyst preferably further comprises ligands selected from aromatic rings. Such ligands generally have higher tactility, i.e., they coordinate to the metal center via two or more atoms, specifically via an uninterrupted, continuous series of atoms. Generally, they are η 5 or η 6 It acts as a ligand. Typical aromatic η 5 and η 6The ligands are substituted or unsubstituted benzenes and substituted or unsubstituted cyclopentadienes. The aromatic ring is preferably selected from Cp, Cp*, benzene, p-cymene, mesitylene, and hexamethylbenzene, particularly from Cp*, benzene, p-cymene, mesitylene, and hexamethylbenzene, more specifically from Cp*, p-cymene, and mesitylene, and more specifically from Cp*. As a tendency, five-membered aromatic ligands such as Cp and Cp* are more suitable as the central metal Rh or Ir, and six-membered aromatic ligands such as benzene, p-cymene, mesitylene, and hexamethylbenzene are more suitable as the central metal Ru. Therefore, very specifically, when the central metal is Rh or Ir, the aromatic ring is Cp*, and when the central metal is Ru, the aromatic ring is p-cymene or mesitylene.

[0075] Generally, the catalyst comprises one or two further ligands, at least one of which is substituted during the reaction by a hydride ligand from the reducing agent under basic conditions. Generally, the further ligands are halogen (e.g., Cl, Br, or I, with Cl being preferred) or sulfonate (e.g., triflate, mesylate, tosylate, or nonaflate, with triflate being preferred), particularly halogen ligands, particularly Cl.

[0076] Specifically, the chiral transition metal catalyst is selected from a catalyst comprising Ru, Rh, or Ir as a central metal; a chiral ligand selected from the group consisting of TsDPEN, MsDPEN, and CsDPEN in (1R,2R) or (1S,2S) form; a ligand selected from halogen or sulfonate ligands, preferably selected from Cl; and a further ligand selected from Cp*, p-cymene, and mesitylene.

[0077] Many of the ligands and catalysts mentioned above are commercially available or can be prepared by standard reactions starting from suitable catalyst precursors and ligands.

[0078] Catalyst precursors are generally salts of the central metal or complexes of the central metal with a chiral ligand and a different ligand. In the case of preferred catalysts having Ru, Rh, or Ir as the central metal, the catalyst precursor is specifically a dinuclear complex containing an aromatic ring ligand and two halogen ligands. Non-exclusive examples include [Ru(p-cymene)Cl2]2, [Ru(mesitylene)Cl2]2, [Rh(III)Cl2Cp*]2, or [Ir(III)Cl2Cp*]2. Such complexes are generally commercially available or can be prepared by standard methods.

[0079] Pre-formed catalysts are generally prepared by mixing a catalyst precursor with a chiral ligand. The reaction is usually carried out in a solvent. Depending on the catalyst precursor, it may be useful to carry out the reaction in the presence of a base. For example, when the aforementioned dinuclear complex of Ru, Rh, or Ir containing an aromatic ring ligand and two halogen ligands is used as the precursor compound, the presence of a base is useful to facilitate or enable the reaction, i.e., the conversion of the dinuclear complex to a mononuclear complex containing the desired chiral ligand. The catalyst precursor and the chiral ligand are generally mixed in a molar ratio of 2:1 to 1:5, preferably 1.5:1 to 1:4, and particularly 1.2:1 to 1:3, where the molar ratio is based on the amount (moles) of the transition metal in the catalyst precursor. The formed catalyst can be isolated before use in the reaction, or the resulting reaction mixture can be used without isolation of the complex.

[0080] When the catalyst is formed in situ, the catalyst precursor and the chiral ligand are brought into contact with each other in the presence of at least one of the reactants, e.g., starting compound 1, a reducing agent, and / or a base (if used). Depending on the properties of the catalyst precursor, catalyst formation may only begin in the presence of a base. The base may be one of the above-mentioned bases, which is forced to be used when HCOOH is used as the reducing agent, or a formate, which is used when the reducing agent is used in this form. Preferably, the catalyst precursor and the chiral ligand are brought into contact with each other under conditions that allow them to form a catalyst complex (with a central metal bonded to the chiral ligand) before contacting them with starting compound 1. Therefore, preferably, the catalyst precursor and the chiral ligand are brought into contact with a base (if used) and optionally in the presence of a reducing agent or, if no additional base is used, in the presence of a formate, and optionally, if the reaction is not carried out undiluted, the resulting mixture is brought into contact with starting compound 1 for the first time thereafter. The catalyst precursor and chiral ligand are generally used in a molar ratio of 2:1 to 1:5, preferably 1.5:1 to 1:4, and particularly 1.2:1 to 1:3, where the molar ratio is based on the amount of transition metal (moles) in the catalyst precursor.

[0081] In a preferred embodiment, the S enantiomer is concentrated in compound 2 obtained in step (a) (naturally at the expense of the R enantiomer). Therefore, in a preferred embodiment, step (a) is formula 2-S [ka] This helps to prepare 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one in an enantiomer excess, more precisely at an enantiomer excess of at least 55% ee, preferably at least 60% ee, more preferably at least 70% ee, especially at least 80% ee, and specifically at least 90% ee.

[0082] This is obtained by using a suitable chiral catalyst. This is preferably a transition metal catalyst, preferably a group VIII transition metal catalyst, more preferably a group VIII or IX metal catalyst, in particular (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-FsDPEN, (1S,2S)-TripsMesitylDPEN, (1S,2S)-CsDPEN, (1S,2S)-MesitylDPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN and formula (II) in the form of (1S,2S) (wherein R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4 haloalkyl compounds, 8 The catalyst is a Ru, Rh, or Ir catalyst containing a chiral ligand selected from the group consisting of compounds of the following types: -(CH2)3-phenyl or -(CH2)4-phenyl, where the phenyl in the two last mentioned groups may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl, and C1-C4-alkoxy, and m and n are 0), preferably , (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)-MesitylDPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN and formula (II) of the form (1S,2S) (wherein R 7 SO2R 9 And R 9 It may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl, R 8(wherein the two last mentioned groups is -(CH2)3-phenyl or -(CH2)4-phenyl, and the phenyl in the two last mentioned groups may have 1, 2, or 3 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, and m and n are 0) and comprises a chiral ligand selected from the group consisting of compounds.

[0083] In particular, chiral transition metal catalysts used to obtain 2-S in enantiomer excess contain Ru, Rh or Ir as the central metal and contain a chiral ligand selected from the group consisting of (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-FsDPEN, (1S,2S)-TripsMesitylDPEN, (1S,2S)-CsDPEN, (1S,2S)-MesitylDPEN, (1S,2S)-RsDPEN and (1S,2S)-TsDiOMeDPEN, or contain Ru as the central metal and a chiral ligand of formula (II) in (1S,2S) form (wherein R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8The catalyst comprises a ligand selected from compounds of the following types: (where the phenyl in the two last mentioned groups may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl, and C1-C4-alkoxy, and m and n are 0). More specifically, chiral transition metal catalysts used to obtain 2-S in enantiomer excess contain Ru, Rh or Ir as the central metal and contain a chiral ligand selected from the group consisting of (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)-MesitylDPEN, (1S,2S)-RsDPEN and (1S,2S)-TsDiOMeDPEN, or contain Ru as the central metal and a chiral ligand of formula (II) in (1S,2S) form (wherein R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8 The catalyst comprises a ligand selected from compounds of the following types: (where the phenyl in the two last mentioned groups may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl, and C1-C4-alkoxy, and m and n are 0).

[0084] More specifically, the chiral transition metal catalyst used to obtain 2-S in an enantiomer excess is selected from catalysts comprising Ru, Rh, or Ir as the central metal and at least one ligand selected from the group consisting of (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)-MesitylDPEN, (1S,2S)-RsDPEN, and (1S,2S)-TsDiOMeDPEN, or a catalyst of the following formula. [ka]

[0085] More specifically, the chiral transition metal catalyst used to obtain 2-S in an enantiomer excess is selected from catalysts comprising Ru, Rh, or Ir as the central metal and at least one ligand selected from the group consisting of (1S,2S)-TsDPEN, (1S,2S)-MsDPEN, and (1S,2S)-CsDPEN.

[0086] More specifically, the chiral transition metal catalysts used to obtain 2-S with an enantiomer excess include Ru, Rh, or Ir as the central metal, and include (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-FsDPEN, and (1S,2S)-TripsMes It comprises a chiral ligand selected from the group consisting of itylDPEN, (1S,2S)-CsDPEN, (1S,2S)-MesitylDPEN, (1S,2S)-RsDPEN, and (1S,2S)-TsDiOMeDPEN, and further comprises a ligand selected from substituted or unsubstituted benzenes and substituted or unsubstituted cyclopentadienes, such as aromatic rings of Cp, Cp*, benzene, p-cymene, mesitylene, or hexamethylbenzene. As already explained above, 5-membered η such as Cp and Cp* 5Aromatic ligands are more suitable as the central metal of Rh or Ir; therefore, when Rh and Ir are the central metals, the additional aromatic ligands are preferably selected from Cp and Cp*, and in particular from Cp*. When Ru is the central metal, the additional aromatic ligands are preferably selected from cymene and mesitylene. More specifically, the chiral transition metal catalyst used to obtain (2-S) in enantiomer excess comprises Ru, Rh or Ir as the central metal and includes a chiral ligand selected from the group consisting of (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)-MesitylDPEN, (1S,2S)-RsDPEN and (1S,2S)-TsDiOMeDPEN, and in the case of substituted or unsubstituted benzenes and substituted or unsubstituted cyclopentadienes, such as Cp, Cp*, benzene, p-cymene, mesitylene or hexamethylbenzene, and in the case of Rh and Ir as the central metal, specifically η 5 In the case of ligand Cp* and central metal Ru, the specific ligands are cymene or mesitylene.

[0087] Furthermore, the catalyst includes additional ligands, generally halides or sulfonates, preferably halides, specifically Cl, which can be replaced by a hydride from a reducing agent.

[0088] Instead, the catalyst used to obtain 2-S in an enantiomer excess is Ru as the central metal and formula (II) (wherein R) in the (1S,2S) form. 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8is -(CH2)3-phenyl or -(CH2)4-phenyl, and the phenyl in the two last mentioned groups may have 1, 2, or 3 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, and m and n are 0) and comprises at least one ligand selected from the compounds. Generally, this type of catalyst also comprises a further ligand, generally a halide or sulfonate, preferably a halide, specifically Cl, which is replaced by a hydride from a reducing agent. Specifically, this type of catalyst is a compound of the following formula: [ka]

[0089] Specifically, the chiral transition metal catalyst used to obtain 2-S in an enantiomer excess is selected from a catalyst comprising Ru, Rh, or Ir as the central metal, a chiral ligand selected from the group consisting of (1S,2S)-TsDPEN, (1S,2S)-MsDPEN, and (1S,2S)-CsDPEN, a ligand selected from halogen ligands, preferably a Cl ligand, and a further ligand selected from Cp*, p-cymene, and mesitylene.

[0090] In another preferred embodiment, the R enantiomer is concentrated in compound 2 obtained in step (a) (naturally at the expense of the S-enantiomer). Therefore, in a preferred embodiment, step (a) is formula 2-R [ka] This helps to prepare 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one in an enantiomer excess, more precisely at least 55% ee, preferably at least 60% ee, more preferably at least 70% ee, especially at least 80% ee, and specifically at least 90% ee.

[0091] This is obtained by using a suitable chiral catalyst. This is preferably a transition metal catalyst, preferably a group VIII transition metal catalyst, more preferably a group VIII or IX metal catalyst, in particular (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-FsDPEN, (1R,2R)-TripsMesitylDPEN, (1R,2R)-CsDPEN, (1R,2R)-MesitylDPEN, (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN and formula (II) in the form of (1R,2R) (wherein R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4 haloalkyl compounds, 8 The catalyst is a Ru, Rh, or Ir catalyst containing a chiral ligand selected from the group consisting of compounds of the following types: -(CH2)3-phenyl or -(CH2)4-phenyl, where the phenyl in the two last mentioned groups may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl, and C1-C4-alkoxy, and m and n are 0), preferably , (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)-MesitylDPEN, (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN and formula (II) of the form (1R,2R) (wherein R 7 SO2R 9 And R 9 It may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl, R 8(wherein the two last mentioned groups is -(CH2)3-phenyl or -(CH2)4-phenyl, and the phenyl in the two last mentioned groups may have 1, 2, or 3 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, and m and n are 0) and comprises a chiral ligand selected from the group consisting of compounds.

[0092] In particular, chiral transition metal catalysts used to obtain 2-R in enantiomer excess contain Ru, Rh or Ir as the central metal and contain a chiral ligand selected from the group consisting of (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-FsDPEN, (1R,2R)-TripsMesitylDPEN, (1R,2R)-CsDPEN, (1R,2R)-MesitylDPEN, (1R,2R)-RsDPEN and (1R,2R)-TsDiOMeDPEN, or contain Ru as the central metal and a chiral ligand of formula (II) in (1R,2R) form (wherein R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8The catalyst comprises a ligand selected from compounds of the following types: (where the phenyl in the two last mentioned groups may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl, and C1-C4-alkoxy, and m and n are 0). More specifically, chiral transition metal catalysts used to obtain 2-R in enantiomer excess contain Ru, Rh or Ir as the central metal and contain a chiral ligand selected from the group consisting of (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)-MesitylDPEN, (1R,2R)-RsDPEN and (1R,2R)-TsDiOMeDPEN, or contain Ru as the central metal and a chiral ligand of formula (II) in the form of (1R,2R) (wherein R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8 The catalyst comprises a ligand selected from compounds of the following types: (where the phenyl in the two last mentioned groups may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl, and C1-C4-alkoxy, and m and n are 0).

[0093] More specifically, the chiral transition metal catalyst used to obtain 2-R in enantiomer excess is selected from catalysts comprising Ru, Rh, or Ir as the central metal and at least one ligand selected from the group consisting of (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)-MesitylDPEN, (1R,2R)-RsDPEN, and (1R,2R)-TsDiOMeDPEN, or a catalyst of the following formula. [ka]

[0094] More specifically, the chiral transition metal catalyst used to obtain 2-R in an enantiomer excess is selected from catalysts comprising Ru, Rh, or Ir as the central metal and at least one ligand selected from the group consisting of (1R,2R)-TsDPEN, (1R,2R)-MsDPEN, and (1R,2R)-CsDPEN.

[0095] More specifically, the chiral transition metal catalysts used to obtain 2-R with an enantiomer excess include Ru, Rh, or Ir as the central metal, and include (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-FsDPEN, and (1R,2R)-TripsMes It comprises a chiral ligand selected from the group consisting of itylDPEN, (1R,2R)-CsDPEN, (1R,2R)-MesitylDPEN, (1R,2R)-RsDPEN, and (1R,2R)-TsDiOMeDPEN, and further comprises a ligand selected from substituted or unsubstituted benzenes and substituted or unsubstituted cyclopentadienes, such as aromatic rings of Cp, Cp*, benzene, p-cymene, mesitylene, or hexamethylbenzene. As already explained above, 5-membered η such as Cp and Cp* 5Aromatic ligands are more suitable as the central metal of Rh or Ir; therefore, when Rh and Ir are the central metals, the additional aromatic ligands are preferably selected from Cp and Cp*, and in particular from Cp*. When Ru is the central metal, the additional aromatic ligands are preferably selected from cymene and mesitylene. More specifically, the chiral transition metal catalyst used to obtain (2-R) in enantiomer excess comprises Ru, Rh or Ir as the central metal and includes a chiral ligand selected from the group consisting of (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)-MesitylDPEN, (1R,2R)-RsDPEN and (1R,2R)-TsDiOMeDPEN, and includes substituted or unsubstituted benzenes and substituted or unsubstituted cyclopentadienes, such as Cp, Cp*, benzene, p-cymene, mesitylene or hexamethylbenzene, and in the case of Rh and Ir as the central metal, specifically η 5 In the case of ligand Cp* and central metal Ru, the specific ligands are cymene or mesitylene.

[0096] Furthermore, the catalyst includes additional ligands, generally halides or sulfonates, preferably halides, specifically Cl, which can be replaced by a hydride from a reducing agent.

[0097] Instead, the catalyst used to obtain 2-R in an enantiomer excess is Ru as the central metal and formula (II) in the (1R,2R) form (where R 7 SO2R 9 And R 9 R is a phenyl compound that may have one, two, or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl compounds, 8is -(CH2)3-phenyl or -(CH2)4-phenyl, and the phenyl in the two last mentioned groups may have 1, 2, or 3 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, and m and n are 0) and comprises at least one ligand selected from the compounds. Generally, this type of catalyst also comprises a further ligand, generally a halide or sulfonate, preferably a halide, specifically Cl, which is replaced by a hydride from a reducing agent. Specifically, this type of catalyst is a compound of the following formula: [ka]

[0098] Specifically, the chiral transition metal catalyst used to obtain 2-R in an enantiomer excess is selected from a catalyst comprising Ru, Rh, or Ir as the central metal, a chiral ligand selected from the group consisting of (1R,2R)-TsDPEN, (1R,2R)-MsDPEN, and (1R,2R)-CsDPEN, a ligand selected from halogen ligands, preferably a Cl ligand, and a further ligand selected from Cp*, p-cymene, and mesitylene.

[0099] The reactions in both steps (a) and (b) can be carried out in the presence of a solvent. The solvent is preferably selected from the group consisting of polar aprotic solvents, chlorinated alkanes, aromatic solvents, heterocyclic solvents, and mixtures of the aforementioned solvents. In some cases, for example, when PCl3 is used as an activator, a mixture of the organic solvent and a small amount of water may be advantageous. Furthermore, the presence of water is also necessary when formate is used solely as a reducing agent or when it is dominant in the formic acid / formate mixture used as a reducing agent.

[0100] Polar aprotic solvents are polar solvents that do not have functional groups from which protons can dissociate. Suitable examples of polar aprotic solvents include 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 dimethyl sulfoxide (DMSO); nitriles such as acetonitrile; N-methylpyrrolidone (NMP), N-(n-butyl)-pyrrolidone, or N-(tert-butyl) Examples include lactams such as γ-pyrrolidone, sulfones such as sulfolane, carbonate esters such as dimethylcarbonate, ethylenecarbonate, or propylenecarbonate, lactones such as γ-butyrolactone or γ-valerolactone, ureas such as N,N,N',N'-tetramethylurea, N,N,N',N'-tetrabutylurea, dimethylpropyleneurea (DMPU), or 1,3-dimethyl-2-imidazolinone (DMEU, DMI), and nitro compounds such as nitromethane.

[0101] Suitable examples of C1-C4 alkyl acetates are methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.

[0102] Suitable examples of chlorinated alkanes are dichloromethane, trichloromethane, or dichloroethane.

[0103] Examples of suitable aromatic solvents include benzene, toluene, α,α,α-trifluorotoluene (benzotrifluoride), xylene (i.e., 1,2-xylene, 1,3-xylene, or 1,4-xylene), fluorobenzene, chlorobenzene, dichlorobenzene, or anisole (methoxybenzene).

[0104] Suitable heterocyclic solvents include 4-formylmorpholine or dihydrolevoglucocenone (cyrene®).

[0105] When the listed mixtures of organic solvents and water are used, they generally contain up to 15% by weight of water (e.g., 0.5–15% by weight), preferably up to 10% by weight of water (e.g., 1–10% by weight), especially up to 5% by weight of water (e.g., 1–5% by weight), and especially up to 3% by weight of water (e.g., 1–3% by weight), relative to the total weight of the solvent (more precisely, the mixture of organic solvent and water).

[0106] More preferably, the solvent is dimethylformamide, diethylformamide, dibutylformamide, dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane (i.e., 1,3- and 1,4-dioxane), dimethyl sulfoxide, acetonitrile, N-methylpyrrolidone, N-(n-butyl)-pyrrolidone, N-(tert-butyl)-pyrrolidone, sulfolane, dimethylcarbonate, diethylcarbonate, propylenecarbonate, γ-valerolactone, N,N,N',N'-tetrabutylurea, 1,3-dimethyl-2-imidazolinone, ethyl acetate, The following are selected from the group consisting of isopropyl acetate, dichloromethane, trichloromethane, dichloroethane, benzene, toluene, α,α,α-trifluorotoluene, xylene, fluorobenzene, chlorobenzene, dichlorobenzene, anisole, 4-formylmorpholine, dihydrolevoglucocenone (cyrene®), mixtures of the aforementioned solvents, and mixtures of the aforementioned solvents with water, particularly dimethylformamide, dimethylacetamide, dichloromethane, trichloromethane, dichloroethane, and mixtures thereof, specifically dimethylformamide, dimethylacetamide, and mixtures thereof.

[0107] However, if formic acid is used as a reducing agent or is contained in a reducing agent and / or a base that is liquid at the reaction temperature is used, the reaction in step (a) can instead be carried out undiluted.

[0108] When phormate is used as the sole reducing agent, it is preferable to use it in mixture with water. In this case, the solvent preferably also includes water.

[0109] During the reaction in step (a), formic acid or formate is oxidized to CO2. Given that CO2 inhibits the activity of many catalysts, it is advantageous to remove CO2 during the reaction in step (a). This can be done, for example, by blowing an inert gas through the reaction mixture or by applying a vacuum. Therefore, in a preferred embodiment, during the reaction in step (a), an inert gas, which is different from CO2 and preferably selected from the group consisting of argon, nitrogen, and a mixture of oxygen and nitrogen containing 1 to 8 volume percent oxygen relative to the total amount of the oxygen / nitrogen mixture, is blown through the reaction mixture, or alternatively or additionally, the reaction is carried out under reduced pressure. Specifically, CO2 is removed using nitrogen. The inert gas is typically used at a flow rate of 1 to 200 l / h, preferably 1 to 80 l / h, more preferably 1 to 50 l / h, and especially 1 to 20 l / h. On an industrial scale, the flow rate can, of course, be significantly higher, for example, up to 5000 l / h.

[0110] The reactions in steps (a) and (b) can be carried out in the presence of additives that accelerate the reaction rate. Typical additives are diethyl phosphite, borate esters, and zinc salts. Suitable zinc salts include, for example, zinc halides, zinc acetate, or zinc trifluoromethanesulfonate. Specifically, diethyl phosphite or zinc salts, particularly zinc acetate, are used. The additive is preferably used in such an amount that the molar ratio of the additive to compound 1 is in the range of 1:10000 to 10:1, particularly 1:10000 to 5:1, and especially 1:10000 to 2:1.

[0111] The reaction in step (a) is preferably carried out at a temperature of -20 to 120°C. The optimal temperature depends, among other things, on the catalyst used. For example, with some Ru catalysts, higher reaction temperatures may be advantageous, such that the reaction temperature in this case is preferably in the range of 30 to 100°C, for example, 50 to 90°C, but in the case of Rh and Ir, lower reaction temperatures are sufficient, such that the reaction temperature in this case is preferably in the range of -20 to 30°C, particularly in the range of -15 to 25°C. However, Ru catalysts also function at temperatures in this range, particularly 10 to 30°C.

[0112] The reaction time in step (a) depends on various factors such as the reaction temperature and the concentration of reactants in the reaction mixture. Typically, it is in the range of about 0 to 48 hours, preferably 1 to 16 hours. In this regard, a reaction time of "0h" means that after all the components have been added, the reaction may be sufficiently complete to proceed to step (b). This can occur, for example, if the addition of reactants continues for a considerably long time or if it is intended to reuse unreacted starting materials.

[0113] The reaction in step (a) is generally carried out by mixing a reducing agent, optionally a base (mixing with the base is essential if formic acid is used as the sole reducing agent), a chiral catalyst (either in a pre-formed form or in the form of a catalyst precursor and chiral ligand), optionally a solvent, and optionally an additive, or by mixing the components at a desired reaction temperature, and then bringing the temperature to the desired range. The order of addition is not particularly important. For example, (i) Add the reducing agent and optionally a base (in the case of formic acid as the sole reducing agent: a base is required) as a mixture or separately (separate additions can be made simultaneously or sequentially) to the mixture of compound 1 and the chiral catalyst in a solvent, or (ii) Add the chiral catalyst in the solvent to a mixture of compound 1, a reducing agent, optionally a base (if formic acid is the sole reducing agent: a base is required), and optionally a solvent (if formate is used as the sole reducing agent and no liquid base is used: a solvent is required), or (iii) optionally, in a solvent, add the reducing agent to a mixture of compound 1, a chiral catalyst, optionally a base (if formic acid is the sole reducing agent: a base is required), and optionally a solvent (if a liquid base is not used: a solvent is required), or (iv) Compound 1 in the solvent is added to a mixture of a chiral catalyst, a reducing agent, optionally a base (if formic acid is the sole reducing agent: a base is required), and optionally a solvent (if formate is used as the sole reducing agent and no liquid base is used: a solvent is required).

[0114] The reaction mixture obtained in step (a) is reacted in the next step (b) without isolating compound 2. Compound 2 is highly sensitive and can decompose to some extent during storage or even when conventional isolation methods are applied. Not isolating compound 2 tends to yield compound (I) in a higher yield compared to a method in which compound 2 is isolated before being subjected to step (b).

[0115] Generally, reacting the reaction mixture from step (a) in step (b) without isolating compound 2 is done simply by contacting the activating compound with the reaction mixture obtained in step (a), that is, by adding the activating compound to the reaction mixture obtained in step (a).

[0116] The activator used in step (b) is a compound that enhances the electrophilicity of the carbon atom marked with an asterisk in the compound of formula 2 without promoting racemization of the said carbon atom. The reaction of 2 with compound (I) is an intramolecular nucleophilic substitution in which the unsubstituted nitrogen atom of the pyrimidinone ring attacks the aliphatic carbon atom marked with an asterisk, substituting the OH group and forming a fused ring system. In order to preserve the chiral information of 2 in compound (I) as much as possible, the conditions of this reaction are favorable such that racemization at the carbon atom marked with an asterisk is suppressed or at least minimized. This is because S N This is conveniently carried out by ensuring nucleophilic attack under two conditions. Therefore, the activator is the intermolecular S at the carbon atom indicated by the asterisk in the compound of formula 2. N It is alternatively defined as a compound that facilitates a 2-attack.

[0117] Suitable activators are oxyphilic compounds such as various phosphorus compounds, but also specific compounds or compositions of compounds that possess Lewis acid properties.

[0118] Preferably, the activator is P(OR 1 )2Cl, P(OR 1 )Cl2, P(=O)(OR 1 )2Cl, P(=O)(OR 1)Cl2(where each R in the four compounds 1 These are independently C1-C4 alkyl groups, PCl3, P(=O)Cl3, polyphosphate, P4O 10 The activators are selected from the group consisting of a Mitsunobu-type reagent, triphenylphosphine in combination with a halogenating agent, an SO3 complex with a Lewis base selected from amines, carboxamides, and heteroaromatic compounds containing one, two, or three basic nitrogen ring atoms, (O)Cl2, CH3S(O)2Cl, carbonyldiimidazole (CDI), Vilsmeyer reagent, a complex of N,N-dimethylformamide and / or N,N-dimethylacetamide with a Lewis acid, and a mixture of two or more of the above activators.

[0119] Mitsunobu-type reagents are combinations of triphenylphosphine with azodicarboxylate, such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), or combinations of triphenylphosphine with azodicarboxamide, such as tetramethyl azodicarboxamide (TMAD). These combinations are used as mixtures or mixed in situ during the reaction. Conveniently, they can be used as commercially available mixtures.

[0120] Examples of halogenating agents used in combination with triphenylphosphine include N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), elemental chlorine, elemental bromine, or elemental iodine. These combinations are used as mixtures or mixed in situ during the reaction.

[0121] Examples of SO3 complexes with Lewis bases selected from amines, carboxamides, and heteroaromatic compounds containing one, two, or three basic nitrogen ring atoms include SO3 complexes with trimethylamine, triethylamine, N,N-dimethylaniline, N,N-dimethylformamide, pyridine, or polyvinylpyridine. These combinations are used as mixtures or mixed in situ during the reaction. Conveniently, they can be used as commercially available mixtures.

[0122] The Vilsmeyer reagent is a product of the reaction between phosphoryl chloride (P(O)Cl3), oxalyl chloride (ClC(O)-C(O)Cl), or thionyl chloride (S(O)Cl2) and formamide (HC(O)NR2 (wherein each R is independently C1-C4-alkyl)), and chloroiminium ions (ClHC=NR2) + This results in dimethylformamide being commonly used, where both R's are methyl.

[0123] An example of a Lewis acid in complexes of N,N-dimethylformamide and / or N,N-dimethylacetamide with a Lewis acid is BF3.

[0124] The activator is more preferably P(OR 1 )2Cl, P(OR 1 )Cl2, P(=O)(OR 1 )2Cl(Each R in the three aforementioned compounds 1 These are independently C1-C4 alkyl compounds, PCl3, P(O)Cl3, SO3 / dimethylformamide complex, SOCl2, CH3S(=O)2Cl, CDI and type reagents, especially dimethyl chlorophosphite (P(OCH3)2Cl), diethyl chlorophosphite (P(OCH2CH3)2Cl), methyl dichlorophosphite (P(OCH3)Cl2), ethyl dichlorophosphite (P(OCH2CH3)Cl2), PCl3, P(O)Cl3, SO3 The activator is selected from the group consisting of Cl2, CH3S(=O)2Cl, CDI, and Mitsunobu-type reagents. More specifically, the activator is selected from the group consisting of dimethylchlorophosphite (P(OCH3)2Cl), diethylchlorophosphite (P(OCH2CH3)2Cl), methyldichlorophosphite (P(OCH3)Cl2), ethyldichlorophosphite (P(OCH2CH3)Cl2), PCl3, and P(O)Cl3. Even more specifically, the activator is P(OR 1)2Cl, specifically selected from the group consisting of dimethyl chlorophosphite (P(OCH3)2Cl), diethyl chlorophosphite (P(OCH2CH3)2Cl), and PCl3. Specifically, the activator is dimethyl chlorophosphite (P(OCH3)2Cl) or diethyl chlorophosphite (P(OCH2CH3)2Cl).

[0125] The compound and activator of Formula 2 are preferably used in a molar ratio of 10:1 to 1:10, more preferably 2:1 to 1:5, even more preferably 1:1 to 1:4, particularly 1:1 to 1:3, and specifically 1:1 to 1:2.

[0126] The reaction in step (b) is preferably carried out in the presence of a solvent. If step (a) was carried out in formic acid and / or a liquid base as the solvent without any additional typical solvents, it is advantageous to add such a solvent. Suitable solvents are polar aprotic solvents, mixtures of polar aprotic solvents and water, C1-C4 alkyl acetates, chlorinated alkanes, aromatic solvents, heterocyclic solvents and mixtures thereof. Aqueous solvents generally solubilize ionic leaving groups, thus providing S in substitution reactions. N It is generally believed that one pathway is promoted, and in this case, a mixture of a polar aprotic solvent and water has been found to be suitable, at least in combination with a specific activator such as PCl3; see the above recognition.

[0127] Polar aprotic solvents are polar solvents that do not have functional groups from which protons can dissociate. Suitable examples of polar aprotic solvents include 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 dimethyl sulfoxide (DMSO); nitriles such as acetonitrile; N-methylpyrrolidone (NMP), N-(n-butyl)-pyrrolidone, or N-(tert-butyl) Examples include lactams such as γ-pyrrolidone, sulfones such as sulfolane, carbonate esters such as dimethylcarbonate, ethylenecarbonate, or propylenecarbonate, lactones such as γ-butyrolactone or γ-valerolactone, ureas such as N,N,N',N'-tetramethylurea, N,N,N',N'-tetrabutylurea, dimethylpropyleneurea (DMPU), or 1,3-dimethyl-2-imidazolinone (DMEU, DMI), and nitro compounds such as nitromethane.

[0128] In a mixture of a polar aprotic solvent and water, the mixture preferably contains 0.5 to 15% by weight, preferably 1 to 10% by weight, particularly 1 to 6% by weight, and particularly 1 to 4% by weight of water, based on the total weight of the mixture.

[0129] Suitable examples of C1-C4 alkyl acetates include methyl acetate, ethyl acetate, n-propyl acetate, and isopropyl acetate.

[0130] Suitable examples of chlorinated alkanes are dichloromethane, trichloromethane, or dichloroethane.

[0131] Examples of suitable aromatic solvents include benzene, toluene, α,α,α-trifluorotoluene (benzotrifluoride), xylene (i.e., 1,2-xylene, 1,3-xylene, or 1,4-xylene), fluorobenzene, chlorobenzene, dichlorobenzene, or anisole (methoxybenzene).

[0132] Suitable heterocyclic solvents include 4-formylmorpholine or dihydrolevoglucocenone (cyrene®).

[0133] More preferably, the solvent is dimethylformamide, diethylformamide, dibutylformamide, dimethylacetamide, tetrahydrofuran, a mixture of tetrahydrofuran and water (for example, containing 0.5 to 15% by weight, preferably 1 to 10% by weight, particularly 1 to 6% by weight, particularly 1 to 4% by weight of water, based on the total weight of the THF / water mixture), 2-methyltetrahydrofuran, dioxane (i.e., 1,3-dioxane and 1,4-dioxane), dimethyl sulfoxide, acetonitrile, N-methylpyrrolidone, N-(n-butyl)-pyrrolidone, N- Selected from the group consisting of (tert-butyl)-pyrrolidone, sulfolane, dimethylcarbonate, diethylcarbonate, propylenecarbonate, γ-valerolactone, N,N,N',N'-tetrabutylurea, 1,3-dimethyl-2-imidazolinone, ethyl acetate, isopropyl acetate, dichloromethane, trichloromethane, dichloroethane, benzene, toluene, trifluorotoluene, xylene, chlorobenzene, dichlorobenzene, 4-formyl-morpholine, dihydrolevoglucocenone (cyrene®), and mixtures thereof. In particular, the solvent is selected from the group consisting of dimethylformamide, diethylformamide, dibutylformamide, dimethylacetamide, tetrahydrofuran, mixtures of tetrahydrofuran and water (for example, containing 0.5 to 15% by weight, preferably 1 to 10% by weight, particularly 1 to 6% by weight, particularly 1 to 4% by weight of water, based on the total weight of the THF / water mixture), 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate, dichloromethane, toluene, chlorobenzene and mixtures thereof, in particular dimethylformamide, dimethylacetamide, dichloromethane, trichloromethane and mixtures thereof, specifically dimethylformamide, dimethylacetamide and mixtures thereof.

[0134] If step (a) is not carried out in the presence of a base (the base is different from formate), then a base can be added in step (b). The base is preferably an alkali metal hydroxide, formula NR 1 R 2 R 3 (In the formula, R 1 , R 2 and R 3 R is independently selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, and C1-C4-alkoxy-C1-C4-alkyl. 1 , R 2 and R 3 At least one of them is an amine (not hydrogen), formula NR 1 R 2 -A-NR 3 R 4 (In the formula, R 1 , R 2 , R 3 and R 4A is independently selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy and C1-C4-alkoxy-C1-C4-alkyl, and A is selected from the group consisting of 5 or 6-membered saturated heterocycles comprising a diamine (which is (CH2)2 or (CH2)3) and one nitrogen atom as a ring member, and optionally one further heteroatom selected from N and O as a ring member, and which may have 1 to 6 C1-C4-alkyl groups and / or 1 or 2 OH groups. In particular, the base is selected from the group consisting of LiOH, NaOH, KOH, diethylamine, triethylamine, tributylamine, diisopropylethylamine, dimethylisopropylamine, ethyl-tert-butylamine, isopropyl-tert-butylamine, (2-methoxyethyl)methylamine, N,N-dicyclohexylmethylamine, N-cyclohexyldimethylamine, N,N,N',N'-tetramethylethylenediamine, N,N,N',N'-tetramethylpropylene-1,3-diamine, piperidine, N-methylpiperidine, 2,2,6,6-tetramethylpiperidine, N-methyl-2,6,6-tetramethylpiperidine, N-methyl-4-hydroxy-2,2,6,6-tetramethylpiperidine, morpholine, and N-methylmorpholine, where the base may be used in a supported form (i.e., on a supporting material), specifically selected from the group consisting of triethylamine, tributylamine, and diisopropylethylamine.

[0135] The appropriate support materials are listed above.

[0136] However, the addition of a base in step (b) is not necessary. In this context, the base refers to an additional base, i.e., a base different from the essential reactants. For example, the formate in step (a) is basic, and some activators contain basic components such as amines or heteroaromatic compounds in SO3 complexes with Lewis bases.

[0137] The reaction in step (b) is preferably carried out at a temperature of -80 to 120°C, more preferably -20 to 100°C, and particularly -10 to 90°C. If step (b) is carried out at a different temperature than step (a), this can be conveniently achieved by adjusting the temperature of the reaction mixture obtained in step (a) to the desired temperature before adding the activator.

[0138] The reaction time in step (b) depends on various factors such as the reaction temperature and the concentration of reactants in the reaction mixture. Typically, it ranges from about 15 minutes to 48 hours, preferably 1 to 10 hours.

[0139] The reaction in step (b) is usually carried out by adding an activator to the reaction mixture obtained in step (a). Depending on the activator used, it may be advantageous to add the agent to the reaction mixture obtained in step (a) which has been cooled to -80 to 10°C, for example, -20 to 0°C, and to heat the reaction mixture only after the addition is complete if a reaction temperature higher than the temperature at the time of addition is desired. Depending on the reactivity of the activator, it may be advantageous to add the activator gradually (continuously or in stages) to avoid heat generation. Since the reactivity depends not only on the type of activator but also on its condition after storage, preliminary testing is advisable.

[0140] Alternatively, step (b) is carried out by adding the reaction mixture obtained in step (a) to an activator. For this purpose, the activator is appropriately provided in a solvent. Suitable solvents are those listed above for step (b).

[0141] In preferred embodiments, the method of the present invention helps to prepare (3R)-3-(2-chlorothiazole-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate of formula (IR) with an enantiomer excess of at least 55% ee, preferably at least 60% ee, more preferably at least 70% ee, particularly at least 80% ee, and specifically at least 90% ee. [ka]

[0142] For this purpose, compound 1 is subjected to hydrogenation conditions such that a reaction mixture in which the S enantiomer of compound 2 is dominant, namely the 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidine-4-one of formula 2-S, is obtained with an enantiomer excess of at least 55% ee, preferably at least 60% ee, more preferably at least 70% ee, particularly at least 80% ee, and specifically at least 90% ee. [ka] Next, this is reacted with the activator mentioned above.

[0143] Intramolecular nucleophilic attack primarily proceeds from the opposite side of the OH leaving group, and therefore involves a stereochemical inversion at the chiral carbon atom (given that the nucleophile and the nucleophile have the same priority according to the Cahn-Ingold-Prelog rule, the absolute configuration also changes from S to R).

[0144] The reaction conditions under which a reaction mixture in which the S-enantiomer of compound 2 is dominant are described above in relation to step (a).

[0145] In another preferred embodiment, the method of the present invention helps to prepare (3S)-3-(2-chlorothiazole-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate of formula (IS) with an enantiomer excess of at least 55% ee, preferably at least 60% ee, more preferably at least 70% ee, particularly at least 80% ee, and specifically at least 90% ee. [ka]

[0146] For this purpose, compound 1 is subjected to hydrogenation conditions such that a reaction mixture in which the R enantiomer of compound 2 is dominant, namely a reaction mixture containing 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidine-4-one of formula 1-R, is obtained with an enantiomer excess of at least 55% ee, preferably at least 60% ee, more preferably at least 70% ee, particularly at least 80% ee, specifically at least 90% ee. [ka] Next, this is reacted with the activator mentioned above.

[0147] Intramolecular nucleophilic attack primarily proceeds from the opposite side of the OH leaving group, and therefore involves a stereochemical inversion at the chiral carbon atom (given that the nucleophile and the nucleophile have the same priority according to the Cahn-Ingold-Prelog rule, the absolute configuration also changes from R to S).

[0148] The reaction conditions under which a reaction mixture in which the R enantiomer of compound 2 is dominant are described above in relation to step (a).

[0149] After the reaction is complete, the pyrimidinone of formula (I) in its enantiomerized form is generally isolated from the reaction mixture. Isolation typically involves a step suitable for precipitation of compound (I). For example, the solvent can be optionally partially removed under reduced pressure, after which the desired compound (I) precipitates. Depending on the temperature applied to partially remove the solvent, the amount of solvent removed, and of course the properties of the solvent, it may be advantageous to cool the residual mixture, which may be cooled continuously or stepwise. Alternatively, or in addition, a further solvent having low solubility for compound (I) may be conveniently added after the partial removal of the reaction solvent, on which compound (I) precipitates, which may also occur after cooling (again continuously or stepwise). Suitable solvents having low solubility for compound (I) include, for example, aromatic hydrocarbons such as benzene, toluene, trifluorotoluene, xylene (i.e., 1,2-xylene, 1,3-xylene, or 1,4-xylene), chlorobenzene or dichlorobenzene, C1-C4 alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, and isopropyl acetate, C1-C4 alkanols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, and tert-butanol, glycols such as ethylene glycol, propylene glycol, diethylene glycol, and triethylene glycol, glycerol, water, or mixtures of the aforementioned solvents.

[0150] The precipitate can be isolated by conventional methods such as filtration, centrifugation, sedimentation, and removal of the supernatant, with filtration being preferred. The filtered cake can be further purified by washing with a suitable solvent, such as the solvents mentioned above, which have low solubility of compound (I).

[0151] If necessary, the catalyst can be recycled. For this purpose, the catalyst is recovered, for example, from the mother liquor of the precipitate of the compound of formula (I), e.g., filtrate, centrifugation, or supernatant, purified as necessary, and then used in step (a). The simplest way to recycle the catalyst is, optionally, to use the mother liquor of the concentrated precipitate (e.g., filtrate, centrifugation, or supernatant) in step (a). Instead, only the transition metals, and not the complete catalyst, are recovered. The metals can be recovered by adsorption to a suitable adsorbent material, for example, charcoal or resin. For this purpose, the adsorbent material is added to the mother liquor. On a large scale, the mother liquor can alternatively be passed through one or more columns packed with adsorbent once or several times. Separation of the metals from the adsorbent can be done by elution (especially when using resin), but generally the adsorbent material is simply burned. The metals are then purified and converted into the desired catalyst or catalyst precursor by known methods and can be reused in step (a). Alternatively, the transition metal can be recovered from the mother liquor (optionally after neutralization) by removing the solvent of this phase and burning the remainder. The metal can then be purified and converted into a desired catalyst or catalyst precursor by known methods and reused in the reduction process. The catalyst can also be extracted from the mother liquor first into a suitable organic solvent (e.g., one with a lower boiling point, which is less energy-intensive to remove), and then optionally subjected to the treatment described above after neutralization.

[0152] Compound 1 can be obtained, for example, by the reaction of N-methylthiourea with alkyl 2-phenylmalonate-6-hydroxy-3-methyl-5-phenyl-2-sulfanylpyrimidine-4-one or the corresponding thiolate, and then by the reaction of these with 2-chloro-1-(2-chlorothiazole-5-yl)ethanone.

[0153] These reactions are described in EP Application No. 21153040.7.

[0154] N-methylthiourea and alkyl 2-phenylmalonates are commercially available. 2-chloro-1-(2-chlorothiazole-5-yl)ethanone can be prepared, for example, by the reaction of 2-chlorothiazole with a Grignard reagent to the corresponding chloro-(2-chlorothiazole-5-yl)magnesium species and its reaction with 2-chloro-N-methoxy-N-methylacetamide, as described in International Publication No. 2018 / 197541 or International Publication No. 2018 / 202654. Alternatively, compound 3 can be prepared from thiourea according to the method described by T. Chalopin et al. in Org. Biomol. Chem., 2016, 14, 3913-3925.

[0155] This method yields compound (I) in high yield and with high stereoselectivity.

[0156] The present invention is further illustrated by the following embodiments. [Examples]

[0157] Abbreviation: DMAC N,N-dimethylacetamide DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) HCl ethyl acetate Me-THF 2-methyltetrahydrofuran THF (Tetrahydrofuran) TEA (Triethylamine) rt room temperature t time d day h time min rt retention time

[0158] Example 1: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate 1.1 Preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one In a 20 L jacketed reactor, a solution of N-methylthiourea (778 g, 8.38 mol), NaOCH3 (1584 g, 8.79 mol, 30 wt% solution in methanol), and methanol (384 g, 12 mol) was heated to an internal temperature of 65°C under N2 conditions. Then, diethyl 2-phenylmalonate (2121 g, 8.79 mol) was added over 30 minutes, and the pump was washed with methanol (384 g, 12 mol). The reaction mixture was then stirred at an internal temperature of 65°C for 4 hours, followed by 18 hours at 50°C. During this time, a suspension was formed. Next, a solution of 2-chloro-1-(2-chlorothiazole-5-yl)ethanone (1859 g, 9.00 mol) in ethanol (8.050 g, 175 mol) was added over 30 minutes. The reaction mixture was stirred at 50°C for 75 minutes, resulting in a large solid precipitate. At this point, ethanol (2,300 g, 50 mol) was added and the stirring speed was increased. The reaction mixture was stirred at 50°C for a further 36 hours, and then cooled to 20°C over 16 hours. The resulting solid was then isolated by filtration in three 4 L frit funnels. Each filtration cake was washed with 500 mL of ethanol. The filtration cakes were then returned to a 20 L reactor and slurryed with 15 L of water at 75°C for 1 hour. The slurry was then filtered through two 4 L frit funnels, and each filtration cake was washed three times with 500 mL of room temperature water, and then dried in a vacuum drying oven at 80°C and 5 mbar. After drying, 3040 g (91%) of the labeled compound in the form of a brown solid was isolated with a purity of 99% by weight. 1 H NMR (400MHz, DMSO-d6): δ=8.75(s,1H),7.15-7.45(m,5H),4.9(s,2H),3.46(s,3H).

[0159] 1. Preparation of 1.2(3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate 25.3 g (99%, 1.00 equivalent) of 2-[2-(2-chlorothiazole-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one was dissolved in 165 g of dimethylacetamide, cooled to -5°C, and nitrogen sparged. Subsequently, 8.3 g (99%, 1.00 equivalent) of diisopropylethylamine and 3.5 g (100%, 1.20 equivalent) of formic acid were added, followed by the addition of a solution of 0.13 g (94%, 0.003 equivalent) of the pre-formed catalyst Rh(III)ClCp*·(1S,2S-TsDPEN) (obtained by reacting 1 equivalent of [Rh(III)Cl2Cp*]2 with 2 equivalents of 1S,2S-TsDPEN and 4 equivalents of triethylamine) in 10 g of dimethylacetamide. The reaction mixture was stirred for 2 hours, and 13.6 g (95%, 1.30 equivalents) of diethyl chlorophosphite was added. The reaction mixture was heated to 30°C over 3 hours, and then to 80°C over 2.5 hours. After reducing the pressure to 45 mbar and distilling the solvent (-154 g), the vacuum was broken and 72 g of ethyl acetate was added. The temperature was cooled to 20°C over 4 hours. The precipitate was filtered, washed with ethyl acetate (2 × 63 g) and water (2 × 63 g), and finally dried under vacuum (approximately 100°C). 20.6 g (>99% ee, 99%, yield 83%) of (3R)-3-(2-chlorothiazole-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate was obtained as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ=7.96(s,1H),7.6(d,J=7.5Hz,1H),7.21-7.26(m,2H),7.06-7. 11(m,1H),6.48(d,J=8.1Hz,1H),4.25-4.32(m,1H),3.94(d,J=12Hz,1H),3.42,(s,3H). m / z(M+H + )=378

[0160] Example 2: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate 34.1 g (99%, 1.00 equivalent) of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one was dissolved in 216 g of dimethylacetamide, cooled to -5°C, and nitrogen sparged. 6.7 g of a formic acid (1.10 equivalents) / triethylamine (0.27 equivalents) mixture (molar ratio 4.1:1) was added, followed by the addition of 0.47 g (94%, 0.003 equivalents) of a pre-formed catalyst Rh(III)ClCp*·(1S,2S-TsDPEN) (obtained by reacting 1 equivalent of [Rh(III)Cl2Cp*]2 with 2 equivalents of 1S,2S-TsDPEN and 4 equivalents of triethylamine) in 20 g of dimethylacetamide solution. The reaction mixture was stirred for 1.5 hours, and 15.5 g (95%, 1.10 equivalents) of diethyl chlorophosphite was added. The reaction mixture was heated to 25°C over 2.5 hours, and then to 80°C over 2.5 hours. After reducing the pressure to 45 mbar and distilling the solvent (-205 g), the vacuum was broken and 87 g of ethyl acetate was added. The temperature was cooled to 20°C over 4 hours. The precipitate was filtered, washed with ethyl acetate (2 × 85 g) and water (2 × 85 g), and finally dried under vacuum (approximately 100°C). 28.8 g (>99% ee, 99%, yield 87%) of (3R)-3-(2-chlorothiazole-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate was obtained as an off-white to beige solid.

[0161] Example 3: Preparation of (3S)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate 29.9 g (99%, 1.00 equivalent) of 2-[2-(2-chlorothiazole-5-yl)-2-oxoethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one was dissolved in 230 g of dimethylacetamide, cooled to -5°C, and nitrogen sparged. A mixture of 5.2 g of formic acid (1.50 equivalent) and 3.5 g of diisopropylethylamine (0.36 equivalent) was added, followed by the addition of 0.17 g (92%, 0.003 equivalent) of a pre-formed catalyst Ir(III)ClCp*·(1R,2R-MsDPEN) (obtained by reacting 1 equivalent of [Ir(III)Cl2Cp*]2 with 2.1 equivalents of 1R,2R-MsDPEN in the presence of 4 equivalents of triethylamine) in 10 g of dimethylacetamide. The reaction mixture was stirred for 9 hours, and 21.0 g (95%, 1.70 equivalents) of diethyl chlorophosphite was added. The reaction mixture was heated to 30°C over 3 hours, then to 80°C over 2.5 hours. After reducing the pressure to 45 mbar and distilling the solvent (-207 g), the vacuum was broken and 82 g of ethyl acetate was added. The temperature was cooled to 20°C over 4 hours and stirred overnight. The precipitate was filtered, washed with ethyl acetate (2 × 75 g) and water (2 × 75 g), and finally dried under vacuum (approximately 100°C). 23.5 g (>99% ee, >99%, yield 83%) of (3S)-3-(2-chlorothiazole-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate was obtained as an off-white solid.

[0162] Example 4: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one (30 g, 75.48 mmol, 1 equivalent) was added at -5°C to a solution of dimethylacetamide (165 g) and diisopropylethylamine (11.83 g, 90.58 mmol, 1.20 equivalents), and nitrogen sparging was applied. Next, formic acid (4.21 g, 90.58 mmol, 1.20 equivalents), followed by a solution of [(4S,5S)-2-chloro-1-methylsulfonyl-4,5-diphenyl-1,3-diaza-2Δ4-rhodacyclopenta-2-yl], and 1,2,3,4,5-pentamethylcyclopentadienyl (formed in situ in the solution by mixing [Rh(III)Cl2Cp*]2, 1S,2S-MsDPEN and Hünig base (diisopropylethylamine) in a molar ratio of 1:3:7) in 10 g of dimethylacetamide (assuming 100% conversion: 0.084 g catalyst, 0.151 mmol, 0.002 equivalents) were added sequentially. The reaction mixture was stirred for 4 hours, and then diethyl chlorophosphite (15.7 g, 83.30 mmol, 1.1 equivalents) was added. The reaction mixture was heated to 30°C over 3 hours, then to 80°C over 2.5 hours. The pressure was then reduced to 45 mbar, 154 g of dimethylacetamide was removed by distillation, and then, breaking the vacuum, 72 g of ethyl acetate was added over 1 hour. The temperature was then lowered to 20°C over 4 hours, during which time a suspension was formed. The solid was isolated by filtration, washed with ethyl acetate (2 × 63 g) and water (2 × 63 g), and finally dried in vacuum at 100°C to obtain 24.2 g (>99% ee, yield 85%) of (3R)-3-(2-chlorothiazole-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate as an off-white solid.

[0163] Example 5: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one (5.0 g, 12.65 mmol, 1 equivalent) was dissolved in dimethylformamide (36.3 g), then cooled to 0°C and subjected to nitrogen sparging. A solution of the pre-formed catalyst [(4S,5S)-2-chloro-1-methylsulfonyl-4,5-diphenyl-1,3-diaza-2Δ4-rhodacyclopenta-2-yl] and 1,2,3,4,5-pentamethylcyclopentadienyl (0.051 g, 0.08 mmol, 0.006 equivalents) in 15 ml of dimethylformamide was added, followed by the addition of 0.98 g of formic acid (1.10 equivalents) / triethylamine (0.27 equivalents) mixture (molar ratio 4.1:1). The reaction mixture was stirred for 3 hours, and then diethyl chlorophosphite (3.5 g, 21.51 mmol, 1.7 equivalents) was added. The reaction mixture was heated to room temperature overnight. The pressure was then reduced to 15 mbar (50°C), and dimethylformamide was removed by distillation until 16 g of the reaction mixture remained. 16 g of ethyl acetate was added over 0.5 hours. The temperature was then reduced to 20°C. The solid was isolated by filtration, washed with ethyl acetate (2 × 12.5 g) and water (2 × 12.5 g), and finally dried in vacuum at 100°C to obtain 3.53 g of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate (>99% ee, >99%, yield 76%) as an off-white solid.

[0164] Example 6: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one (30 g, 75.48 mmol, 1 equivalent) was added at -5°C to a solution of dimethylacetamide (120 g) and diisopropylethylamine (11.75 g, 90.58 mmol, 1.20 equivalents), and nitrogen sparging was applied. Next, formic acid (0.70 g, 15.07 mmol, 0.20 equivalents), followed by a solution of [(4S,5S)-2-chloro-1-methylsulfonyl-4,5-diphenyl-1,3-diaza-2Δ4-rhodacyclopenta-2-yl], and 1,2,3,4,5-pentamethylcyclopentadienyl (formed in situ in the aforementioned solution by mixing [Rh(III)Cl2Cp*]2, 1S,2S-MsDPEN, and Hünig base in a molar ratio of 1:3:7) in 10 g of dimethylacetamide (assuming 100% conversion: 0.084 g of catalyst, 0.151 mmol, 0.002 equivalents) were added sequentially. Then, formic acid (3.51 g, 75.59 mmol, 1.00 equivalent) was added over 30 minutes. The reaction mixture was stirred for 4 hours, and then diethyl chlorophosphite (15.7 g, 83.30 mmol, 1.1 equivalents) was added. The reaction mixture was heated to 30°C over 3 hours, and then to 80°C over 2.5 hours. The pressure was then reduced to 45 mbar, 113 g of dimethylacetamide was removed by distillation, the vacuum was broken, and then the temperature was lowered to 20°C over 4 hours. 80 g of ethanol was added over 2 hours. The solid was isolated by filtration and washed with ethanol (1 × 75 g). The solid was resuspended in 96 g of ethanol / water (1:1) at 80°C for 50 hours, filtered, washed with water (2 × 50 g), and finally dried in vacuum at 100°C to obtain 22.8 g (>99% ee, >99%, yield 80%) of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate as an off-white solid.

[0165] Further reaction conditions in step b) were tested, and similar results were obtained.

[0166] [Table 1]

[0167] [Table 2]

[0168] 10 AA = Activator 11 In this case, one equivalent is the weight equivalent of the starting compound.

[0169] Example 7: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate Similar to Example 6, 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one was mixed with 10.93 mmol (1.1 equivalents) of formic acid and 70 g of chloroform at 0°C, with 9.94 mmol (1 equivalent) of diisopropylethylamine as a base and 0.3 mmol (3 mol%) of the catalyst RuClmes(1S,2S-TsDPEN)([RuCl2(mes 8 The compound was reacted in the presence of (obtained by reacting 2 with 1S,2S-TsDPEN), and then reacted with 1.8 equivalents of diethyl chlorophosphite at 10°C. The marked compound was obtained in yield of 77% and >99% ee.

[0170] Example 8: Preparation of (3S)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate Similar to Example 6, 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one was mixed with 14.9 mmol (1.5 equivalents) of formic acid and 14.9 mmol (1.5 equivalents) of diisopropylethylamine as a base and 0.4 mmol (4 mol%) of the catalyst RuClmes(1R,2R-CsDPEN)([RuCl2(mes)) in 46 g of DMAC at 20°C. 8 )]2 was reacted with 1R,2R-CsDPEN; more precisely, in the presence of N-[(1R,2R)-2-amino-1,2-diphenyl-ethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonamide), and then 1.8 equivalents of diethyl chlorophosphite (added in two separate amounts of 1.5 and 0.3 equivalents) yielded the marked compound in 80% and 83% ee yields.

[0171] Example 9: Preparation of (3S)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate Similar to Example 6, 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one was mixed with 10.93 mmol (1.1 equivalents) of formic acid and 9.94 mmol (1 equivalent) of diisopropylethylamine as a base and 0.2 mmol (2 mol%) of the catalyst RuClmes(1R,2R-CsDPEN)([RuCl2(mes)) in 46 g of DMAC at 20°C. 8 )]2 was reacted with 1R,2R-CsDPEN; more precisely, in the presence of N-[(1R,2R)-2-amino-1,2-diphenyl-ethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonamide), and then 1.8 equivalents of diethyl chlorophosphite (added in two separate amounts of 1.5 and 0.3 equivalents) yielded the marked compound in 80% and 85% ee yields.

[0172] Example 10: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate (vacuum, addition to diethyl chlorophosphite) 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one (30.5 g, 76.64 mmol, 1 equivalent) was added at -5°C to a solution of dimethylacetamide (165 g), diisopropylethylamine (9.90 g, 76.64 mmol, 1.00 equivalent), and formic acid (3.88 g, 84.30 mmol, 1.10 equivalent). Next, a vacuum was applied (50 mbar), followed by the addition of 10 g of a solution of RhClCp*(1S,2S-CsDPEN)([Rh(III)Cl2Cp*]2, 1S,2S-CsDPEN (more precisely, N-[(1S,2S)-2-amino-1,2-diphenyl-ethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonamide) (formed in situ in solution by mixing 1S,2S-CsDPEN (more precisely, N-[(1S,2S)-2-amino-1,2-diphenyl-ethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonamide) with diisopropylethylamine used in a molar ratio of 1:3:7) (assuming 100% conversion: 0.107 g catalyst, 0.153 mmol, 0.002 equivalents) in dimethylacetamide. The reaction mixture was stirred for 3 hours, the vacuum was broken, and the mixture was then added at 20°C to a solution of diethyl chlorophosphite (15.60 g, 99.63 mmol, 1.3 equivalents) in dimethylacetamide (36 g). The reaction mixture was stirred for 5 hours, then heated to 80°C over 3 hours and maintained at 80°C for 3 hours. The pressure was then reduced to 20 mbar, and 167 g of dimethylacetamide was removed by distillation. The vacuum was then broken, the mixture was cooled to 60°C, and 86 g of methanol was added over 1 hour. The temperature was then lowered to 0°C over 4 hours, during which time a suspension was formed. The solid was isolated by filtration, washed with methanol (1 × 74 g) and water (1 × 69 g), and finally dried in vacuum at 100°C to obtain 24.0 g (>99% ee, yield 83%) of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate as an off-white solid.

[0173] Example 11: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate 2-[2-(2-chlorothiazole-5-yl)-2-oxoethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one (30.0 g, 75.18 mmol, 1 equivalent) was added to a solution of dimethylacetamide (120 g), cooled to -5°C, and nitrogen sparging was applied. Next, diisopropylethylamine (9.72 g, 75.18 mmol, 1.00 equivalent) and formic acid (3.85 g, 82.69 mmol, 1.10 equivalent) were added sequentially at -5°C, followed by the addition of a solution of RhClCp*(1S,2S-CsDPEN) (formed in situ in solution by mixing [Rh(III)Cl2Cp*]2, 1S,2S-CsDPEN (more precisely, N-[(1S,2S)-2-amino-1,2-diphenyl-ethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonamide) and diisopropylethylamine used in a molar ratio of 1:3:7 in DMAC) (assuming 100% conversion: 0.105 g catalyst, 0.15 mmol, 0.002 equivalents). The reaction mixture was stirred for 2 hours. Diethyl chlorophosphite (16.78 g, 97.73 mmol, 1.3 equivalents) was added at -5°C, and the reaction mixture was heated to 25°C and stirred for 5 hours. Then, it was heated to 80°C over 3 hours and held for 3 hours. Next, the pressure was reduced to 35-45 mbar and dimethylacetamide was removed by distillation. Then, the vacuum was broken and the mixture (71 g) was cooled to 60°C, and 85 g of methanol was added over 1 hour. Next, the temperature was lowered to 20°C over 3 hours. The solid was isolated by filtration, washed with methanol (1 × 71 g) and water (1 × 71 g), and finally dried in vacuum at 100°C to obtain 24.74 g (>99% ee, yield 85%) of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate as an off-white solid.

[0174] Example 12: Various reaction conditions for the preparation of 2-R required for the preparation of (3S)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate Further reaction conditions for step a) were tested. The reaction was carried out in the same manner as the first part of the above examples (i.e., before the reaction with the activator), but using 1 g of the starting compound and DMF (2 ml) as the solvent, and the catalyst and conditions are summarized in the table below. The catalyst was used in a form pre-formed by the reaction of the indicated catalyst precursor with the asymmetric ligand, or generated in situ by adding the indicated catalyst precursor and the asymmetric ligand to the reaction mixture. The reactions were carried out at room temperature, except for Examples 13-17 which were carried out at 0°C.

[0175] [Table 3]

[0176] 1 cat.prec. = catalyst precursor 2 asym.lig.=Asymmetric ligand 3 is = Catalyst is formed in situ (from the indicated catalyst precursor and chiral ligand); pre. = Catalyst is pre-formed (from the indicated catalyst precursor and chiral ligand) 4 Amount of catalyst (calculated as amount of metal) (mol%) relative to the amount (mol) of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one 5 The molar ratio of formic acid to amine. If formate is used instead of formic acid, this is indicated, and the molar ratio is not given. See 6. The amount of HCOOH used is given in molar equivalents relative to the amount of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one used. 6 Instead of formic acid / amine, sodium formate and water were used. 7 C-3-tethr-RuCl-1R,2R-TsDPEN= [ka] 8 mes = mesicilen 9 cym = p-cymene

[0177] Example 13: Various reaction conditions for the preparation of 2-S necessary for the preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate Further reaction conditions for step a) were tested. The reaction was carried out in the same manner as the first part of the above examples (i.e., proceeding before the reaction with the activator), but using 400 mg of the starting compound and 7 ml of solvent, the solvent, catalyst and conditions were as summarized in the table below. The catalyst was used in a form pre-formed by the reaction of the indicated catalyst precursor with the asymmetric ligand, or generated in situ by adding the indicated catalyst precursor and asymmetric ligand to the reaction mixture. Except for Examples 18 and 19 (-5°C) and Examples 20, 22, 37, 39, 42, 45 and 47 (0°C), the reactions were carried out at room temperature.

[0178] [Table 4]

[0179] 12 catalyst:

[0180] Catalyst number 1: The catalyst Rh(III)ClCp*(1S,2S-MsDPEN) obtained by reacting [Rh(III)Cl2Cp*]2 with 1S,2S-MsDPEN is given by the following equation: [ka]

[0181] Catalyst number 2: [RuCl2(mes 8 The catalyst RuClMes·(1S,2S-TsDPEN) obtained by reacting )2 with 1S,2S-TsDPEN is given by the following equation: [ka]

[0182] Catalyst number 2*: Similar to 2, but formed in situ.

[0183] Catalyst number 3: [RuCl2(mes 8 The catalyst RuClMes·(1S,2S-MsDPEN) obtained by reacting )2 with 1S,2S-MsDPEN is given by the following equation: [ka]

[0184] Catalyst number 4: [RuCl2(mes 8 The catalyst RuClMes·(1S,2S-CsDPEN) is obtained by reacting )2 with 1S,2S-CsDPEN (more precisely, N-[(1S,2S)-2-amino-1,2-diphenyl-ethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonamide).

[0185] Catalyst number 5: [RuCl2(mes 8The catalyst RuClMes·(1S,2S-TsDiOMeDPEN) obtained by reacting )2 with N-[(1S,2S)-2-amino-1,2-bis(4-methoxyphenyl)ethyl]-4-methylbenzenesulfonamide is given the following formula: [ka]

[0186] Catalyst number 6: [RuCl2(mes 8 The catalyst RuClMes·(1S,2S-MesitylDPEN) obtained by reacting )2 with 1S,2S-MesitylDPEN is given by the following equation: [ka]

[0187] Catalyst number 7: [RuCl2(mes 8 The catalyst RuClMes·(1S,2S-RsDPEN) obtained by reacting )2 with 1S,2S-RsDPEN is given by the following equation: [ka]

[0188] Example 14: Use of various stereoisomers of (1R,2R)-CsDPEN as ligands in the hydrogenation process (a) To demonstrate that the composition of the camphor moiety of the CsDPEN ligand does not essentially affect the hydrogenation of 2-[2-(2-chlorothiazole-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula 1 and therefore the stereoselectivity in the final product (I), step (a) was carried out using two different (1R,2R)-CsDPEN stereoisomers, namely N-[(1R,2R)-2-amino-1,2-diphenyl-ethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonamide and N-[(1R,2R)-2-amino-1,2-diphenyl-ethyl]-1-[(1R,4S)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonamide. The reaction proceeds similarly to the first part of the above example (i.e., before the reaction with the activator), using DMAC as the solvent, 1.2 equivalents of formic acid, 0.8 equivalents of diisopropylethylamine as the base, and 0.2 mol% of the catalyst RhClCp*(1R,2R-CsDPEN-1)([Rh(III)Cl2Cp*]2, N-[(1R,2R)-2-amino-1,2-diphenyl-ethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonamide in a molar ratio of 1:3:7. The reaction was carried out using either diisopropylethylamine (formed in situ by mixing) or 0.2 mol% of the catalyst RhClCp*(1R,2R-CsDPEN-2)([Rh(III)Cl2Cp*]2, N-[(1R,2R)-2-amino-1,2-diphenyl-ethyl]-1-[(1R,4S)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonamide and diisopropylethylamine used in a molar ratio of 1:3:7, which was formed in situ. The reaction was carried out at -5°C.

[0189] Reactions using RhClCp*·(1R,2R-CsDPEN-1) as a catalyst yielded 2-R with an enantiomer purity of 97% ee (conversion rate: 95%), and reactions using RhClCp*·(1R,2R-CsDPEN-2) as a catalyst yielded 2-R with an enantiomer purity of 98% ee (conversion rate: 98%). Several embodiments are shown below. Item 1 Formula (I) of the enantiomer-enriched form: [ka] (In the formula, an asterisk * indicates the center of the solid.) A method for preparing 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate, (a) Formula 1 [ka] 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one or its tautomers or mixtures of different tautomers thereof, in the presence of a chiral transition metal catalyst and optionally a base, formic acid HC(=O)OH, formula HC(=O)O - M + Formate and formic acid HC(=O)OH and the above formula HC(=O)O - M + A mixture of one or more formates (wherein M + The process involves reduction with a reducing agent selected from the group consisting of (where is the cation equivalent), and when formic acid is used as the reducing agent, the reaction is carried out in the presence of a base, thereby reducing the enantiomerized form of formula 2. [ka] Obtain a reaction mixture containing 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one or its tautomers or mixtures of different tautomers thereof, (b) The reaction mixture obtained in step (a) is reacted with an activator that enhances the electrophilicity of the asterisk-marked carbon atom in the compound of formula 1 without promoting racemization at the carbon atom, thereby obtaining the compound of formula (I) in an enantiomerized form. A method that includes this. Section 2 M + This is an alkali metal cation, formula [NHR 1 R 2 R 3 ] + (In the formula, R 1 、R 2 and R 3 These are, independently of each other, hydrogen and C 1 ~C 6 -alkyl, C 3 ~C6 -Cycloalkyl, C 1 ~C 4 -alkoxy and C 1 ~C 4 -alkoxy-C 1 ~C 4 - Ammonium cations (selected from the group consisting of alkyl groups), formula NR 1 R 2 -A-NR 3 R 4 (In the formula, R 1 、R 2 、R 3 and R 4 These are, independently of each other, hydrogen and C 1 ~C 6 -alkyl, C 3 ~C 6 -Cycloalkyl, C 1 ~C 4 -alkoxy and C 1 ~C 4 -alkoxy-C 1 ~C 4 -Selected from the group consisting of alkyl groups, and A is (CH 2 ) 2 or (CH 2 ) 3 A protonated diamine and a protonated 5 or 6-membered saturated heterocycle comprising one nitrogen atom as a ring member and one further heteroatom optionally selected from N and O as a ring member, wherein 1 to 6 C 1 ~C 4 - Selected from the group consisting of a protonated 5- or 6-membered saturated heterocycle that may have an alkyl group and / or one or two OH groups, M + Preferably, Li + na + 、K + , Cs + NH 4 + [NH 2 (C 2 H 5 ) 2 ] + [NH(C 2 H 5 ) 3 ] + [NH(CH 2 CH 2 CH 2 CH 3 ) 3 ] + [NH(C 2 H 5 )(CH(CH 3 )2 ] + [NH(CH 3 ) 2 (CH(CH 3 )] + [NH 2 (C 2 H 5 )(C(CH 3 ) 3 ] + [NH 2 (CH(CH 3 ) 2 )(C(CH 3 ) 3 ] + [NH 2 (C 2 H 4 OCH 3 )(CH 3 )] + [NH (cyclohexyl) 2 (CH 3 )] + [NH(cyclohexyl)(CH 3 ) 2 ] + , a group consisting of protonated N,N,N',N'-tetramethylethylenediamine, protonated N,N,N',N'-tetramethylpropylene-1,3-diamine, protonated piperidine, protonated N-methylpiperidine, protonated 2,2,6,6-tetramethylpiperidine, protonated N-methyl-2,6,6-tetramethylpiperidine, protonated N-methyl-4-hydroxy-2,2,6,6-tetramethylpiperidine, protonated morpholine and protonated N-methylmorpholine, particularly [NH(C 2 H 5 ) 3 ] + [NH(CH 2 CH 2 CH 2 CH 3 ) 3 ] + and [NH(C 2 H 5 )(CH(CH 3 ) 2 ] + The method described in item 1, selected from the options provided. Section 3 The base used optionally in step (a) is an alkali metal hydroxide, formula NR 1 R 2 R 3 (In the formula, R 1 、R 2 and R 3 These are, independently of each other, hydrogen and C 1 ~C 6 -alkyl, C 3 ~C 6 -Cycloalkyl, C 1 ~C 4 -alkoxy and C 1 ~C 4 -alkoxy-C 1 ~C 4 Selected from the group consisting of -alkyl, R 1 、R 2 and R 3 At least one of them is an amine (not hydrogen), formula NR 1 R 2 -A-NR 3 R 4 (In the formula, R 1 、R 2 、R 3 and R 4 These are, independently of each other, hydrogen and C 1 ~C 6 -alkyl, C 3 ~C 6 -Cycloalkyl, C 1 ~C 4 -alkoxy and C 1 ~C 4 -alkoxy-C 1 ~C 4 -Selected from the group consisting of alkyl groups, and A is (CH 2 ) 2 or (CH 2 ) 3 A 5 or 6-membered saturated heterocycle comprising a diamine (which is a 5- or 6-membered ring ring) and one nitrogen atom as a ring member, and optionally one further heteroatom selected from N and O as a ring member, wherein 1 to 6 C 1 ~C 4 - Selected from the group consisting of alkyl groups and / or 5 or 6-membered saturated heterocycles having one or two OH groups, the base may be used in a supported form. The method according to claim 1 or 2, wherein the base is preferably selected from the group consisting of LiOH, NaOH, KOH, diethylamine, triethylamine, tributylamine, diisopropylethylamine, dimethylisopropylamine, ethyl-tert-butylamine, isopropyl-tert-butylamine, (2-methoxyethyl)methylamine, N,N-dicyclohexylmethylamine, N-cyclohexyldimethylamine, N,N,N',N'-tetramethylethylenediamine, N,N,N',N'-tetramethylpropylene-1,3-diamine, piperidine, N-methylpiperidine, 2,2,6,6-tetramethylpiperidine, N-methyl-2,6,6-tetramethylpiperidine, N-methyl-4-hydroxy-2,2,6,6-tetramethylpiperidine, morpholine, and N-methylmorpholine, particularly triethylamine, tributylamine, and diisopropylethylamine. Section 4 The method according to any one of claims 1 to 3, wherein in step (a), formic acid is used as a reducing agent, and the formic acid and the base are used in a molar ratio of 100:1 to 1:10, preferably 10:1 to 1:5, particularly 10:1 to 1:2, specifically 5:1 to 1:1. Section 5 The chiral transition metal catalyst used in step (a) is selected from a group VIII metal catalyst, preferably a group VIII or group IX metal catalyst, according to any one of claims 1 to 4. Section 6 The method according to item 5, wherein the chiral transition metal catalyst used in step (a) is selected from Ru, Rh, and Ir catalysts. Section 7 The method according to any one of claims 1 to 6, wherein the chiral transition metal catalyst used in step (a) is used in an amount of 0.01 to 10 mol%, preferably 0.05 to 5 mol%, particularly 0.1 to 5 mol%, specifically 0.1 to 2 mol%, based on the transition metal content, per mole of compound 1. Section 8 The method according to any one of claims 1 to 7, wherein the chiral transition metal catalyst comprises one or more chiral ligands coordinated to the transition metal, the chiral ligands are selected from the group consisting of bidentate amine chiral ligands, and the chiral ligands are particularly selected from the group consisting of chiral 1,2-diphenyl-ethylene-1,2-diamine, 1,2-cyclohexanediamine, and 1,2-bis(methylamino)cyclohexane. Section 9 The chiral transition metal catalyst comprises one or more chiral ligands coordinated to the transition metal, wherein the chiral ligands are in a chiral form, of formula (II)

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Claims

1. Formula (I) of the enantiomer-enriched form: 【Chemistry 1】 (In the formula, an asterisk * indicates the center of the solid.) A method for preparing 3-(2-chlorothiazole-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate, (a) Formula 1 【Chemistry 2】 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one or its tautomers or mixtures of different tautomers thereof, in the presence of a chiral transition metal catalyst and optionally a base, formic acid HC(=O)OH, formula HC(=O)O － M ＋ Formate and formic acid HC(=O)OH and the above formula HC(=O)O － M ＋ A mixture of one or more formates (wherein M ＋ The reduction is carried out with a reducing agent selected from the group consisting of (where is the cation equivalent), and when formic acid is used as the reducing agent, the reduction reaction is carried out in the presence of a base, and the enantiomer enriched form is obtained by formula 2 【Transformation 3】 To obtain a reaction mixture containing 2-[2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one or its tautomers or mixtures of different tautomers thereof, (b) The reaction mixture obtained in step (a) is reacted with an activator that enhances the electrophilicity of the asterisk-marked carbon atom in the compound of formula 2 without promoting racemization at the carbon atom, thereby obtaining the compound of formula (I) in an enantiomerized form. Includes, The compound of formula (I) in the enantiomer-enriched form represents a non-racemic compound (I) in which either the S enantiomer or the R enantiomer is dominant, or which exists simply as a stereoisomer. The enantiomer-enriched form of the compound of formula 2 represents a non-racemic compound of formula 2 in which either the S enantiomer or the R enantiomer is dominant, or which exists simply as a stereoisomer. The chiral transition metal catalyst used in step (a) comprises one or more chiral ligands coordinated to the transition metal, wherein the chiral ligands are in chiral form, of formula (II) 【Chemistry 4】 (In the formula, The asterisk indicates the center of the stereochemistry. R5 and R6 are independently selected from the group consisting of OH, halogens, C1-C4-alkyl and C1-C4-alkoxy compounds. R7 and R8 are independently selected from the group consisting of hydrogen, C1-C4-alkyl, -L-phenyl (wherein the phenyl ring may have 1, 2, 3, 4, or 5 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl, and C1-C4-alkoxy), SO2R9. L is a linker selected from the group consisting of C2-C6-alkylene, C1-C3-alkylene-O-(CH2)p (wherein p is 0, 1, or 2), and C1-C3-alkylene-(1,2-phenylene)-(CH2)r (wherein r is 0, 1, or 2). R9 is selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl, phenyl, phenyl-C1-C3-alkyl (wherein phenyl and phenyl-C1-C3-alkyl may have 1, 2, 3, 4, or 5 substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy), naphthyl, C6-C10-bicycloalkyl-C1-C3-alkyl (wherein the bicycloalkyl ring may be substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of C1-C4-alkyl and oxo), and NR10 R11. R10 is hydrogen or C1-C4-alkyl, R11 is a phenyl-C1-C3-alkyl group, and the phenyl ring may have 1, 2, 3, 4, or 5 substituents selected from the group consisting of halogens, C1-C4-alkyl groups, C1-C4-haloalkyl groups, and C1-C4-alkoxy groups, and m and n are independently 0, 1, 2, 3, 4, or 5. Selected from the group consisting of 1,2-diphenyl-ethylene-1,2-diamine, The activator used in step (b) is P(OR1)2Cl, P(OR1)Cl2, P(=O)(OR1)2Cl, P(=O)(OR1)Cl2 (wherein each of the four aforementioned compounds R1 is independently C1-C4-alkyl), PCl3, P(=O)Cl3, polyphosphate, P4O10, Mitsunobu-type reagent, triphenylphosphine in combination with a halogenating agent, amines, carboxamides, and a Lewis base selected from heteroaromatic compounds containing one, two or three basic nitrogen ring atoms, SO3 complex with a Lewis base, S(O)Cl2, CH3S(O)2 A mixture of two or more of the following: Cl, carbonyldiimidazole (CDI), Vilsmeyer reagent, a complex of N,N-dimethylformamide and / or N,N-dimethylacetamide with a Lewis acid, and the aforementioned activator. method.

2. M ＋ is an alkali metal cation, an ammonium cation of the formula [NHR １ R ２ R ３ ＋ (wherein R １ , R ２ and R ３ are each independently hydrogen, C １ - C ６ - alkyl, C ３ - C ６ - cycloalkyl, C １ - C ４ - alkoxy and C １ - C ４ - alkoxy - C １ - C ４ - alkyl selected from the group consisting of), a protonated diamine of the formula NR １ R ２ - A - NR ３ R ４ (wherein R １ , R ２ , R ３ and R ４ are each independently hydrogen, C １ - C ６ - alkyl, C ３ - C ６ - cycloalkyl, C １ - C ４ - alkoxy and C １ - C ４ - alkoxy - C １ - C ４ - alkyl selected from the group consisting of, and A is (CH[[ID=)) ２ ２ or (CH ２ ３ ), a protonated 5 - or 6 - membered saturated heterocyclic ring containing one nitrogen atom as a ring member and optionally one additional heteroatom selected from N and O as a ring member, the protonated 5 - or 6 - membered saturated heterocyclic ring being selected from the group consisting of a protonated 5 - or 6 - membered saturated heterocyclic ring which may have 1 to 6 C １ - C ４ - alkyl groups and / or one or two OH groups, the method according to claim 1.​

3. The base optionally used in step (a) is an alkali metal hydroxide, NR １ R ２ R ３ (wherein R １ , R ２ and R ３ are each independently hydrogen, C １ to C ６ -alkyl, C ３ to C ６ -cycloalkyl, C １ to C ４ -alkoxy and C １ to C ４ -alkoxy-C １ to C ４ -alkyl, and at least one of R １ , R ２ and R ３ is not hydrogen), an amine of the formula NR １ R ２ -A-NR ３ R ４ (wherein R １ , R ２ , R ３ and R ４ are each independently hydrogen, C １ to C ６ -alkyl, C ３ to C ６ -cycloalkyl, C １ to C ４ -alkoxy and C １ to C ４ -alkoxy-C １ to C ４ -alkyl, and A is (CH ２ ) ２ or (CH ２ ) ３ ), a 5- or 6-membered saturated heterocyclic ring containing one nitrogen atom as a ring member and optionally one additional heteroatom selected from N and O as a ring member, which may have 1 to 6 C １ to C ４ -alkyl groups and / or one or two OH groups, and the base may be used in a supported form, the method according to claim 1 or 2.

4. The method according to any one of claims 1 to 3, wherein in step (a), formic acid is used as a reducing agent, and the formic acid and the base are used in a molar ratio of 100:1 to 1:

10.

5. The method according to any one of claims 1 to 4, wherein the chiral transition metal catalyst used in step (a) is selected from group VIII metal catalysts.

6. The method according to claim 5, wherein the chiral transition metal catalyst used in step (a) is selected from Group 8 or Group 9 metal catalysts.

7. The method according to claim 6, wherein the chiral transition metal catalyst used in step (a) is selected from Ru, Rh, and Ir catalysts.

8. The method according to any one of claims 1 to 7, wherein the chiral transition metal catalyst used in step (a) is used in an amount of 0.01 to 10 mol% per mole of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidine-4-one of formula 1, calculated based on the transition metal content.

9. The chiral ligand is DPEP, TsDPEP, CF in the (1R, 2R) or (1S, 2S) form ３ TsDPEP, MsDPEP, MeMsDPEP, MeTsDPEP, FsDPEP, TripsMesitylDPEP, CsDPEP, MesitylDPEP, RsDPEP, TsDiOMeDPEP or the formula (II) (where R ７ is SO ２ R ９ and R ９ is C １ to C ４ -alkyl or C １ to C ４ -alkyl and C １ to C ４ -haloalkyl, and may have one, two or three substituents selected from the group consisting of phenyl, R ８ is -(CH ２ ) ３ -phenyl or -(CH ２ ) ４ -phenyl, and the phenyl in -(CH2)3-phenyl and -(CH2)4-phenyl may have one, two or three substituents selected from the group consisting of C １ to C ４ -alkyl, C １ to C ４ -haloalkyl and C １ to C ４ -alkoxy, and m and n are 0), and the method according to any one of claims 1 to 8.

10. The chiral transition metal catalyst comprises Ru, Rh, or Ir as the central metal, and DPEN, TsDPEN, CF in (1R,2R) or (1S,2S) form. ３ A catalyst comprising at least one chiral ligand selected from the group consisting of TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, TripsMestylDPEN, CsDPEN, MestylDPEN, RsDPEN, and TsDiOMeDPEN, and Ru as a central metal, and the above formula (II) in the form of (1R, 2R) or (1S, 2S) (wherein R ７ SO ２ R ９ And R ９ C １ ~C ４ - Alkyl or C １ ~C ４ - Alkyl and C １ ~C ４ - A phenyl compound that may have one, two, or three substituents selected from the group consisting of haloalkyls, R ８ is, -(CH ２ ) ３ -Phenyl or -(CH ２ ) ４ -phenyl, and the phenyl in -(CH2)3-phenyl and -(CH2)4-phenyl is C １ ~C ４ - Alkyl, C １ ~C ４ - Haloalkyl and C １ ~C ４ The method according to claim 9, wherein the catalyst comprises a catalyst comprising: - at least one ligand selected from the compound (which may have one, two, or three substituents selected from the group consisting of alkoxys, and m and n are 0).

11. The method according to claim 10, wherein the chiral transition metal catalyst is selected from a catalyst comprising Ru, Rh, or Ir as a central metal and a chiral ligand selected from the group consisting of TsDPEN, MsDPEN, and CsDPEN in (1R,2R) or (1S,2S) form.

12. R ７ and R ８ Both are -L-phenyl or SO ２ R ９ (In the formula, R ９ is phenyl-C １ ~C ３ - Alkyl or NR １０ R １１ If not, the catalyst further comprises a ligand selected from an aromatic ring, the method according to any one of claims 1 to 11.

13. The method according to claim 12, wherein the aromatic ring is selected from Cp, Cp*, benzene, p-cymene, mesitylene, and hexamethylbenzene.

14. The method according to any one of claims 1 to 13, wherein the chiral transition metal catalyst further comprises a ligand selected from halogens and sulfonate ligands.

15. The method according to any one of claims 1 to 14, wherein the chiral transition metal catalyst is selected from a catalyst comprising Ru, Rh or Ir as a central metal, a chiral ligand selected from the group consisting of TsDPEN, MsDPEN and CsDPEN in (1R,2R) or (1S,2S) form, a ligand selected from halogen ligands, and a further ligand selected from Cp*, p-cymene and mesitylene.

16. In step (a), Equation 2-S 【Transformation 5】 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one or its tautomers or mixtures thereof of different tautomers are prepared with an enantiomer excess of at least 55% ee. For this purpose, the method according to any one of claims 1 to 15, wherein in step (a), a chiral transition metal catalyst comprising a chiral ligand in the (1S, 2S) form as defined in any one of claims 1 and 9 to 11 is used.

17. In step (a), Equation 2-R 【Transformation 6】 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one or its tautomers or mixtures thereof of different tautomers are prepared with an enantiomer excess of at least 55% ee. For this purpose, the method according to any one of claims 1 to 15, wherein in step (a), a chiral transition metal catalyst comprising a chiral ligand in the (1R,2R) form as defined in any one of claims 1 and 9 to 11 is used.

18. The activator used in step (b) is P(OR １ ) ２ Cl, P(OR) １ ) Cl ２ , P (= O) ( OR １ ) ２ Cl (where each R in the three aforementioned compounds) １ Independently, C １ ~C ４ -It is alkyl), PCL ３ P(O)Cl ３ SO ３ / Dimethylformamide complex, SOCl ２ ,CH ３ S (=O) ２ The method according to any one of claims 1 to 17, selected from the group consisting of Cl, CDI, and Mitsunobu-type reagents.

19. The activator used in step (b) is dimethylchlorophosphite (P(OCH) ３ ) ２ Cl) and diethyl chlorophosphite (P(OCH) ２ CH ３ ) ２ The method according to claim 18, selected from the group consisting of Cl).

20. The method according to any one of claims 1 to 19, wherein the activator is used in an amount such that the molar ratio of the compound of formula 1 to the activator is in the range of 10:1 to 1:

10.

21. Formula (IR) 【Transformation 7】 This is for preparing (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate with an enantiomer excess of at least 55% ee. (a.1) Formula 2-S at an enantiomer excess of at least 55% ee 【Transformation 8】 Reducing the compound of formula 1 or a mixture of its tautomers or different tautomers so that a reaction mixture containing 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one or a tautomer therefor or a mixture of its different tautomers or a tautomer therefor is formed, (b.1) The reaction mixture obtained in step (a.1) is reacted with an activator defined in any one of claims 1 or 18 to 20. Includes or Formula (IS) 【Chemistry 9】 This is for preparing (3S)-3-(2-chlorothiazole-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate with an enantiomer excess of at least 55% ee. (a.2) The formula 2-R at an enantiomer excess of at least 55% ee 【Chemistry 10】 Reducing the compound of formula 1 or a mixture of its tautomers or different tautomers so that a reaction mixture containing 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one or a mixture of its tautomers or different tautomers is formed, (b.2) The reaction mixture obtained in step (a.1) is reacted with an activator defined in any one of claims 1 or 18 to 20. The method according to any one of claims 1 to 20, including the method described in any one of claims 1 to 20.

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