Process for the preparation of 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-olium-5-olate in enantiomerically enriched form

Abstract

The present invention relates to a process for the preparation of 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ol salts in enantiomerically enriched form.

Description

[0001] This invention relates to a method for preparing an enantiomeric enriched form of 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxide method. Furthermore, the present invention relates to 2-[2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its enantiomerically enriched form of Formula 2 as shown below, and its presence 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. Technical Background

[0002] 3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-Oxides and their enantiomer-enriched forms have insecticidal properties and are known, for example, by WO 2018 / 177970 or WO 2014 / 167084.

[0003] To date, the preparation of this pyrimidine is 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; R1 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, this is initiated from 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 latter 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 purpose of this invention is to provide a method for preparing 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- An economical method for preparing 5-alkoxides, particularly a method for preparing their enantiomer-enriched forms, which yields the S or R enantiomers with high selectivity.

[0014] This problem stems from a method for preparing an enantiomeric enriched form of formula (I) 3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- The solution is found using 5-alkoxides:

[0015]

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

[0017] The method includes:

[0018] (a) Reduction of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 1, or its tautomer or a mixture thereof, in the presence of a chiral transition metal catalyst and optionally a base, with a reducing agent:

[0019]

[0020] 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;

[0021] A reaction mixture containing enantiomeric enriched form of formula 2, 2-[2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomer or a mixture thereof, is obtained:

[0022] as well as

[0023] (b) React the reaction mixture obtained in step (a) with an activator that enhances the electrophilicity of the asterisked carbon atom in compound 1 without promoting racemization at the carbon atom;

[0024] Compound (I) in enantiomeric enriched form was obtained.

[0025] Furthermore, the present invention relates to 2-[2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one 2 or its tautomers or mixtures of different tautomers thereof and their enantiomeric enriched forms.

[0026] The present invention also relates to 2-[2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers or mixtures thereof or their enantiomeric enriched forms 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-alkoxide (I) and its enantiomer-enriched forms. Invention Details

[0028] definition

[0029] The "enantiomerically enriched form" of formula (I) is 3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxides or compounds in "enantiomer-enriched form" (I), and similar terms, denote non-racemic compounds (I) in which the S or R enantiomer is dominant or even the only stereoisomer. Compound (I) has a single stereosource center at a ring carbon atom marked with an asterisk and bearing a thiazole ring.

[0030] The term "enantiomer-enriched form" of Formula 2, 2-[2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one, or "enantiomer-enriched form" of Compound 2, and similar terms, denote non-racemic compound 2, wherein the S-enantiomer or R-enantiomer is dominant or even present as the sole stereoisomer. Compound 2 has a single stereosource center at an aliphatic carbon atom bearing an OH group and marked with an asterisk.

[0031] 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.

[0032] Formate, in the context of this invention, refers to salts 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.

[0033] The organic structural parts mentioned below, like the term halogen, are collective terms that enumerate individual group members. Prefix C n -Cm In each case, it indicates the possible number of carbon atoms in the group.

[0034] The term halogen in each case means fluorine, bromine, chlorine or iodine, especially fluorine, chlorine or bromine.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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).

[0041] 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.

[0042] "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).

[0043] 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.

[0044] The linear C3-C6 alkylene groups are -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-.

[0045] 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.

[0046] Oxidation is represented by =O; that is, the substituent "oxo" is replaced by a C (=O) group replacing a CH2 group.

[0047] 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.

[0048] Compound 1 can exist as its tautomer or a mixture of different tautomer forms. Examples of tautomer forms of compounds of formula 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] Compound 2 can also exist as its tautomer or a mixture of different tautomer forms. Examples of tautomer forms of compound 2 shown above have the following formula:

[0052]

[0053] A mixture of different tautomer forms is, for example, the tautomer above as a mixture of the tautomers shown in Equation 2.

[0054] For simplicity, only compounds 1 and 2 will be mentioned below. However, all embodiments also involve their tautomers and mixtures of their different tautomer forms.

[0055] The condensed zwitterionic ring of the compound of formula (I) is meso-stabilized. The meso form of this condensed ring can be represented, for example, by different isoelectronic formulas with positive and negative charges distributed on different atoms, as shown below:

[0056]

[0057]

[0058] Embodiment (Ex) of the present invention

[0059] General and preferred embodiments Ex are outlined in the following non-exhaustive enumeration. Other preferred embodiments become apparent in the paragraphs following this enumeration.

[0060] E.1. A method for preparing enantiomeric enriched form of 3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- The method using 5-alkoxides:

[0061]

[0062] The asterisk * indicates the center of the 3D source;

[0063] The method includes:

[0064] (a) Reduction of 2-[2-(2-chlorothiazo-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:

[0065]

[0066] 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;

[0067] A reaction mixture containing the enantiomeric enriched form of formula 2, 2-[2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one, was obtained:

[0068] as well as

[0069] (b) React the reaction mixture obtained in step (a) (without separating compound 2) with an activator that enhances the electrophilicity of the asterisked carbon atom in compound 1 without promoting racemization at the carbon atom.

[0070] Compound (I) in enantiomeric enriched form was obtained.

[0071] 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 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.

[0072] 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.

[0073] 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 3 At least one, preferably at least two, are C1-C6 alkyl groups.

[0074] E.5. According to the method of implementation scheme E.3 or E.4, where M + Selected from [NH(C2H5)3] + [NH(CH2CH2CH2CH3)3] + and [NH(C2H5)(CH(CH3)2] + .

[0075] E.6. The method according to any of the foregoing embodiments, wherein the base used in step (a) is optionally or mandatory 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 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 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.

[0076] E.7. The method according to embodiment E.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, wherein the base may be used in a supported form (i.e., on a support material).

[0077] E.8. The method according to implementation scheme E.6, 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.

[0078] E.9. The method according to implementation scheme E.7 or E.8, wherein the base is selected from triethylamine, tributylamine and diisopropylethylamine.

[0079] E.10. The method according to any of the foregoing embodiments, wherein formic acid is used as a reducing agent in step (a), wherein formic acid and the base are used in a molar ratio of 100:1 to 1:10.

[0080] E.11. The method according to implementation scheme E.10, wherein formic acid and the base are used in a molar ratio of 10:1 to 1:5.

[0081] E.12. The method according to implementation scheme E.11, wherein formic acid and the base are used in a molar ratio of 10:1 to 1:2.

[0082] E.13. The method according to implementation scheme E.12, wherein formic acid and the base are used in a molar ratio of 5:1 to 1:1.

[0083] E.14. 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.

[0084] E.15. The method according to embodiment E.14, wherein compound 1 and the reducing agent are used in a molar ratio of 1:1 to 1:5.

[0085] E.16. 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.

[0086] E.17. The method according to any of the foregoing embodiments, wherein the chiral transition metal catalyst used in step (a) is selected from group VIII metal catalysts.

[0087] E.18. The method according to embodiment E.17, wherein the chiral transition metal catalyst is selected from group 8 and 9 metal catalysts.

[0088] E.19. The method according to embodiment E.18, wherein the chiral transition metal catalyst is selected from Ru, Rh and Ir catalysts.

[0089] E.20. The method according to embodiment E.19, wherein the chiral transition metal catalyst is selected from Rh and Ir catalysts.

[0090] E.21. 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.

[0091] E.22. The method according to embodiment E.21, 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.

[0092] E.23. The method according to embodiment E.22, wherein the chiral transition metal catalyst is used in an amount of 0.1-5 mol%, for example 0.1-2 mol%, relative to 1 mol of compound 1, based on the transition metal content.

[0093] E.24. 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.

[0094] E.25. The method according to embodiment E.24, wherein the chiral ligand is selected from bidentate amino chiral ligands.

[0095] E.26. The method according to embodiment E.25, wherein the chiral ligand is selected from chiral 1,2-diphenyl-1,2-ethylenediamine, 1,2-cyclohexanediamine and 1,2-di(methylamino)cyclohexane.

[0096] E.27. The method according to embodiment E.26, wherein the chiral ligand is selected from chiral 1,2-diphenyl-1,2-ethylenediamine.

[0097] E.28. The method according to embodiment E.27, wherein the chiral ligand is selected from 1,2-diphenyl-1,2-ethylenediamine of formula (II) in chiral form:

[0098]

[0099] in

[0100] The asterisk indicates the center of the stereo source;

[0101] R 5 and R 6 They are independently selected from OH, halogens, C1-C4 alkyl groups, and C1-C4 alkoxy groups;

[0102] 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 ;

[0103] 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;

[0104] 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 ;

[0105] R 10It is hydrogen or C1-C4 alkyl;

[0106] 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

[0107] m and n are independent of each other and can be 0, 1, 2, 3, 4 or 5.

[0108] E.29. The method according to embodiment E.28, wherein in compound (II),

[0109] R 5 and R 6 It is a C1-C4 alkoxy group;

[0110] 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 ;

[0111] 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;

[0112] 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 ;

[0113] R 10 It is hydrogen or C1-C4 alkyl;

[0114] 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

[0115] Both m and n can be 0 or both can be 1, preferably both can be 0.

[0116] E.30. The method according to embodiment E.28 or E.29, 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.

[0117] E.31. The method according to embodiment E.30, 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; and m and n are 0.

[0118] E.32. The method according to implementation scheme E.31, wherein the chiral ligand is selected from TsDPEN, MsDPEN and CsDPEN in (1R,2R) or (1S,2S) form.

[0119] E.33. The method according to embodiment E.30, 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.

[0120] E.34. The method according to any one of embodiments E.31 and E.33, wherein the chiral transition metal catalyst is a catalyst containing 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.

[0121] E.35. The method according to embodiment E.33, 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.

[0122] E.36. 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 TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, etc., selected from the (1R,2R) or (1S,2S) form. Catalysts containing chiral ligands of DPEN, RsDPEN, and TsDiOMeDPEN; or catalysts containing Ru as a central metal and at least one chiral 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; and m and n are 0.

[0123] E.37. The method according to embodiment E.36, 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:

[0124]

[0125] E.38. The method according to embodiment E.37, wherein the chiral transition metal catalyst is a catalyst containing Ru, Rh or Ir as a central metal and a chiral ligand selected from the (1R,2R) or (1S,2S) form of TsDPEN, MeMsDPEN and CsDPEN.

[0126] E.39. The method according to any one of the implementation schemes E.28-E.31 and E.33-E.37, 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.

[0127] E.40. The method according to embodiment E.39, wherein the aromatic ring is selected from Cp, Cp*, benzene, p-isopropyltoluene, And hexamethylbenzene.

[0128] E.41. The method according to embodiment E.40, wherein the aromatic ring is selected from Cp*, benzene, p-isopropyltoluene, And hexamethylbenzene.

[0129] E.42. The method according to embodiment E.41, wherein the aromatic ring is selected from Cp*, p-isopropyltoluene, and

[0130] E.43. The method according to embodiment E.42, wherein the central metal is Rh or Ir and the aromatic ring is Cp*, or the central metal is Ru and the aromatic ring is p-isopropyltoluene or

[0131] E.44. The method according to any of the foregoing embodiments, wherein the chiral transition metal catalyst additionally contains one or two halogen or sulfonate ligands.

[0132] E.45. The method according to embodiment E.44, wherein the chiral transition metal catalyst additionally contains one or two halogen ligands.

[0133] E.46. The method according to embodiment E.45, wherein the chiral transition metal catalyst additionally contains one or two, preferably one Cl ligand.

[0134] E.47. The method according to any one of embodiments E.38-E.46, wherein the chiral transition metal catalyst is a chiral ligand containing Ru, Rh, or Ir as a central metal, selected from TsDPEN, MeMsDPEN, and CsDPEN in (1R,2R) or (1S,2S) form, and selected from Cp*, p-isopropyltoluene, and Catalysts containing ligands and halogen or sulfonate ligands, preferably Cl ligands.

[0135] E.48. The method according to any of the foregoing embodiments for preparing, in step (a) an enantiomeric excess of at least 55% ee of 2-[(2S)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-S:

[0136]

[0137] E.49. The method according to embodiment E.48 is used to prepare 2-[(2S)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of the formula 2-S in an enantiomeric excess of at least 60% ee.

[0138] E.50. The method according to embodiment E.49 is used to prepare 2-[(2S)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of the formula 2-S in an enantiomeric excess of at least 70% ee.

[0139] E.51. The method according to embodiment E.50 is used to prepare 2-[(2S)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of the formula 2-S in an enantiomeric excess of at least 80% ee.

[0140] E.52. The method according to embodiment E.51 is used to prepare 2-[(2S)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of the formula 2-S in an enantiomeric excess of at least 90% ee.

[0141] E.53. The method according to any one of embodiments E.48-E.52, 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... 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 ligand 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; and wherein the chiral ligand is preferably selected from (1S,2S)-TsDPEN, (1S,2S)-CF3TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)- 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)-RsDPEN, are given by 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.

[0142] E.54. The method according to embodiment E.53, wherein the chiral ligand is selected from (1S,2S)-TsDPEN, (1S,2S)-MsDPEN and (1S,2S)-CsDPEN.

[0143] E.55. A method according to any one of embodiments E.48-E.54, 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, 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... 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 catalyst is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl groups 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; wherein preferably the catalyst contains Ru, Rh or Ir as a central metal and contains 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 compounds of formula (II) in the form of (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and (1S,2S)-RsDPEN, 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 It is -(CH2)3-phenyl or -(CH2)4-phenyl; and m and n are 0.

[0144] E.56. A method according to any one of embodiments E.48-E.55, 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, 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. 8 The catalyst is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl groups 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; wherein preferably the catalyst contains Ru, Rh or Ir as a central metal and contains 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; and m and n are 0.

[0145] E.57. The method according to embodiment 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)-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 of the following formula:

[0146]

[0147] E.58. The method according to embodiment E.57, wherein the catalyst comprises Ru, Rh or Ir as a central metal and contains a chiral ligand selected from (1S,2S)-TsDPEN, (1S,2S)-MsDPEN and (1S,2S)-CsDPEN.

[0148] E.59. The method according to any one of embodiments E.1-E.47, for preparing 2-[(2R)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-R in enantiomeric excess at least 55% ee in step (a):

[0149]

[0150] E.60. The method according to embodiment E.59 is used to prepare 2-[(2R)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of the formula 2-R in an enantiomeric excess of at least 60% ee.

[0151] E.61. The method according to embodiment E.60 is used to prepare 2-[(2R)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of the formula 2-R in an enantiomeric excess of at least 70% ee.

[0152] E.62. The method according to embodiment E.61 is used to prepare 2-[(2R)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of the formula 2-R in an enantiomeric excess of at least 80% ee.

[0153] E.63. The method according to embodiment E.62 is used to prepare 2-[(2R)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of the formula 2-R in an enantiomeric excess of at least 90% ee.

[0154] E.64. The method according to any one of embodiments E.59-E.63, wherein the chiral transition metal catalyst comprises a material 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 The ligand 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; wherein preferably the chiral ligand is selected from (1R,2R)-TsDPEN, (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)- Compounds of formula (II) in the form of (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN, and (1R,2R) are denoted as 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.

[0155] E.65. The method according to embodiment E.64, wherein the chiral ligand is selected from (1R,2R)-TsDPEN, (1R,2R)-MsDPEN and (1R,2R)-CsDPEN.

[0156] E.66. The method according to any one of embodiments E.59-E.64, 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 The catalyst is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl groups 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; wherein preferably the catalyst contains Ru, Rh or Ir as a central metal and contains 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 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.

[0157] E.67. A method according to any one of embodiments E.59-E.66, 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 The catalyst is -(CH2)3-phenyl or -(CH2)4-phenyl, wherein the phenyl groups 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; wherein preferably the catalyst contains Ru, Rh or Ir as a central metal and contains 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; and m and n are 0.

[0158] E.68. The method according to embodiment E.67, wherein the chiral transition metal catalyst comprises Ru, Rh, or Ir as a central metal and contains a component selected from (1R,2R)-TsDPEN.

[0159] (1R,2R)-CF3TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN,

[0160] (1R,2R)-MeTsDPEN, (1R,2R)-CsDPEN, (1R,2R)- DPEN base

[0161] Chiral ligands of (1R,2R)-RsDPEN and (1R,2R)-TsDiOMeDPEN, or catalysts of the following formula:

[0162]

[0163] E.69. The method according to embodiment E.68, wherein the catalyst comprises Ru, Rh or Ir as a central metal and contains a chiral ligand selected from (1R,2R)-TsDPEN, (1R,2R)-MsDPEN and (1R,2R)-CsDPEN.

[0164] E.70. The method according to any of the foregoing embodiments, wherein the reaction in step (a) is carried out at a temperature of -20°C to 120°C.

[0165] E.71. The method according to embodiment E.70, wherein the reaction in step (a) is carried out at a temperature of -15°C to 25°C.

[0166] E.72. The method according to embodiment E.70, wherein the reaction in step (a) is carried out at a temperature of 30-100°C.

[0167] E.73. The method according to embodiment E.72, wherein the reaction in step (a) is carried out at a temperature of 50-90°C.

[0168] E.74. The method according to any of the foregoing embodiments, wherein the reactions in steps (a) and (b) are carried out in the presence of a solvent.

[0169] E.75. The method according to embodiment E.74, wherein the solvent is selected from polar aprotic solvents, C1-C4 alkyl esters of acetic acid, chlorinated alkanes, aromatic solvents, heterocyclic solvents, mixtures of the above solvents, and mixtures of the above solvents with water; wherein, in the case of using formic acid and / or a base that is liquid at the reaction temperature, at least the reaction in step (a) can be carried out purely.

[0170] E.76. The method according to embodiment E.75, wherein the solvent is selected from 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.

[0171] E.77. The method according to embodiment E.76, wherein the solvent is selected from dimethylformamide, dimethylacetamide, dichloromethane, trichloromethane, dichloroethane, α,α,α-trifluorotoluene (trifluorotoluene), fluorobenzene, chlorobenzene, dichlorobenzene, anisole (methoxybenzene), and mixtures thereof; particularly selected from dimethylformamide, dimethylacetamide, and mixtures thereof.

[0172] E.78. 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 in step (a); or wherein the reaction is carried out under reduced pressure, either alternatively or additionally.

[0173] E.79. The method according to embodiment E.78, 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.

[0174] E.80. The method according to implementation scheme E.79, wherein the gas other than CO2 is nitrogen.

[0175] E.81. The method according to any of the foregoing embodiments, wherein the reactions in steps (a) and (b) are carried out in the presence of an additive selected from diethyl phosphite, borate esters and zinc salts, wherein the zinc salt is preferably selected from zinc halide, zinc acetate and zinc trifluoromethanesulfonate.

[0176] E.82. The method according to embodiment E.81, wherein the additive is diethyl phosphite or a zinc salt. E.83. The method according to embodiment E.81 or E.82, wherein the additive is used in an amount such that the molar ratio of the additive to compound 1 is in the range of 1:10000 to 10:1.

[0177] E.84. The method according to implementation scheme E.83, wherein the molar ratio of additive to compound 1 is in the range of 1:10000 to 5:1.

[0178] E.85. The method according to embodiment E.84, wherein the molar ratio of additive to compound 1 is in the range of 1:10000 to 2:1.

[0179] E.86. The method according to any of the foregoing embodiments, wherein the activator used in step (b) is selected from P(OR) 1 )2Cl、P(OR 1 Cl2、P(=O)(OR 1 )2Cl、P(=O)(OR 1 Cl2, wherein each of the four compounds mentioned above contains R 1 Independently C1-C4 alkyl; PCl3, P(=O)Cl3, polyphosphoric acid, P4O 10 Mitsunobu-type reagents, triphenylphosphine in combination with halogenating agents, complexes of SO3 with Lewis bases selected from amines, carboxamides and heteroaromatic compounds containing 1, 2 or 3 basic nitrogen ring atoms; S(O)Cl2, CH3S(O)2Cl, carbonyl diimidazole (CDI), Vilsmeier reagent, complexes of N,N-dimethylformamide and / or N,N-dimethylacetamide with Lewis acids; and mixtures of two or more of the above activators.

[0180] E.87. The method according to embodiment E.86, wherein the activator used in step (b) is selected from P(OR) 1 )2Cl、P(OR 1 Cl2、P(=O)(OR 1 )2Cl, wherein each of the three compounds mentioned above contains R 1 Independently C1-C4 alkyl; PCl3, P(O)Cl3, SO3 / dimethylformamide complexes, SOCl2, CH3S(=O)2Cl, CDI and Mitsunobu type reagents; especially selected from P(OR 1 )2Cl, where each R 1 Independently, it is a C1-C4 alkyl group; and PCl3.

[0181] E.88. The method according to embodiment E.87, wherein the activator used in step (b) is selected from dimethyl phosphite (P(OCH3)2Cl), diethyl phosphite (P(OCH2CH3)2Cl), methyl phosphite (P(OCH3)Cl2), ethyl phosphite (P(OCH2CH3)Cl2), PCl3, P(O)Cl3, SOCl2, CH3S(=O)2Cl, CDI and Mitsunobu type reagents; preferably selected from dimethyl phosphite (P(OCH3)2Cl), diethyl phosphite (P(OCH2CH3)2Cl), methyl phosphite (P(OCH3)Cl2), ethyl phosphite (P(OCH2CH3)Cl2), PCl3, P(O)Cl3, CH3S(=O)2Cl and CDI.

[0182] E.89. The method according to embodiment E.88, wherein the activator used in step (b) is selected from dimethyl phosphite (P(OCH3)2Cl), diethyl phosphite (P(OCH2CH3)2Cl), methyl phosphite (P(OCH3)Cl2), ethyl phosphite (P(OCH2CH3)Cl2), PCl3 and P(O)Cl3, particularly selected from dimethyl phosphite (P(OCH3)2Cl), diethyl phosphite (P(OCH2CH3)2Cl) and PCl3.

[0183] E.90. The method according to embodiment E.89, wherein the activator used in step (b) is selected from dimethyl chlorophosphite (P(OCH3)2Cl) and diethyl chlorophosphite (P(OCH2CH3)2Cl).

[0184] E.91. The method according to any of the foregoing embodiments, wherein the activator is used in an amount such that the molar ratio of the compound of formula 1 to the activator is in the range of 10:1 to 1:10.

[0185] E.92. The method according to embodiment E.91, wherein the activator is used in an amount such that the molar ratio of the compound of formula 1 to the activator is in the range of 2:1 to 1:5, preferably 1:1 to 1:4.

[0186] E.93. The method according to embodiment E.92, wherein the activator is used in an amount such that the molar ratio of the compound of formula 1 to the activator is in the range of 1:1 to 1:3.

[0187] E.94. The method according to embodiment E.93, wherein the activator is used in an amount such that the molar ratio of the compound of formula 1 to the activator is in the range of 1:1 to 1:2.

[0188] E.95. The method according to any of the foregoing embodiments, wherein the reaction in step (b) is carried out at a temperature of -80°C to 120°C.

[0189] E.96. The method according to embodiment E.95, wherein the reaction in step (b) is carried out at a temperature of -20°C to 100°C.

[0190] E.97. The method according to embodiment E.96, wherein the reaction in step (b) is carried out at a temperature of -10°C to 90°C.

[0191] E.98. The method according to any of the foregoing embodiments for preparing (IR) of (3R)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- in an enantiomeric excess of at least 55% ee. -5-alkoxide:

[0192]

[0193] The method includes:

[0194] (a.1) Reduction of compound 1, thereby forming a reaction mixture containing at least 55% ee enantiomeric excess of 2-[(2S)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-S:

[0195] as well as

[0196] (b.1) React the reaction mixture obtained in step (a.1) with an activator as defined in any of embodiments E.1 or E.86-E.94.

[0197] E.99. The method according to embodiment E.98 for preparing (IR) of (3R)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- in an enantiomeric excess of at least 60% ee. 5-alkoxide, the method comprising:

[0198] (a.1) Reduction of compound 1, thereby forming a reaction mixture containing 2-[(2S)-2-(2-chlorothiazolin-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-S in an enantiomeric excess of at least 60% ee; and

[0199] (b.1) React the reaction mixture obtained in step (a.1) with an activator as defined in any of embodiments E.86-E.94.

[0200] E.100. The method according to embodiment E.99 for preparing (IR) of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- in an enantiomeric excess of at least 70% ee. 5-alkoxide, the method comprising:

[0201] (a.1) Reduction of compound 1, thereby forming a reaction mixture containing 2-[(2S)-2-(2-chlorothiazolin-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-S in an enantiomeric excess of at least 70% ee; and

[0202] (b.1) React the reaction mixture obtained in step (a.1) with an activator as defined in any of embodiments E.86-E.94.

[0203] E.101. The method according to embodiment E.100 for preparing (3R)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- in an enantiomeric excess of at least 80% ee. 5-alkoxide, the method comprising:

[0204] (a.1) Reduction of compound 1, thereby forming a reaction mixture containing 2-[(2S)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-S in enantiomeric excess of at least 80% ee; and

[0205] (b.1) React the reaction mixture obtained in step (a.1) with an activator as defined in any of embodiments E.86-E.94.

[0206] E.102. The method according to embodiment E.101 for preparing (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- in an enantiomeric excess of at least 90% ee. 5-alkoxide, the method comprising:

[0207] (a.1) Reduction of compound 1, thereby forming a reaction mixture containing 2-[(2S)-2-(2-chlorothiazolin-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-S in an enantiomeric excess of at least 90% ee; and

[0208] (b.1) React the reaction mixture obtained in step (a.1) with an activator as defined in any of embodiments E.86-E.94.

[0209] E.103. The method according to any one of embodiments E.1-E.97 for preparing (3S)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- of the formula (IS) in an enantiomeric excess of at least 55% ee. -5-alkoxide:

[0210]

[0211] The method includes:

[0212] (a.2) Reduction of compound 1, thereby forming a reaction mixture containing at least 55% ee enantiomeric excess of 2-[(2R)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-R:

[0213] as well as

[0214] (b.2) React the reaction mixture obtained in step (a.1) with an activator as defined in any of embodiments E.1 or E.86-E.94.

[0215] E.104. The method according to embodiment E.103 for preparing (3S)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- of formula (IS) in an enantiomeric excess of at least 60% ee. 5-alkoxide, the method comprising:

[0216] (a.2) Reduction of compound 1, thereby forming a reaction mixture containing 2-[(2R)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-R in enantiomeric excess at least 60% ee; and

[0217] (b.2) React the reaction mixture obtained in step (a.1) with an activator as defined in any of embodiments E.86-E.94.

[0218] E.105. The method according to embodiment E.104 for preparing (3S)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- of formula (IS) in enantiomeric excess of at least 70% ee. 5-alkoxide, the method comprising:

[0219] (a.2) Reduction of compound 1, thereby forming a reaction mixture containing 2-[(2R)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-R in enantiomeric excess at least 70% ee; and

[0220] (b.2) React the reaction mixture obtained in step (a.1) with an activator as defined in any of embodiments E.86-E.94.

[0221] E.106. The method according to embodiment E.105 for preparing (3S)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- of the formula (IS) in an enantiomeric excess of at least 80% ee. 5-alkoxide, the method comprising:

[0222] (a.2) Reduction of compound 1, thereby forming a reaction mixture containing 2-[(2R)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-R in enantiomeric excess at least 80% ee; and

[0223] (b.2) React the reaction mixture obtained in step (a.1) with an activator as defined in any of embodiments E.86-E.94.

[0224] E.107. The method according to embodiment E.106 for preparing (3S)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- of formula (IS) in enantiomeric excess of at least 90% ee. 5-alkoxide, the method comprising:

[0225] (a.2) Reduction of compound 1, thereby forming a reaction mixture containing 2-[(2R)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-R in enantiomeric excess at least 90% ee; and

[0226] (b.2) React the reaction mixture obtained in step (a.1) with an activator as defined in any of embodiments E.86-E.94.

[0227] The reaction sequence can be shown below:

[0228]

[0229] 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.

[0230] The reaction in step (a) can be classified as asymmetric transfer hydrogenation. The reaction in step (b) can be classified as intramolecular S... N reaction.

[0231] 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.

[0232] 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 R 4 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.

[0233] 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 .

[0234] 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.

[0235] 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(C2H4O CH3)(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 R3 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] + .

[0236] 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.

[0237] 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.

[0238] In the context of this invention, the base optionally or necessarily used is different from formate HC(=O)O. - M + Alkali.

[0239] 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.

[0240] 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.

[0241] 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 them 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.

[0242] 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) brand of commercially available materials.

[0243] If formate HC(=O)O - M + When used as the sole reducing agent, it is advantageous to mix it with water.

[0244] 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.

[0245] Formic acid is preferably used as a reducing agent. Therefore, the reaction is forced to take place in the presence of a base.

[0246] 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 10:1 to 1:2, specifically 5:1 to 1:1.

[0247] 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.

[0248] 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.

[0249] The chiral transition metal catalyst is preferably used in an amount of 0.01-10 mol%, more preferably 0.05-5 mol%, especially 0.1-5 mol%, for example 0.1-2 mol%, relative to 1 mol of compound 1, based on the transition metal content.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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:

[0254]

[0255] in

[0256] The asterisk indicates the center of the stereo source;

[0257] R 5 and R 6 They are independently selected from OH, halogens, C1-C4 alkyl groups, and C1-C4 alkoxy groups;

[0258] 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 ;

[0259] 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;

[0260] 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-C10 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 ;

[0261] R 10 It is hydrogen or C1-C4 alkyl;

[0262] 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

[0263] m and n are independent of each other and can be 0, 1, 2, 3, 4 or 5.

[0264] Preferably in compound (II),

[0265] R 5 and R 6 It is a C1-C4 alkoxy group;

[0266] 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 ;

[0267] 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;

[0268] 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 ;

[0269] R 10It is hydrogen or C1-C4 alkyl;

[0270] R 11 It is phenyl-(CH2) s Alkyl 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

[0271] Both m and n can be 0 or both can be 1, preferably both are 0.

[0272] 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.

[0273] 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:

[0274]

[0275]

[0276] 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.

[0277] 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 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 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, 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.

[0278] 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. 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 specifically selected from those containing Ru, Rh or Ir as a central metal and at least one selected from (1R,2R) or (1S,2S) forms of TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, 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. 8It 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.

[0279] More 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 forms: TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, etc., in the form of (1R,2R) or (1S,2S). Catalysts containing ligands of DPEN, RsDPEN, and TsDiOMeDPEN; and catalysts of the following formula:

[0280]

[0281] More specifically, the chiral transition metal catalyst is selected from catalysts containing Ru, Rh or Ir as the central metal and at least one ligand selected from TsDPEN, MsDPEN and CsDPEN in the form of (1R,2R) or (1S,2S).

[0282] This chiral transition metal catalyst typically contains only one of the aforementioned dienodentine ligands.

[0283] 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.

[0284] 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 6The 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...

[0285] 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.

[0286] Specifically, the chiral transition metal catalyst is selected from chiral ligands containing Ru, Rh, or Ir as the central metal, from TsDPEN, MsDPEN, and CsDPEN in the (1R,2R) or (1S,2S) form, from halogen or sulfonate ligands, preferably Cl, and from Cp*, p-isopropyltoluene, and Catalysts with other ligands.

[0287] Many of the ligands and catalysts mentioned above are commercially available or can be prepared from suitable catalyst precursors and ligands using standard reactions.

[0288] 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... [Cl2]2, [Rh(III)Cl2Cp*]2, or [Ir(III)Cl2Cp*]2. These complexes are usually commercially available or can be prepared by standard methods.

[0289] 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.

[0290] 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.

[0291] In a preferred embodiment, the S enantiomer is enriched in compound 2 obtained in step (a) (at the expense of the R enantiomer). Therefore, in a preferred embodiment, step (a) is used to prepare 2-[(2S)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-S with an enantiomer excess, more precisely at least 55% ee, preferably at least 60% ee, more preferably at least 70% ee, especially at least 80% ee, specifically at least 90% ee:

[0292]

[0293] 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; and preferably 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, 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.

[0294] Chiral transition metal catalysts for obtaining 2-S 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. 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 2-S 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.

[0295] More specifically, the chiral transition metal catalyst for obtaining 2-S in enantiomeric excess 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:

[0296]

[0297] Very specifically, the chiral transition metal catalyst for obtaining 2-S in enantiomeric excess is selected from catalysts containing Ru, Rh or Ir as the central metal and at least one ligand selected from (1S,2S)-TsDPEN, (1S,2S)-MsDPEN and (1S,2S)-CsDPEN.

[0298] More specifically, the chiral transition metal catalyst for obtaining 2-S in enantiomeric excess 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 (2-S) in enantiomeric excess contain Ru, Rh, or Ir as the central metal and contain a compound 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.

[0299] In addition, the catalyst contains other ligands to be replaced by hydrides from the reducing agent, typically halides or sulfonates, preferably halides, specifically Cl.

[0300] Alternatively, the catalyst for obtaining 2-S in enantiomeric excess contains Ru as the 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 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:

[0301]

[0302] Specifically, the chiral transition metal catalyst used to obtain 2-S in enantiomeric excess is selected from those containing Ru, Rh, or Ir as the central metal, chiral ligands selected from (1S,2S)-TsDPEN, (1S,2S)-MsDPEN, and (1S,2S)-CsDPEN, ligands selected from halogen ligands, preferably Cl ligands, and ligands selected from Cp*, p-isopropyltoluene, and... Catalysts with other ligands.

[0303] In another preferred embodiment, the R enantiomer is enriched in compound 2 obtained in step (a), at the expense of the S enantiomer. Therefore, in a preferred embodiment, step (a) is used to prepare 2-[(2R)-2-(2-chlorothiazolyl-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-R with an enantiomer excess, more precisely at least 55% ee, preferably at least 60% ee, more preferably at least 70% ee, especially at least 80% ee, specifically at least 90% ee:

[0304]

[0305] 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 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; and preferably 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, 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.

[0306] Chiral transition metal catalysts for obtaining 2-R enantiomeric excess 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. 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 2-R 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.

[0307] More specifically, the chiral transition metal catalyst used to obtain 2-R in enantiomeric excess 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:

[0308]

[0309] Very specifically, the chiral transition metal catalyst for obtaining 2-R in enantiomeric excess is selected from catalysts containing Ru, Rh or Ir as the central metal and at least one ligand selected from (1R,2R)-TsDPEN, (1R,2R)-MsDPEN and (1R,2R)-CsDPEN.

[0310] More specifically, the chiral transition metal catalyst for obtaining 2-R enantiomeric excess 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, in the case of Rh and Ir as the central metal, the additional aromatic ligand is preferably selected from Cp and Cp*, specifically Cp*. In the case of Ru as the central metal, the additional aromatic ligand is preferably selected from isopropyltoluene and... More specifically, the chiral transition metal catalyst for obtaining (2-R) in enantiomeric excess comprises Ru, Rh, or Ir as the 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, 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.

[0311] In addition, the catalyst contains other ligands to be replaced by hydrides from the reducing agent, typically halides or sulfonates, preferably halides, specifically Cl.

[0312] Alternatively, the catalyst used to obtain 2-R in enantiomeric excess 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:

[0313]

[0314] Specifically, the chiral transition metal catalyst used to obtain 2-R enantiomeric excess is selected from those containing Ru, Rh, or Ir as the central metal, chiral ligands selected from (1R,2R)-TsDPEN, (1R,2R)-MsDPEN, and (1R,2R)-CsDPEN, ligands selected from halogen ligands, preferably Cl ligands, and ligands selected from Cp*, p-isopropyltoluene, and Catalysts with other ligands.

[0315] The reactions in steps (a) and (b) can both be carried out in the presence of a solvent. This solvent is preferably selected from polar aprotic solvents, chlorinated alkanes, aromatic solvents, heterocyclic solvents, and mixtures of the above. In some cases, such as when PCl3 is used as an activator, a mixture of the organic solvent and a small amount of water may be advantageous. Furthermore, the presence of water is also necessary if the formate is used as the sole reducing agent or if it dominates in a formic acid / formate mixture used as a reducing agent.

[0316] 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.

[0317] Examples of suitable C1-C4 alkyl acetates are methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.

[0318] Examples of suitable chlorinated alkanes are dichloromethane, trichloromethane, or dichloroethane.

[0319] 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).

[0320] Examples of suitable heterocyclic solvents are 4-formylmorpholine or dihydrolevulinone.

[0321] 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).

[0322] More preferably, the solvent is selected from dimethylformamide, diethylformamide, dibutylformamide, dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, etc. 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, dichloromethane, chloroform, dichloroethane and mixtures thereof; specifically selected from dimethylformamide, dimethylacetamide and mixtures thereof.

[0323] 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 in step (a) can be carried out in a purer manner.

[0324] 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.

[0325] In the reaction process of step (a), formic acid or formate is oxidized to CO2. Given that CO2 inhibits the activity of many catalysts, it is advantageous to remove CO2 during the reaction process of step (a). This can be done, for example, by injecting an inert gas into the reaction mixture or by applying a vacuum. Therefore, in a preferred embodiment, during the reaction process of step (a), an inert gas, different from CO2 and preferably selected from argon, nitrogen, and a mixture of oxygen and nitrogen containing 1-8 vol% oxygen relative to the total oxygen / nitrogen mixture, is injected into the reaction mixture; 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.

[0326] The reactions in steps (a) and (b) can be carried out in the presence of additives that accelerate the reaction rate. Typical additives are diethyl phosphite, borate esters, and zinc salts. Suitable zinc salts are, 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 in the range of 1:10000-2:1.

[0327] The reaction in step (a) is carried out at a temperature preferably 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 is preferably 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 at 10-30°C.

[0328] The reaction time of step (a) depends on various factors, such as reaction temperature, 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 sense, that the reaction can be fully completed and step (b) can continue after all components have been completely added. This may be possible, for example, if the addition of reactants continues for a considerable period of time or if it is intended to recycle unreacted raw materials.

[0329] The reaction in step (a) is typically carried out by mixing the reducing agent, optional base (where mixing with the base is mandatory when formic acid is used as the sole reducing agent), chiral catalyst (in preformed form or in the form of a catalyst precursor and chiral ligand), 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.

[0330] For example,

[0331] (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

[0332] (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

[0333] (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

[0334] (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).

[0335] The reaction mixture obtained in step (a) is reacted in a subsequent step (b) without separating compound 2. Compound 2 is very sensitive and may degrade to some extent during storage or even when conventional separation methods are applied. In trend, not separating compound 2 yields compound (I) in a higher yield compared to methods in which compound 2 is separated prior to step (b).

[0336] The reaction mixture from step (a) is reacted in step (b) without separating compound 2, typically by simply contacting the activating compound with the reaction mixture obtained in step (a), i.e., by adding the activating compound to the reaction mixture obtained in step (a).

[0337] The activator used in step (b) is a compound that enhances the electrophilicity of the asterisked carbon atom in compound 2 without promoting racemization at said carbon atom. The reaction of 2 to compound (I) is an intramolecular nucleophilic substitution, in which the unsubstituted nitrogen atom of the pyrimidinone ring attacks the asterisked aliphatic carbon atom and substitutes the OH group, thereby forming a condensed ring system. In order to preserve the chiral information of 2 to the greatest extent possible in compound (I), the reaction conditions should advantageously be such that racemization at the asterisked carbon atom is suppressed or at least minimized. This is advantageously achieved by ensuring that racemization at the S... N This is achieved through nucleophilic attack under condition 2. Therefore, the activator is alternatively defined as promoting intermolecular S at the carbon atoms marked with an asterisk in the compound of formula 2. N 2. The compound attacked.

[0338] Suitable activators are oxyphilic compounds, such as various phosphorus compounds, but also certain compounds or combinations of compounds with Lewis acid properties.

[0339] Preferably, the activator is selected from P(OR) 1 )2Cl、P(OR 1 Cl2、P(=O)(OR 1 )2Cl、P(=O)(OR 1 Cl2, of which R in each of the four compounds mentioned above 1 Independently C1-C4 alkyl; PCl3, P(=O)Cl3, polyphosphoric acid, P4O 10Mitsunobu-type reagents, triphenylphosphine in combination with halogenating agents, complexes of SO3 with Lewis bases selected from amines, carboxamides and heteroaromatic compounds containing 1, 2 or 3 basic nitrogen ring atoms; S(O)Cl2, CH3S(O)2Cl, carbonyl diimidazole (CDI), Vilsmeier reagent, complexes of N,N-dimethylformamide and / or N,N-dimethylacetamide with Lewis acids; and mixtures of two or more of the above activators.

[0340] Mitsunobu-type reagents are combinations of triphenylphosphine with azodicarbonate esters such as diethyl azodicarbonate (DEAD) or diisopropyl azodicarbonate (DIAD), or combinations of triphenylphosphine with azodicarbonamides such as tetramethylazodicarbonamide (TMAD). These combinations are used as mixtures or mixed in situ during the reaction. Advantageously, they can be used as commercially available mixtures.

[0341] Examples of halogenating agents that can be used in combination with triphenylphosphine include N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), elemental chlorine, elemental bromine, or elemental iodine. These combinations are used as mixtures or mixed in situ during the reaction.

[0342] Examples of complexes of SO3 with Lewis bases selected from amines, carboxamides, and heteroaromatic compounds containing one, two, or three basic nitrogen ring atoms include complexes of SO3 with trimethylamine, triethylamine, N,N-dimethylaniline, N,N-dimethylformamide, pyridine, or polyvinylpyridine. These combinations are used as mixtures or mixed in situ during the reaction. Advantageously, they can be used as commercially available mixtures.

[0343] Vilsmeier's reagent is the reaction product of formamide (HC(O)NR2, where each R is independently a C1-C4 alkyl group) with phosphoryl chloride (P(O)Cl3), oxalyl chloride (ClC(O)-C(O)Cl), or thionyl chloride (S(O)Cl2), which yields ammonium chloride ions (ClHC=NR2). + Dimethylformamide is typically used, where both R's are methyl groups.

[0344] An example of a Lewis acid in complexes of N,N-dimethylformamide and / or N,N-dimethylacetamide with a Lewis acid is BF3.

[0345] The activator is more preferably selected from P(OR) 1 )2Cl、P(OR 1 Cl2、P(=O)(OR 1 )2Cl, wherein each of the three compounds mentioned above contains R 1Independently C1-C4 alkyl; PCl3, P(O)Cl3, SO3 / dimethylformamide complex, SOCl2, CH3S(=O)2Cl, CDI and Mitsunobu type reagents; especially selected from dimethyl chlorophosphite (P(OCH3)2Cl), diethyl chlorophosphite (P(OCH2CH3)2Cl), methyl dichlorophosphite (P(OCH3)Cl2), ethyl dichlorophosphite (P(OCH2CH3)Cl2), PCl3, P(O)Cl3, SOCl2, CH3S(=O)2Cl, CDI and Mitsunobu type reagents. The activator is more specifically selected from dimethyl chlorophosphite (P(OCH3)2Cl), diethyl chlorophosphite (P(OCH2CH3)2Cl), methyl dichlorophosphite (P(OCH3)Cl2), ethyl dichlorophosphite (P(OCH2CH3)Cl2), PCl3, and P(O)Cl3. The activator is even more specifically selected from P(OR)Cl3. 1 The activator is 2Cl, specifically dimethyl chlorophosphite (P(OCH3)2Cl) and diethyl chlorophosphite (P(OCH2CH3)2Cl), as well as PCl3. Specifically, the activator is dimethyl chlorophosphite (P(OCH3)2Cl) or diethyl chlorophosphite (P(OCH2CH3)2Cl).

[0346] The compound of Formula 2 and the activator are preferably used in a molar ratio of 10:1-1:10, more preferably 2:1-1:5, even more preferably 1:1-1:4, especially 1:1-1:3, specifically 1:1-1:2.

[0347] The reaction in step (b) is preferably carried out in the presence of a solvent. If step (a) has already been carried out in formic acid and / or liquid base as solvents without any additional typical solvents, it is advantageous to add that solvent. Suitable solvents are polar aprotic solvents, mixtures of polar aprotic solvents and water, C1-C4 alkyl esters of acetate, chlorinated alkanes, aromatic solvents, heterocyclic solvents, and mixtures thereof. Although aqueous solvents are generally considered to promote S in substitution reactions... N One approach is to use solvents that solubilize typically ionic leaving groups, but in this case, a mixture of polar aprotic solvents and water has been found to be suitable; at least in combination with certain activators such as PCl3; see the comments above.

[0348] 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.

[0349] In the mixture of polar aprotic solvent and water, the mixture contains water in an amount preferably 0.5-15% by weight, more preferably 1-10% by weight, especially 1-6% by weight, and specifically 1-4% by weight, based on the total weight of the mixture.

[0350] Examples of suitable C1-C4 alkyl acetates are methyl acetate, ethyl acetate, n-propyl acetate, and isopropyl acetate.

[0351] Examples of suitable chlorinated alkanes are dichloromethane, trichloromethane, or dichloroethane.

[0352] 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).

[0353] Examples of suitable heterocyclic solvents are 4-formylmorpholine or dihydrolevulinone.

[0354] More preferably, the solvent is selected from dimethylformamide, diethylformamide, dibutylformamide, dimethylacetamide, tetrahydrofuran, a mixture of tetrahydrofuran and water (e.g., containing water in an amount of 0.5-15% by weight, preferably 1-10% by weight, especially 1-6% by weight, specifically 1-4% by weight, based on the total weight of the THF / water mixture), 2-methyltetrahydrofuran, dimethylformamide, diethylformamide, dimethyl ... 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, trifluorotoluene, xylene derivatives, chlorobenzene, dichlorobenzene, 4-formylmorpholine, dihydro-L-glucosidone The solvent is particularly selected from dimethylformamide, diethylformamide, dibutylformamide, dimethylacetamide, tetrahydrofuran, mixtures of tetrahydrofuran and water (e.g., containing water in an amount of 0.5-15% by weight, preferably 1-10% by weight, especially 1-6% by weight, specifically 1-4% by weight, based on the total weight of the THF / water mixture), 2-methyltetrahydrofuran, 1,4-dimethylformamide, di ... Alkanes, acetonitrile, ethyl acetate, dichloromethane, toluene, chlorobenzene and mixtures thereof; particularly selected from dimethylformamide, dimethylacetamide, dichloromethane, chloroform and mixtures thereof; specifically selected from dimethylformamide, dimethylacetamide and mixtures thereof.

[0355] If step (a) has not yet been carried out in the presence of a base (which is different from a formate), the base may be added in step (b). This base is preferably selected from alkali metal hydroxides of the 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 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 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. The base is particularly 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); specifically selected from triethylamine, tributylamine, and diisopropylethylamine.

[0356] Suitable carrier materials are listed above.

[0357] However, the addition of a base in step (b) is not necessary. A base in this context refers to an additional base, i.e., a base different from the mandatory reactant. For example, the formate in step (a) is basic; some activators contain basic components, such as amines or heteroaromatic compounds in the complex of SO3 with a Lewis base.

[0358] The reaction in step (b) is carried out at a temperature preferably from -80°C to 120°C, more preferably from -20°C to 100°C, and especially from -10°C to 90°C. If step (b) is to be carried out at a different temperature than that in step (a), this is advantageously achieved by adjusting the temperature of the reaction mixture obtained in step (a) to the desired temperature before adding the activator.

[0359] The reaction time of step (b) depends on various factors, such as reaction temperature, concentration of reactants in the reaction mixture, etc. It typically ranges from about 15 minutes to 48 hours, preferably in the range of 1-10 hours.

[0360] The reaction in step (b) is typically carried out by adding the activator to the reaction mixture obtained in step (a). Depending on the activator used, it may be advantageous to add the agent to the reaction mixture obtained in step (a) cooled to -80°C to 10°C, for example -20°C to 0°C, and if a reaction temperature higher than the addition temperature is required, the reaction mixture is warmed only after the addition is complete. Depending on the reactivity of the activator, it may be advantageous to add the latter gradually (continuously or in batches) to avoid heat generation. Reactivity depends not only on the type of activator but also on its state after storage, thus preliminary testing is advantageous.

[0361] Alternatively, step (b) is carried out by adding the reaction mixture obtained in step (a) to an activator. For this purpose, the activator is appropriately provided in a solvent. Suitable solvents are those listed above for step (b).

[0362] In a preferred embodiment, the method of the present invention is used to prepare (3R)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4-in 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, in an enantiomeric excess of at least 55% ee, preferably at least 60% ee, more preferably at least 70% ee, particularly at least 80% ee, and specifically at least 90% ee. -5-alkoxide:

[0363]

[0364] Therefore, compound 1 is hydrogenated under conditions in which the S enantiomer of compound 2 is predominant, i.e., in an enantiomer excess of at least 55% ee, preferably at least 60% ee, more preferably at least 70% ee, especially at least 80% ee, specifically at least 90% ee, containing 2-[(2S)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-S:

[0365] This is then reacted with the activator described above.

[0366] The intramolecular nucleophilic attack proceeds primarily from the opposite side of the OH leaving group, and thus results in configuration inversion at the asymmetric carbon atom (given that the nucleophile and the non-nucleophile have equal priority according to the Cahn-Ingold-Prelog rule, the absolute configuration also changes from S to R).

[0367] The reaction conditions for obtaining the reaction mixture in which the S enantiomer of compound 2 is dominant are as described above for step (a).

[0368] In another preferred embodiment, the method of the invention is used to prepare (3S)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4-in 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, in 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. -5-alkoxide:

[0369]

[0370] Therefore, compound 1 is hydrogenated under conditions in which the R enantiomer of compound 2 is predominant, i.e., in an enantiomer excess of at least 55% ee, preferably at least 60% ee, more preferably at least 70% ee, especially at least 80% ee, specifically at least 90% ee, containing 2-[(2R)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 1-R:

[0371] This is then reacted with the activator described above.

[0372] The intramolecular nucleophilic attack proceeds primarily from the opposite side of the OH leaving group, and thus results in configuration inversion at the asymmetric carbon atom (given that the nucleophile and the non-nucleophile have equal priority according to the Cahn-Ingold-Prelog rule, the absolute configuration also changes from R to S).

[0373] The reaction conditions for obtaining the reaction mixture in which the R enantiomer of compound 2 is dominant are as described above for step (a).

[0374] After the reaction is complete, the enantiomeric enriched form of the pyrimidinone of formula (I) is typically separated from the reaction mixture. Separation usually involves steps suitable for precipitating compound (I). For example, the solvent can be partially removed, optionally under reduced pressure, at which point the desired compound (I) precipitates. Depending on the temperature applied to partially remove the solvent, the amount of solvent removed, and of course the nature of the solvent, it may be advantageous to cool the residual mixture, where cooling can be continuous or gradual. Alternatively or additionally, another solvent in which compound (I) has low solubility can be added, advantageously after partial removal of the reaction solvent, at which point compound (I) precipitates; or, depending on the circumstances, after cooling (again, continuously or gradually). The suitable solvent in which compound (I) has low solubility is, for example, an aromatic hydrocarbon such as benzene, toluene, trifluorotoluene, xylenes (i.e., 1,2-xylene, 1,3-xylene or 1,4-xylene), chlorobenzene or dichlorobenzene; C1-C4 alkyl esters of acetate, such as methyl acetate, ethyl acetate, n-propyl acetate and isopropyl acetate; C1-C4 alkanols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol and tert-butanol; diols, such as ethylene glycol, propylene glycol, diethylene glycol and triethylene glycol; glycerol, water or a mixture of the above solvents.

[0375] The precipitate can be separated by conventional methods such as filtration, centrifugation, sedimentation, and removal of the supernatant, with filtration being preferred. The filter cake can be further purified by washing with a suitable solvent, such as one of the solvents listed above that has low solubility for compound (I).

[0376] If necessary, the catalyst can be recycled. For this purpose, the catalyst can be recovered, for example, from the mother liquor of the precipitate of the compound of formula (I), such as filtrate, centrifuge, or supernatant; purified if necessary, and subsequently used in step (a). The most straightforward way to recycle the catalyst is to use the mother liquor of the precipitate (e.g., filtrate, centrifuge, or supernatant) in step (a), optionally after concentration. Alternatively, 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 mother liquor. On a larger scale, the mother liquor 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 usually 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 step (a). Alternatively, the transition metal can be recovered from the mother liquor (optionally after neutralization) 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 reduction processes. Alternatively, the catalyst can be first extracted from the mother liquor into a suitable organic solvent (e.g., an organic solvent with a lower boiling point, which requires less energy to remove) before the aforementioned treatment, optionally after neutralization.

[0377] Compound 1 can be obtained, for example, 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.

[0378] These reactions are described in European application number 21153040.7.

[0379] 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.

[0380] The method of the present invention yields compound (I) with high yield and high stereoselectivity.

[0381] The invention is further illustrated in the following embodiments. Example

[0382] abbreviation:

[0383] DMAC N,N-dimethylacetamide

[0384] DMF N,N-dimethylformamide

[0385] DMSO (dimethyl sulfoxide)

[0386] EtOAc (ethyl acetate)

[0387] Me-THF 2-methyltetrahydrofuran

[0388] THF Tetrahydrofuran

[0389] TEA Triethylamine

[0390] rt room temperature

[0391] t time

[0392] d day

[0393] h hours

[0394] min minutes

[0395] rt retention time

[0396] Example 1: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxide

[0397] 1.1 Preparation of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one

[0398] 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%.

[0399] 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).

[0400] 1.2 Preparation of (3R)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxide

[0401] 25.3 g (99%, 1.00 eq) of 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one was dissolved in 165 g of dimethylacetamide, cooled to -5 °C, and injected with nitrogen. Then, 8.3 g (99%, 1.00 eq) of diisopropylethylamine and 3.5 g (100%, 1.20 eq) of formic acid were added, followed by a solution of 0.13 g (94%, 0.003 eq) of the preformed catalyst Rh(III)ClCp*·(1S,2S-TsDPEN) (obtained by reacting 1 equivalent of [Rh(III)Cl2Cp*]2 with 2 equivalents of 1S,2S-TsDPEN in the presence of 4 equivalents of triethylamine) in 10 g of dimethylacetamide. The reaction mixture was stirred for 2 h and 13.6 g (95%, 1.30 eq) of diethyl chlorophosphite was added. The reaction mixture was heated to 30 °C over 3 h, and then to 80 °C over 2.5 h. The solvent (-154 g) was distilled off under reduced pressure to 45 mbar, then the vacuum was broken and 72 g of ethyl acetate was added. The temperature was cooled to 20 °C over 4 h. The precipitate was filtered, washed with ethyl acetate (2 × 63 g) and water (2 × 63 g), and finally dried under vacuum (~100 °C). 20.6 g (>99% ee, 99%, 83% yield) (3R)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- 5-alkoxide.

[0402] 1 H NMR (400MHz, DMSO-d6): δ=7.96 (s, 1H), 7.6 (d, J=7.5Hz, 1H), 7.21-7.26 (m, 2H), 7.06-7 .11 (m, 1H), 6.48 (d, J=8.1Hz, 1H), 4.25-4.32 (m, 1H), 3.94 (d, J=12Hz, 1H), 3.42 (s, 3H).

[0403] m / z(M+H + ) = 378

[0404] Example 2: Preparation of (3R)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxide

[0405] 34.1 g (99%, 1.00 eq) of 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one was dissolved in 216 g of dimethylacetamide, cooled to -5 °C, and injected with nitrogen. A mixture of 6.7 g formic acid (1.10 eq) and triethylamine (0.27 eq) (molar ratio 4.1:1) was added, followed by a solution of 0.47 g (94%, 0.003 eq) of the preformed catalyst Rh(III)ClCp*·(1S,2S-TsDPEN) (obtained by reacting 1 equivalent of [Rh(III)Cl2Cp*]2 with 2 equivalents of 1S,2S-TsDPEN in the presence of 4 equivalents of triethylamine) in 20 g of dimethylacetamide. The reaction mixture was stirred for 1.5 h and 15.5 g (95%, 1.10 eq) of diethyl chlorophosphite was added. The reaction mixture was heated to 25 °C over 2.5 h, and then to 80 °C over 2.5 h. The solvent (-205 g) was distilled under reduced pressure to 45 mbar, then the vacuum was broken and 87 g of ethyl acetate was added. The temperature was cooled to 20 °C over 4 h. The precipitate was filtered, washed with ethyl acetate (2 × 85 g) and water (2 × 85 g), and finally dried under vacuum (~100 °C). 28.8 g (>99% ee, 99%, 87% yield) of (3R)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- 5-alkoxide.

[0406] Example 3: Preparation of (3S)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxide

[0407] 29.9 g (99%, 1.00 eq) of 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one was dissolved in 230 g of dimethylacetamide, cooled to -5 °C, and injected with nitrogen. A mixture of 5.2 g formic acid (1.50 eq) and 3.5 g diisopropylethylamine (0.36 eq) was added, followed by a solution of 0.17 g (92%, 0.003 eq) of the preformed catalyst Ir(III)ClCp*·(1R,2R-MsDPEN) (obtained by reacting 1 equivalent of [Ir(III)Cl2Cp*]2 with 2.1 equivalents of 1R,2R-MsDPEN in the presence of 4 equivalents of triethylamine) in 10 g of dimethylacetamide. The reaction mixture was stirred for 9 h and 21.0 g (95%, 1.70 eq) of diethyl chlorophosphite was added. The reaction mixture was heated to 30 °C over 3 h and then to 80 °C over 2.5 h. The solvent (-207 g) was distilled off under reduced pressure to 45 mbar, then the vacuum was broken and 82 g of ethyl acetate was added. The temperature was cooled to 20 °C over 4 h and stirred overnight. The precipitate was filtered, washed with ethyl acetate (2 × 75 g) and water (2 × 75 g), and finally dried under vacuum (~100 °C). 23.5 g (>99% ee, >99%, 83% yield) (3S)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- 5-alkoxide.

[0408] Example 4: Preparation of (3R)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxide

[0409] At -5°C, 30 g (75.48 mmol, 1 eq.) of 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (165 g, 90.58 mmol, 1.20 eq.) was added to a solution of dimethylacetamide (165 g) and diisopropylethylamine (11.83 g, 90.58 mmol, 1.20 eq.) and nitrogen gas was injected. Then, formic acid (4.21 g, 90.58 mmol, 1.20 eq) was added sequentially, followed by [(4S,5S)-2-chloro-1-methanesulfonyl-4,5-diphenyl-1,3-diaza-2Δ4-rhodiumcyclopentanyl]; 1,2,3,4,5-pentamethylcyclopentadienyl (formed in situ in the solution by mixing [Rh(III)Cl2Cp*]2, 1S,2S-MsDPEN and Hünig base (diisopropylethylamine) in a molar ratio of 1:3:7) (assuming 100% conversion: 0.084 g catalyst, 0.151 mmol, 0.002 eq) in 10 g dimethylacetamide. The reaction mixture was stirred for 4 h, and then diethyl chlorophosphite (15.7 g, 83.30 mmol, 1.1 eq) was added. The reaction mixture was heated to 30°C over 3 hours, and then to 80°C over 2.5 hours. The pressure was then reduced to 45 mbar, and 154 g of dimethylacetamide was removed by distillation. The vacuum was then broken, and 72 g of ethyl acetate was added over 1 hour. The temperature was then lowered to 20°C over 4 hours, during which time a suspension was formed. The solid was separated by filtration, washed with ethyl acetate (2 × 63 g) and water (2 × 63 g), and finally dried under vacuum at 100°C to give 24.2 g (>99% ee, 85% yield) (3R)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- 5-alkoxide.

[0410] Example 5: Preparation of (3R)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxide

[0411] 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (5.0 g, 12.65 mmol, 1 eq.) was dissolved in dimethylformamide (36.3 g), then cooled to 0 °C and injected with nitrogen. A solution of pre-formed catalyst [(4S,5S)-2-chloro-1-methanesulfonyl-4,5-diphenyl-1,3-diaza-2Δ4-rhodiumcyclopentanyl]; 1,2,3,4,5-pentamethylcyclopentadienyl (0.051 g, 0.08 mmol, 0.006 eq) in 15 mL of dimethylformamide was added, followed by the addition of a mixture of 0.98 g formic acid (1.10 eq) / triethylamine (0.27 eq) (molar ratio 4.1:1). The reaction mixture was stirred for 3 h, then diethyl chlorophosphite (3.5 g, 21.51 mmol, 1.7 eq) was added. The reaction mixture was warmed to room temperature overnight. The pressure was then reduced to 15 mbar (50 °C) and dimethylformamide was distilled off until 16 g of the reaction mixture remained. 16 g of ethyl acetate was added over 0.5 h. The temperature was then lowered to 20 °C. The solid was separated by filtration, washed with ethyl acetate (2 × 12.5 g) and water (2 × 12.5 g), and finally dried under vacuum at 100 °C to give 3.53 g (>99% ee, >99%, 76% yield) (3R)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- 5-alkoxide.

[0412] Example 6: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxide

[0413] At -5°C, 30 g (75.48 mmol, 1 eq.) of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (120 g, 90.58 mmol, 1.20 eq.) was added to a solution of dimethylacetamide (120 g) and diisopropylethylamine (11.75 g, 90.58 mmol, 1.20 eq.) and nitrogen gas was injected. Then, formic acid (0.70 g, 15.07 mmol, 0.20 eq) was added sequentially, followed by [(4S,5S)-2-chloro-1-methanesulfonyl-4,5-diphenyl-1,3-diaza-2Δ4-rhodiumcyclopentanyl]; 1,2,3,4,5-pentamethylcyclopentadienyl (formed in situ in the solution by mixing [Rh(III)Cl2Cp*]2, 1S,2S-MsDPEN and Hünig base in a molar ratio of 1:3:7) (assuming 100% conversion: 0.084 g catalyst, 0.151 mmol, 0.002 eq) in a solution of 10 g dimethylacetamide. Formic acid (3.51 g, 75.59 mmol, 1.00 eq) was then added over 30 min. The reaction mixture was stirred for 4 h, and then diethyl chlorophosphite (15.7 g, 83.30 mmol, 1.1 eq) was added. The reaction mixture was heated to 30 °C over 3 h, and then to 80 °C over 2.5 h. The pressure was then reduced to 45 mbar, and 113 g of dimethylacetamide was removed by distillation. The vacuum was then broken and the temperature was lowered to 20 °C over 4 h. 80 g of ethanol was added over 2 h. The solid was separated by filtration and washed with ethanol (1 × 75 g). The solid was resuspended in 96 g of ethanol / water (1:1) at 80 °C for 50 h, filtered, washed with water (2 × 50 g), and finally dried under vacuum at 100 °C to give 22.8 g (>99% ee, >99%, 80% yield) (3R)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- 5-alkoxide.

[0414] Test the following other reaction conditions in step b) and obtain similar results:

[0415]

[0416]

[0417] Me = methyl; Et = ethyl; Ph = phenyl; PPA = polyphosphoric acid; Pyr = pyridine; DMF = dimethylformamide; DMA = dimethylamide; NCS = N-chlorosuccinimide; CMDMC = Vilsmeyer's reagent; (chloromethylene)-N,N-dimethylimino chloride (CHCl = N(CH3)2) +Cl - TEA = triethylamine; MTBE = methyl tert-butyl ether; THF = tetrahydrofuran

[0418] 10 AA = Activator

[0419] 11 In this regard, 1eq is the weight equivalent relative to the starting compound.

[0420] Example 7: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxide

[0421] Similar to Example 6, 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one was reacted with 10.93 mmol (1.1 eq.) formic acid in 9.94 mmol (1 eq.) diisopropylethylamine as a base and 0.3 mmol (3 mol%) of catalyst RuClmes·(1S,2S-TsDPEN) (by reacting [RuCl2(mes... 8 The reaction of 1,2S-TsDPEN with 2 was carried out in 70 g of chloroform at 0 °C, followed by reaction with 1,8 eq. diethyl chlorophosphite at 10 °C. The title compound was given in 77% yield and >99% ee.

[0422] Example 8: Preparation of (3S)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxide

[0423] Similar to Example 6, 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one was reacted with 14.9 mmol (1.5 eq.) formic acid in 14.9 mmol (1.5 eq.) diisopropylethylamine as a base and 0.4 mmol (4 mol%) of catalyst RuClmes·(1R,2R-CsDPEN) (by reacting [RuCl2(mes... 8The compound was given by reaction of 1R,2R-CsDPEN; more precisely, by reaction with N-[(1R,2R)-2-amino-1,2-diphenylethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxonorbornen-1-yl]methanesulfonamide] in 46 g of DMAC at 20 °C; then reacted with 1.8 eq. diethyl chlorophosphite (added in two portions of 1.5 and 0.3 eq.). The title compound was given in 80% yield and 83% ee.

[0424] Example 9: Preparation of (3S)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxide

[0425] Similar to Example 6, 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one was reacted with 10.93 mmol (1.1 eq.) formic acid in 9.94 mmol (1 eq.) diisopropylethylamine as a base and 0.2 mmol (2 mol%) of catalyst RuClmes·(1R,2R-CsDPEN) (by reacting [RuCl2(mes... 8 The compound was given by reaction of 1R,2R-CsDPEN; more precisely, by reaction with N-[(1R,2R)-2-amino-1,2-diphenylethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxonorbornen-1-yl]methanesulfonamide] in 46 g of DMAC at 20 °C; then reacted with 1.8 eq. diethyl chlorophosphite (added in two portions of 1.5 and 0.3 eq.). The title compound was given in 80% yield and 85% ee.

[0426] Example 10: Preparation of (3R)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-Alkyl salt (vacuum, addition with diethyl chlorophosphite)

[0427] 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (30.5 g, 76.64 mmol, 1 eq.) was added at -5 °C to a solution of dimethylacetamide (165 g), diisopropylethylamine (9.90 g, 76.64 mmol, 1.00 eq), and formic acid (3.88 g, 84.30 mmol, 1.10 eq). A vacuum (50 mbar) was then applied, and RhClCp*·(1S,2S-CsDPEN) (formed in situ in the solution by mixing [Rh(III)Cl2Cp*]2, 1S,2S-CsDPEN (more precisely N-[(1S,2S)-2-amino-1,2-diphenylethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxonorbornen-1-yl]methanesulfonamide) and diisopropylethylamine in a molar ratio of 1:3:7) (assuming 100% conversion: 0.107 g catalyst, 0.153 mmol, 0.002 eq) in a solution of 10 g dimethylacetamide. The reaction mixture was stirred for 3 h, the vacuum was broken, and the mixture was then added at 20 °C to a solution of diethyl chlorophosphite (15.60 g, 99.63 mmol, 1.3 eq) in dimethylacetamide (36 g). The reaction mixture was stirred for 5 h, then heated to 80 °C over 3 h and maintained for 3 h. The pressure was then reduced to 20 mbar and 167 g of dimethylacetamide was removed by distillation. The vacuum was then broken, the mixture was cooled to 60 °C, and 86 g of methanol was added over 1 h. The temperature was then lowered to 0 °C over 4 h, during which time a suspension was formed. The solid was separated by filtration, washed with methanol (1 × 74 g) and water (1 × 69 g), and finally dried under vacuum at 100 °C to give 24.0 g (>99% ee, 83% yield) of (3R)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- 5-alkoxide.

[0428] Example 11: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxide

[0429] 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (30.0 g, 75.18 mmol, 1 eq.) was added to a solution of dimethylacetamide (120 g), cooled to -5 °C, and nitrogen was injected. Then, diisopropylethylamine (9.72 g, 75.18 mmol, 1.00 eq) and formic acid (3.85 g, 82.69 mmol, 1.10 eq) were added sequentially at -5 °C, followed by the addition of a solution of RhClCp*·(1S,2S-CsDPEN) (formed in situ in the solution by mixing [Rh(III)Cl2Cp*]2, 1S,2S-CsDPEN (more precisely N-[(1S,2S)-2-amino-1,2-diphenylethyl]-1-[(1S,4R)-7,7-dimethyl-2-oxonorbornen-1-yl]methanesulfonamide) and diisopropylethylamine in a molar ratio of 1:3:7 in DMAC) (assuming 100% conversion: 0.105 g catalyst, 0.15 mmol, 0.002 eq). The reaction mixture was stirred for 2 h. Diethyl chlorophosphite (16.78 g, 97.73 mmol, 1.3 eq) was added at -5 °C. The reaction mixture was heated to 25 °C and stirred for 5 h, then heated to 80 °C over 3 h and held for 3 h. The pressure was then reduced to 35-45 mbar, and dimethylacetamide was removed by distillation. The vacuum was then broken, and the mixture (71 g) was cooled to 60 °C and 85 g of methanol was added over 1 h. The temperature was then lowered to 20 °C over 3 h. The solid was separated by filtration, washed with methanol (1 × 71 g) and water (1 × 71 g), and finally dried under vacuum at 100 °C to give 24.74 g (>99% ee, 85% yield) (3R)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- 5-alkoxide.

[0430] Example 12: Preparation of (3S)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- Various reaction conditions required for 2-R by -5-alkoxides

[0431] Other reaction conditions for test step a). This reaction was carried out similarly to the first part of the above examples (i.e., prior to the reaction with the activator), but using 1 g of the starting compound, DMF (2 ml) as the solvent, and the catalysts and conditions compiled in the table below. The catalyst was used in preform form by the reaction of the catalyst precursor and the asymmetric ligand shown, or generated in situ by adding the catalyst precursor and the asymmetric ligand shown to the reaction mixture. The reaction was carried out at room temperature, but Examples 13-17 were carried out at 0 °C.

[0432]

[0433] 1 cat.prec. = catalyst precursor

[0434] 2 asym.lig. = asymmetric ligand

[0435] 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).

[0436] 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)

[0437] 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 .

[0438] 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.

[0439] 6 Instead of formic acid / amine, use sodium formate and water.

[0440]

[0441] 7 C-3-tethr-RuCl-1R,2R-TsDPEN=

[0442] 8

[0443] 9 cym = p-isopropyltoluene

[0444] Example 13: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- Various reaction conditions for 2-S required by 5-alkoxides

[0445] Other reaction conditions for test step a). This reaction was carried out similarly to the first part of the above examples (i.e., prior to the reaction with the activator), but using 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 was used in preform 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 was carried out at room temperature, except for Examples 18 and 19 (-5°C) and Examples 20, 22, 37, 39, 42, 45, and 47 (0°C).

[0446]

[0447]

[0448] 12 catalyst:

[0449] 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:

[0450]

[0451] Cat.2: Catalyst RuClMes·(1S,2S-TsDPEN) of the following formula; preforming; by making [RuCl2(mes 8 The reaction of ]2 with 1S,2S-TsDPEN yields:

[0452]

[0453] Cat.2*: Similar to 2, but formed in situ.

[0454] 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:

[0455]

[0456] 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 is reacted with [RuCl2(mes 8 The reaction of ]2 with N-[(1S,2S)-2-amino-1,2-bis(4-methoxyphenyl)ethyl]-4-methylbenzenesulfonamide yields:

[0457]

[0458] Cat. 6: The catalyst of the following formula is RuClMes·(1S,2S-) (Base DPEN), by making [RuCl2(mes) 8 )]2 and 1S,2S- Obtained by the DPEN reaction

[0459]

[0460] 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

[0461]

[0462] Example 14: Using various stereoisomers of (1R,2R)-CsDPEN as ligands in hydrogenation step (a)

[0463] To demonstrate that the configuration of the camphor moiety of the CsDPEN ligand has little effect on the stereoselectivity during the hydrogenation of 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of Formula 1, and therefore has little effect on the final product (I), step (a) was performed using 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. The reaction was carried out similarly to the first part of the above example (i.e., before reacting with the activator), using DMAC as the solvent, 1.2 eq. formic acid, 0.8 eq. diisopropylethylamine as the 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- (Formed in situ by mixing [Rh(III)Cl2Cp*]2, N-[(1R,2R)-2-amino-1,2-diphenylethyl]-1-[(1R,4S)-7,7-dimethyl-2-oxonorborn-1-yl]methanesulfonamide and diisopropylethylamine) in a molar ratio of 1:3:7. The reaction was carried out at -5 °C.

[0464] The reaction using RhClCp*·(1R,2R-CsDPEN-1) as a catalyst yielded 2-R with an enantiomeric purity of 97% ee (conversion: 95%); the reaction using RhClCp*·(1R,2R-CsDPEN-2) as a catalyst yielded 2-R with an enantiomeric purity of 98% ee (conversion: 98%).

Claims

1. A method for preparing enantiomeric enriched form of 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- The method using 5-alkoxides: Among them, the asterisk Display the center of the stereo source; The method includes: (a) Reduction of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 1, or its tautomer or a mixture thereof, in the presence of a chiral transition metal catalyst and optionally a base, with a reducing agent: 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; 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 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 may have 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; A reaction mixture containing enantiomeric enriched form of formula 2, 2-[2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomer or a mixture thereof, is obtained: ； as well as (b) React the reaction mixture obtained in step (a) with an activator that enhances the electrophilicity of the asterisked carbon atom in compound 1 without promoting racemization at the carbon atom. Compound of formula (I) was obtained in enantiomeric enriched form. The activator used in step (b) is selected from P(OR) 1 )2Cl、P(OR 1 Cl2、P(=O)(OR) 1 )2Cl, wherein each of the three compounds mentioned above contains R 1 Independently C1-C4 alkyl; PCl3, P(=O)Cl3, polyphosphoric acid, P4O 10 Mitsunobu-type reagents, triphenylphosphine in combination with halogenating agents, complexes of SO3 with Lewis bases selected from trimethylamine, triethylamine, dimethylformamide or pyridine; CH3S(O)2Cl, carbonyl diimidazole (CDI), Vilsmeier reagent, complexes of N,N-dimethylformamide and / or N,N-dimethylacetamide with BF3; and mixtures of two or more of the above activators.

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 ring may 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 [NH(C2H5)3] + [NH(CH2CH2CH2CH3)3] + and [NH(C2H5)(CH (CH3)2] + .

5. The method of claim 1, wherein optionally the base used in step (a) 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 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 may have 1-6 C1-C4 alkyl groups and / or 1 or 2 OH groups, wherein the base may be used in a supported form.

6. The method of claim 2, wherein optionally the base used in step (a) 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 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 may have 1-6 C1-C4 alkyl groups and / or 1 or 2 OH groups, wherein the base may be used in a supported form.

7. The method of claim 5, 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 of claim 5, wherein the base is selected from triethylamine, tributylamine, and diisopropylethylamine.

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

1.

16. The method according to any one of claims 1-12, wherein the chiral transition metal catalyst used in step (a) is used in an amount of 0.01-10 mol% relative to 1 mol of compound 1, calculated based on the transition metal content.

17. The method of claim 16, wherein the chiral transition metal catalyst used in step (a) is used in an amount of 0.05-5 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 used in step (a) is used in an amount of 0.1-5 mol% relative to 1 mol of compound 1, calculated based on the transition metal content.

19. The method of claim 16, wherein the chiral transition metal catalyst used in step (a) is used in an amount of 0.1-2 mol% relative to 1 mol of compound 1, calculated based on the transition metal content.

20. The method according to any one of claims 1-12, wherein the chiral ligand is selected from DPEN, TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, Trips in the (1R,2R) or (1S,2S) form. DPEN, CsDPEN, DPEN, RsDPEN, TsDiOMeDPEN or 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.

21. The method of claim 16, wherein the chiral ligand is selected from (1R,2R) or (1S,2S) forms of DPEN, TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, Trips DPEN, CsDPEN, DPEN, RsDPEN, TsDiOMeDPEN or 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.

22. The method of claim 20, 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 a phenyl group that may have 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.

23. The method of claim 20, 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, 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 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.

24. 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 TsDPEN, CF3TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, Catalysts containing chiral 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 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.

25. The method of claim 23, wherein the chiral transition metal catalyst is selected from catalysts containing Ru, Rh or Ir as the central metal and chiral ligands selected from TsDPEN, MsDPEN and CsDPEN in the form of (1R,2R) or (1S,2S).

26. The method according to any one of claims 1-12, 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.

27. The method of claim 21, 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.

28. The method of claim 26, 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.

29. The method according to any one of claims 1-12, wherein the chiral transition metal catalyst is selected from chiral ligands containing Ru, Rh, or Ir as the central metal, selected from TsDPEN, MsDPEN, and CsDPEN in the form of (1R,2R) or (1S,2S), selected from halogen ligands, and selected from Cp. p-Isopropyltoluene and Catalysts with other ligands.

30. The method of claim 28, wherein the chiral transition metal catalyst is selected from chiral ligands containing Ru, Rh, or Ir as the central metal, selected from TsDPEN, MsDPEN, and CsDPEN in (1R,2R) or (1S,2S) forms, selected from halogen ligands, and selected from Cp. p-Isopropyltoluene and Catalysts with other ligands.

31. The method according to any one of claims 1-12, wherein in step (a) at least 55% ee enantiomeric excess, 2-[(2S)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomer or mixture of different tautomers of the formula 2-S is prepared: ， For this purpose, a chiral transition metal catalyst comprising a chiral ligand in the form of (1S,2S) as defined in any one of claims 1-25 is used in step (a).

32. The method of claim 30, wherein in step (a) at least 55% ee enantiomeric excess is used to prepare 2-S[(2S)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomer or mixture of different tautomers: ， For this purpose, a chiral transition metal catalyst comprising a chiral ligand in the form of (1S,2S) as defined in any one of claims 1-25 is used in step (a).

33. The method of claim 31, wherein in step (a) 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomer or mixture of different tautomers of the formula 2-S is prepared in an enantiomeric excess of at least 60% ee.

34. The method of claim 31, wherein in step (a) at least 70% ee enantiomeric excess is used to prepare 2-S-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomer or mixture of different tautomers.

35. The method of claim 31, wherein in step (a) at least 80% ee enantiomeric excess is used to prepare 2-S[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomer or mixture of different tautomers thereof.

36. The method of claim 31, wherein in step (a) 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomer or mixture of different tautomers of the formula 2-S is prepared in an enantiomeric excess of at least 90% ee.

37. The method of claim 31, wherein a chiral transition metal catalyst comprising a chiral ligand in the form of (1S, 2S) as defined in any one of claims 1-30 is used.

38. The method according to any one of claims 1-12, wherein in step (a) at least 55% ee enantiomeric excess, 2-[(2R)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-R, or a tautomer of the same or a mixture thereof, is prepared: ， For this purpose, a chiral transition metal catalyst comprising a chiral ligand in the form of (1R, 2R) as defined in any one of claims 1-25 is used in step (a).

39. The method of claim 30, wherein in step (a) at least 55% ee enantiomeric excess is used to prepare 2-[(2R)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-R or a tautomer thereof or a mixture of different tautomers thereof: ， For this purpose, a chiral transition metal catalyst comprising a chiral ligand in the form of (1R, 2R) as defined in any one of claims 1-25 is used in step (a).

40. The method of claim 38, wherein in step (a) 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-R or a tautomer thereof or a mixture thereof is prepared in enantiomeric excess of at least 60% ee.

41. The method of claim 38, wherein in step (a) 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-R or a tautomer thereof or a mixture thereof is prepared in enantiomeric excess of at least 70% ee.

42. The method of claim 38, wherein in step (a) 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-R or a tautomer thereof or a mixture thereof is prepared in an enantiomeric excess of at least 80% ee.

43. The method of claim 38, wherein in step (a) 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-R or a tautomer thereof or a mixture thereof is prepared in enantiomeric excess of at least 90% ee.

44. The method of claim 38, wherein a chiral transition metal catalyst comprising a chiral ligand in the form of (1R,2R) as defined in any one of claims 1-30 is used.

45. The method according to any one of claims 1-12, wherein the activator used in step (b) is selected from P(OR) 1 )2Cl、P(OR 1 Cl2, wherein each R in the two of the above compounds 1 Independently C1-C4 alkyl; PCl3, P(O)Cl3, SO3 / dimethylformamide complex, CH3S(=O)2Cl, CDI and Mitsunobu type reagents.

46. ​​The method of claim 39, wherein the activator used in step (b) is selected from P(OR) 1 )2Cl、P(OR 1 Cl2, wherein each R in the two of the above compounds 1 Independently C1-C4 alkyl; PCl3, P(O)Cl3, SO3 / dimethylformamide complex, CH3S(=O)2Cl, CDI and Mitsunobu type reagents.

47. The method according to claim 45, wherein the activator used in step (b) is selected from dimethyl phosphite (P(OCH3)2Cl), diethyl phosphite (P(OCH2CH3)2Cl), methyl phosphite (P(OCH3)Cl2), ethyl phosphite (P(OCH2CH3)Cl2), PCl3, P(O)Cl3, SO3 / dimethylformamide complex, CH3S(=O)2Cl, CDI and Mitsunobu type reagents.

48. The method according to claim 45, wherein the activator used in step (b) is selected from dimethyl chlorophosphite (P(OCH3)2Cl), diethyl chlorophosphite (P(OCH2CH3)2Cl), methyl dichlorophosphite (P(OCH3)Cl2), ethyl dichlorophosphite (P(OCH2CH3)Cl2), PCl3 and P(O)Cl3.

49. The method of claim 45, wherein the activator used in step (b) is selected from dimethyl chlorophosphite (P(OCH3)2Cl) and diethyl chlorophosphite (P(OCH2CH3)2Cl).

50. The method according to any one of claims 1-12, wherein the activator is used in an amount such that the molar ratio of the compound of formula 1 to the activator is in the range of 10:1 to 1:

10.

51. The method of claim 46, wherein the activator is used in an amount such that the molar ratio of the compound of formula 1 to the activator is in the range of 10:1 to 1:

10.

52. The method of claim 50, wherein the activator is used in an amount such that the molar ratio of the compound of formula 1 to the activator is in the range of 2:1 to 1:

5.

53. The method of claim 50, wherein the activator is used in an amount such that the molar ratio of the compound of formula 1 to the activator is in the range of 1:1 to 1:

3.

54. The method of claim 50, wherein the activator is used in an amount such that the molar ratio of the compound of formula 1 to the activator is in the range of 1:1 to 1:

2.

55. The method according to any one of claims 1-12, for preparing (IR)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- in an enantiomeric excess of at least 55% ee. -5-alkoxide: ； The method includes: (a.1) A reaction mixture or a mixture thereof containing, in an enantiomeric excess of at least 55% ee, 2-[(2S)-2-(2-chlorothiazolin-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-S, or a mixture thereof, or a mixture thereof: ； as well as (b.1) React the reaction mixture obtained in step (a.1) with an activator as defined in any one of claims 1-54; or For the preparation of (3S)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- in an enantiomeric excess of at least 55% ee. -5-alkoxide: ； The method includes: (a.2) A reaction mixture containing, or a mixture of, a compound of formula 1 or its tautomers or different tautomers, in an enantiomeric excess of at least 55% ee of 2-[(2R)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-R or its tautomers or different tautomers or a mixture of its tautomers or different tautomers: ； as well as (b.2) React the reaction mixture obtained in step (a.1) with an activator as defined in any one of claims 1-54.

56. The method of claim 51, for preparing (IR)-3R-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- in an enantiomeric excess of at least 55% ee. -5-alkoxide: ； The method includes: (a.1) A reaction mixture or a mixture thereof containing, in an enantiomeric excess of at least 55% ee, 2-[(2S)-2-(2-chlorothiazolin-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-S, or a mixture thereof, or a mixture thereof: ； as well as (b.1) React the reaction mixture obtained in step (a.1) with an activator as defined in any one of claims 1-54; or For the preparation of (3S)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- in an enantiomeric excess of at least 55% ee. -5-alkoxide: ； The method includes: (a.2) A reaction mixture containing, or a mixture of, a compound of formula 1 or its tautomers or different tautomers, in an enantiomeric excess of at least 55% ee of 2-[(2R)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-R or its tautomers or different tautomers or a mixture of its tautomers or different tautomers: ； as well as (b.2) React the reaction mixture obtained in step (a.1) with an activator as defined in any one of claims 1-54.

57. The method of claim 55, for preparing (IR)-3R-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- with an enantiomeric excess of at least 60% ee. 5-alkoxide.

58. The method of claim 55, for preparing (IR)-3R-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- with an enantiomeric excess of at least 70% ee. 5-alkoxide.

59. The method of claim 55, for preparing (IR)-3R-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- with an enantiomeric excess of at least 80% ee. 5-alkoxide.

60. The method of claim 55, for preparing (IR)-3R-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- with an enantiomeric excess of at least 90% ee. 5-alkoxide.

61. The method of claim 55, wherein in (a.1) a reaction mixture containing at least 60% ee of an enantiomeric excess of 2-[(2S)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-S or a tautomer of the same or a mixture of different tautomers thereof is formed.

62. The method of claim 55, wherein in (a.1) a reaction mixture containing at least 70% ee of 2-[(2S)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or a tautomer thereof or a mixture of different tautomers thereof is formed.

63. The method of claim 55, wherein in (a.1) a reaction mixture containing at least 80% ee of an enantiomeric excess of 2-[(2S)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-S or a tautomer of the same or a mixture of different tautomers thereof is formed.

64. The method of claim 55, wherein in (a.1) a reaction mixture containing at least 90% ee enantiomeric excess of 2-[(2S)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-S or a tautomer of the same or a mixture of different tautomers thereof is formed.

65. The method of claim 55, for preparing (3S)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- of the formula (IS) with an enantiomeric excess of at least 60% ee. 5-alkoxide.

66. The method of claim 55, for preparing (3S)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- of the formula (IS) with an enantiomeric excess of at least 70% ee. 5-alkoxide.

67. The method of claim 55, for preparing (3S)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- of the formula (IS) with an enantiomeric excess of at least 80% ee. 5-alkoxide.

68. The method of claim 55, for preparing (3S)-3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- of the formula (IS) with an enantiomeric excess of at least 90% ee. 5-alkoxide.

69. The method of claim 55, wherein in (a.2) a reaction mixture containing at least 60% ee of an enantiomeric excess of 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-R or a tautomer of or a mixture of different tautomers of or a mixture of different tautomers of or a mixture of different tautomers of or a tautomer of or a tautomer of or a mixture of different tautomers of or a tautomer of or a tautomer of or a tautomer of or a tautomer of or a tautomer of or a tautomer of is formed.

70. The method of claim 55, wherein in (a.2) a reaction mixture containing at least 70% ee of an enantiomeric excess of 2-[(2R)-2-(2-chlorothiazo-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-R or a tautomer of or a mixture of different tautomers of or a mixture of different tautomers of or a mixture of different tautomers of or a tautomer ...

71. The method of claim 55, wherein in (a.2) a reaction mixture containing at least 80% ee of 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or a tautomer of or a mixture of different tautomers of formula 2-R is formed.

72. The method of claim 55, wherein in (a.2) a reaction mixture containing at least 90% ee of 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxyethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula 2-R or a tautomer of or a mixture of different tautomers of or a mixture of different tautomers of or a mixture of different tautomers of or a tautomer of or a tautomer of or a mixture of different tautomers of or a tautomer of or a tautomer of or a tautomer of is formed.

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