A process for the preparation of 2-[2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one in enantiomerically enriched form

Abstract

The present invention relates to a process for the preparation of 2-[2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers or its enantiomerically enriched forms, to 2-[2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers or its enantiomerically enriched forms, and to the use thereof as intermediates in the preparation of 2,3-dihydrothiazolo[3,2-a]pyrimidine compounds, in particular 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ol salts and its enantiomerically enriched forms.

Description

[0001] This invention relates to a method for preparing 2-[2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers or enantiomers enriched in form thereof of formula (I) shown below, and relates to 2-[2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers or enantiomers enriched in form thereof of formula (I) shown below, and relates to its application in the preparation of 2,3-dihydrothiazo[3,2-a]pyrimidine The compound, specifically, is 3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- Use as an intermediate in 5-alkoxides and their enantiomer-enriched forms. Technical Background

[0002] It has been found that when 2-[2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one is used in an enantiomeric enrichment form, 2-[2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (I) (or its tautomer) in 2,3-dihydrothiazo[3,2-a]pyrimidine The compound, more specifically 3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxides and their enantiomer-enriched forms are valuable intermediates in the preparation of pyrimidines. The compound has insecticidal properties and is known, for example, by WO 2018 / 177970 or WO 2014 / 167084.

[0003] To date, methods for preparing these pyrimidines are known. The compound method is cumbersome and unsatisfactory.

[0004] In WO 2018 / 177970, WO 2018 / 197541 and WO 2018 / 202654, non-racemic 2,3-dihydrothiazo[3,2-a]pyrimidine The compound was prepared by reacting a non-racemic 4-heteroaryl-substituted thiazoline-2-imine with a 2-substituted malonic acid derivative. In WO 2018 / 177970 and WO 2018 / 197541, the non-racemic 4-heteroaryl-substituted thiazoline-2-imine was subsequently prepared by catalytic asymmetric hydrogenation of a 1-heteroaryl-substituted ethylimine with a leaving group at the 2-position. The resulting amine was then reacted with an isothiocyanate to regenerate the thiazoline-2-imine. The reaction sequence is described in WO 2018 / 197541 as follows:

[0005]

[0006] R A It is sulfanyl or sulfinyl, phosphoroxy, alkoxy, or benzyl; Het is optionally substituted pyridin-3-yl, thiazolyl-5-yl, or pyrimidin-5-yl; W and LG are leaving groups; R 1 It is an aliphatic (cyclic) group and R 2 It consists of 5 or 6 carbon rings or heterocycles.

[0007] In WO 2018 / 177970, amine VII is obtained via another reaction pathway from the corresponding sulfinimide.

[0008] WO 2018 / 177970 and WO 2018 / 202654 describe an alternative route for obtaining non-racemic 4-heteroaryl-substituted thiazolyl-2-imines. Here, the preparation begins with a heteroaryl methyl ketone, wherein the methyl group carries a leaving group, which is converted to an alkyl carbonyloxy group. The latter is hydrolyzed to a hydroxyl group, and the resulting heteroaryl hydroxymethyl ketone is reacted with an aminosulfonyl halide to form 4-heteroaryl-5H-oxathiazolium 2,2-dioxide. The oxathiazolium is then subjected to catalytic asymmetric hydrogenation to yield non-racemic 4-heteroaryloxathiazolium 2,2-dioxide, which is then reacted with an isothiocyanate to form the thiazolyl-2-imine. The reaction sequence is described in WO 2018 / 202654 as follows:

[0009]

[0010] Het is optionally substituted with pyridin-3-yl, thiazo-5-yl, or pyrimidin-5-yl, W and LG are leaving groups, and M is a substituted group. 2 For Li, Na, K, Al, Ba, Cs, Ca, or Mg, R AC For alkyl carbonyl, X 1 For halogens, R 1 It is an aliphatic (cyclic) group and R 2 It consists of 5 or 6 carbon rings or heterocycles.

[0011] However, these methods are not very economical. Some reagents are expensive, recycling of unused or incompletely used reagents is difficult, the overall yield is not satisfactory, and too many reaction steps are involved. Invention Overview

[0013] The object of this invention is to provide an economical method for preparing 2-[2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one, and in particular a method for preparing its enantiomer-enriched form, which yields the S or R enantiomer with high selectivity.

[0014] This problem is solved by a method for preparing enantiomeric enriched forms of 2-[2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers:

[0015]

[0016] The asterisk * indicates the center of the 3D source;

[0017] This method comprises reducing 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomer of formula 1 with a reducing agent in the presence of a chiral transition metal catalyst and optionally a base:

[0018]

[0019] The reducing agent is selected from formic acid HC(=O)OH, formula HC(=O)O - M + Formate salts and formic acid HC(=O)OH and one or more of the formula HC(=O)O - M + A mixture of formates, wherein M + It is a cationic equivalent; wherein, when formic acid is used as a reducing agent, the reaction is carried out in the presence of a base;

[0020] The enantiomeric enriched form of the pyrimidinone of formula (I) or its tautomer is obtained.

[0021] Furthermore, this invention relates to 2-[2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (I) or its tautomers and their enantiomeric enriched forms:

[0022]

[0023] Formula (I) is equivalent to Formula (I) shown above for the method of the present invention; however, Formula (I) shown for the method of the present invention more clearly shows the stereo source center of the molecule.

[0024] The present invention also relates to 2-[2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (I) or its tautomers or enantiomers enriched in 2,3-dihydrothiazo[3,2-a]pyrimidine The compound, specifically, is 3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- Use as an intermediate in the preparation of 5-alkoxides and their enantiomer-enriched forms. Invention Details

[0026] definition

[0027] The term "enantiomerically enriched form" refers to 2-[2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (I), or compounds (I) in "enantiomerically enriched form," and similar terms denote non-racemic compounds (I) in which the S enantiomer or R enantiomer is dominant or even the only stereoisomer. Compound (I) has a single stereosource center at an aliphatic carbon atom bearing an OH group and marked with an asterisk.

[0028] M + It is a cation equivalent. It represents a metal cation or an ammonium cation (in this case, ammonium refers to the ammonium cation in its proper sense, NH4). + However, it also indicates a substituted ammonium cation). In the case of cations with di or tricharges, the cation equivalent can be expressed as (M n+ ) 1 / n , where n is the number of charges.

[0029] Formate, in the context of this invention, refers to a salt of formic acid (HC(=O)O). - M + M + (For cationic equivalents). The term also refers to the anion of formic acid (HC(=O)O). - However, in the context of this invention, the term does not refer to ester unless explicitly mentioned otherwise.

[0030] The organic structural parts mentioned below, like the term halogen, are collective terms that list individual group members separately. Prefix C n -C mIn each case, it indicates the possible number of carbon atoms in the group.

[0031] The term halogen in each case means fluorine, bromine, chlorine or iodine, especially fluorine, chlorine or bromine.

[0032] The term "alkyl" as used herein, and in the alkyl structure section of alkoxy groups, refers to a saturated straight-chain (linear) or branched hydrocarbon group having 1-3 ("C1-C3 alkyl"), 1-4 ("C1-C4 alkyl"), or 1-6 ("C1-C6 alkyl") carbon atoms. C1-C3 alkyl represents a saturated linear or branched aliphatic group having 1-3 carbon atoms. Examples are methyl, ethyl, n-propyl, or isopropyl. C1-C4 alkyl represents a saturated linear or branched aliphatic group having 1-4 carbon atoms. Examples are 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 1-6 carbon atoms. Examples, in addition to those mentioned for C1-C4 alkyl groups, include 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.

[0033] As used herein, the term "C1-C4 haloalkyl"—also expressed as "partially or completely halogenated alkyl"—refers to a straight-chain or branched alkyl group having 1-4 carbon atoms (as described above), wherein some or all of the hydrogen atoms in these groups are replaced by halogen atoms as described above. Examples include chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichloromonofluoromethyl, monochlorodifluoromethyl, 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 haloalkyl groups 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-trifluoropropyl-2-yl, 3-chloropropyl, 4-chlorobutyl, etc.

[0034] As used in this article, "C3-C6 cycloalkyl" refers to a saturated monocyclic hydrocarbon group having 3-6 carbon atoms as the (only) ring member. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0035] Term C6-C 10 Bicyclic alkyl groups refer to bicyclic bridged saturated hydrocarbon groups containing 6-10 carbon atoms as the (sole) ring member. Examples include bicyclic [2.2.1]heptyl, bicyclic [3.1.1]heptyl, bicyclic [2.2.2]octyl, bicyclic [3.2.1]octyl, etc. C6-C atoms substituted with alkyl groups and / or oxo groups... 10 Examples of bicycloalkyl groups are 7,7-dimethyl-bicyclo[2.2.1]hept-1-yl and 7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-yl.

[0036] Term C6-C 10 Bicycloalkyl-C1-C3 alkyl refers to a straight-chain or branched alkyl group having 1-3 carbon atoms as defined above, wherein one hydrogen atom is a C6-C3 alkyl group as defined above. 10 Bicycloalkyl substitution.

[0037] The term "C1-C4 alkoxy" refers to a C1-C4 alkyl group as defined above, which is attached to the rest 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).

[0038] The term "C1-C4 alkoxy-C1-C4 alkyl" refers to a straight-chain or branched alkyl group having 1-4 carbon atoms as defined above, wherein one hydrogen atom is replaced by a C1-C4 alkoxy group as 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, and 1-methoxypropyl. 1-Ethoxypropyl, 1-Propoxypropyl, 1-Isopropoxypropyl, 1-n-Butoxypropyl, 1-Second-Butoxypropyl, 1-Isobutoxypropyl, 1-Tertiary-Butoxypropyl, 2-Methoxypropyl, 2-Ethoxypropyl, 2-Propoxypropyl, 2-Isopropoxypropyl, 2-n-Butoxypropyl, 2-Second-Butoxypropyl, 2-Isobutoxypropyl, 2-Tertiary-Butoxypropyl, 3-Methoxypropyl, 3-Ethoxypropyl, 3-Propoxypropyl, 3-Isopropoxypropyl, 3-n-Butoxypropyl, 3-Second-Butoxypropyl, 3-Isobutoxypropyl, 3-Tertiary-Butoxypropyl, etc.

[0039] "Phenyl-C1-C3 alkyl" refers to a straight-chain or branched alkyl group having 1-3 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).

[0040] Alkylenes are linear or branched divalent alkyl groups. C1-C3 alkylenes are linear or branched divalent alkyl groups having 1, 2, or 3 carbon atoms. Examples are -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 2, 3, 4, 5, or 6 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.

[0041] The linear C3-C6 alkylene groups are -(CH2)3-, -(CH2)4-, -(CH2)5- or -(CH2)6-.

[0042] A 5- or 6-membered saturated heterocycle containing one nitrogen atom as a ring member and optionally another heteroatom selected from N and O as a ring member, such as pyrrolidine, pyrazolidine, imidazoline, etc. azole, isopropanone Azoxystrobin, piperidine, piperazine, or morpholine.

[0043] Oxidation is represented by =O; that is, the substituent "oxo" is replaced by a C (=O) group replacing a CH2 group.

[0044] Group VIII metal catalysts are catalysts with a Group VIII metal as the center metal in the periodic system. Group VIII refers to the IUPAC group definitions that were valid before 1985 and corresponds to groups 8, 9, and 10 in the current IUPAC group nomenclature.

[0045] Compound (I) can exist as its tautomer or a mixture of different tautomer forms. Examples of tautomer forms of compounds of formula (I) shown above have the following formula:

[0046]

[0047] A mixture of different tautomer forms is, for example, the tautomer above as a mixture of the tautomers shown in formula (I).

[0048] Compound 1 can also exist as its tautomers or mixtures of different tautomer forms. Examples of tautomer forms of the compound 1 shown above have the following formula:

[0049]

[0050] A mixture of different tautomer forms is, for example, the tautomer above as a mixture of the tautomers shown in Formula 1.

[0051] For simplicity, only compounds (I) and 1 will be mentioned below. However, all embodiments also involve their tautomers and mixtures of their different tautomer forms.

[0052] Embodiment (Ex) of the present invention

[0053] General and preferred embodiments Ex are outlined in the following non-exhaustive enumeration. Other preferred embodiments become apparent in the paragraphs following this enumeration.

[0054] E.1. A method for preparing the enantiomeric enriched form of 2-[2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (I):

[0055]

[0056] The asterisk * indicates the center of the 3D source;

[0057] This method comprises reducing 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 1 with a reducing agent in the presence of a chiral transition metal catalyst and optionally a base:

[0058]

[0059] The reducing agent is selected from formic acid HC(=O)OH, formula HC(=O)O - M + Formate salts and formic acid HC(=O)OH and one or more of the formula HC(=O)O - M + A mixture of formates, wherein M + It is a cationic equivalent; wherein, when formic acid is used as a reducing agent, the reaction is carried out in the presence of a base;

[0060] The pyrimidinone of formula (I) was obtained in an enantiomeric enriched form.

[0061] E.2. According to the method of implementation scheme E.1, where M + Selected from alkali metal cations, formula [NHR] 1 R 2 R 3 ] + ammonium cations, of which R 1 R 2 and R 3 Independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, and C1-C4 alkoxy-C1-C4 alkyl, formula NR 1 R 2 -A-NR 3 R 4 The protonated diamine, in which R 1 R 2 R 3 and R 4The ring is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy and C1-C4 alkoxy-C1-C4 alkyl, and A is (CH2)2 or (CH2)3; and a protonated 5 or 6-membered saturated heterocycle containing a nitrogen atom as a ring member and optionally containing another heteroatom selected from N and O as a ring member, wherein the ring may have 1 to 6 C1-C4 alkyl groups and / or 1 or 2 OH groups.

[0062] E.3. According to the method of implementation scheme E.2, where M + Selected from 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] + Protonated N,N,N',N'-tetramethylethylenediamine, protonated N,N,N',N'-tetramethyl-1,3-propanediamine, 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.

[0063] E.4. According to the method of implementation scheme E.2, where M + Selected from alkali metal cations and formula [NHR] 1 R 2 R 3 ] + ammonium cations, of which R 1 R 2 and R 3 The components are independently selected from hydrogen and C1-C6 alkyl groups, with R being preferred. 1 R 2 and R 3At least one, preferably at least two, are C1-C6 alkyl groups.

[0064] E.5. According to the method of implementation scheme E.3 or E.4, where M + Selected from Na + K + [NH(C2H5)3] + [NH(CH2CH2CH2CH3)3] + and [NH(C2H5)(CH(CH3)2] + .

[0065] E.6. The method according to any one of the implementation schemes E.3-E.5, wherein M + Selected from [NH(C2H5)3] + [NH(CH2CH2CH2CH3)3] + and [NH(C2H5)(CH(CH3)2] + .

[0066] E.7. The method according to any one of the implementation schemes E.3-E.5, wherein M + for Na + or K + .

[0067] E.8. The method according to any of the foregoing embodiments, wherein the base is selected from alkali metal hydroxides of formula NR 1 R 2 R 3 amines, of which R 1 R 2 and R 3 Independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, and C1-C4 alkoxy-C1-C4 alkyl, wherein R 1 R 2 and R 3 At least one of them is not hydrogen; formula NR 1 R 2 -A-NR 3 R 4 diamine, wherein R 1 R 2 R 3 and R 4 The ring is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, and C1-C4 alkoxy-C1-C4 alkyl, and A is (CH2)2 or (CH2)3; and a 5- or 6-membered saturated heterocycle containing a nitrogen atom as a ring member and optionally containing another heteroatom selected from N and O as a ring member, wherein the ring may have 1-6 C1-C4 alkyl groups and / or 1 or 2 OH groups.

[0068] E.9. The method according to embodiment E.8, wherein the base is selected from 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'-tetramethyl-1,3-propanediamine, 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, wherein the base may be used in a supported form (i.e., on a support material).

[0069] E.10. The method according to embodiment E.8, wherein the base is selected from formula NR. 1 R 2 R 3 amines, of which R 1 R 2 and R 3 Independently selected from hydrogen and C1-C6 alkyl groups, wherein R 1 R 2 and R 3 At least one of them is a C1-C6 alkyl group.

[0070] E.11. The method according to embodiment E.9 or E.10, wherein the base is selected from triethylamine, tributylamine and diisopropylethylamine.

[0071] E.12. The method according to implementation scheme E.9, wherein the base is selected from NaOH and KOH.

[0072] E.13. The method according to any of the foregoing embodiments, wherein formic acid is used as a reducing agent, and wherein formic acid and the base are used in a molar ratio of 100:1 to 1:10.

[0073] E.14. The method according to implementation scheme E.13, wherein formic acid and the base are used in a molar ratio of 10:1 to 1:5.

[0074] E.15. The method according to implementation scheme E.14, wherein formic acid and the base are used in a molar ratio of 10:1 to 1:2.

[0075] E.16. The method according to embodiment E.15, wherein formic acid and the base are used in a molar ratio of 5:1 to 1:5.

[0076] E.17. The method according to implementation scheme E.16, wherein formic acid and the base are used in a molar ratio of 5:1 to 1:1.

[0077] E.18. The method according to any of the foregoing embodiments, wherein compound 1 and the reducing agent are used in a molar ratio of 1:1 to 1:10.

[0078] 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.

[0079] E.20. The method according to any of the foregoing embodiments, wherein one or more chiral ligands in the chiral transition metal catalyst are coordinated and bonded to the central transition metal.

[0080] E.21. The method according to any of the foregoing embodiments, wherein the chiral transition metal catalyst is selected from group VIII metal catalysts.

[0081] E.22. The method according to embodiment E.21, wherein the chiral transition metal catalyst is selected from group 8 and 9 metal catalysts.

[0082] E.23. The method according to embodiment E.22, wherein the chiral transition metal catalyst is selected from Ru, Rh and Ir catalysts.

[0083] E.24. The method according to embodiment E.23, wherein the chiral transition metal catalyst is selected from Rh and Ir catalysts.

[0084] E.25. The method according to any of the foregoing embodiments, wherein the chiral transition metal catalyst is used in an amount of 0.01-10 mol% relative to 1 mol of compound 1, calculated based on the transition metal content.

[0085] E.26. The method according to embodiment E.25, wherein the chiral transition metal catalyst is used in an amount of 0.05-5 mol% relative to 1 mol of compound 1, calculated based on the transition metal content.

[0086] E.27. The method according to embodiment E.26, wherein the chiral transition metal catalyst is used in an amount of 0.1-5 mol% relative to 1 mol of compound 1, calculated based on the transition metal content.

[0087] E.28. The method according to embodiment E.27, wherein the chiral transition metal catalyst is used in an amount of 0.1-2 mol% relative to 1 mol of compound 1, calculated based on the transition metal content.

[0088] E.29. The method according to any of the foregoing embodiments, wherein the chiral transition metal catalyst is preformed and contains one or more chiral ligands coordinated with the transition metal; or formed in situ by reaction of a transition metal precursor compound with one or more chiral ligands.

[0089] E.30. The method according to embodiment E.29, wherein the chiral ligand is selected from bidentate amino chiral ligands.

[0090] E.31. The method according to embodiment E.30, wherein the chiral ligand is selected from chiral 1,2-diphenyl-1,2-ethylenediamine, 1,2-cyclohexanediamine and 1,2-di(methylamino)cyclohexane.

[0091] E.32. The method according to embodiment E.31, wherein the chiral ligand is selected from chiral 1,2-diphenyl-1,2-ethylenediamine.

[0092] E.33. The method according to embodiment E.32, wherein the chiral ligand is selected from 1,2-diphenyl-1,2-ethylenediamine of formula (II) in chiral form:

[0093]

[0094] in

[0095] The asterisk indicates the center of the stereo source;

[0096] R 5 and R 6 They are independently selected from OH, halogens, C1-C4 alkyl groups, and C1-C4 alkoxy groups;

[0097] R 7 and R 8 The components are independently selected from hydrogen, C1-C4 alkyl, and -L-phenyl, wherein the phenyl ring may have 1, 2, 3, 4, or 5 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy; and SO2R 9 ;

[0098] L is selected from the following linking groups: C2-C6 alkylene, C1-C3 alkylene-O-(CH2). p Where p is 0, 1, or 2, and C1-C3 alkylene-(1,2-phenylene)-(CH2) r , where r is 0, 1, or 2;

[0099] R 9 Selected from C1-C4 alkyl, C1-C4 haloalkyl, phenyl, phenyl-C1-C3 alkyl, wherein the phenyl group in two of the above groups may have 1, 2, 3, 4 or 5 substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; naphthyl, C6-C 10 Bicycloalkyl-C1-C3 alkyl, wherein the bicycloalkyl ring may be substituted with 1, 2, 3, 4 or 5 substituents selected from C1-C4 alkyl and oxo groups; and NR 10 R 11 ;

[0100] R 10 It is hydrogen or C1-C4 alkyl;

[0101] R 11 It is a phenyl-C1-C3 alkyl group, wherein the phenyl ring may have 1, 2, 3, 4 or 5 substituents selected from halogens, C1-C4 alkyl groups, C1-C4 haloalkyl groups and C1-C4 alkoxy groups; and

[0102] m and n are independent of each other and can be 0, 1, 2, 3, 4 or 5.

[0103] E.34. The method according to embodiment E.33, wherein in compound (II),

[0104] R 5 and R 6 It is a C1-C4 alkoxy group;

[0105] R 7 and R 8 One of them is selected from hydrogen, C1-C4 alkyl, and -L-phenyl, wherein the phenyl may have 1, 2, 3, 4, or 5 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy; and R 7 and R 8 Another one is selected from hydrogen and SO2R. 9 ;

[0106] L is selected from the following linking groups: linear C3-C6 alkylene groups, (CH2) o -O-(CH2) p , where p and o are independently 1 or 2; and (CH2) q -(1,2-phenylene)-(CH2) r , where q and r are independently 0, 1 or 2, and at least one of q and r is not 0;

[0107] R 9 Selected from C1-C4 alkyl, C1-C4 haloalkyl, and may contain 1, 2, 3, 4 or 5 substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; C7 bicycloalkylmethyl, wherein the bicycloalkyl ring may be substituted with 1, 2 or 3 substituents selected from C1-C4 alkyl and oxo; and NR 10 R 11 ;

[0108] R 10 It is hydrogen or C1-C4 alkyl;

[0109] R 11 It is phenyl-(CH2) sAlkyl group, wherein s is 2 or 3 and wherein the phenyl ring may have 1, 2, 3, 4 or 5 substituents selected from halogens, C1-C4 alkyl groups, C1-C4 haloalkyl groups and C1-C4 alkoxy groups; and

[0110] Both m and n can be 0 or both can be 1, preferably both can be 0.

[0111] E.35. The method according to embodiment E.33 or E.34, wherein the chiral ligand is selected from DPEN, TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, Trips in (1R,2R) or (1S,2S) form. DPEN, CsDPEN, DPEN, RsDPEN, TsDiOMeDPEN and compounds of formula (II), wherein R in formula (II) 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0112] E.36. The method according to embodiment E.35, wherein the chiral ligand is selected from (1R,2R) or (1S,2S) forms of TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, DPEN, RsDPEN, TsDiOMeDPEN and compounds of formula (II), wherein R in formula (II) 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0113] E.37. The method according to embodiment E.36, wherein the chiral ligand is selected from (1R,2R) or (1S,2S) forms of TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, DPEN, RsDPEN, TsDiOMeDPEN and compounds of formula (II), wherein R in formula (II) 7 For O2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0.

[0114] E.38. The method according to embodiment E.35, wherein the chiral transition metal catalyst contains Ru, Rh or Ir as a central metal and at least one DPEN, TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, Trips in the form of (1R,2R) or (1S,2S). DPEN, CsDPEN, Catalysts for ligands of DPEN, RsDPEN, TsDiOMeDPEN and compounds of formula (II), wherein R in formula (II) 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0115] E.39. The method according to embodiment E.38, wherein the chiral transition metal catalyst contains Ru, Rh or Ir as a central metal and at least one TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, etc., selected from the (1R,2R) or (1S,2S) form. Catalysts for ligands of DPEN, RsDPEN, TsDiOMeDPEN and compounds of formula (II), wherein R in formula (II) 7 SO2R 9 , where R 9R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0116] E.40. The method according to embodiment E.39, wherein the chiral transition metal catalyst contains Ru, Rh or Ir as a central metal and at least one TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, etc., selected from the (1R,2R) or (1S,2S) form. Catalysts for ligands of DPEN, RsDPEN, TsDiOMeDPEN and compounds of formula (II), wherein R in formula (II) 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0.

[0117] E.41. The method according to embodiment E.38, wherein the chiral transition metal catalyst contains Ru, Rh or Ir as a central metal and at least one DPEN, TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, Trips in the form of (1R,2R) or (1S,2S). DPEN, CsDPEN, Catalysts containing ligands of DPEN, RsDPEN, and TsDiOMeDPEN; or catalysts containing Ru as a central metal and at least one ligand selected from compounds of formula (II) in the form of (1R,2R) or (1S,2S), wherein R 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0118] E.42. The method according to embodiment E.41, wherein the chiral transition metal catalyst contains Ru, Rh or Ir as a central metal and at least one TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, etc., selected from the (1R,2R) or (1S,2S) form. Catalysts with chiral ligands such as DPEN, RsDPEN, and TsDiOMeDPEN; or catalysts with the following formula:

[0119]

[0120] E.43. The method according to any one of the implementation schemes E.33-E.42, wherein in R 7 and R 8 Neither of them are -L-phenyl or SO2R 9 , where R 9 It is a phenyl-C1-C3 alkyl or NR 10 R 11 In some cases, the catalyst additionally contains ligands selected from aromatic rings.

[0121] E.44. The method according to embodiment E.43, wherein the aromatic ring is selected from Cp, Cp*, benzene, p-isopropyltoluene, And hexamethylbenzene.

[0122] E.45. The method according to embodiment E.44, wherein the aromatic ring is selected from Cp*, benzene, p-isopropyltoluene, And hexamethylbenzene.

[0123] E.46. The method according to embodiment E.45, wherein the aromatic ring is selected from Cp*, p-isopropyltoluene, and

[0124] E.47. The method according to embodiment E.46, wherein the central metal is Rh or Ir and the aromatic ring is Cp*, or the central metal is Ru and the aromatic ring is p-isopropyltoluene or

[0125] E.48. The method according to any of the foregoing embodiments, wherein the chiral transition metal catalyst additionally contains one or two halogen or sulfonate ligands.

[0126] E.49. The method according to embodiment E.48, wherein the chiral transition metal catalyst additionally contains one or two halogen ligands.

[0127] E.50. The method according to embodiment E.49, wherein the chiral transition metal catalyst additionally contains one or two, preferably one Cl ligand.

[0128] E.51. The method according to any of the foregoing embodiments for preparing 2-[(2S)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (IS) in enantiomeric excess of at least 55% ee:

[0129]

[0130] E.52. The method according to embodiment E.51 is used to prepare 2-[(2S)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (IS) in enantiomeric excess of at least 60% ee.

[0131] E.53. The method according to embodiment E.52 is used to prepare 2-[(2S)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (IS) in enantiomeric excess of at least 70% ee.

[0132] E.54. The method according to embodiment E.53 is used to prepare 2-[(2S)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (IS) in enantiomeric excess of at least 80% ee.

[0133] E.55. The method according to embodiment E.54 is used to prepare 2-[(2S)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (IS) in enantiomeric excess of at least 90% ee.

[0134] E.56. A method according to any one of embodiments E.51-E.55, wherein the chiral transition metal catalyst comprises a material selected from (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-FsDPEN, and (1S,2S)-Trips. DPEN, (1S,2S)-CsDPEN, (1S,2S)- Chiral ligands of compounds of formula (II) in the form of (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S)-RsDPEN, where R is a base DPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S)-TsDiOMeDPEN, are provided. 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0135] E.57. The method according to embodiment E.56, wherein the chiral transition metal catalyst comprises a material selected from (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)- Chiral ligands of compounds of formula (II) in the form of (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S)-RsDPEN, where R is a base DPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S)-TsDiOMeDPEN, are provided. 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0136] E.58. The method according to embodiment E.57, wherein the chiral transition metal catalyst comprises a material selected from (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)- Chiral ligands of compounds of formula (II) in the form of (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S)-RsDPEN, where R is a base DPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S)-TsDiOMeDPEN, are provided. 7 SO2R9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0.

[0137] E.59. A method according to any one of embodiments E.51-E.56, wherein the chiral transition metal catalyst comprises Ru, Rh or Ir as a central metal and contains a mixture selected from (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-FsDPEN,

[0138] (1S,2S)-Trips DPEN, (1S,2S)-CsDPEN, (1S,2S)- DPEN base

[0139] Chiral ligands of compounds of formula (II) in the form of (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S) form, wherein R 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0140] E.60. The method according to embodiment E.59, wherein the chiral transition metal catalyst comprises Ru, Rh, or Ir as a central metal and contains a mixture selected from (1S,2S)-TsDPEN.

[0141] (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN,

[0142] (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)- DPEN base

[0143] Chiral ligands of compounds of formula (II) in the form of (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S) form, wherein R 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0144] E.61. The method according to embodiment E.60, wherein the chiral transition metal catalyst comprises Ru, Rh, or Ir as a central metal and contains a mixture selected from (1S,2S)-TsDPEN.

[0145] (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN,

[0146] (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)- DPEN base

[0147] Chiral ligands of compounds of formula (II) in the form of (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S) form, wherein R 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0.

[0148] E.62. The method according to any one of embodiments E.51-E.59, wherein the chiral transition metal catalyst comprises Ru, Rh or Ir as a central metal and contains a component selected from (1S,2S)-DPEN.

[0149] (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-

[0150] MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-FsDPEN, (1S,2S)-

[0151] Trips DPEN, (1S,2S)-CsDPEN, (1S,2S)- DPEN, (1S,2S)-

[0152] Chiral ligands of RsDPEN and (1S,2S)-TsDiOMeDPEN; or catalysts containing Ru as a central metal and at least one ligand selected from compounds of formula (II) in the (1S,2S) form, wherein R 7 SO2R 9 , where R 9 It is a C1-C4 alkyl group or may contain C1-C4 alkyl groups.

[0153] 1, 2, or 3 phenyl groups selected from C1-C4 alkyl and C1-C4 haloalkyl substituents, R 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0154] E.63. The method according to embodiment E.62, wherein the chiral transition metal catalyst comprises Ru, Rh, or Ir as a central metal and contains materials selected from (1S,2S)-TsDPEN, (1S,2S)-

[0155] CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-

[0156] MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)- DPEN, (1S,2S)-

[0157] Chiral ligands of RsDPEN and (1S,2S)-TsDiOMeDPEN; or catalysts of the following formula:

[0158]

[0159] E.64. The method according to any one of embodiments E.1-E.50 for preparing 2-[(2R)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (IR) in enantiomeric excess at a rate of at least 55%ee:

[0160]

[0161] E.65. The method according to embodiment E.64 is used to prepare 2-[(2R)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (IR) in an enantiomeric excess of at least 60% ee.

[0162] E.66. The method according to embodiment E.65 is used to prepare 2-[(2R)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (IR) in enantiomeric excess of at least 70% ee.

[0163] E.67. The method according to embodiment E.66 is used to prepare 2-[(2R)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (IR) in enantiomeric excess of at least 80% ee.

[0164] E.68. The method according to embodiment E.67 is used to prepare 2-[(2R)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (IR) in enantiomeric excess of at least 90% ee.

[0165] E.69. The method according to any one of embodiments E.64-E.68, wherein the chiral transition metal catalyst comprises a material selected from (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-

[0166] CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-

[0167] MeTsDPEN, (1R,2R)-FsDPEN, (1R,2R)-Trips DPEN, (1R,2R)-CsDPEN, (1R,2R)- Chiral ligands of compounds of formula (II) in the form of DPEN, (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN, and (1R,2R) are provided, where R is a ligand in formula (II). 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups.8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may be borne by

[0168] 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0169] E.70. The method according to embodiment E.69, wherein the chiral transition metal catalyst comprises a material selected from (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)- Chiral ligands of compounds of formula (II) in the form of DPEN, (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN, and (1R,2R) are provided, where R is a ligand in formula (II). 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0170] E.71. The method according to embodiment E.70, wherein the chiral transition metal catalyst comprises a material selected from (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)- Chiral ligands of compounds of formula (II) in the form of DPEN, (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN, and (1R,2R) are provided, where R is a ligand in formula (II). 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0.

[0171] E.72. The method according to any one of embodiments E.64-E.69, wherein the chiral transition metal catalyst comprises Ru, Rh or Ir as a central metal and contains a mixture selected from (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-FsDPEN, and (1R,2R)-Trips. DPEN, (1R,2R)-CsDPEN, (1R,2R)- Chiral ligands of compounds of formula (II) in the form of DPEN, (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN, and (1R,2R) are provided, where R is a ligand in formula (II). 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0172] E.73. The method according to embodiment E.72, wherein the chiral transition metal catalyst comprises Ru, Rh, or Ir as a central metal and contains a mixture selected from (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)- Chiral ligands of compounds of formula (II) in the form of DPEN, (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN, and (1R,2R) are provided, where R is a ligand in formula (II). 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0173] E.74. The method according to embodiment E.73, wherein the chiral transition metal catalyst comprises Ru, Rh, or Ir as a central metal and contains a mixture selected from (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)- Chiral ligands of compounds of formula (II) in the form of DPEN, (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN, and (1R,2R) are provided, where R is a ligand in formula (II). 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0.

[0174] E.75. The method according to any one of embodiments E.64-E.72, wherein the chiral transition metal catalyst comprises Ru, Rh or Ir as a central metal and contains a mixture selected from (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-FsDPEN, and (1R,2R)-Trips. DPEN, (1R,2R)-CsDPEN, (1R,2R)- Chiral ligands of DPEN, (1R,2R)-RsDPEN, and (1R,2R)-TsDiOMeDPEN, or catalysts containing Ru as a central metal and at least one ligand selected from compounds of formula (II) in the (1R,2R) form, wherein R 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0175] E.76. The method according to embodiment E.75, wherein the chiral transition metal catalyst comprises Ru, Rh, or Ir as a central metal and contains a mixture selected from (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)- Chiral ligands of DPEN, (1R,2R)-RsDPEN, and (1R,2R)-TsDiOMeDPEN, or catalysts of the following formula:

[0176]

[0177] E.77. The method according to any of the foregoing embodiments, wherein the reaction is carried out at a temperature of -20°C to 120°C.

[0178] E.78. The method according to embodiment E.77, wherein the reaction is carried out at a temperature of -15°C to 25°C.

[0179] E.79. The method according to embodiment E.77, wherein the reaction is carried out at a temperature of 30-100°C.

[0180] E.80. The method according to embodiment E.79, wherein the reaction is carried out at a temperature of 50-90°C.

[0181] E.81. The method according to any of the foregoing embodiments, wherein the reaction is carried out in the presence of a solvent.

[0182] E.82. The method according to embodiment E.81, wherein the solvent is selected from polar protic solvents, polar aprotic solvents, C1-C4 alkyl esters of acetate, chlorinated alkanes, aromatic solvents, heterocyclic solvents, mixtures of the above solvents, and mixtures of the above solvents with water; wherein the reaction can be carried out purely by using formic acid and / or a base that is liquid at the reaction temperature.

[0183] E.83. The method according to embodiment E.82, wherein the solvent is selected from C1-C4 alkanols, diols, dimethylformamide, diethylformamide, dibutylformamide, dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, etc. Alkanes, dimethyl sulfoxide, acetonitrile, N-methylpyrrolidone, N-n-butylpyrrolidone, N-tert-butylpyrrolidone, sulfolane, dimethyl carbonate, diethyl carbonate, propylene carbonate, γ-valerol, N,N,N',N'-tetrabutylurea, 1,3-dimethyl-2-imidazolinone, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, dichloroethane, benzene, toluene, α,α,α-trifluorotoluene (trifluorotoluene), xylenes, fluorobenzene, chlorobenzene, dichlorobenzene, anisole (methoxybenzene), 4-formylmorpholine, dihydro-L-glucosinolate The mixture of the above solvents and the mixture of the above solvents with water at a weight of up to 15% by weight, preferably up to 10% by weight, especially up to 5% by weight, specifically up to 3% by weight relative to the total weight of the solvents.

[0184] E.84. The method according to embodiment E.83, wherein the solvent is selected from dimethylformamide, dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, sulfolane, ethyl acetate, ethanol, dichloromethane, chloroform, dichloroethane, α,α,α-trifluorotoluene (trifluorotoluene), fluorobenzene, chlorobenzene, dichlorobenzene, anisole (methoxybenzene), and mixtures thereof.

[0185] E.85. The method according to embodiment E.84, wherein the solvent is selected from dimethylformamide, dimethylacetamide and mixtures thereof.

[0186] E.86. The method according to any of the foregoing embodiments, wherein an inert gas other than CO2 is injected through the reaction mixture during the reaction; or wherein the reaction is carried out under reduced pressure, either alternatively or additionally.

[0187] E.87. The method according to embodiment E.86, wherein the gas other than CO2 is selected from argon, nitrogen, and a mixture of oxygen and nitrogen containing 1-8% by volume oxygen relative to the total amount of the oxygen / nitrogen mixture.

[0188] E.88. The method according to implementation scheme E.87, wherein the gas other than CO2 is nitrogen.

[0189] E.89. The method according to any of the foregoing embodiments, wherein the reaction is carried out in the presence of an additive selected from diethyl phosphite, borate ester and zinc salt.

[0190] E.90. The method according to embodiment E.89, wherein the additive is selected from diethyl phosphite and zinc salt.

[0191] E.91. The method according to embodiment E.90, wherein the additive is diethyl phosphite.

[0192] E.92. The method according to any one of embodiments E.889-E.91, wherein the zinc salt is selected from zinc halides, zinc acetate, and zinc trifluoromethanesulfonate.

[0193] E.93. The method according to embodiment E.92, wherein the additive is zinc acetate.

[0194] E.94. The method according to any one of embodiments E.89-E.93, wherein the additive is used in an amount such that the molar ratio of the additive to compound 1 is in the range of 1:10000 to 10:1.

[0195] E.95. The method according to embodiment E.94, wherein the molar ratio of the additive to compound 1 is in the range of 1:10000 to 5:1.

[0196] E.96. The method according to embodiment E.95, wherein the molar ratio of the additive to compound 1 is in the range of 1:10000-2:1, for example 1:10000-1:2 or 1:10000-1:10.

[0197] E.97. The method according to any of the foregoing embodiments, wherein after the reaction is complete, the pyrimidinone of formula (I) is separated from the reaction mixture in an enantiomeric enrichment form, wherein the separation comprises adding water to the reaction mixture, separating and optionally purifying the pyrimidinone of formula (I) precipitated upon the addition of water; or wherein the separation comprises setting the pH of the reaction mixture to acidic; removing at least a portion of the solvent (if any) to obtain a concentrate; adding water and a solvent having low miscibility or no miscibility with water to the concentrate; extracting the pyrimidinone of formula (I) into a solvent having low miscibility or no miscibility with water; and separating the pyrimidinone of formula (I) from the extract.

[0198] E.98. The method according to embodiment E.97, wherein the solvent having low miscibility or no miscibility with water is selected from 2-methyltetrahydrofuran, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl isopropyl ketone, and chlorobenzene.

[0199] E.99. 2-[2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its enantiomeric enriched forms of formula (I):

[0200]

[0201] The asterisk (*) indicates the center of the 3D source.

[0202] The reaction sequence of the method of the present invention can be as follows:

[0203]

[0204] Formate is shown here only as a 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) may be used instead.

[0205] This reaction can be classified as asymmetric transfer hydrogenation.

[0206] M + Preferably selected from alkali metal cations, formula [NHR] 1 R 2 R 3 ] + ammonium cations, of which R 1 R 2 and R 3 Independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, and C1-C4 alkoxy-C1-C4 alkyl, formula NR 1 R 2 -A-NR 3 R 4 The protonated diamine, in which R 1 R 2 R 3 and R 4 The ring is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy and C1-C4 alkoxy-C1-C4 alkyl, and A is (CH2)2 or (CH2)3; and a protonated 5 or 6-membered saturated heterocycle containing a nitrogen atom as a ring member and optionally containing another heteroatom selected from N and O as a ring member, wherein the ring may have 1 to 6 C1-C4 alkyl groups and / or 1 or 2 OH groups.

[0207] In the formula [NHR] derived from monoamines 1 R 2 R 3 ] + Among the ammonium cations, R is preferred. 1 R 2 and R 3 At most one of them is hydrogen, and the other two or all three are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy-C1-C4 alkyl. This class of ammonium cations is the corresponding amine NR. 1 R 2 R 3 The protonated form. In diamine NR 1 R 2 -A-NR 3 R 4 Among them, R is preferred. 1 R 2 R 3 and R4 At least one of them is not hydrogen. More preferably, R 1 R 2 R 3 and R 4 Neither of them is hydrogen. R is preferred. 1 R 2 R 3 and R 4 They are C1-C4 alkyl groups, each independent of the others.

[0208] Protonated diamine NR 1 R 2 -A-NR 3 R 4 It can be monoprotonized ([NHR) 1 R 2 -A-NR 3 R 4 ] + ) or diprotonated ([NHR) 1 R 2 -A-NHR 3 R 4 ] 2+ In the latter case, M + More accurately described as (M) 2+ ) 1 / 2 or ([NHR) 1 R 2 -A-NHR 3 R 4 ] 2+ ) 1 / 2 .

[0209] Protonation of 5- or 6-membered saturated heterocycles is preferably derived from pyrrolidine, pyrazolidine, or imidazoline. azole, isopropanone Alzolidine, piperidine, piperazine, or morpholine. In the case of two nitrogen ring atoms, such as in pyrazolidine, imidazoline, or piperazine, the ring can also be diprotonated. The protonated 5- or 6-membered saturated heterocycle may have 1-6 C1-C4 alkyl groups and / or 1 or 2 hydroxyl groups on the nitrogen and / or carbon ring atoms. In particular, the protonated saturated heterocycle is 6-membered and therefore preferably derived from piperidine, piperazine, or morpholine, which may have 1-6 C1-C4 alkyl groups and / or 1 or 2 hydroxyl groups on the nitrogen and / or carbon ring atoms.

[0210] M + Especially selected from 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] + Protonated N,N,N',N'-tetramethylethylenediamine, protonated N,N,N',N'-tetramethyl-1,3-propanediamine, 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. M + More specifically selected from alkali metal cations (such as Li) + Na + K + or Cs + ) and formula [NHR 1 R 2 R 3 ] + ammonium cations, of which R 1 R 2 and R 3 The components are independently selected from hydrogen and C1-C6 alkyl groups, with R being preferred. 1 R 2 and R 3 At least one, preferably at least two, are C1-C6 alkyl groups (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] + M + Specifically selected from Na + K + [NH(C2H5)3] +[NH(CH2CH2CH2CH3)3] + and [NH(C2H5)(CH(CH3)2] + More specifically selected from Na + K + [NH(C2H5)3] + [NH(CH2CH2CH2CH3)3] + and [NH(C2H5)(CH(CH3)2] + It is very specifically selected from [NH(C2H5)3]. + [NH(CH2CH2CH2CH3)3] + and [NH(C2H5)(CH(CH3)2] + .

[0211] The reducing agent is selected from formic acid HC(=O)OH, formula HC(=O)O - M + Formate salts and formic acid HC(=O)OH and one or more of the formula HC(=O)O - M + A mixture of formates, wherein M + The formic acid is a cationic equivalent. If 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 salt.

[0212] Formula HC(=O)O - M + Formate salts and formic acid HC(=O)OH and one or more of the formula HC(=O)O - M + The mixture of formate salts can be used in the reaction in a pre-formed form or can be formed in situ by mixing formic acid with the corresponding base in a sufficient molar ratio. To obtain M... + Formate is a metal cation, such as an alkali metal cation, or a mixture of formic acid and formate, for example, by mixing formic acid with a metal hydroxide, such as an alkali metal hydroxide, or with a metal carbonate, such as an alkali metal carbonate. To obtain M... + Formate or a mixture of formic acid and formate, as described above, consisting of an ammonium cation, a protonated diamine, or a protonated heterocycle, is suitable if the formic acid is reacted with the corresponding monoamine NR as defined above. 1 R 2 R 3 diamine NR 1 R 2 -A-NR 3 R 4 It may be a mixture of 5 or 6 saturated heterocyclic rings.

[0213] In the context of this invention, the base optionally or necessarily used is different from formate HC(=O)O. - M + Alkali.

[0214] The base, which may be used arbitrarily or compulsorily depending on the reducing agent, is preferably selected from alkali metal hydroxides, formula NR. 1 R 2 R 3 amines, of which R 1 R 2 and R 3 Independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, and C1-C4 alkoxy-C1-C4 alkyl, wherein R 1 R 2 and R 3 At least one of them is not hydrogen; formula NR 1 R 2 -A-NR 3 R 4 diamine, wherein R 1 R 2 R 3 and R 4 The ring is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, and C1-C4 alkoxy-C1-C4 alkyl, and A is (CH2)2 or (CH2)3; and a 5- or 6-membered saturated heterocycle containing a nitrogen atom as a ring member and optionally containing another heteroatom selected from N and O as a ring member, wherein the ring may have 1-6 C1-C4 alkyl groups and / or 1 or 2 OH groups.

[0215] If formate or a mixture of formic acid and formate is used as a reducing agent, the base preferably corresponds to the cation M in the formate. + Especially if M + Derived from monoamine NR 1 R 2 R 3 diamine NR 1 R 2 -A-NR 3 R 4 Or, if it is a 5- or 6-membered saturated heterocycle.

[0216] More preferably, the base is selected from 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'-tetramethyl-1,3-propanediamine, 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, wherein the base can be used in a supported form (i.e., on a support material). Among these, amine NR is preferred. 1 R 2 R 3 , where R 1 R 2 and R 3 Independently selected from hydrogen and C1-C6 alkyl groups, wherein R 1 R 2 and R 3 At least one of the components is 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 preferred.

[0217] Suitable support materials for alkali / supported alkalis include, for example, silica (SiO2) and organic polymers such as polystyrene or acrylate-based supports. Examples of such supports include polymers commonly used in ion exchange resins, such as styrene (co)polymers containing sulfonic acid groups, specifically styrene-divinylbenzene copolymers containing sulfonic acid groups. Commercially available examples of this type of ion exchanger support are... (Lanxess) (The Purolite Company) (DowChemical Company) (Rohm and Haas Company) or (Rohm and Haas Company) commercialized materials.

[0218] If formate HC(=O)O - M + When used as the sole reducing agent, it is advantageous to mix it with water.

[0219] If formic acid HC(=O)OH and one or more HC(=O)O - M +When a mixture of formate salts is used as a reducing agent, formic acid and formate salts 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 salts are 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.

[0220] Formic acid is preferably used as a reducing agent. Therefore, the reaction is forced to take place in the presence of a base.

[0221] Formic acid and the base are preferably used in a molar ratio of 100:1 to 1:10, more preferably 10:1 to 1:5, especially 5:1 to 1:5, specifically 5:1 to 1:1.

[0222] 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.

[0223] The chiral transition metal catalyst is preferably selected from Group VIII metal catalysts. Group VIII metal catalysts refer to catalysts with a Group VIII metal from the periodic system as the central metal. Group VIII refers to the IUPAC group definitions valid before 1985 and corresponds to groups 8, 9, and 10 in the current IUPAC nomenclature. 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 9 metal catalysts are preferred. Among these, Ru, Rh, and Ir catalysts are particularly preferred. Specifically, the chiral transition metal catalyst is a catalyst with Rh or Ir as the central atom.

[0224] The chiral transition metal catalyst is preferably used in an amount of 0.01-10 mol%, more preferably 0.05-5 mol%, or even more preferably 0.1-5 mol%, specifically 0.1-2 mol%, relative to 1 mol of compound 1, based on the transition metal content.

[0225] The chirality of this chiral transition metal catalyst is preferably based on the presence of one or more chiral ligands coordinated to the central transition metal.

[0226] This chiral transition metal catalyst can be used in a preformed form. In the preformed catalyst, the central metal is coordinated and bonded to one or more chiral ligands. Alternatively, the chiral transition metal catalyst can be formed in situ via a reaction of a transition metal precursor compound and one or more chiral ligands.

[0227] The chiral ligand is preferably selected from bidentate amino chiral ligands. Suitable bidentate amino chiral ligands are based on 1,2-ethylenediamine, which is substituted such that at least one carbon atom bearing an amino group is asymmetric; that is, a stereosource center. Preferably, one or two carbon atoms of the 1,2-ethylenediamine ligand have a phenyl, naphthyl, or cyclohexyl ring, or two carbon atoms are part of a chiral ring system. More preferably, the chiral ligand is selected from chiral 1,2-diphenyl-1,2-ethylenediamine, 1,2-cyclohexanediamine, and 1,2-di(methylamino)cyclohexane.

[0228] Even more preferred are chiral ligands selected from chiral 1,2-diphenyl-1,2-ethylenediamine, especially chiral form of formula (II) 1,2-diphenyl-1,2-ethylenediamine:

[0229]

[0230] in

[0231] The asterisk indicates the center of the stereo source;

[0232] R 5 and R 6 They are independently selected from OH, halogens, C1-C4 alkyl groups, and C1-C4 alkoxy groups;

[0233] R 7 and R 8 The components are independently selected from hydrogen, C1-C4 alkyl, and -L-phenyl, wherein the phenyl ring may have 1, 2, 3, 4, or 5 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy; and SO2R 9 ;

[0234] L is selected from the following linking groups: C2-C6 alkylene, C1-C3 alkylene-O-(CH2). p Where p is 0, 1, or 2, and C1-C3 alkylene-(1,2-phenylene)-(CH2) r , where r is 0, 1, or 2;

[0235] R 9 Selected from C1-C4 alkyl, C1-C4 haloalkyl, phenyl, phenyl-C1-C3 alkyl, wherein the phenyl group in two of the above groups may have 1, 2, 3, 4 or 5 substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; naphthyl, C6-C 10 Bicycloalkyl-C1-C3 alkyl, wherein the bicycloalkyl ring may be substituted with 1, 2, 3, 4 or 5 substituents selected from C1-C4 alkyl and oxo groups; and NR 10 R 11 ;

[0236] R 10 It is hydrogen or C1-C4 alkyl;

[0237] R 11 It is a phenyl-C1-C3 alkyl group, wherein the phenyl ring may have 1, 2, 3, 4 or 5 substituents selected from halogens, C1-C4 alkyl groups, C1-C4 haloalkyl groups and C1-C4 alkoxy groups; and

[0238] m and n are independent of each other and can be 0, 1, 2, 3, 4 or 5.

[0239] Preferably in compound (II),

[0240] R 5 and R 6 It is a C1-C4 alkoxy group;

[0241] R 7 and R 8 One of them is selected from hydrogen, C1-C4 alkyl, and -L-phenyl, wherein the phenyl may have 1, 2, 3, 4, or 5 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy; and R 7 and R 8 Another one is selected from hydrogen and SO2R. 9 ;

[0242] L is selected from the following linking groups: linear C3-C6 alkylene groups, (CH2) o -O-(CH2) p , where p and o are independently 1 or 2; and (CH2) q -(1,2-phenylene)-(CH2) r , where q and r are independently 0, 1 or 2, and at least one of q and r is not 0;

[0243] R 9 Selected from C1-C4 alkyl, C1-C4 haloalkyl, and may contain 1, 2, 3, 4 or 5 substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; C7 bicycloalkylmethyl, wherein the bicycloalkyl ring may be substituted with 1, 2 or 3 substituents selected from C1-C4 alkyl and oxo; and NR 10 R 11 ;

[0244] R 10 It is hydrogen or C1-C4 alkyl;

[0245] R 11 It is phenyl-(CH2) sAlkyl group, wherein s is 2 or 3 and wherein the phenyl ring may have 1, 2, 3, 4 or 5 substituents selected from halogens, C1-C4 alkyl groups, C1-C4 haloalkyl groups and C1-C4 alkoxy groups; and

[0246] Both m and n can be 0 or both can be 1, preferably both can be 0.

[0247] For a system to be chiral, the two stereo source centers (i.e., the carbon atoms marked with an asterisk in Formula II) must be in the R configuration or both must be in the S configuration. If one is S and the other is R, then an achiral meso compound system is obtained.

[0248] These ligands are known from Noyori-type asymmetric transfer hydrogenation and are generally commercially available. Preferred formula (II) ligands are chiral forms (i.e., (1S,2S) or (1R,2R) forms; the 1 and 2 positions involve the two carbon atoms of the phenyl ring and amino group marked with an asterisk in formula II) such as DPEN, TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, and Trips. DPEN, CsDPEN, DPEN, RsDPEN, TsDiOMeDPEN and compounds of formula (II), wherein R in formula (II) 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl group in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy groups; and m and n are 0. The acronym corresponds to the following formula:

[0249]

[0250] In addition to the two carbon atoms marked with an asterisk in Formula II, bearing a phenyl ring and an amino group, CsDPEN has two additional stereosource centers in the camphor moiety (more precisely, on the norbornene ring), namely at the carbon atoms forming the bridging points (positions 1 and 4; position 1 is a carbon ring atom bonded to -CH2-SO2-NH-...). However, the stereochemistry of this camphor moiety does not significantly affect the stereoselectivity of the hydrogenation reaction, and therefore CsDPEN derived from racemic camphor or any camphor enantiomer (1S,4R or 1R,4S) or a non-racemic mixture of enantiomers can be used. However, in certain embodiments, CsDPEN is derived from the 1S,4R enantiomer, specifically N-[(1S,2S)-2-amino-1,2-diphenylethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxonorbornan-1-yl]methanesulfonamide as (1S,2S)-CsDPEN and N-[(1R,2R)-2-amino-1,2-diphenylethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxonorbornan-1-yl]methanesulfonamide as (1R,2R)-CsDPEN.

[0251] This chiral transition metal catalyst is particularly selected from those containing Ru, Rh, or Ir as the central metal and at least one selected from the (1R,2R) or (1S,2S) form of DPEN, TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, Trips DPEN, CsDPEN, Catalysts for ligands of DPEN, RsDPEN, TsDiOMeDPEN and compounds of formula (II), wherein R in formula (II) 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0252] The chiral transition metal catalyst is more particularly selected from those containing Ru, Rh or Ir as the central metal and at least one selected from the (1R,2R) or (1S,2S) form of TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, etc. Catalysts for ligands of DPEN, RsDPEN, TsDiOMeDPEN and compounds of formula (II), wherein R in formula (II) 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 The phenyl group is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl group in the two last mentioned groups may have one, two, or three substituents selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy groups; and m and n are 0. This chiral transition metal catalyst is even more particularly selected from those containing Ru, Rh, or Ir as the central metal and at least one TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, etc., selected from the (1R,2R) or (1S,2S) forms. Catalysts for ligands of DPEN, RsDPEN, TsDiOMeDPEN and compounds of formula (II), wherein R in formula (II) 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0.

[0253] Specifically, the chiral transition metal catalyst is selected from those containing Ru, Rh, or Ir as the central metal and at least one DPEN, TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, or Trips in the form of (1R,2R) or (1S,2S). DPEN, CsDPEN, Catalysts containing ligands of DPEN, RsDPEN, and TsDiOMeDPEN; and catalysts containing Ru as a central metal and at least one ligand selected from compounds of formula (II) in the form of (1R,2R) or (1S,2S), wherein R 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8The phenyl group is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl group in the two last mentioned groups may have one, two, or three substituents selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy groups; and m and n are 0. The chiral transition metal catalyst is more specifically selected from those containing Ru, Rh, or Ir as the central metal and at least one TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, etc., selected from the (1R,2R) or (1S,2S) forms. Catalysts containing ligands of DPEN, RsDPEN, and TsDiOMeDPEN; and catalysts containing Ru as a central metal and at least one ligand selected from compounds of formula (II) in the form of (1R,2R) or (1S,2S), wherein R 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0254] Very specifically, the chiral transition metal catalyst is selected from those containing Ru, Rh, or Ir as the central metal and at least one of the following selected from (1R,2R) or (1S,2S) forms: TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, etc. Catalysts containing ligands of DPEN, RsDPEN, and TsDiOMeDPEN; and catalysts of the following formula:

[0255]

[0256] This chiral transition metal catalyst typically contains only one of the aforementioned dienodentine ligands.

[0257] As R 7 or R 8 The meaning of the optional substituted phenyl ring in -L-phenyl, as R 9 The meaning of phenyl-C1-C3 alkyl groups with optional substituted phenyl rings and as R 11 The optional substituted phenyl ring in the phenyl-C1-C3 alkyl group is often used as an additional (tethered) ligand for the central metal. Complexes containing aromatic ligands tethered to ethylenediamine ligands are commonly known as Wills catalysts.

[0258] In R 7 and R 8 Neither of them are -L-phenyl or SO2R 9 , where R 9 It is a phenyl-C1-C3 alkyl or NR 10 R 11 In this case, the catalyst preferably contains additional ligands selected from aromatic rings. These ligands typically have a higher hapticity, meaning they are coordinated to the metal center via more than one atom, specifically via a continuous and uninterrupted series of atoms. They are commonly used as η... 5 or η 6 Ligands. Typical aromatic η 5 and η 6 The ligands are substituted or unsubstituted benzene and substituted or unsubstituted cyclopentadiene. The aromatic rings are preferably selected from Cp, Cp*, benzene, p-isopropyltoluene, etc. And hexamethylbenzene, especially Cp*, benzene, p-isopropyltoluene, and hexamethylbenzene, specifically selected from Cp*, p-isopropyltoluene and More specifically, Cp* is selected. In terms of trend, 5-membered aromatic ligands, such as Cp and Cp*, are better suited for Rh or Ir as the central metal; while 6-membered aromatic ligands, such as benzene, p-isopropyltoluene, ... And hexamethylbenzene, Ru is a better fit as the central metal. Therefore, very specifically, if the central metal is Rh or Ir, the aromatic ring is Cp*, and if the central metal is Ru, the aromatic ring is p-isopropyltoluene or...

[0259] The catalyst typically contains one or two other ligands, at least one of which is replaced by a hydride ligand from the reducing agent during the reaction under basic conditions. This other ligand is typically a halogen (e.g., Cl, Br, or I; preferably Cl) or a sulfonate (e.g., trifluoromethanesulfonate, methanesulfonate, toluenesulfonate, or perfluorobutylsulfonate; preferably trifluoromethanesulfonate) ligand, especially a halogen ligand, specifically Cl.

[0260] Catalyst precursors are typically salts of a central metal or complexes of a central metal with ligands other than chiral ligands. When catalysts with Ru, Rh, or Ir as the central metal are preferred, the catalyst precursor is specifically a binuclear complex containing an aromatic ring ligand and two halogen ligands. Non-exhaustive examples include [Ru(p-isopropyltoluene)Cl2]2, [Ru( [Rh(III)Cl2Cp*]2, [Rh(III)Cl2Cp*]2, or [Ir(III)Cl2Cp*]2. These complexes are usually commercially available or can be prepared by standard methods.

[0261] Preformed catalysts are typically 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, if the aforementioned binuclear complexes containing an aromatic ring ligand and two halogen ligands (Ru, Rh, or Ir) are used as precursor compounds, the presence of a base is useful for simplifying or allowing the reaction—i.e., converting the binuclear complex into a mononuclear complex containing the desired chiral ligand. The catalyst precursor and chiral ligand are typically mixed in a molar ratio of 2:1 to 1:5, preferably 1.5:1 to 1:4, and especially 1.2:1 to 1:3, where the molar ratio is based on the amount (mol) of the transition metal in the catalyst precursor. The resulting catalyst can be separated before use in the reaction or the resulting reaction mixture can be used without separating the complex.

[0262] If the catalyst is formed in situ, the catalyst precursor and the chiral ligand are contacted in the presence of at least one reactant, such as starting compound 1, a reducing agent, and / or a base (if used). Depending on the nature of the catalyst precursor, the formation of the catalyst may begin only in the presence of a base. This base may be the aforementioned base that is mandatory if HCOOH is used as a reducing agent, or it may be a formate if the reducing agent is used in this form. Preferably, the catalyst precursor and the chiral ligand are contacted before contact with starting compound 1 under conditions that allow the catalyst precursor and the chiral ligand to form a catalyst complex (in which the central metal is bonded to the chiral ligand). Therefore, it is preferred that the catalyst precursor and the chiral ligand be contacted in the presence of a base (if used) and optionally a reducing agent, or, if no additional base is used, in the presence of a formate; and if the reaction is not carried out purely, the catalyst precursor and the chiral ligand are optionally contacted in the presence of a solvent; and only subsequently is the resulting mixture contacted with starting compound 1. The catalyst precursor and chiral ligand are typically used in a molar ratio of 2:1 to 1:5, preferably 1.5:1 to 1:4, and especially 1.2:1 to 1:3, where the molar ratio is based on the amount (mol) of transition metal in the catalyst precursor.

[0263] In a preferred embodiment, the method of the present invention is used to prepare 2-[(2S)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (IS) with an enantiomeric excess, more precisely at least 55%ee, preferably at least 60%ee, more preferably at least 70%ee, especially at least 80%ee, and specifically at least 90%ee, with an enantiomeric 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:

[0264]

[0265] This is achieved by using a suitable chiral catalyst. This is preferably a transition metal catalyst, more preferably a Group VIII transition metal catalyst, and even more preferably a Group 8 or 9 metal catalyst, especially containing catalysts selected from (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-FsDPEN, and (1S,2S)-Trips. DPEN, (1S,2S)-CsDPEN, (1S,2S)- Ru, Rh, or Ir catalysts containing chiral ligands of formula (II) in the form of DPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S) form, wherein R is a base DPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S) form of compounds, wherein R is a base DPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and ... 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl group in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0; preferably containing substituents selected from (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)- Ru, Rh, or Ir catalysts containing chiral ligands of formula (II) in the form of DPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S) form, wherein R is a base DPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S) form of compounds, wherein R is a base DPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and ... 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl group in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0; more preferably it contains substituents selected from (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)- Ru, Rh, or Ir catalysts containing chiral ligands of formula (II) in the form of DPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S) form, wherein R is a base DPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S) form of compounds, wherein R is a base DPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and ... 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0.

[0266] Chiral transition metal catalysts for obtaining (IS) enantiomeric excess particularly contain Ru, Rh, or Ir as the central metal and contain a compound selected from (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-FsDPEN, and (1S,2S)-Trips. DPEN, (1S,2S)-CsDPEN, (1S,2S)- Chiral ligands of DPEN, (1S,2S)-RsDPEN, and (1S,2S)-TsDiOMeDPEN; or catalysts containing Ru as a central metal and at least one ligand selected from compounds of formula (II) in the (1S,2S) form, wherein R 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8The phenyl group is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl group in the two last mentioned groups may have 1, 2, or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy groups; and m and n are 0. More particularly, the chiral transition metal catalyst for obtaining (IS) in enantiomeric excess comprises Ru, Rh, or Ir as the central metal and comprises a group selected from (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)- Chiral ligands of DPEN, (1S,2S)-RsDPEN, and (1S,2S)-TsDiOMeDPEN; or catalysts containing Ru as a central metal and at least one ligand selected from compounds of formula (II) in the (1S,2S) form, wherein R 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0267] More specifically, the chiral transition metal catalyst is selected from those containing Ru, Rh, or Ir as the central metal and at least one selected from (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)- Catalysts with ligands of DPEN, (1S,2S)-RsDPEN, and (1S,2S)-TsDiOMeDPEN, or catalysts of the following formula:

[0268]

[0269] More specifically, the chiral transition metal catalyst for enantiomeric excess (IS) comprises Ru, Rh, or Ir as the central metal and contains a compound selected from (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-FsDPEN, and (1S,2S)-Trips. DPEN, (1S,2S)-CsDPEN, (1S,2S)- Chiral ligands of DPEN, (1S,2S)-RsDPEN, and (1S,2S)-TsDiOMeDPEN, and additionally comprising aromatic rings such as substituted or unsubstituted benzenes and substituted or unsubstituted cyclopentadienes, such as Cp, Cp*, benzene, p-isopropyltoluene, etc. Or a ligand of hexamethylbenzene. As explained above, 5-membered η 5 Aromatic ligands, such as Cp and Cp*, are better suited to Rh or Ir as the central metal; therefore, in the case of Rh and Ir as the central metal, the additional aromatic ligands are preferably selected from Cp and Cp*, specifically Cp*. In the case of Ru as the central metal, the additional aromatic ligands are preferably selected from isopropyltoluene and... Even more specifically, the chiral transition metal catalysts used to obtain (IS) enantiomeric excess contain Ru, Rh, or Ir as the central metal and contain a mixture selected from (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)- Chiral ligands of DPEN, (1S,2S)-RsDPEN, and (1S,2S)-TsDiOMeDPEN, and additionally comprising aromatic rings such as substituted or unsubstituted benzenes and substituted or unsubstituted cyclopentadienes, such as Cp, Cp*, benzene, p-isopropyltoluene, etc. Or a ligand of hexamethylbenzene; specifically η in the case of Rh and Ir as the central metal. 5 The ligand Cp*; specifically isopropyltoluene or, in the case of Ru as the central metal.

[0270] In addition, the catalyst contains other ligands, typically halides, specifically Cl, that are to be replaced by hydrides from the reducing agent.

[0271] Alternatively, the catalyst contains Ru as a central metal and at least one ligand selected from compounds of formula (II) in the (1S,2S) form, where R 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 The phenyl group is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl group in the two last mentioned groups may have one, two, or three substituents selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy groups; and m and n are 0. These catalysts typically also contain other ligands to be replaced by hydrides from the reducing agent, usually halides or sulfonates, preferably halides, specifically Cl. These catalysts are specifically compounds of the following formula:

[0272]

[0273] In another preferred embodiment, the method of the present invention is used to prepare 2-[(2R)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (IR) with an enantiomeric excess, more precisely at least 55%ee, preferably at least 60%ee, more preferably at least 70%ee, especially at least 80%ee, and specifically at least 90%ee:

[0274]

[0275] This is achieved by using a suitable chiral catalyst. This is preferably a transition metal catalyst, more preferably a Group VIII transition metal catalyst, and even more preferably a Group 8 or 9 metal catalyst, especially containing catalysts selected from (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-FsDPEN, and (1R,2R)-Trips. DPEN, (1R,2R)-CsDPEN, (1R,2R)- Ru, Rh, or Ir catalysts for chiral ligands of compounds of formula (II) in the form of DPEN, (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN, and (1R,2R) are used, where R is a ligand in formula (II). 7 SO2R 9 , where R 9R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl group in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0; preferably containing substituents selected from (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)- Ru, Rh, or Ir catalysts for chiral ligands of compounds of formula (II) in the form of DPEN, (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN, and (1R,2R) are used, where R is a ligand in formula (II). 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl group in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0; more preferably, it contains substituents selected from (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)- Ru, Rh, or Ir catalysts for chiral ligands of compounds of formula (II) in the form of DPEN, (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN, and (1R,2R) are used, where R is a ligand in formula (II). 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0.

[0276] Chiral transition metal catalysts for enantiomeric excess (IR) particularly contain Ru, Rh, or Ir as the central metal and contain a compound selected from (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-FsDPEN, and (1R,2R)-Trips. DPEN, (1R,2R)-CsDPEN, (1R,2R)- Chiral ligands of DPEN, (1R,2R)-RsDPEN, and (1R,2R)-TsDiOMeDPEN; or catalysts containing Ru as a central metal and at least one ligand selected from compounds of formula (II) in the (1R,2R) form, wherein R 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 The phenyl group is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl group in the two last mentioned groups may have 1, 2, or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy groups; and m and n are 0. More particularly, the chiral transition metal catalyst for obtaining (IR) in enantiomeric excess comprises Ru, Rh, or Ir as the central metal and comprises a group selected from (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)- Chiral ligands of DPEN, (1R,2R)-RsDPEN, and (1R,2R)-TsDiOMeDPEN; or catalysts containing Ru as a central metal and at least one ligand selected from compounds of formula (II) in the (1R,2R) form, wherein R 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl in the two last mentioned groups may have 1, 2 or 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and m and n are 0.

[0277] More specifically, the chiral transition metal catalyst is selected from those containing Ru, Rh, or Ir as the central metal and at least one selected from (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)- Catalysts with ligands of DPEN, (1R,2R)-RsDPEN, and (1R,2R)-TsDiOMeDPEN, or catalysts of the following formula:

[0278]

[0279] More specifically, the chiral transition metal catalyst for enantiomeric excess (IR) comprises Ru, Rh, or Ir as the central metal and contains a compound selected from (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-FsDPEN, and (1R,2R)-Trips. DPEN, (1R,2R)-CsDPEN, (1R,2R)- Chiral ligands of DPEN, (1R,2R)-RsDPEN, and (1R,2R)-TsDiOMeDPEN, and additionally comprising aromatic rings such as substituted or unsubstituted benzenes and substituted or unsubstituted cyclopentadienes, such as Cp, Cp*, benzene, p-isopropyltoluene, etc. Or a ligand of hexamethylbenzene. As explained above, 5-membered η 5 Aromatic ligands, such as Cp and Cp*, are better suited to 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*, specifically Cp*. When Ru is the central metal, the additional aromatic ligand is preferably selected from isopropyltoluene and... Even more specifically, the chiral transition metal catalysts used to obtain (IS) enantiomeric excess contain Ru, Rh, or Ir as the central metal and contain a mixture selected from (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)- Chiral ligands of DPEN, (1R,2R)-RsDPEN, and (1R,2R)-TsDiOMeDPEN, and additionally comprising aromatic rings such as substituted or unsubstituted benzenes and substituted or unsubstituted cyclopentadienes, such as Cp, Cp*, benzene, p-isopropyltoluene, etc. Or a ligand of hexamethylbenzene; specifically η when Rh or Ir is the central metal. 5 The ligand Cp*; specifically isopropyltoluene or, in the case of Ru as the central metal.

[0280] In addition, the catalyst contains other ligands, typically halides, specifically Cl, that are to be replaced by hydrides from the reducing agent.

[0281] Alternatively, the catalyst contains Ru as a central metal and at least one ligand selected from compounds of formula (II) in the form of (1R,2R), where R... 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or a phenyl group that may have 1, 2, or 3 substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 The phenyl group is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl group in the two last mentioned groups may have one, two, or three substituents selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy groups; and m and n are 0. These catalysts typically also contain other ligands to be replaced by hydrides from the reducing agent, usually halides or sulfonates, preferably halides, specifically Cl. These catalysts are specifically compounds of the following formula:

[0282]

[0283] The reaction can be carried out in the presence of a solvent. The solvent is preferably selected from polar protic solvents, polar aprotic solvents, chlorinated alkanes, aromatic solvents, heterocyclic solvents, mixtures of the above solvents, and mixtures of the above solvents with water.

[0284] Polar protic solvents are solvents that lack functional groups from which protons can be dissociated. Examples of suitable polar protic solvents are C1-C4 alkanols, C1-C4 fluoroalkanols, 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 C1-C4 fluoroalkanols include 2-fluoroethanol, 3-fluoropropanol, 1-fluoroprop-2-ol, 4-fluorobutanol, 1,1-difluoroethanol, 2,2-difluoroethanol, 2,2-difluoropropanol, 3,3-difluoropropanol, 1,1-difluoroprop-2-ol, 2,2,2-trifluoroethanol, 3,3,3-trifluoropropanol, and 4,4,4-trifluorobutanol. Examples of glycols are ethylene glycol, diethylene glycol, and triethylene glycol.

[0285] Polar aprotic solvents are polar solvents that lack functional groups from which protons can be dissociated. Examples of suitable polar aprotic solvents are amides, such as dimethylformamide (DMF), diethylformamide, dibutylformamide, and dimethylacetamide; and cyclic ethers, such as tetrahydrofuran, 2-methyltetrahydrofuran, and 1,3-dimethylformamide. Alkane and 1,4-di Alkanes; sulfoxides, such as dimethyl sulfoxide (DMSO); nitriles, such as acetonitrile; lactams, such as N-methylpyrrolidone (NMP), N-n-butylpyrrolidone, or N-tert-butylpyrrolidone; sulfones, such as sulfolane; carbonates, such as dimethyl carbonate, ethylene carbonate, or propylene carbonate; lactones, such as γ-butyrolactone or γ-valerolactone; ureas, such as N,N,N',N'-tetramethylurea, N,N,N',N'-tetrabutylurea, dimethylpropylene urea (DMPU), or 1,3-dimethyl-2-imidazolinone (DMEU; DMI); and nitro compounds, such as nitromethane.

[0286] Examples of suitable C1-C4 alkyl acetates are methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.

[0287] Examples of suitable chlorinated alkanes are dichloromethane, trichloromethane, or dichloroethane.

[0288] Examples of suitable aromatic solvents include benzene, toluene, α,α,α-trifluorotoluene (trifluorotoluene), xylenes (i.e., 1,2-xylene, 1,3-xylene or 1,4-xylene), fluorobenzene, chlorobenzene, dichlorobenzene or anisole (methoxybenzene).

[0289] Examples of suitable heterocyclic solvents are 4-formylmorpholine or dihydrolevulinone.

[0290] If a mixture of the listed organic solvents and water is used, the mixture typically contains up to 15% by weight of water (e.g., 0.5-15% by weight), preferably up to 10% by weight (e.g., 1-10% by weight), especially up to 5% by weight (e.g., 1-5% by weight), and specifically up to 3% by weight (e.g., 1-3% by weight).

[0291] More preferably, the solvent is selected from C1-C4 alkanols, glycols, dimethylformamide, diethylformamide, dibutylformamide, dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, and dimethylformamide. Alkanes (i.e., 1,3-dialkylene oxides) Alkane and 1,4-di Alkane), dimethyl sulfoxide, acetonitrile, N-methylpyrrolidone, N-n-butylpyrrolidone, N-tert-butylpyrrolidone, sulfolane, dimethyl carbonate, diethyl carbonate, propylene carbonate, γ-valerol, N,N,N',N'-tetrabutylurea, 1,3-dimethyl-2-imidazolinone, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, dichloroethane, benzene, toluene, α,α,α-trifluorotoluene, xylene derivatives, fluorobenzene, chlorobenzene, dichlorobenzene, anisole, 4-formylmorpholine, dihydro-L-glucosidone The mixture of the above solvents and the mixture of the above solvents with water; particularly selected from dimethylformamide, dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, sulfolane, ethyl acetate, ethanol, dichloromethane, chloroform, dichloroethane, α,α,α-trifluorotoluene (trifluorotoluene), fluorobenzene, chlorobenzene, dichlorobenzene, anisole (methoxybenzene), and mixtures thereof; specifically selected from dimethylformamide, dimethylacetamide, and mixtures thereof.

[0292] However, if formic acid is used as a reducing agent or contained in a reducing agent and / or a base that is liquid at the reaction temperature is used, the reaction can be carried out in a purer manner.

[0293] If formate is used as the sole reducing agent, it is advantageous to mix it with water. In this case, the solvent preferably also contains water.

[0294] In this 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 this reaction. This can be done, for example, by injecting an inert gas, which is inert to the reaction, through the reaction mixture or by applying a vacuum. Therefore, in a preferred embodiment, a gas other than CO2, preferably selected from argon, nitrogen, and mixtures of oxygen and nitrogen containing 1-8 vol% oxygen relative to the total oxygen / nitrogen mixture, is injected through the reaction mixture during the reaction; or alternatively or additionally, the reaction is carried out under reduced pressure. Specifically, nitrogen is used to remove CO2. The inert gas is typically used at a flow rate of 1-200 l / h, preferably 1-80 l / h, more preferably 1-50 l / h, and especially 1-20 l / h. On an industrial scale, the flow rate can, of course, be significantly higher, for example, up to 5000 l / h.

[0295] This reaction can be carried out in the presence of additives that accelerate the reaction rate. Typical additives are diethyl phosphite, borate esters, and zinc salts. Suitable zinc salts include, for example, zinc halides, zinc acetate, or zinc trifluoromethanesulfonate. Specifically, diethyl phosphite or zinc salts, especially zinc acetate, are used. The additive is preferably used in an amount such that the molar ratio of the additive to compound 1 is in the range of 1:10000-10:1, especially 1:10000-5:1, specifically 1:10000-2:1, for example, 1:10000-1:2 or 1:10000-1:10.

[0296] The reaction is preferably carried out at a temperature between -20°C and 120°C. The optimal temperature depends particularly on the catalyst used. For example, higher reaction temperatures may be advantageous for some Ru catalysts, thus in which case the reaction temperature can also be in the range of 30-100°C, for example, 50-90°C, while in the case of Rh and Ir, lower reaction temperatures are sufficient, thus in which case the reaction temperature is preferably in the range of -20°C to 30°C, especially in the range of -15°C to 25°C. However, Ru catalysts also work at temperatures within this range, especially in the range of 10-30°C.

[0297] The reaction time depends on various factors, such as reaction temperature, the concentration of reactants in the reaction mixture, etc. It is typically in the range of about 0-48 h, preferably 1-16 h. A reaction time of "0 h" means, in this context, that after all components have been completely added, the reaction can be fully completed and the separation of the desired compound (I) can continue. This may be the case, for example, if the addition of reactants continues for a considerable period of time or if it is intended to recycle unreacted raw materials.

[0298] The reaction is typically carried out by mixing a reducing agent, an optional base (where mixing with the base is mandatory when formic acid is used as the sole reducing agent), a chiral catalyst (in preformed form or in the form of a catalyst precursor and chiral ligand), an optional solvent, and optional additives at the desired reaction temperature, or by mixing the components and then bringing the temperature to the desired range. The order of addition is not particularly critical.

[0299] For example,

[0300] (i) The reducing agent and optional base (in the case of formic acid as the sole reducing agent: the use of a base is mandatory) are added as a mixture or separately (where the separate additions can be made simultaneously or sequentially) to the mixture of Compound 1 and the chiral catalyst in a solvent; or

[0301] (ii) Add the chiral catalyst in the solvent to a mixture of compound 1, a reducing agent, an optional base (in the case of formic acid as the sole reducing agent: the base is mandatory), and an optional solvent (if the formate is used as the sole reducing agent and no liquid base is used: the solvent is mandatory); or

[0302] (iii) Add the reducing agent (optionally in a solvent) to a mixture of compound 1, a chiral catalyst, an optional base (in the case of formic acid as the sole reducing agent: the base is mandatory), and an optional solvent (if a liquid base is not used: the solvent is mandatory); or

[0303] (iv) Compound 1 in solvent is added to a mixture of a chiral catalyst, a reducing agent, an optional base (in the case of formic acid as the sole reducing agent: the use of a base is mandatory) and an optional solvent (if formate is used as the sole reducing agent and no liquid base is used: the use of a solvent is mandatory).

[0304] After the reaction is complete, the enantiomeric enriched form of the pyrimidinone of formula (I) is typically separated from the reaction mixture. Separation typically involves adding water to the reaction mixture, separating and optionally purifying the pyrimidinone of formula (I) precipitated upon the addition of water. Alternatively and preferably, separation involves setting the pH of the reaction mixture to acidic; removing at least a portion of the solvent (if any) to obtain a concentrate; adding water and a solvent that is poorly miscible or immiscible with water to the concentrate; extracting the pyrimidinone of formula (I) into a solvent that is poorly miscible or immiscible with water; and separating the pyrimidinone of formula (I) from the extract. The solvent that is poorly miscible or immiscible with water is preferably selected from 2-methyltetrahydrofuran, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl isopropyl ketone, and chlorobenzene.

[0305] If necessary, the catalyst can be recycled. For this purpose, the catalyst can be recovered, for example, from the reaction mixture obtained after reduction or from one or more liquid phases obtained after the post-treatment following the pyrimidinone of formula (I). (Depending on the solvent used in the reaction and post-treatment, the catalyst may be found in an aqueous phase, an organic phase, or both.) In one embodiment, only the transition metal is recovered, not the entire catalyst. This metal can be recovered, for example, by adsorption onto a suitable adsorbent material, such as charcoal or resin. For this purpose, the adsorbent material is added to the reaction mixture obtained after reduction or to one or more liquid phases obtained in the post-treatment. On a larger scale, the reaction mixture obtained after reduction or one or more liquid phases obtained in the post-treatment 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 carried out by elution (especially when using resin), but typically simply by burning the adsorbent material. The metal can then be refined 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 in the post-treatment that does not contain compound (I) by removing the solvent from the phase and burning the residue. The metal can then be refined and converted into the desired catalyst or catalyst precursor by known methods and reused in the reduction process. If the liquid phase is aqueous, it is advantageous to extract the catalyst from it into a suitable organic solvent before proceeding with the treatment.

[0306] Compound 1 can be obtained by reacting N-methylthiourea with alkyl 2-phenylmalonate to 6-hydroxy-3-methyl-5-phenyl-2-thioalkylpyrimidin-4-one or the corresponding thiolate, and then reacting it with 2-chloro-1-(2-chlorothiazol-5-yl)ethyl ketone to regenerate compound 1. These reactions are described in more detail in European application number 21153040.7.

[0307] N-methylthiourea and alkyl 2-phenylmalonate are commercially available. 2-Chloro-1-(2-chlorothiazol-5-yl)ethyl ketone can be prepared, for example, as described in WO 2018 / 197541 or WO 2018 / 202654, by reacting 2-chlorothiazolium with a Grignard reagent to the corresponding chloro-(2-chlorothiazol-5-yl)magnesium substance and then reacting it with 2-chloro-N-methoxy-N-methylacetamide. 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.

[0308] The method of the present invention yields compound (I) with high yield and high stereoselectivity.

[0309] Furthermore, this invention relates to 2-[2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (I), its tautomers, and their enantiomeric enriched forms:

[0310]

[0311] Formula (I) is equivalent to Formula (I) shown in the method of the present invention; however, Formula (I) shown in the method of the present invention more clearly shows the stereosource center of the molecule.

[0312] This invention particularly relates to enantiomeric excess, preferably at least 55% ee, more preferably at least 60% ee, even more preferably at least 70% ee, especially at least 80% ee, specifically at least 90% ee, of the formula (IS) 2-[(2S)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one and its tautomers:

[0313]

[0314] In another specific embodiment, the invention relates to enantiomeric excess, preferably at least 55% ee, more preferably at least 60% ee, even more preferably at least 70% ee, especially at least 80% ee, specifically at least 90% ee, of the formula (IR) 2-[(2R)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one and its tautomers:

[0315]

[0316] Compound (I) can be converted to 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- in only one additional step. -5-alkoxides, especially their enantiomeric enriched forms. To this end, compound (I) is internally cyclized via nucleophilic attack of the unsubstituted nitrogen atom of the pyrimidine ring on the carbon atom with an aliphatic OH group. This reaction is described in European application number 21153038.1.

[0317] Therefore, the present invention also relates to 2-[2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (I) or its tautomers or enantiomers enriched in 2,3-dihydrothiazo[3,2-a]pyrimidine The compound, specifically, is 3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- Use as an intermediate in the preparation of 5-alkoxides and their enantiomer-enriched forms.

[0318] Although compound (I) can be converted to 3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- in just one step -5-alkoxides and their enantiomer-enriched forms, but they can also be modified first, such as etherification of the hydroxyl group on the pyrimidine ring, substitution of the Cl atom on the thiazole ring, or introduction of substituents on the phenyl ring, to allow the formation of 3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- 2,3-Dihydrothiazo[3,2-a]pyrimidines other than 5-olates Compounds.

[0319] The invention is further illustrated in the following embodiments. Example

[0320] abbreviation:

[0321] DIPEA (diisopropylethylamine)

[0322] DMAC N,N-dimethylacetamide

[0323] DMF N,N-dimethylformamide

[0324] DMSO (dimethyl sulfoxide)

[0325] Ethyl acetate (EtOAc)

[0326] Me-THF 2-methyltetrahydrofuran

[0327] THF tetrahydrofuran

[0328] TEA Triethylamine

[0329] TFA (trifluoroacetic acid)

[0330] rt room temperature

[0331] t time

[0332] h hours

[0333] min minutes

[0334] rt retention time

[0335] method

[0336] Compounds were characterized by high performance liquid chromatography / mass spectrometry (HPLC / MS), NMR, or melting point.

[0337] HPLC method: Agilent Eclipse XDB-C18, 150mm × 4.6mm ID × 5μm

[0338] Gradient A = 0.5% H₂SO₄ aqueous solution, B = acetonitrile

[0339] Flow rate = 1.1 mL / min, column oven temperature = 30℃

[0340] Gradient program = 20%B - 100%B - 15min

[0341] Running time = 15min

[0342] Chiral HPLC method: Agilent series 1260, Chiralpak AD-RH 5μm 150*4.6mm

[0343] Gradient A = 0.1% H3PO4 aqueous solution, B = acetonitrile / 2-propanol (1:1).

[0344] Flow rate = 1.2 mL / min, column oven temperature = 50℃

[0345] gradient procedure

[0346] 0 30 1.2 10 50 1.2 15 100 1.2 20 100 1.2 20.1 50 1.2

[0347] Running time = 25 minutes

[0348] LCMS Method 1: C18 column (50mm × 2.1mm × 1.7μm)

[0349] Gradient A = 0.1% TFA aqueous solution, B = acetonitrile

[0350] Flow rate = 0.8 mL / min to 1.0 mL / min over 1.5 min, column oven temperature = 60℃

[0351] Gradient program = 10% B to 100% B over 15 min, hold at 100% B for 1 min, then reduce to 10% B for 1 min.

[0352] Run time: 1.75 min

[0353] 1¹H-NMR: The signal is characterized by its chemical shift (ppm) relative to tetramethylsilane, its multiplicity, and its integral (for a given relative number of hydrogen atoms). The following abbreviations are used to characterize the multiplicity of the signal: m = multiply, q = quartet, t = triplet, d = doublet, s = singlet, dd = doublet. Example 1: Preparation of 2-[(2S)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one

[0354] 1.1 Preparation of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one

[0355] In a 20L jacketed reactor, a solution of N-methylthiourea (778 g, 8.38 mol), NaOCH3 (1584 g, 8.79 mol, 30 wt% methanol solution), and methanol (384 g, 12 mol) was heated to an internal temperature of 65°C under N2. Then, over 30 min, diethyl 2-phenylmalonate (2121 g, 8.79 mol) was added, and the pump was washed with methanol (384 g, 12 mol). The reaction was then stirred at an internal temperature of 65°C for 4 h, followed by stirring at 50°C for 18 h. A suspension was formed during this time. Then, over 30 min, a solution of 2-chloro-1-(2-chlorothiazol-5-yl)acetone (1859 g, 9.00 mol) in ethanol (8.050 g, 175 mol) was added. The reaction was stirred at 50°C for 75 min, resulting in a large amount of solid precipitate. Ethanol (2.300 g, 50 mol) was added at this point, and the stirring speed was increased. The reaction was stirred at 50 °C for another 36 h, and then cooled to 20 °C over 16 h. The resulting solid was then separated by filtration in three 4 L sintered funnels. Each filter cake was washed with 500 mL of ethanol. The filter cake was then returned to a 20 L reactor and slurried with 15 L of water at 75 °C for 1 h. The slurry was then filtered in two 4 L sintered funnels, and each filter 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 title compound was separated as a brown solid with a purity of 99 wt%.

[0356] 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).

[0357] 1.2 Preparation of 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (IS)

[0358] A solution of 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (20.0 g, 50.4 mmol, 99% purity, 1.00 eq) and 158.3 g of dimethylacetamide was cooled to -5 °C and nitrogen injection was turned on (pump, 13 Nl / h). A mixture of 6.0 g formic acid (1.54 eq) and diisopropylethylamine (0.375 eq) (molar ratio 4.1:1) was added, followed by a solution of the preformed 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 10 g of dimethylacetamide. The reaction mixture was stirred for 2 hours, and then H₂SO₄ (10 g, 100 mmol, 98% purity) was added over 2 hours, maintaining an internal temperature <0 °C. The pressure on the reactor was reduced to 5 mbar and the temperature on the hood was increased to 57 °C to remove 117 g of dimethylacetamide by distillation. Then 178 g of 2-methyltetrahydrofuran and 100 g of water were added to the reactor. The two phases formed were homogenized for 15 min 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 min 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 with the addition of 170 g of 2-methyltetrahydrofuran. The two phases were homogenized for 15 min and then separated. The bottom aqueous phase was removed from the reactor. The 2-methyltetrahydrofuran phase was then returned to the reactor, the pressure reduced to 350 mbar, and the hood set to 59 °C to remove water via a Dean-Stark trap azeotropic reaction until <200 ppm of water remained in the 2-methyltetrahydrofuran phase. Removal of the 2-methyltetrahydrofuran phase yielded the title product in 87% yield and 95% ee.

[0359] 1 ¹H NMR (400 MHz, 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). Example 2: Preparation of 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (IR) using various reaction conditions.

[0360] The procedure is similar to that in Example 1.2, but uses 1 g of starting compound, DMF (2 ml) as solvent, the catalysts and conditions compiled in the table below, the reaction is carried out at room temperature and the reaction mixture is quenched with ethanol. The catalyst is used in preformed form by the reaction of the catalyst precursor and asymmetric ligand shown, or is generated in situ by adding the catalyst precursor and asymmetric ligand shown to the reaction mixture.

[0361]

[0362] 1 cat.prec. = catalyst precursor

[0363] 2 asym.lig. = asymmetric ligand

[0364] 3 is = (catalyst formed in situ from the catalyst precursor and asymmetric ligand shown); pre. = (catalyst preformed from the catalyst precursor and asymmetric ligand shown).

[0365] 4 Catalyst amount (calculated as a metal content), mol%, relative to the amount of 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (mol)

[0366] 5 Formic acid:amine molar ratio. This is shown when formate salts are used instead of formic acid, and the molar ratio is not given; see [link to relevant documentation]. 6 .

[0367] The amount of HCOOH used is given in molar equivalents relative to the amount (mol) of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one used.

[0368] 6 Instead of formic acid / amine, use sodium formate and water (2 ml).

[0369] 7

[0370] 8

[0371] 9 cym = p-Isopropyltoluene

[0372] Example 3: Preparation of 2-[(2R)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one under various reaction conditions

[0373] The procedure is similar to that in Example 1.2, but uses the catalyst and conditions compiled in the table below and is carried out at 0°C.

[0374]

[0375] Example 4: Preparation of 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (IS) under various reaction conditions

[0376] The procedure is similar to that in Example 1.2, but uses the solvents compiled in the table below.

[0377] 18 DMAC / sulfolane (1:1 v / v) >95 19 DMSO / THF (1:1 v / v) 91 20 DMSO / ethyl acetate (1:1 v / v) 100

[0378] Example 5: Preparation of 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (IS) under various reaction conditions

[0379] The procedure is similar to that of Example 1.2, but uses 400 mg of the starting compound and 7 ml of solvent, wherein the solvent, catalyst, and conditions are compiled in the table below. The catalyst is used in preformed form by the reaction of the catalyst precursor and asymmetric ligand shown, or generated in situ by adding the catalyst precursor and asymmetric ligand shown to the reaction mixture. The reaction is carried out at room temperature, except for Examples 21 and 22 (-5°C) and Examples 23, 25, 40, 42, 45, 48, and 50 (0°C).

[0380]

[0381]

[0382] 10 catalyst:

[0383] Cat. 1: The catalyst Rh(III)ClCp*(1S,2S-MsDPEN) of the following formula is obtained by reacting [Rh(III)Cl2Cp*]2 with 1S,2S-MsDPEN:

[0384]

[0385] Cat.2: The catalyst RuClMes(1S,2S-TsDPEN) of the following formula; preforming; by making [RuCl2(mes) 8 The reaction of ]2 with 1S,2S-TsDPEN yields:

[0386]

[0387] Cat.2*: Similar to 2, but formed in situ.

[0388] Cat. 3: The catalyst RuClMes(1S,2S-MsDPEN) of the following formula is obtained by making [RuCl2(mes...] 8 The reaction of )]2 with 1S,2S-MsDPEN yields:

[0389]

[0390] Cat. 4: Catalyst RuClMes(1S,2S-CsDPEN), by making [RuCl2(mes 8 Cat. 5: The catalyst RuClMes (1S,2S-TsDiOMeDPEN) of the following formula is reacted with 1S,2S-CsDPEN (more precisely, N-[(1S,2S)-2-amino-1,2-diphenylethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxonorbornen-1-yl]methanesulfonamide) to give Cat. 5: the catalyst RuClMes (1S,2S-TsDiOMeDPEN) of the following formula, by reacting [RuCl2(mes... 8 The reaction of ]2 with N-[(1S,2S)-2-amino-1,2-bis(4-methoxyphenyl)ethyl]-4-methylbenzenesulfonamide yields:

[0391]

[0392] Cat. 6: The catalyst RuClMes(1S,2S-) is of the following formula. (Base DPEN), by making [RuCl2(mes) 8 )]2 and 1S,2S- Obtained by the DPEN reaction

[0393]

[0394] Cat. 7: The catalyst RuClMes(1S,2S-RsDPEN) of the following formula is obtained by making [RuCl2(mes)] 8 The reaction of 2 with 1S,2S-RsDPEN yields

[0395]

[0396] Example 6: Preparation of 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (IR)

[0397] The procedure was similar to that in Example 1.2, but used 4 g (9.93 mmol) of the starting compound, ethanol (46 g) as the solvent, triethylamine as the base (5.98 mmol; 0.6 eq.), 27.09 mmol (2.73 eq.) of formic acid (formic acid:base = 4.5:1) and C-3-tethr-RuCl-1R,2R-TsDPEN as the catalyst (4 mol%):

[0398]

[0399] The title product was obtained with a yield of 86% and an ee of 87%.

[0400] Example 7: Preparation of 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (IS) under various reaction conditions

[0401] The procedure was similar to that of Example 1.2, but the reaction conditions compiled in the table below were used and the reaction was carried out at -5°C to 2°C. The solvent was DMAC, except in Examples 51 and 67, where DMF was used, and in Example 70, where DMSO was used. The catalyst was used in preform form via the reaction of the catalyst precursor and asymmetric ligand shown, or produced in situ by adding the catalyst precursor and asymmetric ligand shown to the reaction mixture. Results were obtained at 94-98% ee (15%) throughout the experiment.

[0402]

[0403]

[0404] **N-[(1S,2S)-2-amino-1,2-diphenylethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxonorbornen-1-yl]methanesulfonamide

[0405] # Additionally, in the presence of 5 mol% diethyl phosphite

[0406] ## Additionally, in the presence of 0.0125 mol% zinc acetate, the product was obtained with >99% ee.

[0407] Example 8: Preparation of 2-[(2R)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (IR) using various stereoisomers of (1R,2R)-CsDPEN as ligands

[0408] To demonstrate that the configuration of the camphor moiety of the CsDPEN ligand has little effect on the stereoselectivity in the product (I) of the reaction of 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one 1, two different (1R,2R)-CsDPEN stereoisomers, namely N-[(1R,2R)-2-amino-1,2-diphenylethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxonorbornan-1-yl]methanesulfonamide and N-[(1R,2R)-2-amino-1,2-diphenylethyl]-1-[(1R,4S)-7,7-dimethyl-2-oxonorbornan-1-yl]methanesulfonamide, were hydrogenated. The reaction was carried out similarly to that in Example 1.2, using DMAC as solvent, 1.2 eq. formic acid, 0.8 eq. diisopropylethylamine as base, and 0.2 mol% catalyst RhClCp*(1R,2R-CsDPEN-1) (by mixing [Rh(III)Cl2Cp*]2, N-[(1R,2R)-2-amino-1,2-diphenylethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxo-diethyl]-1-[ ... The reaction is formed in situ by mixing [Rh(III)Cl2Cp*]2, N-[(1R,2R)-2-amino-1,2-diphenylethyl]-1-[(1R,4S)-7,7-dimethyl-2-oxonorbornan-1-yl]methanesulfonamide and diisopropylethylamine in a molar ratio of 1:3:7. The reaction is carried out at -5 °C.

[0409] The reaction using RhClCp*(1R,2R-CsDPEN-1) as a catalyst was obtained with an enantiomeric purity of 97% ee (IR) (conversion: 95%); the reaction using RhClCp*(1R,2R-CsDPEN-2) as a catalyst was obtained with an enantiomeric purity of 98% ee (IR) (conversion: 98%).

Claims

1. A method for preparing enantiomeric enriched forms of 2-[2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or tautomers thereof of formula (I): Among the asterisks Display the center of the stereo source; The method comprises reducing 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomer of formula 1 with a reducing agent in the presence of a chiral transition metal catalyst and optionally a base: The reducing agent is selected from formic acid HC(=O)OH, formula HC(=O)O - M + Formate salts and formic acid HC(=O)OH and one or more of the formula HC(=O)O - M + A mixture of formates, wherein M + It is a cationic equivalent; wherein, when formic acid is used as a reducing agent, the reaction is carried out in the presence of a base; To obtain pyrimidinones of formula (I) or their tautomers in the enantiomeric enriched form; The chiral transition metal catalyst is selected from Ru, Rh, and Ir catalysts, and comprises one or more chiral ligands coordinated with the transition metal, wherein the chiral ligand is selected from 1,2-diphenyl-1,2-ethylenediamine of formula (II) in chiral form: in The asterisk indicates the center of the stereo source; R 5 and R 6 They are independently selected from C1-C4 alkoxy groups; R 7 and R 8 One of them is SO2R 9 And R 7 and R 8 The other is selected from hydrogen, C1-C4 alkyl and -L-phenyl, wherein the phenyl ring optionally has 1, 2, 3, 4 or 5 substituents selected from C1-C4 alkyl; L is a linker group selected from C2-C6 alkylene groups; R 9 The group is selected from C1-C4 alkyl, phenyl, phenyl-C1-C3 alkyl, wherein the phenyl group in either of the above groups optionally has 1, 2, 3, 4 or 5 substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; and C7 bicycloalkylmethyl, wherein the bicycloalkyl ring is substituted by 1, 2 or 3 substituents selected from C1-C4 alkyl and oxo; and m and n are independently 0 or 1; The catalyst further contains a halogen ligand, and wherein in R 7 and R 8 Neither of them are -L-phenyl or SO2R 9 , where R 9 In the case of a phenyl-C1-C3 alkyl group, the catalyst additionally contains a component selected from Cp, Cp Benzene, p-isopropyltoluene ligands of hexamethylbenzene.

2. The method according to claim 1, wherein M + Selected from alkali metal cations, formula [NHR] 1 R 2 R 3 ] + ammonium cations, of which R 1 R 2 and R 3 Independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, and C1-C4 alkoxy-C1-C4 alkyl, formula NR 1 R 2 -A-NR 3 R 4 The protonated diamine, in which R 1 R 2 R 3 and R 4 The rings are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, and C1-C4 alkoxy-C1-C4 alkyl, and A is (CH2)2 or (CH2)3; and protonated 5- or 6-membered saturated heterocycles containing a nitrogen atom as a ring member and optionally containing another heteroatom selected from N and O as a ring member, wherein the rings optionally have 1-6 C1-C4 alkyl groups and / or 1 or 2 OH groups.

3. The method of claim 2, wherein M + Selected from 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] + Protonated N,N,N',N'-tetramethylethylenediamine, protonated N,N,N',N'-tetramethyl-1,3-propanediamine, 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.

4. The method of claim 2, wherein M + Selected from Na + K + [NH(C2H5)3] + [NH(CH2CH2CH2CH3)3] + and [NH(C2H5)(CH(CH3)2] + .

5. The method of claim 1, wherein the base is selected from alkali metal hydroxides, formula NR 1 R 2 R 3 amines, of which R 1 R 2 and R 3 Independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, and C1-C4 alkoxy-C1-C4 alkyl, wherein R 1 R 2 and R 3 At least one of them is not hydrogen; formula NR 1 R 2 -A-NR 3 R 4 diamine, wherein R 1 R 2 R 3 and R 4 The base is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, and C1-C4 alkoxy-C1-C4 alkyl, and A is (CH2)2 or (CH2)3; and a 5- or 6-membered saturated heterocycle containing a nitrogen atom as a ring member and optionally containing another heteroatom selected from N and O as a ring member, wherein the ring optionally has 1-6 C1-C4 alkyl groups and / or 1 or 2 OH groups, wherein the base is optionally used in a supported form.

6. The method of claim 2, wherein the base is selected from alkali metal hydroxides, formula NR 1 R 2 R 3 amines, of which R 1 R 2 and R 3 Independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, and C1-C4 alkoxy-C1-C4 alkyl, wherein R 1 R 2 and R 3 At least one of them is not hydrogen; formula NR 1 R 2 -A-NR 3 R 4 diamine, wherein R 1 R 2 R 3 and R 4 The base is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, and C1-C4 alkoxy-C1-C4 alkyl, and A is (CH2)2 or (CH2)3; and a 5- or 6-membered saturated heterocycle containing a nitrogen atom as a ring member and optionally containing another heteroatom selected from N and O as a ring member, wherein the ring optionally has 1-6 C1-C4 alkyl groups and / or 1 or 2 OH groups, wherein the base is optionally used in a supported form.

7. The method according to claim 5 or 6, wherein the base is selected from 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'-tetramethyl-1,3-propanediamine, 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.

8. The method according to claim 5 or 6, wherein the base is selected from NaOH, KOH, triethylamine, tributylamine and diisopropylethylamine.

9. The method of claim 1, wherein formic acid is used as a reducing agent, and wherein formic acid and the base are used in a molar ratio of 100:1 to 1:

10.

10. The method of claim 2, wherein formic acid is used as a reducing agent, and wherein formic acid and the base are used in a molar ratio of 100:1 to 1:

10.

11. The method of claim 5, wherein formic acid is used as a reducing agent, and wherein formic acid and the base are used in a molar ratio of 100:1 to 1:

10.

12. The method of claim 6, wherein formic acid is used as a reducing agent, and wherein formic acid and the base are used in a molar ratio of 100:1 to 1:

10.

13. The method according to any one of claims 9-12, wherein formic acid is used as a reducing agent, and wherein formic acid and the base are used in a molar ratio of 10:1 to 1:

5.

14. The method according to any one of claims 9-12, wherein formic acid is used as a reducing agent, and wherein formic acid and the base are used in a molar ratio of 10:1 to 1:

2.

15. The method according to any one of claims 9-12, wherein formic acid is used as a reducing agent, and wherein formic acid and the base are used in a molar ratio of 5:1 to 1:

1.

16. The method according to any one of claims 1-6 and 9-12, wherein the chiral transition metal catalyst is selected from Rh and Ir catalysts.

17. The method according to any one of claims 1-6 and 9-12, wherein the chiral transition metal catalyst is used in an amount of 0.01-10 mol% relative to 1 mol of compound 1, calculated based on the transition metal content.

18. The method of claim 16, wherein the chiral transition metal catalyst is used in an amount of 0.01-10 mol% relative to 1 mol of compound 1, calculated based on the transition metal content.

19. The method of claim 17, wherein the chiral transition metal catalyst is used in an amount of 0.05-5 mol% relative to 1 mol of compound 1, calculated based on the transition metal content.

20. The method of claim 17, wherein the chiral transition metal catalyst is used in an amount of 0.1-5 mol% relative to 1 mol of compound 1, calculated based on the transition metal content.

21. The method of claim 20, wherein the chiral transition metal catalyst is used in an amount of 0.1-2 mol% relative to 1 mol of compound 1, calculated based on the transition metal content.

22. The method according to any one of claims 1-6 and 9-12, wherein the chiral transition metal catalyst is preformed and contains one or more chiral ligands coordinated with the transition metal; or is formed in situ by reacting a transition metal precursor compound with one or more chiral ligands.

23. The method of claim 18, wherein the chiral transition metal catalyst is preformed and contains one or more chiral ligands coordinated with the transition metal; or is formed in situ by a reaction of a transition metal precursor compound with one or more chiral ligands.

24. The method according to any one of claims 1-6 and 9-12, wherein the chiral transition metal catalyst is selected from those containing Ru, Rh or Ir as the central metal and at least one selected from the (1R,2R) or (1S,2S) form of DPEN, TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, Trips DPEN, CsDPEN, Catalysts containing chiral ligands of DPEN, RsDPEN, TsDiOMeDPEN, or compounds of formula (II), wherein R in formula (II) 7 SO2R 9 , where R 9 It is a C1-C4 alkyl group or optionally a phenyl group with one, two, or three substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups; R 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0.

25. The method of claim 23, wherein the chiral transition metal catalyst is selected from those containing Ru, Rh, or Ir as a central metal and at least one selected from the (1R,2R) or (1S,2S) form of DPEN, TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, Trips DPEN, CsDPEN, Catalysts containing chiral ligands of DPEN, RsDPEN, TsDiOMeDPEN, or compounds of formula (II), wherein R in formula (II) 7 SO2R 9 , where R 9 It is a C1-C4 alkyl group or optionally a phenyl group with one, two, or three substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups; R 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0.

26. The method of claim 24, wherein the chiral transition metal catalyst is selected from those containing Ru, Rh, or Ir as a central metal and at least one selected from the (1R,2R) or (1S,2S) form of DPEN, TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, Trips DPEN, CsDPEN, Catalysts containing ligands of DPEN, RsDPEN, and TsDiOMeDPEN; and catalysts containing ligands of formula (II) with Ru as the central metal and at least one ligand selected from the (1R,2R) or (1S,2S) form, wherein R in formula (II) 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or optionally a phenyl group with one, two, or three substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0.

27. The method of claim 26, wherein the chiral transition metal catalyst is selected from those containing Ru, Rh, or Ir as a central metal and at least one selected from the (1R,2R) or (1S,2S) form of TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, Catalysts containing ligands of DPEN, RsDPEN, and TsDiOMeDPEN; and catalysts containing ligands of formula (II) with Ru as the central metal and at least one ligand selected from the (1R,2R) or (1S,2S) form, wherein R in formula (II) 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or optionally a phenyl group with one, two, or three substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0.

28. The method of claim 24, wherein in R 7 and R 8 Neither of them are -L-phenyl or SO2R 9 , where R 9 In the case of a phenyl-C1-C3 alkyl group, the catalyst additionally contains a component selected from Cp. Benzene, p-isopropyltoluene ligands of hexamethylbenzene.

29. The method according to any one of claims 25-27, wherein in R 7 and R 8 Neither of them are -L-phenyl or SO2R 9 , where R 9 In the case of a phenyl-C1-C3 alkyl group, the catalyst additionally contains a component selected from Cp. Benzene, p-isopropyltoluene ligands of hexamethylbenzene.

30. The method of claim 28, wherein in R 7 and R 8 Neither of them are -L-phenyl or SO2R 9 , where R 9 In the case of a phenyl-C1-C3 alkyl group, the catalyst additionally contains a component selected from Cp. p-Isopropyltoluene and ligands.

31. The method according to any one of claims 1-6 and 9-12, for preparing 2-[(2S)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers of formula (IS) in enantiomeric excess of at least 55% ee: Chiral transition metal catalysts are used in this process. The chiral transition metal catalyst comprises Ru, Rh, or Ir as the central metal and contains a compound selected from (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-FsDPEN, and (1S,2S)-Trips. DPEN, (1S,2S)-CsDPEN, (1S,2S)- Chiral ligands of compounds of formula (II) in the form of (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S)-RsDPEN, where R is a base DPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S)-TsDiOMeDPEN, are provided. 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or optionally a phenyl group with one, two, or three substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0; Alternatively, it can be used to prepare 2-[(2R)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers in formula (IR) with an enantiomeric excess of at least 55% ee: The catalyst used is a chiral transition metal catalyst comprising Ru, Rh, or Ir as a central metal and containing a compound selected from (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-FsDPEN, and (1R,2R)-Trips. DPEN, (1R,2R)-CsDPEN, (1R,2R)- Chiral ligands of compounds of formula (II) in the form of DPEN, (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN, and (1R,2R) are provided, where R is a ligand in formula (II). 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or optionally a phenyl group with one, two, or three substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0.

32. The method of claim 29, for preparing 2-[(2S)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers of formula (IS) in an enantiomeric excess of at least 55% ee: The catalyst used is a chiral transition metal catalyst comprising Ru, Rh, or Ir as a central metal and containing a compound selected from (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-FsDPEN, and (1S,2S)-Trips. DPEN, (1S,2S)-CsDPEN, (1S,2S)- Chiral ligands of compounds of formula (II) in the form of (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S)-RsDPEN, where R is a base DPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S)-TsDiOMeDPEN, are provided. 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or optionally a phenyl group with one, two, or three substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0; Alternatively, it can be used to prepare 2-[(2R)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers in formula (IR) with an enantiomeric excess of at least 55% ee: The catalyst used is a chiral transition metal catalyst comprising Ru, Rh, or Ir as a central metal and containing a compound selected from (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-FsDPEN, and (1R,2R)-Trips. DPEN, (1R,2R)-CsDPEN, (1R,2R)- Chiral ligands of compounds of formula (II) in the form of DPEN, (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN, and (1R,2R) are provided, where R is a ligand in formula (II). 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or optionally a phenyl group with one, two, or three substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0.

33. The method of claim 31, used to prepare, in an enantiomeric excess of at least 60% ee, 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers of formula (IS) or 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers of formula (IR).

34. The method of claim 31, used to prepare, in enantiomeric excess of at least 70% ee, 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers of formula (IS) or 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers of formula (IR).

35. The method of claim 31, for preparing 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomer of formula (IS) or 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomer of formula (IR) in an enantiomeric excess of at least 80% ee.

36. The method of claim 31, for preparing 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomer of formula (IS) or 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomer of formula (IR) in an enantiomeric excess of at least 90% ee.

37. The method of claim 31 for preparing 2-[(2S)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers in formula (IS) with an enantiomeric excess of at least 70% ee, wherein the chiral transition metal catalyst comprises Ru, Rh or Ir as a central metal and comprises a material selected from (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-FsDPEN, (1S,2S)-Trips DPEN, (1S,2S)-CsDPEN, (1S,2S)- Chiral ligands of DPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN; or catalysts comprising Ru as a central metal and at least one ligand selected from compounds of formula (II) in the (1S,2S) form, wherein R 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or optionally a phenyl group with one, two, or three substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0; Alternatively, it can be used to prepare 2-[(2R)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers in the form of (IR) with an enantiomeric excess of at least 70% ee, wherein the chiral transition metal catalyst comprises Ru, Rh or Ir as a central metal and contains a compound selected from (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-FsDPEN, (1R,2R)-Trips DPEN, (1R,2R)-CsDPEN, (1R,2R)- Chiral ligands of DPEN, (1R,2R)-RsDPEN, and (1R,2R)-TsDiOMeDPEN; or catalysts comprising Ru as a central metal and at least one ligand selected from compounds of formula (II) in the (1R,2R) form, wherein R 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or optionally a phenyl group with one, two, or three substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0.

38. The method of claim 37, wherein the preparation of 2-[(2S)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers in formula (IS) with an enantiomeric excess of at least 70% ee, wherein the chiral transition metal catalyst comprises Ru, Rh or Ir as a central metal and comprises a material selected from (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)- Chiral ligands of DPEN, (1S,2S)-RsDPEN, and (1S,2S)-TsDiOMeDPEN; or catalysts comprising Ru as a central metal and at least one ligand selected from compounds of formula (II) in the (1S,2S) form, wherein R 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or optionally a phenyl group with one, two, or three substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0; Alternatively, it can be used to prepare 2-[(2R)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers in formula (IR) with an enantiomeric excess of at least 70% ee, wherein the chiral transition metal catalyst comprises Ru, Rh or Ir as a central metal and contains a compound selected from (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)- Chiral ligands of DPEN, (1R,2R)-RsDPEN, and (1R,2R)-TsDiOMeDPEN; or catalysts comprising Ru as a central metal and at least one ligand selected from compounds of formula (II) in the (1R,2R) form, wherein R 7 SO2R 9 , where R 9 R is a C1-C4 alkyl group or optionally a phenyl group with one, two, or three substituents selected from C1-C4 alkyl and C1-C4 haloalkyl groups. 8 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0.

39. The method of claim 37 or 38, wherein the preparation is carried out in an enantiomeric excess of at least 80% ee of 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomer or of formula (IR).

40. The method of claim 37 or 38, wherein the preparation is carried out in an enantiomeric excess of at least 90% ee of 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomer or of formula (IR).

41. The method according to any one of claims 1-6 and 9-12, wherein a gas other than CO2 is injected through the reaction mixture during the reaction; or wherein, alternatively or additionally, the reaction is carried out under reduced pressure.

42. The method of claim 32, wherein a gas other than CO2 is injected through the reaction mixture during the reaction; or wherein, alternatively or additionally, the reaction is carried out under reduced pressure.

43. The method of claim 41, wherein the gas is selected from argon, nitrogen, and a mixture of oxygen and nitrogen containing 1-8% by volume oxygen relative to the total amount of the oxygen / nitrogen mixture.

44. The method according to any one of claims 1-6 and 9-12, wherein the reaction is carried out in the presence of an additive selected from diethyl phosphite, borate esters and zinc salts.

45. The method of claim 42, wherein the reaction is carried out in the presence of an additive selected from diethyl phosphite, borate esters and zinc salts.

46. ​​The method of claim 44, wherein the reaction is carried out in the presence of diethyl phosphite or a zinc salt.

47. The method of claim 44, wherein the additive is used in an amount such that the molar ratio of the additive to compound 1 is in the range of 1:10000 to 10:

1.

48. The method of claim 44, wherein the additive is used in an amount such that the molar ratio of the additive to compound 1 is in the range of 1:10000 to 1:

50.

49. 2-[2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (I), or its enantiomeric enriched form or its tautomer: Among the asterisks Display the center of the stereo source.

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