Process for preparing 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one

Abstract

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

Description

[Technical Field]

[0001] The present invention relates to a process for preparing 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one or a tautomer thereof, to 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one or a tautomer thereof and to its use as an intermediate in the preparation of 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds, in particular 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate and its enantiomerically enriched forms. The method also relates to 2-hydroxy-4-methyl-5-phenyl-2-sulfanyl-pyrimidinone, to thiolate salts and to their tautomers, and to their use as intermediates in the preparation of 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds, in particular 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate and its enantiomerically enriched forms. [Background technology]

[0002] 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one (or its tautomers) and its precursor, 2-hydroxy-4-methyl-5-phenyl-2-sulfanyl-pyrimidinone in its thiol or thiolate form (or its tautomers), have proven to be valuable intermediates in the preparation of 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds, more specifically 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate and its enantiomerically enriched forms. These pyrimidinium compounds have insecticidal properties and are known, for example, from WO 2018 / 177970 or WO 2014 / 167084.

[0003] The methods known so far for the preparation of these pyrimidinium compounds are cumbersome and still unsatisfactory.

[0004] In WO 2018 / 177970, WO 2018 / 197541, and WO 2018 / 202654, non-racemic 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds are prepared by reacting non-racemic 4-heteroaryl-substituted thiazolidine-2-imines with 2-substituted malonic acid derivatives. In WO 2018 / 177970 and WO 2018 / 197541, non-racemic 4-heteroaryl-substituted thiazolidine-2-imines are then prepared by catalytic asymmetric hydrogenation of 1-heteroaryl-substituted ethanimines bearing a leaving group at the 2-position. The resulting amine is then reacted with an isothiocyanate to produce the thiazolidine-2-imine. The reaction sequence is described in WO 2018 / 197541 as follows: [ka] R Ais a sulfanyl or sulfinyl group, a phosphoroxy group, an alkoxy group or a benzyl group; Het is an optionally substituted pyridin-3-yl, thiazol-5-yl or pyrimidin-5-yl; W and LG are leaving groups; R 1 is a (cyclo)aliphatic group, and R 2 is a 5- or 6-membered carbocyclic or heterocyclic ring. In WO 2018 / 177970, amine VII is obtained from the corresponding sulfinyl imine via another reaction route.

[0005] WO 2018 / 177970 and WO 2018 / 202654 describe additional routes to non-racemic 4-heteroaryl-substituted thiazolidin-2-imines. These are prepared by starting with a heteroaryl methyl ketone in which the methyl group bears a leaving group, converting the leaving group to an alkylcarbonyloxy group, hydrolyzing the latter to a hydroxyl group, and reacting the resulting heteroaryl hydroxymethyl ketone with a sulfamoyl halide to produce a 4-heteroaryl-5H-oxathiazole-2,2-dioxide, which is subjected to catalytic asymmetric hydrogenation to produce a non-racemic 4-heteroaryl oxathiazolidine-2,2-dioxide, which is reacted with an isothiocyanate to produce a thiazolidin-2-imine. The reaction sequence is described in WO 2018 / 202654 as follows: [ka] Het is optionally substituted pyridin-3-yl, thiazol-5-yl or pyrimidin-5-yl, W and LG are leaving groups, M 2 is Li, Na, K, Al, Ba, Cs, Ca or Mg, and R AC is alkylcarbonyl, and X 1 is a halogen and R 1 is a (cyclo)aliphatic group, and R 2 is a 5- or 6-membered carbocyclic or heterocyclic ring.

[0006] However, these methods are not very economical: some reagents are expensive, recycling of some reagents that are not consumed or not completely consumed is difficult, the overall yields are not satisfactory, and too many reaction steps are involved.

[0007] WO 2015 / 200619 describes the preparation of 2-[2-phenyl-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one by reacting N-methylthiourea with dimethyl 2-phenylmalonate to produce 6-hydroxy-3-methyl-5-phenyl-2-sulfanyl-pyrimidin-4-one, which, after isolation, is then reacted with 2-bromo-1-phenyl-ethanone. A similar reaction sequence is applied to the synthesis of 2-[2-phenyl-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one with a substituent on the phenyl ring. However, this reference does not teach or suggest preparing heteroaromatic analogs of these compounds or modifying the halogen atom in the ethanone reactant. Furthermore, the yields are rather modest. Summary of the Invention [Means for solving the problem]

[0008] The object of the present invention is to provide a more economical process for the preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one which avoids the drawbacks of the prior art methods.

[0009] This problem is related to the formula (I): [ka] or a tautomer thereof, This method is (a) reacting N-methylthiourea of ​​formula 1 with 2-phenylmalonate of formula 2 in the presence of a base [ka] (In the formula, R 1 and R 2 are, independently of one another, C1-C4-alkyl), obtaining a reaction mixture containing a pyrimidinone compound of formula 3 or a tautomer thereof; [ka] (In the formula, M + is the cation equivalent) and (b) optionally isolating the pyrimidinone compound of formula 3 (or a tautomer thereof) from the reaction mixture obtained in step (a) in its salt form (i.e., as compound 3 shown above) or thiol form (i.e., as compound 3-SH shown below); (c) reacting either the reaction mixture obtained in step (a) (without isolation of 3 or its tautomer) or the compound obtained in step (b) with 1-(2-chlorothiazol-5-yl)ethanone of formula 4 to give [ka] wherein X is a leaving group; obtaining a compound of formula (I) or a tautomer thereof.

[0010] The present invention further relates to 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of formula (I) above or its tautomer. As mentioned above, this compound is a useful intermediate in the preparation of insecticidal 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds, more specifically 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate and its enantiomerically enriched forms. The present invention therefore also relates to the use of the aforementioned compounds (or their tautomers) as intermediates in the preparation of 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds, in particular 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate and enantiomerically enriched forms thereof.

[0011] The present invention also relates to 2-hydroxy-4-methyl-5-phenyl-2-sulfanyl-pyrimidinone and its thiolate salts and tautomers. The thiolate salts are shown above as Formula 3. These thiol and thiolate compounds are valuable intermediates in the preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one (I), and therefore also valuable intermediates in the preparation of downstream insecticidal 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds, more specifically 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate and its enantiomerically enriched forms. The present invention therefore also relates to the use of the aforementioned thiol or thiolate compounds (or tautomers thereof) as intermediates in the preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of formula (I) and their use as intermediates in the preparation of 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds, in particular 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate and its enantiomerically enriched forms. DETAILED DESCRIPTION OF THE INVENTION

[0012] definition Halogen as used in connection with the present invention is F, Cl, Br or I.

[0013] The term C1-C4-alkyl denotes a saturated, linear or branched aliphatic radical having 1 to 4 carbon atoms. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

[0014] C1-C4-Alkanols are saturated aliphatic monoalcohols, i.e. C1-C4-alkyl radicals as defined above, in which one of the hydrogen atoms is replaced by a hydroxyl group. Examples are methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol and tert-butanol.

[0015] C1-C4-Alkanolates are salts of C1-C4-alkanols, i.e. in which the hydrogen atom of the hydroxyl group is replaced by a cationic equivalent, for example a metal cation. Examples are methanolate, ethanolate, n-propanolate, isopropanolate, n-butanolate, sec-butanolate, isobutanolate and tert-butanolate.

[0016] Glycols are saturated aliphatic diols, examples of which include ethylene glycol, propylene glycol, diethylene glycol and triethylene glycol.

[0017] C1-C4-Alkyl acetates are C1-C4-alkyl esters of acetic acid. Examples are methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, sec-butyl acetate, isobutyl acetate and tert-butyl acetate.

[0018] M + is the cation equivalent. It represents a metal cation or an ammonium cation (ammonium in this case is the proper ammonium cation NH4 + (This term refers to both substituted ammonium cations as well as doubly or triply charged cations.) In the case of doubly or triply charged cations, the cation equivalent is (M n+ ) 1 / n where n is the number of charges. In compound 3, M +is generally derived from the base used in step (a). Thus, for example, when an alkali metal alkanolate, alkali metal carbonate, alkali metal hydroxide, or alkali metal phosphate is used as the base in step (a), M in compound 3 + is generally an alkali metal cation, and when an alkaline earth metal carbonate or alkaline earth metal hydroxide is used as the base, M in compound 3 + is generally an alkaline earth metal cation [(M 2+ ) 1 / 2 and when a non-nucleophilic organic base is used in step (a), M in compound 3 + is generally the protonated form of the base. However, M + may also be derived from the base used in the work-up of the reaction mixture of step (a) in the isolation step (b).

[0019] Compound (I) can exist as its tautomer or as a mixture of different tautomeric forms. Examples of tautomeric forms of compounds of formula (I) above are of the following formula: [ka]

[0020] A mixture of different tautomeric forms is, for example, a mixture of the tautomers shown above as this tautomer, formula (I).

[0021] Additionally, the compound of formula 3 and its neutral thiol form 3-H can exist as their tautomers or as a mixture of different tautomeric forms. An example of a tautomeric form of the compound of formula 3 shown above is the following formula: [ka]

[0022] In thiolates, there can also be a negative charge on the oxygen atom, as shown below: [ka] Generally, however, it is present primarily on sulfur atoms.

[0023] Examples of tautomeric forms of the thiol form 3-H are: [ka]

[0024] For simplicity, in the following only reference will be made to compounds (I), 3 and 3-H, nevertheless all embodiments also relate to their tautomers and mixtures of their different tautomeric forms.

[0025] Embodiment (Ex) of the present invention Typical and preferred embodiments Ex are summarized in the following non-exhaustive list: Further preferred embodiments will become apparent from the paragraphs that follow this list.

[0026] E.1. Method for preparing 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of formula (I): [ka] This method is (a) reacting N-methylthiourea of ​​formula 1 with 2-phenylmalonate of formula 2 in the presence of a base [ka] (In the formula, R 1 and R 2 are, independently of one another, C1-C4-alkyl), obtaining a reaction mixture containing a pyrimidinone compound of formula 3 [ka] (In the formula, M + is the cation equivalent) and (b) optionally isolating the pyrimidinone compound of formula 3 in its salt form or in its thiol form from the reaction mixture obtained in step (a); (c) reacting either the reaction mixture obtained in step (a) (without isolation of 3) or the compound obtained in step (b) with 1-(2-chlorothiazol-5-yl)ethanone of formula 4 [ka] wherein X is a leaving group; Obtaining a compound of formula (I).

[0027] E.2.R 1 and R 2 The method of embodiment E.1, wherein each is independently methyl or ethyl.

[0028] E.3.R 1 and R 2 The method of embodiment E.2, wherein both are methyl or both are ethyl.

[0029] E.4. The method of any of embodiments E.1-E.3, wherein the base used in step (a) is selected from the group consisting of alkali metal C1-C4-alkanolates, alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal phosphates, non-nucleophilic organic bases, and mixtures thereof.

[0030] E.5. The method of embodiment E.4, wherein the base used in step (a) is selected from the group consisting of alkali metal C1-C4-alkanolates, alkali metal carbonates, and mixtures thereof, in particular alkali metal C1-C4-alkanolates.

[0031] E.6. The method of embodiment E.5, wherein the base used in step (a) is selected from the group consisting of sodium methanolate, sodium ethanolate, sodium isopropanolate, sodium tert-butanolate, potassium methanolate, potassium ethanolate, potassium tert-butanolate, lithium methanolate, and mixtures thereof.

[0032] E.7. The method of embodiment E.6, wherein the base used in step (a) is selected from the group consisting of sodium methanolate, potassium methanolate, sodium ethanolate, potassium ethanolate, and mixtures thereof, specifically sodium methanolate or potassium methanolate.

[0033] E.8. The method of any of embodiments E.1 to E.7, wherein in step (a), 2-phenylmalonate 2 is used in an amount of 0.8 to 2.0 moles per mole of N-methylthiourea 1.

[0034] E.9. The method of embodiment E.8, wherein in step (a), 2-phenylmalonate 2 is used in an amount of 1.0 to 1.3 moles per mole of N-methylthiourea 1.

[0035] E.10. The method of any of embodiments E.1 to E.9, wherein in step (a), the base is used in an amount of 0.8 to 1.5 moles per mole of N-methylthiourea.

[0036] E.11. The method of embodiment E.10, wherein in step (a), the base is used in an amount of 1.0 to 1.5 moles per mole of N-methylthiourea.

[0037] E.12. The method of any one of embodiments E.1-E.11, wherein the reacting in steps (a) and (c) is carried out in a solvent.

[0038] E.13. The method of embodiment E.12, wherein the solvent is selected from the group consisting of polar protic solvents, polar aprotic solvents, C1-C4-alkyl acetates, dialkyl ethers, aromatic solvents, heterocyclic solvents, and mixtures thereof.

[0039] E.14. The method of embodiment E.13, wherein the solvent is selected from the group consisting of C1-C4-alkanols, glycols, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, C1-C4-alkyl acetates, di-n-propyl ether, di-n-butyl ether, methyl tert-butyl ether, acetonitrile, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, N-methylpyrrolidone, and mixtures thereof.

[0040] E.15. The method of embodiment E.14, wherein the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, isobutanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, toluene, chlorobenzene, N-methylpyrrolidone, and mixtures thereof, preferably from the group consisting of methanol, ethanol, dimethylacetamide, toluene, chlorobenzene, and mixtures thereof.

[0041] E.16. The method of embodiment E.15, wherein step (a) is carried out in a solvent selected from the group consisting of methanol, ethanol, mixtures of methanol and ethanol, and mixtures of methanol and / or ethanol with at least one further solvent selected from the group consisting of dimethylacetamide, toluene, and chlorobenzene, and step (c) is carried out in a solvent selected from the group consisting of methanol, ethanol, dimethylacetamide, toluene, chlorobenzene, and mixtures of at least two of the foregoing solvents.

[0042] E.17. The method of any one of embodiments E.1-E.16, wherein step (a) is carried out at a temperature from 10° C. to the reflux temperature of the reaction mixture.

[0043] E.18. The method of embodiment E.17, wherein step (a) is carried out at a temperature from 20° C. to the reflux temperature of the reaction mixture.

[0044] E.19. The method of embodiment E.18, wherein step (a) is carried out at a temperature of 45 to 75°C.

[0045] E.20. The method of any one of embodiments E.1 to E.19, wherein the reaction time in step (a) is from 1 hour to 60 hours.

[0046] E.21. The method of embodiment E.20, wherein the reaction time in step (a) is 4 hours to 18 hours.

[0047] E.22. The method according to any one of embodiments E.1 to E.21, wherein in step (a): (a.1) 2-phenylmalonate 2 is added to an optionally heated solution of methylthiourea 1 and a base in a solvent; or (a.2) optionally in a solvent, a base is added to an optionally heated mixture of methylthiourea 1, 2-phenylmalonate 2, and optionally a solvent; or (a.3) a mixture of methylthiourea 1, 2-phenylmalonate 2, a base and optionally a solvent is prepared and reacted, optionally under heating; or (a.4) optionally in a solvent, methylthiourea 1 is added to an optionally heated mixture of 2-phenylmalonate 2, a base, and optionally a solvent; The procedure according to (a.1) or (a.2) is preferred.

[0048] E.23. The method of any one of embodiments E.1-E.22, wherein in step (c), the reaction mixture obtained in step (a) is reacted with a compound of Formula 4.

[0049] E.24. The method of any one of embodiments E.1-E.23, wherein X in the compound of Formula 4 is selected from the group consisting of halogen, triflate, mesylate, tosylate, and nonaflate.

[0050] E.25. The method of embodiment 24, wherein X of the compound of formula 4 is selected from the group consisting of Cl, Br, and I.

[0051] E.26. The method of embodiment 25, wherein X of the compound of formula 4 is selected from the group consisting of Cl and Br.

[0052] E.27. The method of embodiment 26, wherein X in the compound of formula 4 is Cl.

[0053] E.28. The method of any of embodiments E.1 to E.27, wherein in step (c), 1-(2-chlorothiazol-5-yl)ethanone 4 is used in an amount of 0.8 to 1.5 moles per mole of N-methylthiourea 1 used in step (a).

[0054] E.29. The method of embodiment E.28, wherein in step (c), 1-(2-chlorothiazol-5-yl)ethanone 4 is used in an amount of 1.0 to 1.5 moles per mole of N-methylthiourea 1 used in step (a).

[0055] E.30. The method of any one of embodiments E.1 to E.29, wherein step (c) is carried out at a temperature of -20 to 120°C.

[0056] E.31. The method of embodiment E.30, wherein step (c) is carried out at a temperature of 25 to 80°C.

[0057] E.32. The method of embodiment E.31, wherein step (c) is carried out at a temperature of 40 to 80°C.

[0058] E.33. The method of any one of embodiments E.1-E.32, wherein step (c) is carried out in the presence of an additive selected from the group consisting of alkali metal bromides, alkali metal iodides, ammonium bromide, ammonium iodide, and mixtures thereof.

[0059] E.34. The method of embodiment E.33, wherein the additive is selected from the group consisting of NaBr, KBr, NaI, KI, tetrabutylammonium bromide, and mixtures thereof.

[0060] E.35. The method according to any one of embodiments E.33 or E.34, wherein the additive is used in an amount such that the molar ratio of additive to 1-(2-chlorothiazol-5-yl)ethanone 4 is preferably in the range of 1:100 to 10:1, more preferably 1:20 to 2:1, and in particular 1:2 to 2:1.

[0061] E.36. The method according to any one of embodiments E.1 to E.35, wherein in step (c): (c.1) the reaction mixture obtained in step (a) or the product obtained in step (b) is added to a solution of 1-(2-chlorothiazol-5-yl)ethanone 4, or (c.2) A process in which a solution or melt of 1-(2-chlorothiazol-5-yl)ethanone 4 is added to the reaction mixture obtained in step (a) or to a solution of the product obtained in step (b).

[0062] E.37. The method of embodiment E.36, wherein step (c) is carried out according to procedure (c.2).

[0063] The method according to any of embodiments E.36 or E.37, wherein in the procedure according to E.38.(c.2), a solution or melt of 1-(2-chlorothiazol-5-yl)ethanone 4 is added to the reaction mixture obtained in step (a) or to the solution of the product obtained in step (b) within 15 minutes to 12 hours.

[0064] E.39. The method of embodiment E.38, wherein a solution or melt of 1-(2-chlorothiazol-5-yl)ethanone 4 is added to the reaction mixture obtained in step (a) or to the solution of the product obtained in step (b) within 0.5 hours to 6 hours.

[0065] E.40. The method of any of embodiments E.1 to E.39, wherein after mixing the reaction mixture obtained in step (a) or the product obtained in step (b) and the entire amount of 1-(2-chlorothiazol-5-yl)ethanone 4, the reaction mixture is reacted for 0 to 60 hours.

[0066] E.41. The method of embodiment E.40, wherein the reaction mixture is reacted for 1 hour to 40 hours.

[0067] E.42. The method of embodiment E.41, wherein the reaction mixture is reacted for 1 to 18 hours.

[0068] E.43. 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of formula (I): [ka]

[0069] E.44. Pyrimidinone Compounds of Formula 3 [ka] (In the formula, M + is a cation equivalent, preferably an alkali metal cation, especially Na + or K + That is, or its corresponding thiol (i.e., -S - M + Instead of -SH).

[0070] The reaction sequence of the process of the present invention can be represented as follows: [ka]

[0071] The brackets around compound 3 indicate that the reaction can be carried out with or without isolating compound 3.

[0072] In the 2-phenylmalonate of formula 2, R 1 and R 2 are each independently preferably methyl or ethyl. In particular, R 1 and R 2 are both methyl or both ethyl.

[0073] The base used in step (a) is preferably selected from the group consisting of alkali metal C1-C4-alkanolates, alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal phosphates, non-nucleophilic organic bases and mixtures thereof.

[0074] Alkali metal cations suitable as countercations in the alkanolates, carbonates, hydroxides and phosphates are, for example, Li + , Na + , K. + , and Cs + Among these, Na + and K. + Suitable alkaline earth metals as counter cations in the alkanolates, carbonates and hydroxides are, for example, Mg 2+ and Ca 2+ is.

[0075] Examples of suitable alkali metal C1-C4-alkanolates are lithium, sodium, potassium or cesium methanolate, lithium, sodium, potassium or cesium ethanolate, lithium, sodium, potassium or cesium n-propanolate, lithium, sodium, potassium or cesium isopropanolate, lithium, sodium, potassium or cesium n-butanolate, lithium, sodium, potassium or cesium sec-butanolate, lithium, sodium, potassium or cesium isobutanolate and lithium, sodium, potassium or cesium tert-butanolate.

[0076] Examples of suitable alkali metal carbonates are lithium carbonate, sodium carbonate, potassium carbonate, or cesium carbonate.

[0077] Examples of suitable alkaline earth metal carbonates are magnesium carbonate and calcium carbonate.

[0078] Examples of suitable alkali metal phosphates are lithium, sodium, potassium, or cesium phosphates.

[0079] Non-nucleophilic organic bases are generally sterically hindered organic bases such that a proton can be attached to the basic center, but alkylation and complexation are inhibited. Examples include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

[0080] The base used in step (a) is preferably selected from the group consisting of alkali metal C1-C4-alkanolates, such as those listed above, alkali metal carbonates, such as those listed above, and mixtures thereof. More preferably, the base is selected from alkali metal C1-C4-alkanolates.

[0081] In particular, the base used in step (a) is selected from the group consisting of sodium methanolate, sodium ethanolate, sodium isopropanolate, sodium tert-butanolate, potassium methanolate, potassium ethanolate, potassium tert-butanolate, lithium methanolate, and mixtures thereof, more particularly selected from the group consisting of sodium methanolate, potassium methanolate, sodium ethanolate, potassium ethanolate, and mixtures thereof, in particular sodium methanolate or potassium methanolate.

[0082] 2-Phenylmalonate 2 is preferably used in step (a) in an amount of 0.8 to 2.0 moles per mole of N-methylthiourea 1, in particular in an amount of 1.0 to 1.3 moles per mole of N-methylthiourea 1.

[0083] The base is preferably used in step (a) in an amount of 0.8 to 1.5 moles per mole of N-methylthiourea, in particular in an amount of 1.0 to 1.5 moles per mole of N-methylthiourea.

[0084] The reactions of steps (a) and (c) are preferably carried out in a solvent.

[0085] The solvent is preferably selected from the group consisting of polar protic solvents, polar aprotic solvents, C1-C4 alkyl acetates, dialkyl ethers, aromatic solvents, heterocyclic solvents, and mixtures thereof. Polar protic solvents are, for example, alkanols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, and tert-butanol, and glycols such as ethylene glycol, propylene glycol, diethylene glycol, and triethylene glycol. Polar aprotic solvents are, for example, cyclic ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane (i.e., 1,3- and 1,4-dioxane), dimethylformamide, dimethylacetamide, dimethyl sulfoxide, or acetonitrile. C1-C4 alkyl acetates are, for example, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, sec-butyl acetate, isobutyl acetate, and tert-butyl acetate. Dialkyl ethers are, for example, diethyl ether, di-n-propyl ether, di-n-butyl ether, or methyl tert-butyl ether. Aromatic solvents are, for example, benzene, toluene, xylene, chlorobenzene, or dichlorobenzene. A suitable heterocyclic solvent is, for example, methylpyrrolidone.

[0086] More preferably, the solvent is selected from the group consisting of C1-C4-alkanols, glycols, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, C1-C4-alkyl acetates, di-n-propyl ether, di-n-butyl ether, methyl tert-butyl ether, acetonitrile, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, N-methylpyrrolidone, and mixtures thereof. More preferably, the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, isobutanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, toluene, chlorobenzene, N-methylpyrrolidone, and mixtures thereof, in particular methanol, ethanol, dimethylacetamide, toluene, chlorobenzene, and mixtures thereof.

[0087] In certain embodiments, step (a) is carried out in a solvent selected from the group consisting of methanol, ethanol, a mixture of methanol and ethanol, and a mixture of methanol and / or ethanol with at least one additional solvent selected from the group consisting of dimethylacetamide, toluene, and chlorobenzene, and step (c) is carried out in a solvent selected from the group consisting of methanol, ethanol, dimethylacetamide, toluene, chlorobenzene, and a mixture of at least two of the foregoing solvents. More specifically, step (a) is carried out in a solvent selected from the group consisting of methanol, ethanol, and a mixture of methanol and ethanol, and step (c) is carried out in a solvent selected from the group consisting of methanol, ethanol, dimethylacetamide, toluene, chlorobenzene, and a mixture of at least two of the foregoing solvents.

[0088] Step (a) is preferably carried out at a temperature of from 10°C to the reflux temperature of the reaction mixture, more preferably from 20°C to the reflux temperature of the reaction mixture, especially from 45 to 75°C.

[0089] The reaction time of step (a) depends on various factors such as the reaction temperature, the concentration of the reactants in the reaction mixture, etc. Typically, it ranges from about 1 hour to 60 hours, preferably from 4 hours to 18 hours.

[0090] The order of addition of the reactants, solvent, if present, and base in step (a) is not critical. For example, (a.1) 2-phenylmalonate 2 can be added to an optionally heated solution of methylthiourea 1 and a base in a solvent; or (a.2) optionally in a solvent, a base can be added to an optionally heated mixture of methylthiourea 1, 2-phenylmalonate 2, and optionally a solvent; or (a.3) A mixture of all components, i.e., methylthiourea 1, 2-phenylmalonate 2, a base and optionally a solvent, is prepared and reacted, optionally under heating, or (a.4) Methylthiourea 1 can be added to an optionally heated mixture of 2-phenylmalonate 2, a base and optionally a solvent, optionally in a solvent.

[0091] However, the procedure according to (a.1) or (a.2) is preferred.

[0092] In optional step (b), the pyrimidinone compound of formula 3 can be isolated from the reaction mixture obtained in step (a) by conventional methods, for example, by partially or completely removing the solvent, optionally under reduced pressure, or by adding a solvent to the reaction mixture in which 3 is insoluble or poorly soluble, optionally after concentrating the reaction mixture. Suitable solvents include, for example, aliphatic and alicyclic hydrocarbons such as pentane, hexane, heptane, and cyclohexane; acyclic ethers such as diethyl ether, di-n-propyl ether, di-n-butyl ether, and methyl tert-butyl ether; aromatic solvents such as benzene, toluene, xylene, chlorobenzene, or dichlorobenzene; and halogenated alkanes such as dichloromethane, trichloromethane, and dichloroethane. Depending on the reaction conditions in step (a), particularly the reaction temperature and solvent used, compound 3 may precipitate simply by cooling the reaction mixture. The precipitate can then be isolated by conventional means, such as filtration. Further purification of the isolated product can be carried out, if necessary, by conventional methods, such as trituration or recrystallization. Generally, however, the product can be used in step (c) without further purification.

[0093] Formula 3-SH [ka] Compound 3 can be acidified, typically in solution, to give the corresponding thiol, which is compound (a). Acidification can also, in principle, be carried out before isolating compound 3 from the reaction mixture obtained in step (a). Suitable acids can be inorganic (e.g., HCl, H2SO4, H3PO4, etc.) or organic (e.g., acetic acid, trifluoroacetic acid, etc.).

[0094] In step (c), the reaction mixture obtained in step (a) (without isolation of 3) or compound 3 or the corresponding thiol 3-SH obtained in step (b) is reacted with a compound of formula 4. If thiol 3-SH is used as starting material, it is convenient to first convert it to thiolate 3 or to carry out step (c) in the presence of a base. Suitable bases are those listed above in connection with step (a).

[0095] However, it is preferred to react the reaction mixture obtained in step (a) with 4, ie, omit the isolation step (b).

[0096] In 1-(2-chlorothiazol-5-yl)ethanone 4, X is a leaving group. Suitable leaving groups are, for example, halogen atoms, particularly Cl, Br, or I, and sulfonates such as triflate, mesylate, tosylate, or nonaflate. X is preferably a halogen atom, preferably Cl, Br, or I, more preferably Cl or Br, and especially Cl.

[0097] In step (c), 1-(2-chlorothiazol-5-yl)ethanone 4 is used in an amount of preferably 0.8 to 1.5 moles per mole of N-methylthiourea 1, in particular 1.0 to 1.5 moles per mole of N-methylthiourea 1 used in step (a).

[0098] In step (c), when compound 3 obtained in step (b) or the corresponding thiol 3-SH is reacted with a compound of formula 4, 1-(2-chlorothiazol-5-yl)ethanone 4 is preferably used in an amount of 0.8 to 1.5 mol per mol of N-methylthiourea 1, in particular 1.0 to 1.5 mol per mol of compound 3 or 3-SH.

[0099] Step (c) is preferably carried out at a temperature of from -20 to 120°C, more preferably from 25 to 80°C, particularly from 40 to 80°C.

[0100] In certain embodiments, step (c) is carried out in the presence of an additive (especially when X is Cl, see the discussion below). Such additives are intended to mitigate nucleophilic attack of the thiol or thiolate group in 3 on the X-substituted aliphatic carbon atom in 4. The effect of such additives is particularly relevant when X is Cl. Suitable additives are selected from the group consisting of alkali metal bromides, alkali metal iodides, ammonium bromide, ammonium iodide, and mixtures thereof, and the additive is preferably selected from the group consisting of NaBr, KBr, NaI, KI, tetrabutylammonium bromide, and mixtures thereof. Without wishing to be bound by theory, it is believed that when X is Cl, bromide or iodide replaces some of the CH-bonded Cl in 4. One aspect is that bromide and iodide are generally more reactive than chloride, thereby facilitating the reaction. Another aspect is that C—Br and C—I are softer reaction centers than C—Cl. According to the HSAB concept, this facilitates reaction with soft thiol or thiolate nucleophiles 3.

[0101] The additive is used in an amount such that the molar ratio of additive to 1-(2-chlorothiazol-5-yl)ethanone 4 is preferably in the range of 1:100 to 10:1, more preferably 1:20 to 2:1, especially 1:2 to 2:1.

[0102] The order of addition of the reactants in step (c) is not critical. For example, (c.1) The reaction mixture obtained in step (a) or the product obtained in step (b) can be added to a solution of 1-(2-chlorothiazol-5-yl)ethanone 4, or (c.2) A solution or melt of 1-(2-chlorothiazol-5-yl)ethanone 4 can be added to the reaction mixture obtained in step (a) or to the product obtained in step (b).

[0103] In (c.1), the product obtained in step (b) can be added as such (generally obtained as a solid) or in solution or dispersion. If the product is added in dissolved or dispersed form, the solvent used for this purpose is suitably the solvent in which step (c) is carried out.

[0104] If in (c.2) a solution or melt of 1-(2-chlorothiazol-5-yl)ethanone 4 is added to the product obtained in step (b), the product is expediently present in dissolved or dispersed form, and the solvent used for this purpose is again suitably the solvent in which step (c) is carried out.

[0105] The procedure according to (c.2) is preferred.

[0106] When step (c) is carried out according to the procedure of (c.2), the solution or melt of 1-(2-chlorothiazol-5-yl)ethanone 4 is preferably added within 15 minutes to 12 hours, in particular within 0.5 hours to 6 hours, to the reaction mixture obtained in step (a) or to the product obtained in step (b), suitably to a solution or dispersion thereof.

[0107] After mixing the reaction mixture obtained in step (a) or the product obtained in step (b) with the entire amount of 1-(2-chlorothiazol-5-yl)ethanone 4, the reaction mixture is preferably reacted for 0 to 60 hours, more preferably 1 to 40 hours, and particularly 1 to 18 hours. In this context, a reaction time of "0 hours" means that after the addition of the reactants is complete, the reaction is sufficiently complete that isolation of the desired compound (I) can proceed. This may be the case, for example, when the addition of the reactants continues for a significantly long time or when the aim is to recycle unreacted starting materials.

[0108] Compound (I) can be isolated from the reaction mixture by known means. Given its low solubility at room temperature in most solvents, especially more polar ones, preferably used in step (c), it can be isolated, for example, by precipitation. Part of the product precipitates during the reaction, especially if the reaction is carried out at a fairly low temperature, e.g., below 30°C, and if the reaction mixture is not too dilute. Precipitation can be further promoted by lowering the temperature, removing some of the solvent, and / or adding water to the reaction mixture.

[0109] The precipitate can be isolated by conventional methods such as filtration, centrifugation, settling, and removal of the supernatant, with filtration being preferred. The filter cake can be further purified by washing with a suitable solvent, such as methanol, ethanol, isopropanol, toluene, dimethylacetamide, water, a basic aqueous solution, e.g., aqueous NaHCO3, Na2CO3, K2CO3, NaOH, KOH, or NH3 solution, or a mixture thereof. Washing with water or an aqueous solution can be carried out over a wide temperature range, e.g., 0 to 100°C, preferably 25 to 80°C. Washing with an organic solvent can also be carried out over a wide temperature range, e.g., 0 to 100°C, but is preferably carried out using a solvent having a temperature of 0 to 35°C, particularly 10 to 25°C.

[0110] Compounds 1 and 2 are commercially available or can be prepared by standard methods.

[0111] Compound 4 can be prepared by reacting 2-chlorothiazole with a Grignard reagent to generate the corresponding chloro-(2-chlorothiazol-5-yl)magnesium species, followed by reaction with 2-halogeno-N-methoxy-N-methyl-acetamide, as described, for example, in WO 2018 / 197541 or WO 2018 / 202654. Alternatively, compound 4 can be prepared from thiourea according to the method described by T. Chalopin et al. in Org. Biomol. Chem., 2016, 14, 3913-3925.

[0112] This method provides compound (I) in high yield and purity and requires only a few steps, starting from readily available starting materials. In contrast to the method described in WO 2015 / 200619, it does not require the use of rather expensive organic bromine compounds as starting materials. Nevertheless, it is of course possible to use bromine or even iodine compounds, i.e., compound 4 where X is Br or I. However, given that compound 4 where X is another leaving group, especially Cl, provides superior yields, the use of compound 4 where X is Br or I is not essential, but merely an alternative option.

[0113] The present invention further relates to 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of formula (I), or a tautomer or a mixture of tautomeric forms thereof, which is a valuable intermediate in the preparation of insecticidal 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds, more particularly 3-(2-chlorothiazol-5)-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate and enantiomerically enriched forms thereof. The present invention also relates to the use of compound (I), or a tautomer or a mixture of tautomeric forms thereof, as an intermediate in the preparation of 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds, specifically 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate and enantiomerically enriched forms thereof.

[0114] Compound (I) (or a tautomer or a mixture of tautomeric forms thereof) can be further converted in just two steps to 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate, particularly its enantiomerically enriched form. To obtain the enantiomerically enriched form, compound (I) (or a tautomer or a mixture of tautomeric forms thereof) is subjected to asymmetric hydrogenation of the keto group in the enantiomerically enriched form to the respective alcohol, which is then subjected to internal cyclization by nucleophilic attack of the unsubstituted nitrogen atom of the pyrimidine ring at the carbon atom bearing the aliphatic OH group. Of course, the hydrogenation of (I) (or its tautomer or mixture of its tautomeric forms) can be carried out under achiral conditions to obtain the racemic form of 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate. The reaction sequence can be represented as follows: [ka]

[0115] These reactions are described in further detail in EP 21153034.0, EP 21153036.5, and EP 21153038.1.

[0116] The present invention also relates to pyrimidinone compounds of formula 3 as defined above or to a tautomer or a mixture of tautomeric forms thereof, and to the corresponding thiol 3-SH or to a tautomer or a mixture of tautomeric forms thereof, and to their use as intermediates in the preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of formula (I) or to a tautomer or a mixture of tautomeric forms thereof, and to their use as intermediates in the preparation of 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds, in particular 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate and its enantiomerically enriched forms.

[0117] The thiol of 3 has the formula 3-SH: [ka]

[0118] As can be seen from the above, compound 3 or 3-SH (or its tautomer or mixture of its tautomeric forms) can be further converted to 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate, particularly its enantiomerically enriched form, in three steps, the first being the reaction of 3 or 3-SH with 4 to produce compound (I) (or its tautomer or mixture of its tautomeric forms).

[0119] The present invention is further illustrated by the following examples. [Example]

[0120] method Compounds can be characterized by coupled high performance liquid chromatography / mass spectrometry (HPLC / MS), NMR, or melting point.

[0121] HPLC method: Agilent Eclipse XDB-C18, 150mm x 4.6mm ID x 5μm Gradient A = 0.5% H2SO4 in water, B = acetonitrile. Flow rate=1.1mL / min Column oven temperature = 30°C Gradient program: 20%B-100%B-15 min Run time = 15 minutes LCMS method 1: C18 column (50 mm x 2.1 mm x 1.7 μm) Gradient A = 0.1% TFA in water, B = acetonitrile Flow rate = 0.8 mL / min to 1.0 mL / min in 1.5 minutes Column oven temperature = 60°C Gradient program: 10% B to 100% B in 15 min, hold at 100% B for 1 min, then 10% B for 1 min Run Time: 1.75 minutes

[0122] 1 H-NMR: A signal is characterized by its chemical shift (ppm) relative to tetramethylsilane, its multiplicity, and its integral (relative number of hydrogen atoms given). The following abbreviations are used to characterize the multiplicity of a signal: m = multiplet, q = quartet, t = triplet, d = doublet, and s = singlet.

[0123] The abbreviations used are as follows: h is hour, min is minute, rt is retention time, rt is room temperature (20-25°C), and TFA is trifluoroacetic acid.

[0124] Example 1: Preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one In a 20 L jacketed reactor, a solution of N-methylthiourea (778 g, 8.38 mol), NaOCH (1584 g, 8.79 mol, 30 wt % solution in methanol), and methanol (384 g, 12 mol) was warmed to an internal temperature of 65° C. under N. Diethyl 2-phenylmalonate (2121 g, 8.79 mol) was then added over 30 minutes, and the pump was rinsed with methanol (384 g, 12 mol). The reaction was then stirred at an internal temperature of 65° C. for 4 hours and then at 50° C. for 18 hours, during which time a suspension formed. A solution of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone (1859 g, 9.00 mol) in ethanol (8.050 g, 175 mol) was then added over 30 minutes. The reaction was stirred at 50° C. for 75 minutes, during which time a large amount of solid precipitated. At this point, ethanol (2.300 g, 50 mol) was added and the stirring rate increased. The reaction was stirred at 50° C. for an additional 36 hours, and then the reaction was cooled to 20° C. over 16 hours. The solid that formed was then isolated by filtration through three 4 L fritted funnels. Each filter cake was washed with 500 mL of ethanol. The filter cake was then returned to the 20 L reactor and slurried with 15 L of water at 75° C. for 1 hour. The slurry was then filtered through two 4 L fritted funnels, and each filter cake was washed three times with 500 mL of room temperature water, then dried in a vacuum drying oven at 80° C. and 5 mbar. After drying, 3040 g (91%) of the title compound was isolated in the form of a brown solid with a purity of 99% by weight. 1 H NMR (400MHz, DMSO-d6): δ=8.75(s,1H),7.15-7.45(m,5H),4.9(s,2H),3.46(s,3H).

[0125] Example 2: Preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one In a 20 L jacketed reactor, a solution of N-methylthiourea (778 g, 8.38 mol), NaOCH (1584 g, 8.79 mol, 30 wt % solution in methanol), and methanol (384 g, 12 mol) was warmed to an internal temperature of 65°C under N. Diethyl 2-phenylmalonate (2121 g, 8.79 mol) was then added over 30 minutes, and the pump was rinsed with methanol (384 g, 12 mol). The reaction was then stirred at an internal temperature of 65°C for 4 hours and then at 50°C for 18 hours, during which time a suspension formed. A solution of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone (1859 g, 9.00 mol) in ethanol (10,000 g, 217 mol) was then added over 6 hours. The pump was rinsed with ethanol (350 g, 7.61 mol). After the addition was complete, the reaction was stirred at 50°C for 36 hours, and then cooled to 20°C over 16 hours. Two hours after the start of the addition of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone, a beige suspension formed in the reactor. The solids that formed were isolated by filtration through three 4-L fritted funnels. Each filter cake was washed three times with 500 mL of ethanol. The filter cake was then returned to the 20-L reactor and slurried with 15 L of water at 75°C for 1 hour. The slurry was then filtered through two 4-L fritted funnels, and each filter cake was washed three times with 500 mL of room-temperature water, followed by drying in a vacuum drying oven at 80°C and 5 mbar. After drying, 3055 g (91%) of the title compound was isolated in the form of a light brown solid with a purity of 99% by weight.

[0126] Example 3: Preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one A solution of N-methylthiourea (15.56 g, 167.4 mmol) and diethyl 2-phenylmalonate (42.38 g, 175.8 mmol) was prepared in a 500 mL round-bottom flask equipped with an overhead stirrer and reflux condenser at 35 °C under N 2 . To this solution was then added NaOCH 3 (31.56 g, 175.8 mmol, 30 wt % solution in methanol) over 2 hours, during which time a suspension formed. The reaction was stirred at 35 °C for an additional 24 hours, and then a solution of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone (35.8 g, 180.0 mmol) in ethanol (204 g, 444 mmol) was added over 2 hours. After the addition was complete, the reaction was stirred at 50 °C for 36 hours and then cooled to 20 °C. The solid that formed was isolated by filtration through a fritted funnel. The filter cake was washed three times with 100 mL of ethanol until the filtrate was colorless. The filter cake was then returned to the reactor and slurried with 400 g of water at 70° C. for 1 hour. The slurry was filtered through a fritted funnel, and the filter cake was washed three times with 40 mL of room temperature water and dried in a vacuum drying oven at 80° C. and 5 mbar to give 59.1 g (90% yield) of the title compound in the form of a cream-colored solid.

[0127] Example 4: Preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one A solution of N-methylthiourea (15.56 g, 167.4 mmol) and diethyl 2-phenylmalonate (42.38 g, 175.8 mmol) was prepared in a 500 mL round-bottom flask equipped with an overhead stirrer and reflux condenser at 20 °C under N 2 . To this solution was then added NaOCH 3 (31.56 g, 175.8 mmol, 30 wt % solution in methanol) over 2 hours, during which time a suspension formed. The reaction was stirred for an additional 48 hours at 20 °C, and then a solution of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone (35.8 g, 180.0 mmol) in ethanol (204 g, 444 mmol) was added over 2 hours. After the addition was complete, the reaction was stirred for 48 hours at 20 °C and then cooled to 20 °C. The solid that formed was isolated by filtration through a fritted funnel. The filter cake was washed three times with 100 mL of ethanol until the filtrate was colorless. The filter cake was then returned to the reactor and slurried with 400 g of water at 70° C. for 1 hour. The slurry was then filtered through a fritted funnel, and the filter cake was washed three times with 40 mL of room temperature water and then dried in a vacuum drying oven at 80° C. and 5 mbar to give 43.3 g (65% yield) of the title compound in the form of a cream-colored solid.

[0128] Example 5: Preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one 10 g of N-methylthiourea (97%, 1.0 equivalent) and 28.5 g of diethyl 2-phenylmalonate (98%, 1.1 equivalents) were mixed and heated to 50°C. 21.3 g of sodium methylate (30% in methanol, 1.1 equivalents) was added, and the reaction mixture was stirred at reflux for 12 hours. 26.4 g of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone dissolved in 90 g of toluene was added over 1 hour, and the reaction mixture was stirred at reflux for 10 hours. After cooling to room temperature, 150 g of water was added, and the mixture was stirred for 2 hours. The precipitate was filtered, and the filter cake was washed with toluene (2 x 50 g). The solid was suspended in water (120 g), stirred for 3 hours, filtered, and washed with water (100 g). The product was dried in vacuo overnight to give 40.0 g (98%, 92% yield) of the title compound.

[0129] Example 6: Preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one 10 g of N-methylthiourea (97%, 1.0 equivalent) and 28.5 g of diethyl 2-phenylmalonate (98%, 1.1 equivalents) were dissolved in 25 g of methanol and heated to 50°C. 21.3 g of sodium methylate (30% in methanol, 1.1 equivalents) was added, and the reaction mixture was stirred at reflux for 12 hours. 26.4 g of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone dissolved in 75 g of dimethylacetamide was added, and the reaction mixture was stirred at 70°C for 15 hours. 200 g of water was added, and the mixture was cooled to 20°C. The precipitate was filtered, and the filter cake was washed with water (400 g). The product was dried in vacuo overnight to give 44.0 g (93%, 96% yield) of the title compound.

[0130] Example 7: Preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one 10 g of N-methylthiourea (97%, 1.0 equivalent) and 23.7 g of dimethyl 2-phenylmalonate (99%, 1.05 equivalents) were dissolved in 100 g of methanol at 25 °C. 21.3 g of sodium methylate (30%, 1.1 equivalents in methanol) was added, and the reaction mixture was heated to reflux over time. 28.9 g of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone (95%, 1.3 equivalents) dissolved in 70 g of methanol was added at 50 °C, and the reaction mixture was further diluted with 150 g of methanol and stirred for 15 hours. After cooling to room temperature, the precipitate was filtered and washed with 2 × 50 g of water. The filter cake was transferred to a flask, and 400 g of water was added. The suspension was stirred for 1 hour, filtered, and the filter cake was washed with water (2 × 50 g). The product was dried in vacuo overnight to give 36.5 g (98%, 85% yield) of the title compound.

[0131] Example 8: Preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one with isolation of intermediate compound 3 8.1 Intermediate 3(M + Na + Preparation of To a solution of methylthiourea (20.0 g, 218.7 mmol) and sodium methylate (42.6 g, 236.7 mmol, using a 30% methanol solution) and methanol (20 g) at 25° C. was added diethyl-2-phenylpropanedioate (57.1 g, 236.7 mmol). The reaction was then heated at 70° C. for 6 hours. The reaction was then cooled to 25° C., and a precipitate formed. The precipitate was isolated by filtration, and the filter cake was triturated with methyl tert-butyl ether (100 g), filtered, and then dried at 100° C. for 48 hours to provide the title compound as a light brown solid. 1H NMR(400MHz,DMSO-d6):δ=10.62(s,1H),7.70(dd,2H,J=1.33,8.37Hz),7.13(dd,2H,J=7 .11,8.35Hz),6.98-6.90(m,1H),3.50-3.47(m,1H),3.50-3.47(s,3H),3.21-3.15(m,1H)

[0132] 8.2 Preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one Intermediate 3 (M) obtained in step 8.1 in methanol (50 g) + Na + To a suspension of 2-chloro-1-(2-chlorothiazol-5-yl)ethenone (20.0 g, 69.45 mmol) in methanol (50 g) at 75° C. was added a solution of 2-chloro-1-(2-chlorothiazol-5-yl)ethenone (16.2 g, 81.97 mmol) over 30 minutes. The reaction was stirred at 50° C. for 3 hours. The reaction was then cooled to 50° C., and water (50 g) was added over 15 minutes. The reaction was then stirred at 50° C. for 2 hours, then cooled to 25° C., and stirred for 30 minutes, forming a suspension. Water (100 g) was added, and the formed solid was isolated by filtration. The filter cake was washed with water (100 g) and dried in vacuo at 80° C. for 18 hours to give the title compound as a brown solid (27.4 g, 95% yield).

[0133] Example 9: Preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one A solution of N-methylthiourea (47.5 g, 500 mmol), diethyl 2-phenylmalonate (125.9 g, 525 mmol), and chlorobenzene (60 g) was prepared in a 500 mL round-bottom flask equipped with an overhead stirrer and reflux condenser at 60 °C under N2. To this solution, NaOCH3 (99.1 g, 550 mmol, 30 wt% solution in methanol) was added over 30 minutes. The reaction was stirred at 60 °C for an additional 16 hours, during which time a suspension formed. The temperature was then increased to 70 °C, and a solution of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone (115.6 g, 560 mmol) in chlorobenzene (230 g) was added over 2 hours. After the addition was complete, the reaction was stirred at 70 °C for 2 hours and then cooled to 20 °C. Water (460 g) was added and the mixture was stirred at 20° C. for 1 hour, forming a suspension. The solid that formed was isolated by filtration on a fritted funnel. The filter cake was washed three times with 35 g of chlorobenzene until the filtrate was colorless. The filter cake was washed twice with 225 g of water and then dried in a vacuum drying oven at 80° C. and 5 mbar for 48 hours to give 164 g (83% yield) of the title compound in the form of a light brown solid.

[0134] Example 10: Preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one A solution of N-methylthiourea (7.78 g, 83.7 mmol), KOCH (24.7 g, 87.9 mmol, 25 wt% solution in methanol), and methanol (4 g) was prepared in a 500 mL round-bottom flask equipped with an overhead stirrer and reflux condenser at 60-65 °C under N2. Diethyl 2-phenylmalonate (21.21 g, 87.9 mmol) was then added over 30 min. The reaction was stirred at 65 °C for an additional 16 h, during which time a suspension formed, and then a solution of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone (18.6 g, 90.0 mmol) in ethanol (100 g) was added over 1 h. After the addition was complete, the reaction was cooled to 50 °C and stirred at 50 °C for 16 h. The reaction was then cooled to 20 °C, and the solid that formed was isolated by filtration through a fritted funnel. The filter cake was washed three times with 50 g of ethanol until the filtrate was colorless. The filter cake was then returned to the reactor and slurried with 150 g of water at 75° C. for 1 hour. The slurry was then filtered through a fritted funnel, and the filter cake was washed three times with 40 mL of room temperature water and dried in a vacuum drying oven at 90° C. and 5 mbar to give 29.4 g (89% yield) of the title compound in the form of a cream-colored solid.

[0135] Example 11 Preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one In a 500 mL round-bottom flask equipped with an overhead stirrer and reflux condenser, a solution of N-methylthiourea (15.56 g, 167.4 mmol) and NaOCH (31.56 g, 175.8 mmol, 30 wt % solution in methanol) was prepared under N at 60° C. To this solution was then added diethyl 2-phenylmalonate (42.38 g, 175.8 mmol) over 30 minutes, during which time a suspension formed. The reaction was stirred at 60°C for an additional 10 hours, and then a solution of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone (35.8 g, 180.0 mmol) in ethanol (204 g, 444 mol) was added over 6 hours. After the addition was complete, the reaction was stirred at 60°C for 8 hours and then cooled to 20°C. The solid that formed was isolated by filtration through a fritted funnel. The filter cake was washed once with 100 mL of ethanol, followed by two 400 g washes of water at 70°C for 1 hour each, and then dried in a vacuum drying oven at 100°C and 5 mbar to give 60.4 g (92% yield) of the title compound in the form of a cream-colored solid with a purity of 99% by weight. The following are examples of embodiments of the present invention. [Embodiment 1] Formula (I): [ka] 2. A process for preparing 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of the formula: (a) reacting N-methylthiourea of ​​formula 1 with 2-phenylmalonate of formula 2 in the presence of a base [ka] (In the formula, R 1 and R 2 are independent of each other, C 1 ~C 4 -alkyl), obtaining a reaction mixture comprising a pyrimidinone compound of formula 3 and / or a tautomer thereof; [ka] (In the formula, M + is the cation equivalent) and (b) optionally isolating the pyrimidinone compound of formula 3 or its tautomer from the reaction mixture obtained in step (a) in the form of its salt or in the form of a thiol; (c) reacting either the reaction mixture obtained in step (a) (without isolation of 3 or its tautomer) or the compound obtained in step (b) with 1-(2-chlorothiazol-5-yl)ethanone of formula 4 to give

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Claims

1. Formula (I): 【Chemistry 1】 2. A process for preparing 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of the formula: (a) reacting N-methylthiourea of ​​formula 1 with 2-phenylmalonate of formula 2 in the presence of a base; 【Chemistry 2】 (In the formula, R １ and R ２ are, independently of each other, C １ ~C ４ -alkyl), obtaining a reaction mixture containing a pyrimidinone compound of formula 3 and / or a tautomer thereof; 【Transformation 3】 (In the formula, M ＋ is the cation equivalent, where the cation equivalent is (M n+ ) 1 / n , where n is the charge number of the cation; (b) optionally isolating the pyrimidinone compound of formula 3 or its tautomer from the reaction mixture obtained in step (a) in the form of its salt or in the form of a thiol; (c) reacting either the reaction mixture obtained in step (a) (without isolation of 3 or its tautomer) or the compound obtained in step (b) with 1-(2-chlorothiazol-5-yl)ethanone of formula 4 to give 【Chemistry 4】 wherein X is a leaving group; obtaining the compound of formula (I) or a tautomer thereof.

2. R １ and R ２ The method of claim 1 , wherein, independently of each other, are methyl or ethyl.

3. The base used in step (a) is an alkali metal C １ ~C ４ 3. The method according to claim 1 or 2, wherein the base is selected from the group consisting of alkanolates, alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal phosphates, non-nucleophilic organic bases and mixtures thereof.

4. 4. The process of claim 3, wherein the base used in step (a) is selected from the group consisting of sodium methanolate, sodium ethanolate, sodium isopropanolate, sodium tert-butanolate, potassium methanolate, potassium ethanolate, potassium tert-butanolate, lithium methanolate, and mixtures thereof.

5. 5. The method according to claim 1, wherein in step (a), the 2-phenylmalonate 2 is used in an amount of 0.8 to 2.0 moles per mole of N-methylthiourea 1.

6. 6. The method according to claim 1, wherein in step (a), the base is used in an amount of 0.8 to 1.5 moles per mole of N-methylthiourea.

7. The method according to any one of claims 1 to 6, wherein the reactions in steps (a) and (c) are carried out in a solvent.

8. The method of claim 7, wherein the solvent is selected from the group consisting of polar protic solvents, polar aprotic solvents, C1-C4-alkyl acetates, dialkyl ethers, aromatic solvents, heterocyclic solvents and mixtures thereof.

9. The method of claim 8, wherein the solvent is selected from the group consisting of C1-C4-alkanols, glycols, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, C1-C4-alkyl acetates, di-n-propyl ether, di-n-butyl ether, methyl tert-butyl ether, acetonitrile, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, N-methylpyrrolidone, and mixtures thereof.

10. 10. The method of any one of claims 7 to 9, wherein the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, isobutanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, toluene, chlorobenzene, N-methylpyrrolidone, and mixtures thereof.

11. 11. The method according to claim 10, wherein step (a) is carried out in a solvent selected from the group consisting of methanol, ethanol, mixtures of methanol and ethanol, and mixtures of methanol and / or ethanol with at least one further solvent selected from the group consisting of dimethylacetamide, toluene, and chlorobenzene, and step (c) is carried out in a solvent selected from the group consisting of methanol, ethanol, dimethylacetamide, toluene, chlorobenzene, and mixtures of at least two of the foregoing solvents.

12. The method according to any one of claims 1 to 11, wherein in step (c), the reaction mixture obtained in step (a) is reacted with the compound of formula 4.

13. 13. The method of any one of claims 1 to 12, wherein X of the compound of formula 4 is selected from the group consisting of halogen, triflate, mesylate, tosylate, and nonaflate.

14. 14. The method of claim 13, wherein X of the compound of formula 4 is Cl.

15. 15. The method according to claim 1, wherein in step (c), the 1-(2-chlorothiazol-5-yl)ethanone 4 is used in an amount of 0.8 to 1.5 moles per mole of N-methylthiourea 1.

16. 16. The method of any one of claims 1 to 15, wherein step (c) is carried out in the presence of an additive selected from the group consisting of alkali metal bromides, alkali metal iodides, ammonium bromide, ammonium iodide, and mixtures thereof.

17. The formula (I): 【Transformation 5】 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one or a tautomer thereof.

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