A process for the preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]sulfanyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one

Abstract

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

Description

[0001] This invention relates to a method for preparing 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers, specifically relating to 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers and their relationship in 2,3-dihydrothiazo[3,2-a]pyrimidine The compound, specifically, is 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- The method also relates to the use of 2-hydroxy-4-methyl-5-phenyl-2-thioalkylpyrimidinone, its thiolates and tautomers, and their use as intermediates in the preparation of 2,3-dihydrothiazo[3,2-a]pyrimidine. The compound, specifically, is 3-(2-chlorothiazol-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] 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (or its tautomer) and its precursor 2-hydroxy-4-methyl-5-phenyl-2-thioalkylpyrimidinone—in its thiol or thiolate form—(or its tautomer) have been found in 2,3-dihydrothiazo[3,2-a]pyrimidine The compound, more specifically 3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxides and their enantiomer-enriched forms are valuable intermediates in the preparation of these pyrimidines. The compound has insecticidal properties and is known, for example, by WO 2018 / 177970 or WO 2014 / 167084.

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

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

[0005]

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

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

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

[0009]

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

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

[0012] WO 2015 / 200619 describes the preparation of 2-[2-phenyl-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one by reacting N-methylthiourea with dimethyl 2-phenylmalonate to 6-hydroxy-3-methyl-5-phenyl-2-thioalkylpyrimidin-4-one, followed by separation and reaction of the latter with 2-bromo-1-phenylethyl ketone. A similar reaction sequence was used to synthesize 2-[2-phenyl-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one with substituents on the phenyl ring. However, this reference neither teaches nor implies the preparation of heteroaromatic analogs of these compounds, nor does it teach or imply the modification of the halogen atom on the ketone reactant. Furthermore, the yields are fairly moderate. Invention Overview

[0014] The purpose of this invention is to provide a more economical method for preparing 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one, which avoids the disadvantages of existing methods.

[0015] This problem is solved by a method for preparing 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomer of formula (I):

[0016]

[0017] The method includes:

[0018] (a) Reaction of N-methylthiourea of ​​Formula 1 with 2-phenylmalonate of Formula 2 in the presence of a base:

[0019]

[0020] Where R 1 and R 2 Each is independently a C1-C4 alkyl group;

[0021] A reaction mixture containing a pyrimidinone compound of formula 3 or its tautomers is obtained:

[0022]

[0023] Where M + It is a cationic equivalent;

[0024] (b) Optionally, the pyrimidinone compound of formula 3 (or its tautomer) is separated from the reaction mixture obtained in step (a) in its salt form (i.e., as compound 3 shown above) or in its thiol form (i.e., as compound 3-SH shown below); and

[0025] (c) React the reaction mixture obtained in step (a) (without separating 3 or its tautomers) or the compound obtained in step (b) with 1-(2-chlorothiazol-5-yl)acetone of formula 4:

[0026]

[0027] Where X is a leaving group.

[0028] The compound of formula (I) or its tautomer is obtained.

[0029] Furthermore, the present invention relates to 2-[2-(2-chlorothiazolin-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers of formula (I) shown above. As described, this compound is an insecticidal 2,3-dihydrothiazo[3,2-a]pyrimidin. The compound, more specifically 3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxides and their enantiomerically enriched forms are useful intermediates in the preparation of 2,3-dihydrothiazo[3,2-a]pyrimidines. Therefore, the present invention also relates to the compounds (or their tautomers) in the preparation of 2,3-dihydrothiazo[3,2-a]pyrimidines. The compound, specifically, is 3-(2-chlorothiazol-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.

[0030] This invention also relates to 2-hydroxy-4-methyl-5-phenyl-2-thioalkylpyrimidinone and its thiolates and tautomers. The thiolates are shown above as Formula 3. These thiols and thiolate compounds are used in the preparation of 2-[2-(2-chlorothiazolin-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one (I) and therefore also in the downstream insecticidal formulation of 2,3-dihydrothiazo[3,2-a]pyrimidine. The compound, more specifically 3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxides and their enantiomerically enriched forms are valuable intermediates. Therefore, the present invention also relates to the use of said thiols or thiolate compounds (or their tautomers) as intermediates in the preparation of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (I) and their use in 2,3-dihydrothiazo[3,2-a]pyrimidine The compound, specifically, is 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- Use as an intermediate in the preparation of 5-alkoxides and their enantiomer-enriched forms. Invention Details

[0032] definition

[0033] The halogens used in this invention are F, Cl, Br or I.

[0034] The term C1-C4 alkyl refers to 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.

[0035] C1-C4 alkanols are saturated aliphatic monools, i.e., C1-C4 alkyl groups as defined above, in which one hydrogen atom is replaced by a hydroxyl group. Examples are methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, and tert-butanol.

[0036] C1-C4 alkanols are salts of C1-C4 alkanols, in which the hydrogen atom of the hydroxyl group is replaced by a cation equivalent, such as a metal cation. Examples are methoxides, ethanoloxides, n-propoxides, isopropoxides, n-butoxides, sec-butoxides, isobutoxides, and tert-butoxides.

[0037] Diols are saturated aliphatic diols. Examples include ethylene glycol, propylene glycol, diethylene glycol, and triethylene glycol.

[0038] C1-C4 alkyl esters of acetate 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.

[0039] 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 charge number. In compound 3, M + Typically derived from the base used in step (a). Therefore, if, for example, an alkali metal alkanoate, alkali metal carbonate, alkali metal hydroxide, or alkali metal phosphate is used as the base in step (a), then M in compound 3... + It is usually an alkali metal cation; if an alkaline earth metal carbonate or alkaline earth metal hydroxide is used as the base, then M in compound 3... + Typically alkaline earth metal cations [(M 2+ ) 1 / 2 ], and if a non-nucleophilic organic base is used in step (a), then M in compound 3 + It is usually the protonated form of this base. However, M + The base may also be derived from the reaction mixture of step (a) and used in the post-treatment of the separation step (b).

[0040] Compound (I) can exist as its tautomer or a mixture of different tautomer forms. An example of a tautomer form of compound (I) as shown above is the following:

[0041]

[0042] A mixture of different tautomer forms is, for example, the tautomer above as a mixture of the tautomers shown in formula (I).

[0043] Compounds of Formula 3 and their neutral thiol form 3-H can also exist as tautomers or mixtures of different tautomers. Examples of tautomers of the compounds of Formula 3 shown above are as follows:

[0044]

[0045] In thiolates, the negative charge can also exist on the oxygen atom, as shown below:

[0046]

[0047] However, it is usually found primarily on sulfur atoms.

[0048] Examples of tautomerism in the 3-H form of thiols are as follows:

[0049]

[0050] For simplicity, only compounds (I), 3, and 3-H will be mentioned below. However, all embodiments also involve their tautomers and mixtures of their different tautomer forms.

[0051] Embodiment (Ex) of the present invention

[0052] General and preferred embodiments Ex are outlined in the following non-exhaustive enumeration. Other preferred embodiments become apparent in the paragraphs following this enumeration.

[0053] E.1. A method for preparing 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (I):

[0054]

[0055] The method includes:

[0056] (a) Reaction of N-methylthiourea of ​​Formula 1 with 2-phenylmalonate of Formula 2 in the presence of a base:

[0057]

[0058] Where R 1 and R 2 Each is independently a C1-C4 alkyl group;

[0059] A reaction mixture containing the pyrimidinone compound of formula 3 was obtained:

[0060]

[0061] Where M + It is a cationic equivalent;

[0062] (b) Optionally, the pyrimidinone compound of formula 3 is separated from the reaction mixture obtained in step (a) in its salt form or in its thiol form; and

[0063] (c) React the reaction mixture obtained in step (a) (without separation 3) or the compound obtained in step (b) with 1-(2-chlorothiazol-5-yl)acetone of formula 4:

[0064]

[0065] Where X is a leaving group.

[0066] Compound of formula (I) was obtained.

[0067] E.2. According to the method of implementation scheme E.1, where R 1 and R 2 They are methyl or ethyl, independent of each other.

[0068] E.3. According to the method of implementation scheme E.2, where R 1 and R 2 All are methyl or all are ethyl.

[0069] E.4. The method according to any of the foregoing embodiments, wherein the base used in step (a) is selected from 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.

[0070] E.5. The method according to embodiment E.4, wherein the base used in step (a) is selected from alkali metal C1-C4 alkanols, alkali metal carbonates and mixtures thereof; particularly selected from alkali metal C1-C4 alkanols.

[0071] E.6. The method according to embodiment E.5, wherein the base used in step (a) is selected from sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium methoxide, and mixtures thereof.

[0072] E.7. The method according to implementation scheme E.6, wherein the base used in step (a) is selected from sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide and mixtures thereof; specifically sodium methoxide or potassium methoxide.

[0073] E.8. The method according to any of the foregoing embodiments, wherein in step (a) the 2-phenylpropionate 2 is used in an amount of 0.8-2.0 mol / mol N-methylthiourea 1.

[0074] E.9. The method according to embodiment E.8, wherein in step (a) the 2-phenylpropionate 2 is used in an amount of 1.0-1.3 mol / mol N-methylthiourea 1.

[0075] E.10. The method according to any of the foregoing embodiments, wherein in step (a) the base is used in an amount of 0.8-1.5 mol / mol N-methylthiourea 1.

[0076] E.11. The method according to embodiment E.10, wherein in step (a) the base is used in an amount of 1.0-1.5 mol / mol N-methylthiourea 1.

[0077] E.12. The method according to any of the foregoing embodiments, wherein the reactions in steps (a) and (c) are carried out in a solvent.

[0078] E.13. The method according to embodiment E.12, wherein the solvent is selected from polar protic solvents, polar aprotic solvents, C1-C4 alkyl esters of acetate, dialkyl ethers, aromatic solvents, heterocyclic solvents, and mixtures thereof.

[0079] E.14. The method according to embodiment E.13, wherein the solvent is selected from C1-C4 alkanols, glycols, tetrahydrofurans, 2-methyltetrahydrofurans, di ... Alkanes, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, C1-C4 alkyl esters of acetate, di-n-propyl ether, di-n-butyl ether, methyl tert-butyl ether, acetonitrile, benzene, toluene, xylene derivatives, chlorobenzene, dichlorobenzene, N-methylpyrrolidone and mixtures thereof.

[0080] E.15. The method according to embodiment E.14, wherein the solvent is selected from methanol, ethanol, n-propanol, isopropanol, isobutanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dimethylpropanol, etc. Alkane, dimethylformamide, dimethylacetamide, toluene, chlorobenzene, N-methylpyrrolidone and mixtures thereof; preferably selected from methanol, ethanol, dimethylacetamide, toluene, chlorobenzene and mixtures thereof.

[0081] E.16. The method according to embodiment E.15, wherein step (a) is carried out in a solvent selected from methanol, ethanol, a mixture of methanol and ethanol and a mixture of methanol and / or ethanol with at least one other solvent selected from dimethylacetamide, toluene and chlorobenzene, and step (c) is carried out in a solvent selected from methanol, ethanol, dimethylacetamide, toluene, chlorobenzene and a mixture of at least two of the above solvents.

[0082] E.17. The method according to any of the foregoing embodiments, wherein step (a) is carried out at a temperature of 10°C to the reflux temperature of the reaction mixture.

[0083] E.18. The method according to embodiment E.17, wherein step (a) is carried out at a temperature of 20°C to the reflux temperature of the reaction mixture.

[0084] E.19. The method according to implementation scheme E.18, wherein step (a) is carried out at a temperature of 45-75°C.

[0085] E.20. The method according to any of the foregoing embodiments, wherein the reaction time of step (a) is 1-60 hours.

[0086] E.21. The method according to implementation scheme E.20, wherein the reaction time of step (a) is 4-18 hours.

[0087] E.22. The method according to any of the foregoing embodiments, wherein in step (a):

[0088] (a.1) Add the 2-phenylmalonate 2 to a solution of methylthiourea 1 and the base in a solvent, optionally in a heated solution; or

[0089] (a.2) Add the base (optionally in a solvent) to an optional heated mixture of methylthiourea 1, the 2-phenylmalonate 2, and an optional solvent; or

[0090] (a.3) Prepare a mixture of methylthiourea 1, the 2-phenylmalonate 2, the base and optionally a solvent, and react it, optionally under heating; or

[0091] (a.4) Add methylthiourea 1 (optionally in a solvent) to the 2-phenylmalonate 2, the base and the optional solvent in an optional heated mixture;

[0092] The preferred method is the procedure according to (a.1) or (a.2).

[0093] E.23. The method according to any of the foregoing embodiments, wherein in step (c), the reaction mixture obtained in step (a) is reacted with the compound of formula 4.

[0094] E.24. The method according to any of the foregoing embodiments, wherein X in the compound of formula 4 is selected from halogens, trifluoromethanesulfonate, methanesulfonate, toluenesulfonate, and perfluorobutylsulfonate.

[0095] E.25. The method according to embodiment E.24, wherein X in the compound of formula 4 is selected from Cl, Br and I.

[0096] E.26. The method according to embodiment E.25, wherein X in the compound of formula 4 is selected from Cl and Br.

[0097] E.27. The method according to embodiment E.26, wherein X in the compound of formula 4 is Cl.

[0098] E.28. The method according to any of the foregoing embodiments, wherein in step (c) 1-(2-chlorothiazol-5-yl)acetone 4 is used in an amount of 0.8-1.5 mol / mol of N-methylthiourea 1 used in step (a).

[0099] E.29. The method according to embodiment E.28, wherein in step (c) 1-(2-chlorothiazol-5-yl)acetone 4 is used in an amount of 1.0-1.5 mol / mol of N-methylthiourea 1 used in step (a).

[0100] E.30. The method according to any of the foregoing embodiments, wherein step (c) is performed at a temperature of -20°C to 120°C.

[0101] E.31. The method according to implementation scheme E.30, wherein step (c) is carried out at a temperature of 25-80°C.

[0102] E.32. The method according to implementation scheme E.31, wherein step (c) is carried out at a temperature of 40-80°C.

[0103] E.33. The method according to any of the foregoing embodiments, wherein step (c) is carried out in the presence of an additive selected from alkali metal bromides, alkali metal iodides, ammonium bromide, ammonium iodide and mixtures thereof.

[0104] E.34. The method according to embodiment E.33, wherein the additive is selected from NaBr, KBr, NaI, KI, tetrabutylammonium bromide and mixtures thereof.

[0105] E.35. The method according to embodiment E.33 or E.34, wherein the additive is used in an amount such that the molar ratio of the additive to the 1-(2-chlorothiazol-5-yl)acetone 4 is preferably 1:100-10:1, more preferably 1:20-2:1, and especially 1:2-2:1.

[0106] E.36. The method according to any of the foregoing embodiments, wherein in step (c):

[0107] (c.1) Add the reaction mixture obtained in step (a) or the product obtained in step (b) to the solution of 1-(2-chlorothiazol-5-yl)acetone 4; or

[0108] (c.2) Add the solution or melt of the 1-(2-chlorothiazol-5-yl)acetone 4 to the reaction mixture obtained in step (a) or to the solution of the product obtained in step (b).

[0109] E.37. The method according to implementation scheme E.36, wherein step (c) is performed according to procedure (c.2).

[0110] E.38. The method according to embodiment E.36 or E.37, wherein, in accordance with the procedure of (c.2), the solution or melt of 1-(2-chlorothiazol-5-yl)acetone 4 is added to the reaction mixture obtained in step (a) or a solution of the product obtained in step (b) within 15 minutes to 12 hours.

[0111] E.39. The method according to embodiment E.38, wherein a solution or melt of the 1-(2-chlorothiazol-5-yl)acetone 4 is added to the reaction mixture obtained in step (a) or a solution of the product obtained in step (b) within 0.5 to 6 hours.

[0112] E.40. The method according to any of the foregoing embodiments, wherein after mixing the entire amount of the reaction mixture obtained in step (a) or the product obtained in step (b) and the 1-(2-chlorothiazol-5-yl)acetone 4, the reaction mixture is reacted for 0-60 hours.

[0113] E.41. The method according to embodiment E.40, wherein the reaction mixture is reacted for 1-40 hours.

[0114] E.42. The method according to embodiment E.41, wherein the reaction mixture is reacted for 1-18 hours.

[0115] E.43. 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (I):

[0116]

[0117] E.44. Pyrimidinone compounds of Formula 3 or the corresponding thiols (i.e., -SH instead of -S) - M + ):

[0118]

[0119] Where M + The preferred cation is an alkali metal cation, especially Na. + or K + .

[0120] The reaction sequence of the method of the present invention can be as follows:

[0121]

[0122] The parentheses around compound 3 indicate that the reaction can be carried out with or without separating compound 3.

[0123] In the 2-phenylmalonate of formula 2, R 1 and R 2 Methyl or ethyl is preferred, and the two are independent of each other. R 1 and R 2 In particular, all of them are methyl or all of them are ethyl.

[0124] The base used in step (a) is preferably selected from alkali metal C1-C4 alkanol salts, alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal phosphates, non-nucleophilic organic bases, and mixtures thereof.

[0125] Alkali metal cations suitable as counter cations in alkanoates, carbonates, hydroxides, and phosphates include, for example, Li. + Na + K + and Cs + Na is preferred among these. + and K +Alkaline earth metals, such as Mg, are suitable as counter cations in alkoxides, carbonates, and hydroxides. 2+ and Ca 2+ .

[0126] Examples of suitable alkali metal C1-C4 alkanolates are lithium methoxide, sodium, potassium or cesium; lithium ethanol, sodium, potassium or cesium; lithium n-propoxide, sodium, potassium or cesium; lithium isopropoxide, sodium, potassium or cesium; lithium n-butoxide, sodium, potassium or cesium; lithium sec-butoxide, sodium, potassium or cesium; lithium isobutoxide, sodium, potassium or cesium; and lithium tert-butoxide, sodium, potassium or cesium.

[0127] Examples of suitable alkali metal carbonates are lithium carbonate, sodium carbonate, potassium carbonate, or cesium carbonate.

[0128] Examples of suitable alkaline earth metal carbonates are magnesium carbonate and calcium carbonate.

[0129] Examples of suitable alkali metal phosphates are lithium phosphate, sodium phosphate, potassium phosphate, or cesium phosphate.

[0130] Nonnucleophilic organic bases are typically sterically hindered, allowing protons to attach to the basic center, but alkylation and coordination are suppressed. Examples are 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

[0131] The base used in step (a) is preferably selected from alkali metal C1-C4 alkanols, 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 alkanols.

[0132] The base used in step (a) is particularly selected from sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium methoxide and mixtures thereof; more particularly selected from sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide and mixtures thereof; specifically sodium methoxide or potassium methoxide.

[0133] The 2-phenylmalonate 2 is used in step (a) in an amount preferably 0.8-2.0 mol / mol N-methylthiourea 1, especially 1.0-1.3 mol / mol N-methylthiourea 1.

[0134] The base is used in step (a) in an amount preferably 0.8-1.5 mol / mol N-methylthiourea 1, especially 1.0-1.5 mol / mol N-methylthiourea 1.

[0135] The reactions in steps (a) and (c) are preferably carried out in a solvent.

[0136] The solvent is preferably selected from polar protic solvents, polar aprotic solvents, C1-C4 alkyl esters of acetate, dialkyl ethers, aromatic solvents, heterocyclic solvents, and mixtures thereof. Examples of polar protic solvents include alkanols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, and tert-butanol, as well as glycols such as ethylene glycol, propylene glycol, diethylene glycol, and triethylene glycol. Examples of polar aprotic solvents include cyclic ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, and dialkyl ethers. Alkanes (i.e., 1,3- and 1,4-dialkyls) Alkyl groups, such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, or acetonitrile. C1-C4 alkyl esters of acetate, such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, sec-butyl acetate, isobutyl acetate, and tert-butyl acetate. Dialkyl ethers, such as diethyl ether, di-n-propyl ether, di-n-butyl ether, or methyl tert-butyl ether. Aromatic solvents, such as benzene, toluene, xylenes, chlorobenzene, or dichlorobenzene. Suitable heterocyclic solvents, such as methylpyrrolidone.

[0137] More preferably, the solvent is selected from C1-C4 alkanols, glycols, tetrahydrofuran, 2-methyltetrahydrofuran, and dimethyltetrahydrofuran. Alkanes, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, C1-C4 alkyl acetates, di-n-propyl ether, di-n-butyl ether, methyl tert-butyl ether, acetonitrile, benzene, toluene, xylene derivatives, chlorobenzene, dichlorobenzene, N-methylpyrrolidone, and mixtures thereof. More preferably, the solvent is selected from methanol, ethanol, n-propanol, isopropanol, isobutanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dimethylpropanol, dimethylformamide, dimethylacetamide, dimethylformamide, dimethylformamide, dimethylformamide, dimethylformamide, dimethylacet ... Alkane, dimethylformamide, dimethylacetamide, toluene, chlorobenzene, N-methylpyrrolidone and mixtures thereof; particularly selected from methanol, ethanol, dimethylacetamide, toluene, chlorobenzene and mixtures thereof.

[0138] In a specific embodiment, step (a) is carried out in a solvent selected from methanol, ethanol, mixtures of methanol and ethanol, and mixtures of methanol and / or ethanol with at least one other solvent selected from dimethylacetamide, toluene, and chlorobenzene, and step (c) is carried out in a solvent selected from methanol, ethanol, dimethylacetamide, toluene, chlorobenzene, and mixtures of at least two of the above solvents. More specifically, step (a) is carried out in a solvent selected from methanol, ethanol, and mixtures of methanol and ethanol, and step (c) is carried out in a solvent selected from methanol, ethanol, dimethylacetamide, toluene, chlorobenzene, and mixtures of at least two of the above solvents.

[0139] Step (a) is preferably carried out at a temperature of 10°C to the reflux temperature of the reaction mixture, more preferably at 20°C to the reflux temperature of the reaction mixture, and especially at a temperature of 45-75°C.

[0140] 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 1-60 hours, preferably 4-18 hours.

[0141] The order in which the reactants, solvent (if any), and base are added in step (a) is not critical. For example, (a.1) the 2-phenylmalonate 2 can be added to methylthiourea 1 and the base in the solvent, optionally added...

[0142] In hot solutions; or

[0143] (a.2) The base (optionally in a solvent) may be added to an optional heated mixture of methylthiourea 1, the 2-phenylmalonate 2, and an optional solvent; or

[0144] (a.3) Prepare a mixture of all components, namely methylthiourea 1, the 2-phenylmalonate 2, the base and optional solvent, and react it, optionally under heating; or

[0145] (a.4) Methylthiourea 1 (optionally in a solvent) may be added to an optional heated mixture of the 2-phenylmalonate 2, the base and the optional solvent.

[0146] However, the procedure according to (a.1) or (a.2) is preferred.

[0147] In optional step (b), the pyrimidinone compound of formula 3 can be separated from the reaction mixture obtained in step (a) by conventional methods, such as by partial or complete removal of the solvent, optionally under reduced pressure, or by adding a solvent in which 3 is insoluble or has low solubility to the reaction mixture—optionally after concentrating the reaction mixture. Suitable solvents include, for example, aliphatic and alicyclic hydrocarbons such as pentane, hexane, heptane, cyclohexane, etc., 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, xylenes, chlorobenzene, or dichlorobenzene, and haloalkanes such as dichloromethane, trichloromethane, and dichloroethane. Depending on the reaction conditions of step (a), especially the reaction temperature and solvent used, compound 3 may also precipitate simply upon cooling of the reaction mixture. The precipitate can then be separated by conventional means, such as filtration. If necessary, further purification of the separated product can be carried out by conventional methods, such as preparation or recrystallization. However, the product can usually be used in step (c) without further purification.

[0148] To obtain the corresponding thiol for the formula 3-SH compound:

[0149]

[0150] Compound 3 can be acidified, which is usually done in solution. Acidification can also, in principle, be carried out before separating 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.).

[0151] In step (c), the reaction mixture obtained in step (a) (without separating 3) or compound 3 or the corresponding thiol 3-SH obtained in step (b) is reacted with the compound of formula 4. If thiol 3-SH is used as a starting material, it is advantageous 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 for step (a).

[0152] However, it is preferable to react the reaction mixture obtained in step (a) with step 4, i.e., skip the separation step (b).

[0153] In this 1-(2-chlorothiazol-5-yl)acetone 4, X is a leaving group. Suitable leaving groups are, for example, halogen atoms, especially Cl, Br or I, and sulfonates such as trifluoromethanesulfonate, methanesulfonate, toluenesulfonate or perfluorobutylsulfonate. Preferably, X is a halogen atom, preferably Cl, Br or I, more preferably Cl or Br, especially Cl.

[0154] In step (c), the 1-(2-chlorothiazol-5-yl)acetone 4 is used in an amount preferably 0.8-1.5 mol / mol of N-methylthiourea 1 used in step (a), especially 1.0-1.5 mol / mol of N-methylthiourea 1.

[0155] If in step (c) the compound 3 or the corresponding thiol 3-SH obtained in step (b) is reacted with the compound of formula 4, then the 1-(2-chlorothiazol-5-yl)acetone 4 is used in an amount preferably 0.8-1.5 mol / mol N-methylthiourea 1, especially 1.0-1.5 mol / mol compound 3 or 3-SH.

[0156] Step (c) is carried out at a temperature preferably from -20°C to 120°C, more preferably from 25°C to 80°C, and especially from 40°C to 80°C.

[0157] In a specific implementation, step (c) is carried out in the presence of an additive (especially if X is Cl; see explanation below). Such additives facilitate nucleophilic attack by the thiol or thiolate group in 3 on the aliphatic carbon atom substituted by X in 4. The effect of such additives is particularly relevant if X is Cl. Suitable additives are selected from alkali metal bromides, alkali metal iodides, ammonium bromide, ammonium iodide, and mixtures thereof, with NaBr, KBr, NaI, KI, tetrabutylammonium bromide, and mixtures thereof being preferred. Without being bound by theory, it is hypothesized that the bromide or iodide substitutes a portion of the CH2 bonded Cl in 4 for the case where X is Cl. On the one hand, bromides and iodides are generally more reactive than chlorides, which accelerates the reaction. On the other hand, C-Br and Cl are softer reaction centers than C-Cl. According to the HSAB concept, this is therefore favorable for the reaction with the soft thiol or thiolate nucleophile 3.

[0158] The additive is used in an amount such that the molar ratio of the additive to the 1-(2-chlorothiazol-5-yl)acetone 4 is preferably in the range of 1:100-10:1, more preferably 1:20-2:1, and especially in the range of 1:2-2:1.

[0159] The order in which the reactants are added in step (c) is not critical. For example,

[0160] (c.1) The reaction mixture obtained in step (a) or the product obtained in step (b) may be added to the solution of 1-(2-chlorothiazol-5-yl)acetone 4; or

[0161] (c.2) A solution or melt of the 1-(2-chlorothiazol-5-yl)acetone 4 may be added to the reaction mixture obtained in step (a) or the product obtained in step (b).

[0162] In (c.1), the product obtained in step (b) may be added as is (usually as a solid) or as a solution or dispersion. If the product is added in a dissolved or dispersed form, the appropriate solvent for this purpose is the same solvent in which step (c) is carried out.

[0163] If a solution or melt of the 1-(2-chlorothiazol-5-yl)ethyl ketone 4 is added to the product obtained in step (b) in (c.2), the product is advantageously present in a dissolved or dispersed form; the solvent used for this purpose is again suitable to be the solvent in which step (c) is carried out.

[0164] The procedure according to (c.2) is preferred.

[0165] If step (c) is carried out according to the procedure in (c.2), the solution or melt of 1-(2-chlorothiazol-5-yl)acetone 4 is preferably added to the reaction mixture obtained in step (a) or the product obtained in step (b)—suitably its solution or dispersion—within 15 minutes to 12 hours, especially 0.5 to 6 hours.

[0166] After mixing the complete amount of the reaction mixture obtained in step (a) or the product obtained in step (b) with the 1-(2-chlorothiazol-5-yl)acetone 4, the reaction mixture is preferably allowed to react for 0-60 hours, more preferably 1-40 hours, and especially 1-18 hours. "0 hours" in this context means that after the complete addition of reactants, the reaction can be sufficiently completed to allow for the continued separation of the desired compound (I). This may be possible, for example, if the addition of reactants continues for a considerable period or if it is intended to recycle unreacted raw materials.

[0167] Compound (I) can be separated from the reaction mixture by known means. Given its low solubility at room temperature in most solvents preferred for step (c), especially in more polar solvents, it can be separated, for example, by precipitation. The product also partially precipitates during the reaction, especially if the reaction is carried out at relatively low temperatures, such as below 30°C, and if the reaction mixture is not diluted significantly. Precipitation can be promoted by lowering the temperature, removing some of the solvent, and / or adding water to the reaction mixture.

[0168] 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 methanol, ethanol, isopropanol, toluene, dimethylacetamide, water, alkaline aqueous solutions such as NaHCO3, Na2CO3, K2CO3, NaOH, KOH, or NH3 aqueous solutions, or mixtures thereof. Washing with water or aqueous solutions can be carried out over a wide temperature range, such as 0-100°C, preferably 25-80°C. Washing with organic solvents can also be carried out over a wide temperature range, such as 0-100°C, but solvents with temperatures of 0-35°C, especially 10-25°C, are preferred.

[0169] Compounds 1 and 2 are commercially available or can be prepared using standard methods.

[0170] Compound 4 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-halo-N-methoxy-N-methylacetamide. 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.

[0171] The method of this invention yields compound (I) in high yield and purity and requires only a few steps starting from readily available starting materials. Unlike the method described in WO 2015 / 200619, it does not require the use of rather expensive organic bromine compounds as starting materials. However, bromine or even iodine compounds, i.e., compound 4 where X is Br or I, can certainly be used; but given the excellent yield obtained by compound 4 where X is another leaving group, especially Cl, the use of compound 4 where X is Br or I is not urgent, but merely an alternative.

[0172] Furthermore, the present invention relates to 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (I) or its tautomers or mixtures thereof, which, in the insecticidal 2,3-dihydrothiazo[3,2-a]pyrimidine The compound, more specifically 3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxides and their enantiomer-enriched forms are valuable intermediates in the preparation of 2,3-dihydrothiazo[3,2-a]pyrimidines. This invention also relates to compound (I) or its tautomers or mixtures of their tautomers in the preparation of 2,3-dihydrothiazo[3,2-a]pyrimidines. The compound, specifically, is 3-(2-chlorothiazol-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.

[0173] Compound (I) (or its tautomers or mixtures thereof) can be converted to 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- in just two additional steps. -5-alkoxides, especially converted to their enantiomerically enriched forms. To obtain the enantiomerically enriched form, compound (I) (or its tautomers or mixtures thereof) is subjected to ketoasymmetric hydrogenation to the corresponding alcohol in the enantiomerically enriched form, and the alcohol is internally cyclized by nucleophilic attack of the unsubstituted nitrogen atom of the pyrimidine ring on the carbon atom with an aliphatic OH group. Of course, to obtain the racemic form of 3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- -5-alkoxides can be hydrogenated under achiral conditions (I) (or its tautomers or mixtures thereof). The reaction sequence can be as follows:

[0174]

[0175] These reactions are described in more detail in European application numbers 21153034.0, 21153036.5 and 21153038.1.

[0176] The present invention also relates to pyrimidinone compounds of formula 3 as defined above, or mixtures thereof with their tautomers or tautomer forms, and the corresponding thiols 3-SH or mixtures thereof with their tautomers or tautomer forms; and their use as intermediates in the preparation of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one of formula (I), or mixtures thereof with their tautomers or tautomer forms, and their use in 2,3-dihydrothiazo[3,2-a]pyrimidinone The compound, specifically, is 3-(2-chlorothiazol-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.

[0177] Thiols of 3 have the following formula: 3-SH

[0178]

[0179] As understood from the above, compound 3 or 3-SH (or its tautomers or mixtures thereof) can be converted to 3-(2-chlorothiazo-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazo[3,2-a]pyrimidine-4- in three additional steps. -5-alkoxides, especially converted to their enantiomeric enriched forms; wherein the first step is the reaction of 3 or 3-SH with 4 to form compound (I) (or its tautomers or mixtures of its tautomers).

[0180] The invention is further illustrated in the following embodiments. Example

[0181] method

[0182] Compounds can be characterized by high performance liquid chromatography / mass spectrometry (HPLC / MS), NMR, or melting point.

[0183] HPLC method: Agilent Eclipse XDB-C18, 150mm × 4.6mm ID × 5μm

[0184] Gradient A = 0.5% H₂SO₄ aqueous solution, B = acetonitrile

[0185] Flow rate = 1.1 mL / min

[0186] Column oven temperature = 30℃

[0187] Gradient program = 20%B - 100%B - 15min

[0188] Running time = 15min

[0189] LCMS Method 1: C18 column (50mm × 2.1mm × 1.7μm)

[0190] Gradient A = 0.1% TFA aqueous solution, B = acetonitrile

[0191] Flow rate = 0.8 mL / min to 1.0 mL / min over 1.5 min.

[0192] Column oven temperature = 60℃

[0193] Gradient program = 10% B to 100% B over 15 min, hold at 100% B for 1 min, then reduce to 10% B for 1 min.

[0194] Run time: 1.75 min

[0195] 1 H-NMR: The signal is characterized by its chemical shift (ppm) relative to tetramethylsilane, its multiplicity, and its integral (for a given relative number of hydrogen atoms). The following abbreviations are used to characterize the multiplicity of the signal: m = multiply, q = quartet, t = triplet, d = doublet, and s = singlet.

[0196] The abbreviations used are: h for hours, min for minutes, rt for retention time, rt for room temperature (20-25℃), and TFA for trifluoroacetic acid.

[0197] Example 1: Preparation of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one

[0198] 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%.

[0199] 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).

[0200] Example 2: Preparation of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one

[0201] 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 6 h, a solution of 2-chloro-1-(2-chlorothiazol-5-yl)acetone (1859 g, 9.00 mol) in ethanol (10,000 g, 217 mol) was added. The pump was cleaned with ethanol (350 g, 7.61 mol). After the addition of feed was complete, the reaction was stirred at 50°C for 36 h, and then cooled to 20°C over 16 h. Two hours after the initial addition of 2-chloro-1-(2-chlorothiazol-5-yl)ethyl ketone, a beige suspension formed in the reactor. The solids were separated by filtration through three 4L sintered funnels. Each filter cake was washed three times with 500 mL of ethanol. The filter cakes were then returned to a 20L reactor and slurried with 15 L of water at 75°C for 1 h. The slurry was then filtered through two 4L 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, 3055 g (91%) of the title compound was separated as a light brown solid with a purity of 99% by weight.

[0202] Example 3: Preparation of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one

[0203] 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 a high-mounted stirrer and a reflux condenser at 35 °C and N2. NaOCH3 (31.56 g, 175.8 mol, 30 wt% methanol solution) was then added to this solution over 2 h, during which time a suspension was formed. The reaction was stirred at 35 °C for another 24 h, followed by the addition of a solution of 2-chloro-1-(2-chlorothiazol-5-yl)acetone (35.8 g, 180.0 mmol) in ethanol (204 g, 444 mol) over 2 h. After the addition was complete, the reaction was stirred at 50 °C for 36 h, then cooled to 20 °C. The solids formed were separated by filtration in a sintered 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 h. The slurry was filtered in a sintering 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 59.1 g (90% yield) of the title compound as a pale yellow solid.

[0204] Example 4: Preparation of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one

[0205] 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 a raised stirrer and a reflux condenser at 20 °C and N2. NaOCH3 (31.56 g, 175.8 mol, 30 wt% methanol solution) was then added to this solution over 2 h, during which time a suspension was formed. The reaction was stirred at 20 °C for another 48 h, followed by the addition of a solution of 2-chloro-1-(2-chlorothiazol-5-yl)acetone (35.8 g, 180.0 mmol) in ethanol (204 g, 444 mol) over 2 h. After the addition was complete, the reaction was stirred at 20 °C for 48 h, then cooled to 20 °C. The solid formed was separated by filtration in a sintered 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 h. The slurry was then filtered in a sintering 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 as a pale yellow solid.

[0206] Example 5: Preparation of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one

[0207] 10 g of N-methylthiourea (97%, 1.0 eq) and 28.5 g of diethyl 2-phenylmalonate (98%, 1.1 eq) were mixed and heated to 50 °C. 21.3 g of sodium methoxide (30% methanol solution, 1.1 eq) was added, and the reaction mixture was stirred under reflux for 12 h. 26.4 g of 2-chloro-1-(2-chlorothiazol-5-yl)acetone dissolved in 90 g of toluene was added over 1 h, and the reaction mixture was stirred under reflux for 10 h. After cooling to room temperature, 150 g of water was added, and the mixture was stirred for 2 h. The precipitate was filtered, and the filter cake was washed with toluene (2 × 50 g). The solid was suspended in water (120 g) and stirred for 3 h, filtered, and washed with water (100 g). The product was dried under vacuum overnight to give 40.0 g (98%, 92% yield) of the title compound.

[0208] Example 6: Preparation of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one

[0209] 10 g of N-methylthiourea (97%, 1.0 eq) and 28.5 g of diethyl 2-phenylmalonate (98%, 1.1 eq) were dissolved in 25 g of methanol and heated to 50 °C. 21.3 g of sodium methoxide (30% methanol solution, 1.1 eq) was added, and the reaction mixture was stirred under reflux for 12 h. 26.4 g of 2-chloro-1-(2-chlorothiazol-5-yl)acetone dissolved in 75 g of dimethylacetamide was added, and the reaction mixture was stirred at 70 °C for 15 h. 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 under vacuum overnight to give 44.0 g (93%, 96% yield) of the title compound.

[0210] Example 7: Preparation of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one

[0211] 10 g of N-methylthiourea (97%, 1.0 eq) and 23.7 g of dimethyl 2-phenylmalonate (99%, 1.05 eq) were dissolved in 100 g of methanol at 25 °C. 21.3 g of sodium methoxide (30% methanol solution, 1.1 eq) was added, and the reaction mixture was heated to reflux over time. 28.9 g of 2-chloro-1-(2-chlorothiazol-5-yl)acetone (95%, 1.3 eq) 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 h. After cooling to room temperature, the precipitate was filtered off 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 h, filtered, and the filter cake was washed with water (2 × 50 g). The product was dried under vacuum overnight to give 36.5 g (98%, 85% yield) of the title compound.

[0212] Example 8: Preparation of 2-[2-(2-chlorothiazol-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one by separating intermediate compound 3

[0213] 8.1 Preparation of intermediate 3, wherein M + for Na +

[0214] Diethyl 2-phenylmalonate (57.1 g, 236.7 mmol) was added to a solution of methylthiourea (20.0 g, 218.7 mmol), sodium methoxide (42.6 g, 236.7 mmol, using 30% methanol solution), and methanol (20 g) at 25 °C. The reaction was then heated at 70 °C for 6 h. The reaction was then cooled to 25 °C, at which point a precipitate formed. The precipitate was separated by filtration, and the filter cake was prepared with methyl tert-butyl ether (100 g), filtered, and then dried at 100 °C for 48 h to give the title compound as a light brown solid.

[0215] 1 H 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)

[0216] 8.2 Preparation of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one

[0217] At 75°C for 30 minutes, M obtained in step 8.1 was...+ for Na + Intermediate 3 (20.0 g, 69.45 mmol) was added to a suspension in methanol (50 g) containing a solution of 2-chloro-1-(2-chlorothiazol-5-yl)ethenone (16.2 g, 81.97 mmol) in methanol (50 g). The reaction was stirred at 50 °C for 3 h. The reaction was then cooled to 50 °C and water (50 g) was added over 15 min. The reaction was then stirred at 50 °C for 2 h, then cooled to 25 °C and stirred for 30 min, at which point a suspension was formed. Water (100 g) was added and the solid formed was separated by filtration. The filter cake was washed with water (100 g) and dried under vacuum at 80 °C for 18 h to give the title compound (27.4 g, 95% yield) as a brown solid.

[0218] Example 9: Preparation of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one

[0219] 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 a high-mounted stirrer and a reflux condenser under N2 and at 60 °C. NaOCH3 (99.1 g, 550 mmol, 30 wt% methanol solution) was added to this solution over 30 min. The reaction was stirred at 60 °C for another 16 h, during which time a suspension was formed. The temperature was then raised to 70 °C, and a solution of 2-chloro-1-(2-chlorothiazol-5-yl)acetone (115.6 g, 560 mmol) in chlorobenzene (230 g) was added over 2 h. After the addition was complete, the reaction was stirred at 70 °C for 2 h, then cooled to 20 °C. Water (460 g) was added, and the mixture was stirred at 20 °C for 1 h, at which point a suspension was formed. The solid was separated by filtration in a sintering 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 h to give 164 g (83% yield) of the title compound as a light brown solid.

[0220] Example 10: Preparation of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one

[0221] A solution of N-methylthiourea (7.78 g, 83.7 mmol), KOCH3 (24.7 g, 87.9 mmol, 25 wt% methanol solution), and methanol (4 g) was prepared in a 500 mL round-bottom flask equipped with a high-mounted stirrer and a reflux condenser under N2 and at 60–65 °C. Diethyl 2-phenylmalonate (21.21 g, 87.9 mmol) was then added over 30 min. The reaction was stirred at 65 °C for another 16 h, during which time a suspension was formed; then, a solution of 2-chloro-1-(2-chlorothiazol-5-yl)acetone (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 formed was separated by filtration in a sintering 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 h. The slurry was then filtered through a sintering 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 as a pale yellow solid.

[0222] Example 11: Preparation of 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one

[0223] A solution of N-methylthiourea (15.56 g, 167.4 mmol) and NaOCH3 (31.56 g, 175.8 mol, 30 wt% methanol solution) was prepared in a 500 mL round-bottom flask equipped with a raised stirrer and a reflux condenser under N2 and at 60 °C. Diethyl 2-phenylmalonate (42.38 g, 175.8 mmol) was then added to this solution over 30 min, during which time a suspension was formed. The reaction was stirred at 60 °C for another 10 h, followed by the addition of a solution of 2-chloro-1-(2-chlorothiazol-5-yl)acetone (35.8 g, 180.0 mmol) in ethanol (204 g, 444 mol) over 6 h. After the addition was complete, the reaction was stirred at 60 °C for 8 h, and then cooled to 20 °C. The solids formed were separated by filtration in a sintering funnel. The filter cake was washed once with 100 mL of ethanol, then washed twice with 400 g of water at 70 °C for 1 h, 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 as a pale yellow solid with a purity of 99 wt%.

Claims

1. A method for preparing 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomer of formula (I): The method includes: (a) Reaction of N-methylthiourea of ​​Formula 1 with 2-phenylmalonate of Formula 2 in the presence of a base: Where R 1 and R 2 Each is independently a C1-C4 alkyl group; A reaction mixture containing a pyrimidinone compound of formula 3 and / or its tautomers is obtained: Where M + The cation equivalent represents a metal cation or an ammonium cation. In the case of a cation with a double or triple charge, the cation equivalent is expressed as (M n+ ) 1 / n , where n is the number of charges; (b) Optionally, the pyrimidinone compound of formula 3 or its tautomer, either in its salt form or in its thiol form, is separated from the reaction mixture obtained in step (a); and (c) React the reaction mixture obtained in step (a), wherein formula 3 or its tautomers are not separated, or the compound obtained in step (b), with 1-(2-chlorothiazol-5-yl)acetone of formula 4: Where X is a leaving group. The compound of formula (I) or its tautomer is obtained.

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

3. The method of claim 2, wherein R 1 and R 2 All are methyl or all are ethyl.

4. The method according to claim 1, wherein the base used in step (a) is selected from alkali metal C1-C4 alkanols, alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal phosphates, non-nucleophilic organic bases, and mixtures thereof.

5. The method according to claim 2, wherein the base used in step (a) is selected from alkali metal C1-C4 alkanols, alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal phosphates, non-nucleophilic organic bases, and mixtures thereof.

6. The method according to claim 4, wherein the base used in step (a) is selected from alkali metal C1-C4 alkanols, alkali metal carbonates and mixtures thereof.

7. The method according to claim 4, wherein the base used in step (a) is selected from sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium methoxide, and mixtures thereof.

8. The method according to claim 5, wherein the base used in step (a) is selected from sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium methoxide, and mixtures thereof.

9. The method according to claim 7, wherein the base used in step (a) is selected from sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide and mixtures thereof.

10. The method according to claim 7, wherein the base used in step (a) is sodium methoxide or potassium methoxide.

11. The method according to any one of claims 1-10, wherein the 2-phenylmalonate of formula 2 in step (a) is used in an amount of 0.8-2.0 mol / mol of N-methylthiourea of ​​formula 1.

12. The method of claim 11, wherein the 2-phenylmalonate of formula 2 described in step (a) is used in an amount of 1.0-1.3 mol / mol of N-methylthiourea of ​​formula 1.

13. The method according to any one of claims 1-10, wherein the base in step (a) is used in an amount of 0.8-1.5 mol / mol of N-methylthiourea of ​​formula 1.

14. The method according to claim 11, wherein the base in step (a) is used in an amount of 0.8-1.5 mol / mol of N-methylthiourea of ​​Formula 1.

15. The method according to claim 13, wherein the base in step (a) is used in an amount of 1.0-1.5 mol / mol of N-methylthiourea of ​​Formula 1.

16. The method according to any one of claims 1-10, wherein the reactions in steps (a) and (c) are carried out in a solvent.

17. The method of claim 14, wherein the reactions in steps (a) and (c) are carried out in a solvent.

18. The method of claim 16, wherein the solvent is selected from polar protic solvents, polar aprotic solvents, C1-C4 alkyl esters of acetate, dialkyl ethers, aromatic solvents, heterocyclic solvents, and mixtures thereof.

19. The method of claim 16, wherein the solvent is selected from C1-C4 alkanols, glycols, tetrahydrofurans, 2-methyltetrahydrofurans, and dimethyltetrahydrofurans. Alkanes, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, C1-C4 alkyl esters of acetate, di-n-propyl ether, di-n-butyl ether, methyl tert-butyl ether, acetonitrile, benzene, toluene, xylene derivatives, chlorobenzene, dichlorobenzene, N-methylpyrrolidone and mixtures thereof.

20. The method of claim 16, wherein the solvent is selected from methanol, ethanol, n-propanol, isopropanol, isobutanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dimethylpropanol, ethanol ... Alkane, dimethylformamide, dimethylacetamide, toluene, chlorobenzene, N-methylpyrrolidone and mixtures thereof.

21. The method of claim 20, wherein the solvent is selected from methanol, ethanol, dimethylacetamide, toluene, chlorobenzene, and mixtures thereof.

22. The method of claim 20, wherein step (a) is carried out in a solvent selected from methanol, ethanol, mixtures of methanol and ethanol, and mixtures of methanol and / or ethanol with at least one other solvent selected from dimethylacetamide, toluene, and chlorobenzene, and step (c) is carried out in a solvent selected from methanol, ethanol, dimethylacetamide, toluene, chlorobenzene, and mixtures of at least two of the above solvents.

23. The method according to any one of claims 1-10, wherein in step (c), the reaction mixture obtained in step (a) is reacted with the compound of formula 4.

24. The method of claim 22, wherein in step (c), the reaction mixture obtained in step (a) is reacted with the compound of formula 4.

25. The method according to any one of claims 1-10, wherein X in the compound of formula 4 is selected from halogen, trifluoromethanesulfonic acid group, methanesulfonic acid group, toluenesulfonic acid group and perfluorobutylsulfonic acid group.

26. The method of claim 24, wherein X in the compound of formula 4 is selected from halogen, trifluoromethanesulfonic acid group, methanesulfonic acid group, toluenesulfonic acid group and perfluorobutylsulfonic acid group.

27. The method of claim 25, wherein X in the compound of formula 4 is selected from Cl and Br.

28. The method of claim 25, wherein X in the compound of formula 4 is Cl.

29. The method according to any one of claims 1-10, wherein the 1-(2-chlorothiazol-5-yl)acetone of Formula 4 described in step (c) is used in an amount of 0.8-1.5 mol / mol of the N-methylthiourea of ​​Formula 1 used in step (a).

30. The method of claim 28, wherein the 1-(2-chlorothiazol-5-yl)acetone of Formula 4 described in step (c) is used in an amount of 0.8-1.5 mol / mol of the N-methylthiourea of ​​Formula 1 used in step (a).

31. The method of claim 29, wherein the 1-(2-chlorothiazol-5-yl)acetone of Formula 4 described in step (c) is used in an amount of 1.0-1.5 mol / mol of the N-methylthiourea of ​​Formula 1 used in step (a).

32. The method according to any one of claims 1-10, wherein step (c) is carried out in the presence of an additive selected from alkali metal bromides, alkali metal iodides, ammonium bromide, ammonium iodide and mixtures thereof.

33. The method of claim 30, wherein step (c) is carried out in the presence of an additive selected from alkali metal bromides, alkali metal iodides, ammonium bromide, ammonium iodide, and mixtures thereof.

34. The method of claim 32, wherein the additive is selected from NaBr, KBr, NaI, KI, tetrabutylammonium bromide and mixtures thereof.

35. The method of claim 32, wherein the additive is used in an amount such that the molar ratio of the additive to 1-(2-chlorothiazol-5-yl)ethyl ketone of formula 4 is in the range of 1:100 to 10:

1.

36. The method of claim 32, wherein the additive is used in an amount such that the molar ratio of the additive to 1-(2-chlorothiazol-5-yl)ethyl ketone of formula 4 is in the range of 1:20 to 2:

1.

37. The method of claim 32, wherein the additive is used in an amount such that the molar ratio of the additive to 1-(2-chlorothiazol-5-yl)ethyl ketone of formula 4 is in the range of 1:2 to 2:

1.

38. 2-[2-(2-chlorothiazo-5-yl)-2-oxoethyl]thioalkyl-6-hydroxy-3-methyl-5-phenylpyrimidin-4-one or its tautomers of formula (I): 。

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