Method for preparing the enantiomerized concentrated form of 2-[2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one

Abstract

The present invention relates to a process for preparing 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one or its tautomers or enantiomerically enriched forms thereof, to 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one or its tautomers or enantiomerically enriched forms thereof and to its use as an intermediate in the preparation of 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds, in particular 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate and its enantiomerically enriched forms.

Description

[Technical Field]

[0001] The present invention relates to a method for preparing 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula (I) shown below, or its tautomers or enantiomerized forms, and to the use of the following as an intermediate in the preparation of 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula (I) shown below, or its tautomers or enantiomerized forms, and 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 forms. [Background technology]

[0002] 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidine-4-one(I) (or its tautomers) has been found to be a valuable intermediate in the preparation of 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds, more specifically 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 concentrated form, when 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidine-4-one is used in the enantiomerized concentrated form. The aforementioned pyriminidium compounds have 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 these pyriminidium compounds 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 thiazolidined-2-imines with 2-substituted malonic acid derivatives.

[0005] In International Publication No. 2018 / 177970 and International Publication No. 2018 / 197541, non-racemic 4-heteroaryl-substituted thiazolidined-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 thiazolidined-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 atom or a heterocycle.

[0006] In International Publication No. 2018 / 177970, amine VII is obtained from the corresponding sulfinylimine via an alternative reaction pathway. International Publication No. 2018 / 177970 and International Publication No. 2018 / 202654 describe further access to non-racemic 4-heteroaryl-substituted thiazolidined-2-imines. This is prepared herein starting from a heteroarylmethyl ketone, where the methyl group has a leaving group, and involves 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 to thiazolidined-2-imine. The reaction sequence is described in International Publication No. 2018 / 202654 as follows: [ka]

[0007] Het is optionally substituted with 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 atom or a heterocycle.

[0008] 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]

[0009] The object of the present invention was to provide an economical process for preparing 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one, in particular a process for preparing its enantiomer-enriched form which gives the S or R enantiomer with high selectivity.

Means for solving the problem

[0010] This problem is solved by a method for preparing an enantiomer-enriched form of 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of formula (I):

Chemical formula

Chemical formula

[0012] 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)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one(I) or its tautomers or enantiomerized forms as intermediates in the preparation of 2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate and its enantiomerized forms. [Modes for carrying out the invention]

[0013] definition The term "enantiomerized form" and similar terms in relation to compound (I) of formula (I), specifically 2-[2-(2-chlorothiazole-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidine-4-one or the 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, located at an aliphatic carbon atom with 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, or 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. This represents a cross-chain aliphatic group. Examples include, in addition to 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.

[0022] 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.

[0023] 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.

[0024] 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).

[0025] 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.

[0026] "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).

[0027] 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.

[0028] Linear C3-C6 alkylenes are -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-.

[0029] 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.

[0030] Oxo is =O, meaning that the substituent "oxo" replaces the CH2 group with a C(=O) group.

[0031] 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.

[0032] Compound (I) may exist as its tautomers or as mixtures of different tautomer forms. An example of a tautomer of the compound of formula (I) above is given by the following formula: [ka]

[0033] A mixture of different tautomers is, for example, this tautomer, a mixture of the tautomers shown above as formula (I).

[0034] Compound 1 may also exist as its tautomers or mixtures of different tautomer forms. An example of a tautomer of the compound of formula 1 above is given by the following formula. [ka]

[0035] A mixture of different tautomers is, for example, this tautomer, a mixture of tautomers shown above as formula 1.

[0036] For simplicity, only compounds (I) and (1) will be mentioned below. Nevertheless, all embodiments also relate to their tautomers and mixtures of their different tautomer forms.

[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 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one, wherein 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 + A method comprising reducing with a reducing agent selected from the group consisting of (where is a cation equivalent), wherein when formic acid is used as the reducing agent, the reaction is carried out in the presence of a base, to obtain the enantiomerized form of pyrimidinone of formula (I). 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 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 , R 3 and R 4The method according to Embodiment E.1, wherein 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 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, and is selected from the group consisting of protonated 5 or 6-membered saturated heterocycles that 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 R2 R 3 + (wherein R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen and C1-C6-alkyl, and preferably at least one, preferably at least two, of R 1 , R 2 and R 3 is C1-C6-alkyl), and is selected from the group consisting of alkali metal cations and ammonium cations, the method according to embodiment E.2. E.5.M + is Na + , K + [NH(C2H5)3] + , [NH(CH2CH2CH2CH3)3] + and [NH(C2H5)(CH(CH3)2] + and is selected from the group consisting of, the method according to any one of embodiments E.3 or E.4. E.6.M + is [NH(C2H5)3] + , [NH(CH2CH2CH2CH3)3] + and [NH(C2H5)(CH(CH3)2] + and is selected from the group consisting of, the method according to any one of embodiments E.3 to E.5. E.7.M + is Na + or K + and is the method according to any one of embodiments E.3 to E.5. E.8. The base is an alkali metal hydroxide, 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, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy and C1-C4-alkoxy-C1-C4-alkyl, and at least one of R 1 , R 2 and R 3 is not hydrogen), an amine of the formula NR 1 R2 -A-NR 3 R 4 (In the formula, R 1 , R 2 , R 3 and R 4 The method according to any one of Embodiments E.1 to E.7, wherein 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 a 5 or 6-membered saturated heterocycle comprising a diamine (CH2)2 or (CH2)3), one nitrogen atom as a ring member, and optionally one further heteroatom selected from N and O as a ring member, and is selected from the group consisting of 5 or 6-membered saturated heterocycles that may have 1 to 6 C1-C4-alkyl groups and / or 1 or 2 OH groups. E.9. 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 a supported form (i.e., on a supporting material), as described in Embodiment E.8. E.10. The base is of formula NR 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 groups, R 1 , R 2 and R 3The method according to Embodiment E.8, wherein at least one of is selected from the group consisting of amines (which are C1-C6 alkyl). E.11. The base is selected from the group consisting of triethylamine, tributylamine, and diisopropylethylamine, as described in either embodiment E.9 or E.10. E.12. The method according to Embodiment E.9, wherein the base is selected from the group consisting of NaOH and KOH. E.13. The method according to any of Embodiments E1 to E.12, wherein formic acid is used as a reducing agent, and formic acid and the base are used in a molar ratio of 100:1 to 1:10. E.14. The method according to Embodiment E.13, wherein formic acid and a base are used in a molar ratio of 10:1 to 1:5. E.15. The method according to Embodiment E.14, wherein formic acid and a base are used in a molar ratio of 10:1 to 1:2. E.16. The method according to Embodiment E.15, wherein formic acid and a base are used in a molar ratio of 5:1 to 1:5. E.17. The method according to Embodiment E.16, wherein formic acid and a base are used in a molar ratio of 5:1 to 1:1. E.18. The method according to any one of Embodiments E.1 to E.17, wherein Compound 1 and the reducing agent are used in a molar ratio of 1:1 to 1:10. E.19. The method according to Embodiment E.18, wherein compound 1 and the reducing agent are used in a molar ratio of 1:1 to 1:5. E.20. The method according to any one of Embodiments E.1 to E.19, wherein one or more chiral ligands are coordinately bonded to a central transition metal in a chiral transition metal catalyst. E.21. The chiral transition metal catalyst is selected from group VIII metal catalysts, according to any of embodiments E.1 to E.20. E.22. The method according to Embodiment E.21, wherein the chiral transition metal catalyst is selected from Group 8 and Group 9 metal catalysts. E.23. The method according to Embodiment E.22, wherein the chiral transition metal catalyst is selected from Ru catalysts, Rh catalysts, and Ir catalysts. E.24. The chiral transition metal catalyst is selected from Rh catalysts and Ir catalysts as described in Embodiment E.23. E.25. The method according to any of Embodiments E.1 to E.24, 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.26. The method according to Embodiment E.25, 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.27. The method according to Embodiment E.26, wherein the chiral transition metal catalyst is used in an amount of 0.1 to 5 mol% per mole of compound 1, calculated based on the transition metal content. E.28. The method according to Embodiment E.27, wherein the chiral transition metal catalyst is used in an amount of 0.1 to 2 mol% per mole of compound 1, calculated based on the transition metal content. E.29. The method according to Embodiments E.1 to E.28, 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 the reaction of a transition metal precursor compound with one or more chiral ligands. E.30. The chiral ligand is selected from the group consisting of bidentate amine chiral ligands, as described in Embodiment E.29. The method according to Embodiment E.30, 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.32. The method according to Embodiment E.31, wherein the chiral ligand is selected from the group consisting of chiral 1,2-diphenyl-ethylene-1,2-diamine. E.33. Chiral ligands are chiral forms of equation (II) [ka] (In the formula, The asterisk indicates the center of the stereochemistry. R 5 and R6 These are independently selected from the group consisting of OH, halogens, C1-C4-alkyl and C1-C4-alkoxy elements. R 7 and R 8 These are independently selected from the group consisting of hydrogen, C1-C4-alkyl, and -L-phenyl, and the phenyl ring is C1-C4-alkyl, C1-C4-haloalkyl, and C1-C4-alkoxy, as well as SO2R 9 It may have 1, 2, 3, 4, or 5 substituents 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 phenyl in the two 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 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 0, 1, 2, 3, 4, or 5, independently of each other.) The method according to Embodiment E.32, selected from the group consisting of 1,2-diphenyl-ethylene-1,2-diamine. E.34. In compound (II), R 5 and R 6 These 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, and the phenyl atom 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. The method according to Embodiment E.33, wherein m and n are both 0 or both 1, preferably both 0. E.35. 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.33 or E.34, wherein 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. E.36. 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, 8The method according to Embodiment 35, wherein 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). E.37. 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 36, wherein is selected from the group consisting of compounds of -(CH2)3-phenyl or -(CH2)4-phenyl, and m and n are 0. E.38. 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, 8The method according to Embodiment E.35, 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.39. 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 Embodiment E.38, 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.40. 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, 8is -(CH2)3-phenyl or -(CH2)4-phenyl, and m and n are 0), and a method according to embodiment E.39, which is a catalyst comprising at least one ligand selected from the group consisting of compounds of E.41. The chiral transition metal catalyst is a catalyst comprising 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 the (1R,2R) or (1S,2S) form, and Ru as the central metal and a compound of formula (II) in the (1R,2R) or (1S,2S) form (where R 7 is SO2R 9 where R 9 is phenyl which 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 is -(CH2)3-phenyl or -(CH2)4-phenyl, 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), and a method according to embodiment E.38, which is a catalyst comprising at least one ligand selected from the compounds of E.42. The chiral transition metal catalyst is a catalyst comprising Ru, Rh or Ir as the central metal and at least one ligand selected from the group consisting of TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, MesitylDPEN, RsDPEN and TsDiOMeDPEN in the (1R,2R) or (1S,2S) form, or a catalyst of the following formula

Chemical formula

Chemical formula

[0038] The reaction sequence of the method of the present invention can be shown 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] This reaction can be classified as asymmetric transfer hydrogenation.

[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 , R 3 and R 4 A is a protonated 5 or 6-membered saturated heterocycle, which 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 (CH2)2 or (CH2)3) and contains one nitrogen atom as a ring member and optionally contains one further heteroatom selected from N and O as a ring member, and is selected from the group consisting of protonated 5 or 6-membered saturated heterocycles 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 can have 1 to 6 C1-C4-alkyl and / or 1 or 2 hydroxyl groups on the nitrogen and / or carbocyclic atom. In particular, protonated saturated heterocyclic rings are 6-membered and therefore preferably derived from piperidine, piperazine, or morpholine, which can have 1 to 6 C1-C4-alkyl and / or 1 or 2 hydroxyl groups on the nitrogen and / or carbocyclic atom.

[0045] In particular, M + Li + kaNa + , 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 + kaNa + , K + or Cs + ) and formula [NHR 1 R 2 R 3 ] + Selected from the group consisting of ammonium cations, where 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] + ) Specifically, M + 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 + Selected from the group consisting of one or more formates and mixtures thereof, in the formula, M + This 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 NR1 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 The amine (wherein R in the formula) 1 , R 2 and R 3 These are, independently of each other, hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, and C1-C4-alkoxy-C1-C4-alkyl (wherein R is the given element). 1 , R 2 and R 3 (At least one of them is not hydrogen), formula NR 1 R 2 -A-NR 3 R 4 (In the formula, R 1 , R 2 , R 3 and R 4 A is a 5 or 6-membered saturated heterocycle that independently comprises hydrogen, a diamine (selected from the group consisting of C1-C6-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy and C1-C4-alkoxy-C1-C4-alkyl, where A is (CH2)2 or (CH2)3), 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, or is selected from the group consisting of a 6-membered saturated heterocycle.

[0050] When formate or a mixture of formic acid and formate is used as a reducing agent, in particular, M + is monoamine NR 1 R2 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, R 1 , 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. NaOH and KOH are also preferred.

[0052] Suitable support materials for bases / supported bases include, for example, silica (SiO2) and organic polymers, such as polystyrene or acrylic acid 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 are 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 5:1 to 1:5, and especially 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%, even more preferably 0.1 to 5 mol%, and particularly 0.1 to 2 mol%, 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] Selected from the chiral forms of 1,2-diphenyl-ethylene-1,2-diamine, 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 8 These are independently selected from the group consisting of hydrogen, C1-C4-alkyl, and -L-phenyl, and the phenyl ring is C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and SO2R 9 It may have 1, 2, 3, 4, or 5 substituents 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 9C1-C4-alkyl, C1-C4-haloalkyl, phenyl, phenyl-C1-C3-alkyl (wherein the phenyl in the two 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 The molecule is phenyl-C1~C3-alkyl, 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, and m and n are independently 0, 1, 2, 3, 4, or 5.

[0064] Preferably, in compound (II), R 5 and R 6 These 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) rA 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 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 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]

[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, 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] 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, 8The catalyst is selected from a catalyst comprising a central metal Ru, Rh or Ir and at least one ligand selected from the group consisting of compounds of formula (1R,2R) or (1S,2S) form 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 catalyst comprising 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.

[0070] In particular, 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, 8The catalyst is selected from a catalyst comprising 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 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) in (1R,2R) or (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 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).

[0071] More specifically, chiral transition metal catalysts are selected from catalysts 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 are catalysts of the following formula: [ka]

[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 additionally includes ligands preferably selected from aromatic rings. Such ligands generally have higher tactile properties, 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; Cl is preferred among these) or sulfonate (e.g., triflate, mesylate, tosylate, or nonaflate; triflate is preferred among these) ligands, particularly halogen ligands, especially Cl.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] In a preferred embodiment, the method of the present invention is given by formula (IS) [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.

[0080] 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 a Ru, Rh or Ir catalyst containing 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, (1S,2S)-TsDiOMeDPEN and compounds of formula (II) in (1S,2S) form, and 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, 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, 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) in the form of (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 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) comprises a chiral ligand selected from the group consisting of compounds 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, (1S,2S)-TsDiOMeDPEN and formula (II) in the form of (1S,2S) 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 compound comprises a chiral ligand selected from the group consisting of compounds of -(CH2)3-phenyl or -(CH2)4-phenyl, where m and n are 0.

[0081] In particular, chiral transition metal catalysts used to obtain (IS) 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, 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). More specifically, chiral transition metal catalysts used to obtain (IS) 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 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 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).

[0082] More specifically, chiral transition metal catalysts are selected from catalysts comprising Ru, Rh, or Ir as a 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 catalysts of the following formula. [ka]

[0083] More specifically, the chiral transition metal catalysts used to obtain (IS) 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* 5 Aromatic 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 (IS) 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 substituted or unsubstituted benzenes and substituted or unsubstituted cyclopentadienes, e.g., Cp, Cp*, benzene, p-cymene, mesitylene or hexamethylbenzene; in the case of Rh and Ir as the central metal, specifically η 5 Ligand Cp*; In the case of Ru as the central metal, it is specifically cymene or mesitylene.

[0084] Furthermore, the catalyst includes additional ligands, generally halides, specifically Cl, which can be replaced by hydrides from the reducing agent.

[0085] Instead, the catalyst consists of Ru as the central metal and formula (II) in (1S,2S) 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, 8 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 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]

[0086] In another preferred embodiment, the method of the present invention is expressed by formula (IR) [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 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.

[0087] 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 a Ru, Rh or Ir catalyst containing 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 and compounds of formula (II) in (1R,2R) form, and 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 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, 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) in the form of (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(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 (1R,2R)-Form (II) (wherein R is 0) 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 compound comprises a chiral ligand selected from the group consisting of compounds of -(CH2)3-phenyl or -(CH2)4-phenyl, where m and n are 0.

[0088] In particular, chiral transition metal catalysts used to obtain (IR) 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 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 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). More specifically, chiral transition metal catalysts used to obtain (IR) 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 (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, 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).

[0089] More specifically, chiral transition metal catalysts are selected from catalysts comprising Ru, Rh, or Ir as a 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 catalysts of the following formula. [ka]

[0090] More specifically, chiral transition metal catalysts used to obtain (IR) in 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)-TripsMesi It comprises a chiral ligand selected from the group consisting of tylDPEN, (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 for Rh or Ir as the central metal; therefore, when Rh or Ir is the central metal, the additional aromatic ligand is preferably selected from Cp and Cp*, and in particular from Cp*. When Ru is the central metal, the additional aromatic ligand is preferably selected from cymene and mesitylene. More specifically, the chiral transition metal catalyst used to obtain (IS) 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 substituted or unsubstituted benzenes and substituted or unsubstituted cyclopentadienes, e.g., Cp, Cp*, benzene, p-cymene, mesitylene or hexamethylbenzene; in the case of Rh or Ir as the central metal, specifically η 5 Ligand Cp*; In the case of Ru as the central metal, it is specifically cymene or mesitylene.

[0091] Furthermore, the catalyst includes additional ligands, generally halides, specifically Cl, which can be replaced by hydrides from the reducing agent.

[0092] Instead, the catalyst consists of Ru as the central metal and formula (II) in the form of (1R,2R) (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]

[0093] The reaction can be carried out in the presence of a solvent. The solvent is preferably selected from the group consisting of polar protic solvents, polar aprotic solvents, chlorinated alkanes, aromatic solvents, heterocyclic solvents, mixtures of the aforementioned solvents, and mixtures of the aforementioned solvents with water.

[0094] Polar protic solvents are solvents that do not have functional groups from which protons can dissociate. Suitable examples of polar protic solvents are C1-C4 alkanols, fluorinated C1-C4 alkanols, glycols, mixtures thereof, and mixtures thereof with water. Examples of C1-C4 alkanols include methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, and tert-butanol. Examples of fluorinated C1-C4 alkanols include 2-fluoroethanol, 3-fluoropropanol, 1-fluoropropan-2-ol, 4-fluorobutanol, 1,1-difluoroethanol, 2,2-difluoroethanol, 2,2-difluoropropanol, 3,3-difluoropropanol, 1,1-difluoropropan-2-ol, 2,2,2-trifluoroethanol, 3,3,3-trifluoropropanol, and 4,4,4-trifluorobutanol. Examples of glycols include ethylene glycol, diethylene glycol, and triethylene glycol.

[0095] 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; and N-methylpyrrolidone (NMP), N-(n-butyl)-pyrrolidone, or N-(tert-butyl) Examples include lactams such as γ-pyrrolidone; sulfones such as sulfolanes; 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.

[0096] Suitable examples of C1-C4 alkyl acetates are methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.

[0097] Suitable examples of chlorinated alkanes are dichloromethane, trichloromethane, or dichloroethane.

[0098] 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).

[0099] Suitable heterocyclic solvents include 4-formylmorpholine or dihydrolevoglucocenone (cyrene®).

[0100] 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).

[0101] More preferably, the solvent is C1-C4 alkanol, glycol, 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, isopropyl acetate, dichloromethane, trichloromethane, dichloroethane, benzene, toluene, α,α,α-triph Luorotoluene, xylene, fluorobenzene, chlorobenzene, dichlorobenzene, anisole, 4-formylmorpholine, dihydrolevoglucocenone (cyrene®), mixtures of the aforementioned solvents, and mixtures of the aforementioned solvents with water; in particular dimethylformamide, dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, sulfolane, ethyl acetate, ethanol, dichloromethane, trichloromethane, dichloroethane, α,α,α-trifluorotoluene (benzotrifluoride), fluorobenzene, chlorobenzene, dichlorobenzene, anisole (methoxybenzene), and mixtures thereof; specifically, selected from the group consisting of dimethylformamide, dimethylacetamide, and mixtures thereof.

[0102] However, if formic acid is used as a reducing agent, or if a base that is a reducing agent and / or is liquid at the reaction temperature is used, the reaction can instead be carried out undiluted.

[0103] 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.

[0104] During the reaction, 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. This can be done, for example, by blowing an inert gas that is inert to the reaction through the reaction mixture or by applying a vacuum. Therefore, in a preferred embodiment, during the reaction, a gas selected from the group consisting of argon, nitrogen, and a mixture of oxygen and nitrogen, wherein the mixture contains 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.

[0105] The reaction can be carried out in the presence of an additive that accelerates 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 a zinc salt, particularly zinc acetate, is 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, particularly 1:10000 to 2:1, for example, 1:10000 to 1:2 or 1:10000 to 1:10.

[0106] The reaction 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 can be in the range of 30 to 100°C, for example, 50 to 90°C. However, for 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 -15 to 25°C. However, Ru catalysts also function at temperatures within this range, particularly 10 to 30°C.

[0107] The reaction time 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 the reaction can be completed sufficiently after all components have been added to allow for the isolation of the desired compound (I) to be continued. This can occur, for example, if the addition of reactants continues for a considerably long time or if the unreacted starting materials are intended to be reused.

[0108] The reaction is generally carried out by mixing a reducing agent, optionally a base (mixing with the base is essential when using formic acid 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 the 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).

[0109] After the reaction is complete, the enantiomerized concentrated form of pyrimidinone of formula (I) is generally isolated from the reaction mixture. Isolation typically involves adding water to the reaction mixture, isolating the pyrimidinone of formula (I) that precipitates upon addition of water, and optionally purifying it. Alternatively, preferably, isolation involves setting the pH of the reaction mixture to acidic, removing at least a portion of the solvent, if present, to obtain a concentrate, adding water and a solvent that is poorly or improperly miscible with water to the concentrate, extracting the pyrimidinone of formula (I) into a solvent that is poorly or improperly miscible with water, and isolating the pyrimidinone of formula (I) from the extract. The solvent that is poorly or improperly miscible with water is preferably selected from the group consisting of 2-methyltetrahydrofuran, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl isopropyl ketone, and chlorobenzene.

[0110] If necessary, the catalyst can be recycled. For this purpose, the catalyst is recovered, for example, from the reaction mixture obtained after reduction or from one or more liquid phases obtained in the workup process after the isolation of pyrimidinone of formula (I) (depending on the solvents used in the reaction and workup, the catalyst may be found in the aqueous phase, the organic phase, or both). In one embodiment, only the transition metal, and not the entire catalyst, is recovered. The metal 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 reaction mixture obtained after reduction or from one or more liquid phases obtained in the workup. On a larger scale, the reaction mixture obtained after reduction or from one or more liquid phases obtained in the workup can alternatively be passed through one or more columns packed with adsorbent once or several times. Separation of the metal from the adsorbent can be done by elution (especially when using resin), but generally the adsorbent material is simply burned. The metal can then be purified and converted into the desired catalyst or catalyst precursor by known methods and reused in the reduction process. Alternatively, the transition metal can be recovered from the liquid phase obtained by post-treatment free of compound (I) by removing the solvent from this phase and burning the remainder. The metal can then be purified and converted into the desired catalyst or catalyst precursor by known methods and reused in the reduction process. If the liquid phase is aqueous, the catalyst is extracted therefrom into a suitable organic phase and then subjected to the treatment described.

[0111] Compound 1 can be obtained by the reaction of N-methylthiourea with alkyl 2-phenylmalonate and 6-hydroxy-3-methyl-5-phenyl-2-sulfanylpyrimidine-4-one or the corresponding thiolate, and by the reaction of these with 2-chloro-1-(2-chlorothiazole-5-yl)ethanone and Compound 1. These reactions are described in more detail in European Patent Application No. 21153040.7.

[0112] 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 2018 / 197541 or International Publication 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.

[0113] This method yields compound (I) in high yield and with high stereoselectivity.

[0114] The present invention relates to 2-[2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one(I) [ka] The present invention relates further to its tautomers and enantiomer-enriched forms. Formula (I) and formula (I) shown in relation to the method of the present invention are equivalent, however, formula (I) shown in relation to the method of the present invention more clearly indicates the stereocenter of the molecule.

[0115] In particular, the present invention relates to an enantiomer excess, preferably at least 55% ee, more preferably at least 60% ee, even more preferably at least 70% ee, particularly at least 80% ee, specifically at least 90% ee, and the formula (IS) [ka] This relates to 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one and its tautomers.

[0116] In another specific embodiment, the present invention relates to an enantiomer excess of at least 55% ee, preferably at least 60% ee, even more preferably at least 70% ee, particularly at least 80% ee, specifically at least 90% ee, with respect to formula (IR) [ka] This relates to 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one and its tautomers.

[0117] Compound (I) can be converted in one further step to 3-(2-chlorothiazole-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate, in particular to its enantiomerized form. For this purpose, compound (I) undergoes internal cyclization by nucleophilic attack of an unsubstituted nitrogen atom of the pyrimidine ring on a carbon atom having an aliphatic OH group. This reaction is described in European Patent Application No. 21153038.1.

[0118] Accordingly, 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 and its enantiomerized concentrated form) as an intermediate in the preparation of these compounds.

[0119] Compound (I) can be converted to 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 in just one step, but it can also undergo several modifications first, such as etherification of the hydroxyl group on the pyrimidine ring, substitution of the Cl atom on the thiazole ring, or introduction of a substituent on the phenyl ring, in order to enable the formation of 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds other than 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-4-ium-5-oleate.

[0120] The present invention is further illustrated by the following embodiments. [Examples]

[0121] Abbreviation: DIPEA Diisopropylethylamine DMAC N,N-dimethylacetamide DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) HCl ethyl acetate Me-THF 2-methyltetrahydrofuran THF (Tetrahydrofuran) TEA (Triethylamine) TFA (Trifluoroacetic Acid) rt room temperature t time h time min rt retention time

[0122] method The compounds were characterized by combined high-performance liquid chromatography / mass spectrometry (HPLC / MS), NMR, or melting point analysis. HPLC method: Agilent Eclipse XDB-C18, 150mmx4.6mmxIDx5μm Gradient A = 0.5% H2SO4 in water, B = acetonitrile. Flow rate = 1.1 mL / min, Column oven temperature = 30°C Gradient program = 20%B - 100%B - 15 minutes Execution time = 15 minutes

[0123] Chiral HPLC method: Agilent Series 1260, Chiralpak AD-RH 5μm 150*4.6mm Gradient A = 0.1% H3PO4 in water, B = acetonitrile / 2-propanol (1:1). Flow rate = 1.2 mL / min, Column oven temperature = 50°C Gradient program

[0124] [Table 1]

[0125] Execution time = 25 minutes

[0126] LC-MS method 1: C18 column (50mm x 2.1mm x 1.7μm) Gradient A = 0.1% TFA in water, B = acetonitrile Flow rate = 0.8 mL / min to 1.0 mL / min (1.5 min), Column oven temperature = 60°C Gradient program = 10%B to 100%B in 15 minutes, hold at 100%B for 1 minute, then -10%B for 1 minute. Execution time: 1.75 minutes

[0127] 1 1H-NMR: Signals are characterized by their chemical shifts (ppm) relative to tetramethylsilane, their multiplicity, and their integrals (relative number of given hydrogen atoms). The following abbreviations are used to characterize the multiplicity of the signal: m = multiplet, q = quadruplet, t = triplet, d = doublet, s = singlet, dd = doublet of doublets.

[0128] Example 1: Preparation of 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one 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).

[0129] 1.2 Preparation of 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one (IS) A solution of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one (20.0 g, 50.4 mmol, 99% purity, 1.00 equivalent) and 158.3 g of dimethylacetamide was cooled to -5°C and a nitrogen spur was turned on (immersion tube, 13 Nl / h). 6.0 g of formic acid (1.54 equivalent) / diisopropylethylamine (0.375 equivalent) mixture (molar ratio 4.1:1) was added, followed by a solution of the pre-formed catalyst Rh(III)ClCp*(1S,2S-TsDPEN) (obtained by reacting [Rh(III)Cl2Cp*]2 with 1S,2S-TsDPEN) (0.340 g, 0.501 mmol, 94% purity) in dimethylacetamide. The reaction mixture was stirred for 2 hours, and then H2SO4 (10 g, 100 mmol, 98% purity) was added over 2 hours while maintaining the internal temperature at <0°C. The reactor pressure was reduced to 5 mbar, and the mantle temperature was raised to 57°C, and 117 g of dimethylacetamide was removed by distillation. Next, 178 g of 2-methyltetrahydrofuran and 100 g of water were added to the reactor. The two resulting phases were homogenized for 15 minutes and then separated. The bottom aqueous phase was removed from the reactor. 100 g of water and 2 g of H2SO4 were added to the reactor. The two phases were homogenized for 15 minutes and then separated. The bottom aqueous phase and organic phase were removed separately from the reactor. The combined aqueous phase was returned to the reactor, and 170 g of 2-methyltetrahydrofuran was added. The two phases were homogenized for 15 minutes and then separated. The bottom aqueous phase was removed from the reactor. Next, the 2-methyltetrahydrofuran phase was returned to the reactor, the pressure was reduced to 350 mbar, and the mantle was set to 59°C. Water was then removed azeotropically via a Dean-Stark trap until <200 ppm of water remained in the 2-methyltetrahydrofuran phase. Upon removal of the 2-methyltetrahydrofuran phase, the marked product was obtained in yields of 87% and 95% ee. 1H NMR (400MHz, DMSO-d6): δ=11.15(s,1H),7.7(s,1H),7.18-7.47(m,5H),6.5(s,1H),5.2(m,1H),3.72(dd,1H),3.54(dd,1H),3.4(s,3H).

[0130] Example 2: Preparation of 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one (IR) using various reaction conditions The procedure was carried out in the same manner as in Example 1.2, but using 1 g of the starting compound as the solvent, 2 ml of DMF, the catalyst, and the conditions summarized in the table below. The reaction was carried out at room temperature, and the reaction mixture was quenched with ethanol. 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 with the asymmetric ligand to the reaction mixture.

[0131] [Table 2]

[0132] [Table 3]

[0133] Example 3: Preparation of 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one using various reaction conditions The procedure was the same as in Example 1.2, but the catalyst and conditions summarized in the table below were used, and the reaction was carried out at 0°C.

[0134] [Table 4]

[0135] Example 4: Preparation of 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one (IS) using various reaction conditions The procedure was the same as in Example 1.2, but the solvents used were those summarized in the table below.

[0136] [Table 5]

[0137] Example 5: Preparation of 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one (IS) using various reaction conditions The procedure was the same as in Example 1.2, but 400 mg of the starting compound and 7 ml of solvent, solvent, catalyst, and conditions were used, 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 21 and 22 (-5°C) and Examples 23, 25, 40, 42, 45, 48 and 50 (0°C), the reactions were carried out at room temperature.

[0138] [Table 6]

[0139] [Table 7]

[0140] 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]

[0141] Catalyst number 2: [RuCl2(mes 8 The catalyst RuClMes(1S,2S-TsDPEN) is preformed by reacting )2 with 1S,2S-TsDPEN, and the resulting catalyst is given by the following formula: [ka]

[0142] Catalyst number 2*: Similar to 2, but formed in situ.

[0143] 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]

[0144] 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).

[0145] Catalyst number 5: [RuCl2(mes 8 The 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]

[0146] Catalyst number 6: [RuCl2(mes 8The catalyst RuClMes(1S,2S-MesitylDPEN) obtained by reacting )2 with 1S,2S-MesitylDPEN is given by the following equation: [ka]

[0147] 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]

[0148] Example 6: Preparation of 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one (I-R) The procedure was the same as in Example 1.2, but 4 g (9.93 mmol) of the starting compound, ethanol (46 g) as the solvent, triethylamine (5.98 mmol; 0.6 equivalents) as the base, 27.09 mmol (2.73 equivalents) of formic acid (formic acid:base = 4.5:1), and C-3-tethr-RuCl-1R,2R-TsDPEN (4 mol%) of the following formula were used as the catalyst. [ka]

[0149] The title product was obtained in yields of 86% and 87% ee.

[0150] Example 7: Preparation of 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one (IS) using various reaction conditions The procedure was the same as in Example 1.2, but the reaction was carried out at -5°C to 2°C using the reaction conditions summarized in the table below. Except for Examples 51 and 67, which used DMF, and Example 70, which used DMSO, the solvent was DMAC. 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. Throughout the experiments, (IS) was obtained with 94–98% ee.

[0151] [Table 8]

[0152] [Table 9]

[0153] Example 8: Use of various stereoisomers of (1R,2R)-CsDPEN as a ligand in the preparation of 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one (IR) To demonstrate that the composition of the camphor moiety of the CsDPEN ligand does not essentially affect the stereoselectivity of product (I) 2-[2-(2-chlorothiazole-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one 1] in the reaction, hydrogenation 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 is carried out by mixing 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 and diisopropylethylamine used in a molar ratio of 1:3:7. The procedure was carried out in the same manner as in Example 1.2, using either 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) 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). The reaction was carried out at -5°C.

[0154] Reactions using RhClCp*(1R,2R-CsDPEN-1) as a catalyst yielded (IR) with an enantiomer purity of 97% ee (conversion rate: 95%), and reactions using RhClCp*·(1R,2R-CsDPEN-2) as a catalyst yielded (IR) with an enantiomer purity of 98% ee (conversion rate: 98%). Several embodiments are shown below. Item 1 Formula (I) of the enantiomer-enriched form:

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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 2-[2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one or its tautomers, wherein 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 are used in the presence of a chiral transition metal catalyst and optionally a base to form formate 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 reducing with a reducing agent selected from the group consisting of (wherein is the cation equivalent), wherein when formic acid is used as the reducing agent, the reduction reaction is carried out in the presence of a base, thereby obtaining an enantiomerized form of pyrimidinone of formula (I) or its tautomers. 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 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) 【Transformation 3】 (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 halogens, 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 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, independently of one another, hydrogen, C １ - C ６ - alkyl, C ３ - C ６ - cycloalkyl, C １ - C ４ - alkoxy and C １ - C ４ - alkoxy - C[[ID=3​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​

3. The base is an alkali metal hydroxide, 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, 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<00,00064>, R ２ and R ３ is not hydrogen) amine, 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, 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 ) diamine and 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, the 5- or 6-membered saturated heterocyclic ring being selected from the group consisting of 5- or 6-membered saturated heterocyclic rings which may have 1 to 6 C １ to C ４ -alkyl groups and / or 1 or 2 OH groups, the base can 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 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 is selected from group VIII metal catalysts.

6. The method according to claim 5, wherein the chiral transition metal catalyst is selected from Group 8 or Group 9 metal catalysts.

7. The method according to claim 6, wherein the chiral transition metal catalyst 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 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 method according to claim 8, wherein the chiral transition metal catalyst is used in an amount of 0.1 to 5 mol% per mole of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of formula 1, calculated based on the transition metal content.

10. The method according to any one of claims 1 to 9, wherein the chiral transition metal catalyst comprises one or more chiral ligands that are pre-formed and coordinated to a transition metal, or is formed in situ by a reaction between a transition metal precursor compound and one or more chiral ligands.

11. The chiral transition metal catalyst includes one or more chiral ligands coordinated to a transition metal, and 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 [[ID= sixteen]]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, where the phenyl in -(CH2)3-phenyl and -(CH2)4-phenyl is 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 10.

12. 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 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, where 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 11, comprising 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).

13. The chiral transition metal catalyst comprises 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 the formula (II) in (1R,2R) or (1S,2S) form (wherein R7 is SO2R9, R9 is a phenyl which may have one, two or three substituents selected from the group consisting of C1-C4-alkyl or C1-C4-alkyl and C1-C4-haloalkyl, and R8 is -(CH2) The method according to claim 12, wherein the catalyst comprises at least one ligand selected from the compounds (which is 3-phenyl or -(CH2)4-phenyl, and m and n are 0).

14. R ７ and R ８ Both are -L-phenyl or SO ２ R ９ (In the formula, R ９ Phenylen-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 13.

15. The method according to claim 14, wherein the aromatic ring is selected from Cp, Cp*, benzene, p-cymene, mesitylene, and hexamethylbenzene.

16. Formula (IS) 【Chemistry 4】 The preparation of 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one or its tautomers in an enantiomer excess of at least 55% ee, namely (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF ３ TsDPEN, (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 the above formula (II) in the form of (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, where 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 - A chiral transition metal catalyst is used, prepared, or prepared, which includes a chiral ligand selected from the group consisting of compounds having one, two, or three substituents selected from the group consisting of alkoxys, and m and n are 0. Formula (IR) 【Transformation 5】 The preparation of 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one or its tautomers in an enantiomer excess of at least 55% ee, namely (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-CF ３ TsDPEN, (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 the above formula (II) in the form of (1R,2R) (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, where 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 - A chiral transition metal catalyst is used and prepared, comprising a chiral ligand selected from the group consisting of compounds having one, two, or three substituents selected from the group consisting of alkoxys, and m and n being 0. The method according to any one of claims 1 to 15.

17. The method involves preparing 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of the above formula (I-S) or its tautomers in an enantiomer excess of at least 70% ee, wherein the chiral transition metal catalyst contains Ru, Rh or Ir as the central metal and is (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF ３ It contains a chiral ligand selected from the group consisting of TsDPEN, (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 Ru as the central metal and the (1S,2S) form of the aforementioned formula (II) (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, where 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 - 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), to be prepared, or The method involves preparing 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one of the above formula (I-R) or its tautomers in an enantiomer excess of at least 70% ee, wherein the chiral transition metal catalyst contains Ru, Rh or Ir as the central metal, and (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-CF ３ It contains a chiral ligand selected from the group consisting of TsDPEN, (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 Ru as the central metal and the (1R,2R) form of the aforementioned formula (II) (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, where 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 - A catalyst comprising at least one ligand selected from the aforementioned compound (which may have one, two, or three substituents selected from the group consisting of alkoxys, and m and n are 0) to be prepared. The method according to claim 16.

18. During the above reaction, CO ２ The method according to any one of claims 1 to 17, wherein a gas different from the reaction is sparged through the reaction mixture, or alternatively or additionally, the reaction is carried out under reduced pressure.

19. The method according to any one of claims 1 to 18, wherein the reaction is carried out in the presence of an additive selected from the group consisting of diethyl phosphite, borate esters, and zinc salts.

20. Equation (I) 【Transformation 6】 (In the formula, an asterisk * indicates the center of the solid.) 2-[2-(2-chlorothiazole-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidine-4-one or the enantiomerized form of the compound or its tautomer, where the enantiomerized form of the compound of formula (I) is a non-racemic compound (I) in which either the S enantiomer or the R enantiomer is dominant, or which exists simply as a stereoisomer.

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