Method for preparing an enantiomerically enriched form of 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one

Abstract

Process for preparing an enantiomerically enriched form of 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy- ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one (compound (I)) or a tautomer thereof which comprises reducing 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5- phenyl-pyrimidin-4-one (compound (II)) with a reducing agent in the presence of a chiral organoborane compound, where said reducing agent can be different from or identical to said chiral organoborane reagent.

Description

[0001] Method for preparing an enantiomerically enriched form of 2-[2-(2-chlorothiazol-5-yl)-2- hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one

[0002] The present invention relates to a method for preparing 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy- ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of the formula (I) as depicted below or a tautomer thereof or enantiomerically enriched forms thereof.

[0003] Technical

[0004] 2-[2-(2-Chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one (I) (or its tautomer) has been found to be a valuable intermediate in the preparation of 2,3- dihydrothiazolo[3,2-a]pyrimidinium compounds, and more specifically of 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 if 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl- 5-phenyl-pyrimidin-4-one is used in an enantiomerically enriched form. Said pyriminidium compounds have insecticidal properties and are known, for example, from WO 2018 / 177970 or WO 2014 / 167084.

[0005] The methods thus far known for the preparation of these pyriminidium compounds are cumbersome and not yet satisfactory.

[0006] In WO 2018 / 177970, WO 2018 / 197541 and WO 2018 / 202654, non-racemic 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds are prepared by reaction of a non-racemic 4- heteroaryl-substituted thiazolidin-2-imine with a 2-substituted malonic acid derivative. In WO 2018 / 177970 and WO 2018 / 197541 , the non-racemic 4-heteroaryl-substituted thiazolidin-2- imine is in turn prepared by catalytic asymmetric hydrogenation of a 1-heteroaryl-substituted ethanimine carrying in 2-position a leaving group. The resulting amine is then reacted with an isothiocyanate to the thiazolidin-2-imine. The reaction sequence is described in WO 2018 / 197541 as follows: RAis a sulfanyl or sulfinyl, phosphoroxy, alkoxy or benzyl group; Het is optionally substituted pyridin-3-yl, thiazol-5-yl or pyrimidin-5-yl, W and LG are leaving groups, R1is a (cyclo)aliphatic group and R2is 5- or 6-membered carbo- or heterocyclic ring.

[0007] In WO 2018 / 177970 the amine VII is obtained via another reaction path from the corresponding sulfinylimine.

[0008] WO 2018 / 177970 and WO 2018 / 202654 describe a further access to the non-racemic 4- heteroaryl-substituted thiazolidin-2-imine. This is here prepared starting from a heteroaryl methyl ketone, where the methyl group carries a leaving group, conversion of this leaving group into an alkylcarbonyloxy group, hydrolysis of the latter to a hydroxyl group, reaction of the resulting heteroarylhydroxymethyl ketone with a sulfamoyl halide to a 4-heteroaryl-5H-oxathiazole 2,2- dioxide, submission of the latter to a catalytic asymmetric hydrogenation to yield a non-racemic 4-heteroaryloxathiazolidine 2,2-dioxide and reaction thereof with an isothiocyanate to the thiazolidin-2-imine. The reaction sequence is described in WO 2018 / 202654 as follows:

[0009] Het is optionally substituted pyridin-3-yl, thiazol-5-yl or pyrimidin-5-yl, W and LG are leaving groups, M2is Li, Na, K, Al, Ba, Cs, Ca or Mg, RACis alkylcarbonyl, X1is halogen, R1is a (cyclo)aliphatic group and R2is 5- or 6-membered carbo- or heterocyclic ring.

[0010] WO 2022 / 200594 and WO 2022 / 157316 disclose processes for the reduction of compound II using formiates or hydrogen.

[0011] These methods are however not very economic. Some reagents are expensive, recycling of some of the reagents which are not or not entireyl consumed is difficult, the overall yield is not satisfactory and too many reaction steps are involved.

[0012] Summary of the invention

[0013] The present invention is directed to new processes for the preparation of 2-[2-(2-chlorothiazol-5- yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one and especially a process for the preparation of an enantiomerically enriched form thereof which yields the S or R enantiomer with high selectivity. The problem is solved by a method for preparing an enantiomerically enriched form of 2-[2-(2- chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of the formula (I): where the asterisk * shows the stereogenic center; or a tautomer thereof; which method comprises reducing 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3- methyl-5-phenyl-pyrimidin-4-one of the formula (II) or a tautomer thereof with a reducing agent in the presence of a chiral organoborane compound, where said reducing agent can be different from or identical to said chiral organoborane reagent.

[0014] The compound according to formula (I) and its tautomers are herein referred to as “compound

[0015] (I)” or “compound I” or “PAL”.

[0016] The compound according to formula (II) and its tautomers are herein referred to as “compound

[0017] (II)” or “compound II” or “PKET”.

[0018] Detailed description of the invention

[0019] Definitions

[0020] “Enantiomerically enriched form” of compound (I) or the compound (I) “in enantiomerically enriched form” and similar terms denote a non-racemic compound (I) in which either the S enantiomer or the R enantiomer predominates or is even present as only stereoisomer. The compound (I) has one stereogenic center which is at the aliphatic carbon atom carrying the OH group and marked with an asterisk. The organic moieties mentioned below are - like the term halogen - collective terms for individual listings of the individual group members. The prefix Cn-Cmindicates in each case the possible number of carbon atoms in the group.

[0021] The term halogen denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine or bromine.

[0022] The term "alkyl" as used herein and in the alkyl moieties of alkoxy refers to saturated straight-chain (linear) or branched hydrocarbon radicals having 1 to 3 ("C C3-alkyl "), 1 to 4 ("C C4-alkyl "), 1 to 6 ("Ci-C6-alkyl”), 3 to 4 ("C3-C4-alkyl ") or 3 to 6 ("C3- Ce-alkyl”) carbon atoms. Ci-C3-Alkyl denotes a saturated linear or branched aliphatic radical with 1 to 3 carbon atoms. Examples are methyl, ethyl, n-propyl or isopropyl. Ci-C4-Alkyl denotes a saturated linear or branched aliphatic radical with 1 to 4 carbon atoms. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. Ci-Ce-Alkyl denotes a saturated linear or branched aliphatic radical with 1 to 6 carbon atoms. Examples are, in addition to those mentioned for Ci-C4-alkyl, pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dime- thylpropyl, 1-ethylpropyl, 1 , 1-dimethylpropyl, 1 ,2-dimethylpropyl, hexyl, 1 -methylpentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1 -dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethyl- butyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1 ,2-tri- methylpropyl, 1 ,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl. C3-C4-AI- kyl denotes a saturated linear or branched aliphatic radical with 3 or 4 carbon atoms. Examples are n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. C3-Ce-Alkyl denotes a saturated linear or branched aliphatic radical with 3 to 6 carbon atoms. Examples are, in addition to those mentioned for C3-C4-alkyl, pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dime- thylpropyl, 1-ethylpropyl, 1 , 1-dimethylpropyl, 1 ,2-dimethylpropyl, hexyl, 1 -methylpentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 , 1-dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethyl- butyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1 ,2-tri- methylpropyl, 1 ,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl.

[0023] The term " Ci-C4-haloalkyl" as used herein, which can also be expressed as "alkyl” which is partially or fully halogenated", refers to straight-chain or branched alkyl groups having 1 to 4 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above. Examples are chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1 -chloroethyl, 1-bromoethyl, 1 -fluoroethyl, 2-fluoro- ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2- dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl. Ci-C3-haloalkyl is additionally, for example, 1 -fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1 , 1-difluoropropyl, 2,2-difluoropropyl, 1 ,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 1 , 1 , 1 -trifluoroprop- 2-yl, 3-chloropropyl, 4-chlorobutyl and the like.

[0024] The term "Ci-C4-alkoxy" refers to a Ci-C4-alkyl group, as defined above, attached via an oxygen atom to the remainder of the molecule. Examples are methoxy, ethoxy, n-propoxy, 1- methylethoxy (isopropoxy), n-butoxy, 1 -methylpropoxy (sec-butoxy), 2-methylpropoxy (isobutoxy) or 1 ,1 -dimethylethoxy (tert- butoxy).

[0025] If not specified otherwise, amino is NH2.

[0026] Ci-C4-Alkylamino is a group -NHR, where R is a Ci-C4-alkyl group, as defined above. Di-(Ci-C4-alkyl)-amino is a group -NRR’, where R and R’, independently of each other, are a Ci-C4-alkyl group, as defined above.

[0027] Imino is a group containing a C=N double bond. The C=N bond can also be part of a heterocycle.

[0028] Compound (I) can be present as a tautomer thereof or as a mixture of different tautomeric forms. An example for a tautomeric form of the compound of the formula (I) as depicted above is the following formula:

[0029] Mixtures of different tautomeric forms are for example mixtures of this tautomer and the tautomer depicted above as formula (I).

[0030] Also compound II can be present as a tautomer thereof or as a mixture of different tautomeric forms. An example for a tautomeric form of the compound of the formula 1 as depicted above is the following formula:

[0031] Mixtures of different tautomeric forms are for example mixtures of this tautomer and the tautomer depicted above as formula (II).

[0032] For the sake of simplicity, reference is made herein normally only to compounds (I) and (II) are mentioned. Nevertheless, all embodiments also relate to their tautomers and mixtures of different tautomeric forms thereof.

[0033] The reaction sequence of the method of the invention can be depicted as follows: According to the inventive process, the keto group in alpha position to the thiazolyl ring is reduced to give an alcohol group. This is done by through the use of a reducing agent.

[0034] In one embodiment, said reducing agent is a chiral organoborane compound.

[0035] Examples of chiral organoborane compounds capable of acting as reducing agents include

[0036] In one embodiment, said reducing agent is used in combination with a separate chiral organoborane compound. For this embodiment, it is in principle possible to use a broad range of reducing agents. In this embodiment, the reducing agent does not carry any chiral information but effects the actual reduction of compound (II) to compound (I). The skilled person will be able to identify suitable reducing agents, for example be selecting reducing agents with a suitable reactivity.

[0037] In one embodiment, said reducing agent is a borane compound comprising one or more boronhydrogen bonds.

[0038] In one embodiment, said reducing agent is a dialkyl borane which includes cyclic dialkyl borane. Examples of dialkyl boranes are diisiamylborane and 9-borabicyclo[3.3.1]nonane.

[0039] In one embodiment, said reducing agent is a dialkoxy borane which includes cyclic dialkoxy boranes.

[0040] Examples of dialkoxy boranes include catecholborane and pinacolborane.

[0041] In one embodiment, said reducing agent is an adduct of a borane with a lewis base. In one embodiment, said reducing agent is an adduct of a monoborane with a lewis base.

[0042] Suitable lewis bases for such adducts of boranes, especially monoboranes, are in principle known to the skilled persons.

[0043] In one embodiment, said lewis base is an ether. Examples of ethers suitable as lewis bases for borane adducts include tetrahydrofurane.

[0044] In one embodiment, said lewis base is a thioether, also referred to as organic sulfides. Examples of thioethers suitable as lewis bases for borane adducts include dialkylsulfide like dimethylsulfide. In one embodiment, said lewis base is an amine, especially a tertiary amine. Examples of tertiary amines suitable as lewis bases for borane adducts include trialkyl amines like trimethylamine, triethyl amine, or tri n-butylamine; N-substituted anilines like diethyl aniline or aromatic amines like pyridine. In one embodiment, said lewis base is ammonia.

[0045] Suitable boranes in such lewis base adducts can in principle all boranes having boron-hydron bonds. In one embodiment said borane in such lewis base adducts is monoborane (BH3). In one embodiment, said reducing agent is selected from catecholborane or of adducts of monoborane with ethers such as tetrahydrofurane, sulfoethers such as dimethylsulfide, or tertiary amines.

[0046] In one embodiment, said reducing agent is catecholborane. In one embodiment, said reducing agent is an adduct of BH3and tetrahydrofurane. In one embodiment, said reducing agent is an adduct of BH3and dimethylsulfide. In one embodiment, said reducing agent is an adduct of BH3 and pyridine. In one embodiment, said reducing agent is an adduct of BH3 and trimethylamine. In one embodiment, said reducing agent is an adduct of BH3and diethyl amine. In one embodiment, said reducing agent is an adduct of BH3 and ammonia. In one embodiment, said reducing agent is an adduct of BH3 and tributylamine. In one embodiment, said reducing agent is an adduct of BH3and tri-n-butylamine. In one embodiment, said reducing agent is an adduct of BH3and diethyl aniline.

[0047] Typically, such reducing agents are used in at least equimolar amounts, preferably in an excess relative to compound (II). In the context of the reducing agent, it has to be noted that some reducing agents can reduce more or less than one mole of compound (II) to compound (I) per mole of the reducing agent. For example, one mole of “BH3” can reduce more than one mole of compound (II) to compound (I). When it is stated herein that the reducing agent is used in “an equimolar amount”, this shall mean that the reducing agent is used in such an amount that exactly the reducing capacity of the reducing agent is sufficient to reduce one mole of compound (II). Typically, reducing agents are used in an amount of 1.0 to 20.0 mol per mol of compound (II), preferably 1.1 to 10 mol or 1.5 to 8 mol per mol of compound (II).

[0048] Processes of the invention are carried out in the presence of a chiral organoborane compound. Said chiral organoborane compound normally does not comprise any boron-hydrogen bonds. Typically, the boron atom in said chiral organoborane compound is bound to carbon, nitrogen, oxygen or other elements that form bonds with boron that are stable under the reaction conditions of processes of the invention. It is self understood that the boron atom can be bound to different type of elements in one chiral organoborane compound. When reference is made herein to a “chiral borane” compound, this shall be understood to mean “chiral organoborane”.

[0049] Without limiting the invention, it is assumed that the chiral organoborane compound forms some kind of adduct or complex with the keto group in compound (II) and thus determines the chirality of the resulting reaction product of the processes of the invention.

[0050] Typically, such chiral organoborane compound is present in the inventive processes in at least stoichiometric amounts.

[0051] Preferably, the chiral organoborane compound, is used in an amount of 1 to 10 molar equivalents relative to compound (II), more preferably from 1.05 to 5 molar equivalents , even more preferably from 1.1 to 2 molar equivalents, in each case relative to compound (II).

[0052] In one embodiment, said chiral organoborane reagent comprises a moiety having the following structure: where R is an alkyl, cycloalkyl, alkoxy, aryl or aralkyl group that may optionally be further substituted;

[0053] R1is an aryl group that may optionally be further substituted.

[0054] In one embodiment, said chiral organoborane reagent comprises a moiety having one of the following structures: where R is an alkyl, cycloalkyl, alkoxy, aryl or aralkyl group that may optionally be further substituted.

[0055] In one embodiment, said chiral organoborane compound

[0056] In one embodiment, said chiral organoborane compound

[0057] In one embodiment, said chiral organoborane compound

[0058] In one embodiment, said chiral organoborane compound

[0059] In one embodiment, said chiral organoborane compound In one embodiment, said chiral organoborane compound is

[0060] In one embodiment, said chiral organoborane compound is

[0061] In one embodiment, said chiral organoborane compound is

[0062] In one embodiment, said chiral organoborane compound is

[0063] In one embodiment, said chiral organoborane compound is

[0064] In one embodiment, said chiral organoborane compound is

[0065] In one embodiment, said chiral organoborane compound is

[0066] In one embodiment, said chiral organoborane compound is In one embodiment, said chiral organoborane compound is

[0067] In one embodiment, said chiral organoborane compound is

[0068] In one embodiment, said chiral organoborane compound is

[0069] In one embodiment, said chiral organoborane compound is

[0070] In one embodiment, said chiral organoborane compound is

[0071] In one embodiment, said chiral organoborane compound is selected from organoborane compounds being capable of reducing compound (II) in the absence of further reducing agents, said chiral organoborane compound being selected from

[0072] The reaction time depends on various factors, such as the reaction temperature, the concentration of the reactants in the reaction mixture and the like. Typically, it is in the range of from about 0 to 48 h, preferably from 1 to 24 h, in particular from 1 to 18 h, specifically from 10 to 18 h. A reaction time of “0 h” in this context means that after complete addition of all components, the reaction can be sufficiently complete to continue with the isolation of the desired compound (I). This can for example be the case if the addition of the reactants has lasted rather long or if it is intended to recycle the non-reacted starting material.

[0073] The reaction is preferably carried out in the presence of a solvent. The solvent is preferably selected from the group consisting of polar aprotic solvents, polar protic solvents, Ci-C4-alkyl acetates, chlorinated alkanes, open-chained ethers, aromatic solvents and mixtures thereof. In principle many solvents are suitable for carrying out processes of the invention. Typically, said solvent dissolves the chiral organoborane and the reducing under the reaction conditions. Typically, such solvent is chosen such that compound-1, compound II, chiral organoborane and reducing agent are at least partially soluble in solvent under the reaction conditions. In one embodiment, such solvent is chosen such that compound-1, reducing agent and chiral organoborane are completely dissolved in the solvent under the reaction conditions.

[0074] The reaction is preferably carried out in the presence of a solvent. The solvent is preferably selected from the group consisting of polar aprotic solvents or polar protic solvents. In one embodiment the solvent is selected from Ci-C4-alkyl acetates, chlorinated alkanes, open-chained ethers, aromatic solvents and mixtures thereof.

[0075] Polar aprotic solvents are polar solvents without a functional group from which a proton can dissociate. Examples for suitable polar aprotic solvents are amides, such as dimethylformamide (DMF), diethylformamide, dibutylformamide, and dimethylacetamide; cyclic ethers, such as tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,3-dioxane and 1 ,4-dioxane; sulfoxides, such as dimethylsulfoxide (DMSO); nitriles, such as acetonitrile; lactams, such as N-methylpyrrolidone (NMP), N-(n-butyl)-pyrrolidone or N-(tert-butyl)-pyrrolidone; sulfones, such as sulfolane; carbonic acid esters, such as dimethylcarbonate, ethylenecarbonate or propylene carbonate; lactones, such as y-butyrolactone or y-valerolactone; ureas, such as N,N,N’,N’-tetramethyl urea, N,N,N’,N’-tetrabutyl urea, dimethylpropylene urea (DMPLI) or 1 ,3-dimethyl-2-imidazolinone (DMEll; DMI); and nitro compounds, such as nitromethane.

[0076] Polar protic solvents are solvents with a functional group from which a proton can easily dissociate. Examples of suitable polar protic solvents are Ci-C4-alkanols, fluorinated Ci-C4-alkanols, glycols and mixtures thereof. Ci-C4-Alkanols are for example methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol and tert-butanol. Fluorinated Ci-C4-alkanols are for example 2-fluoroethanol, 3-fluoropropanol, 1-fluoropropan-2-ol, 4-fluorobutanol, 1 , 1 -difluoro- ethanol, 2,2-difluoroethanol, 2,2-difluoropropanol, 3,3-difluoropropanol, 1 ,1-difluoropropan-2-ol, 2,2,2-trifluoroethanol, 3,3,3-trifluoropropanol, 4,4,4-trifluorobutanol and the like. Examples for glycols are ethylene glycol, diethylene glycol and triethylene glycol.

[0077] Examples for suitable Ci-C4-alkyl acetates are methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate.

[0078] Examples for suitable chlorinated alkanes are dichloromethane, trichloromethane or dichloroethane.

[0079] Open-chained ethers are compounds of formula R-O-R’, where R and R’, independently of each other, are an aliphatic, cycloaliphatic or aromatic group. In contrast to cyclic ethers, R and R’ do not form together a bridging group; i.e. the ether oxygen atom is not a ring member of a cyclic ring system. Examples are di-(Ci-C4-alkyl)-ethers, such as diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether or methyl-tert-butyl ether; and anisole (methoxybenzene). Examples for suitable aromatic solvents are benzene, toluene, trifluoro toluene, the xylenes (i.e. 1 ,2-xylene, 1 ,3-xylene or 1 ,4-xylene), chlorobenzene, dichlorobenzene or anisole.

[0080] In one embodiment, said solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,3- dioxane, 1 ,4-dioxane, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dime- thylacetamide (DMAC), C1-C4-alkanols, fluorinated C1-C4-alkanols, C1-C4-alkyl acetates, chlorinated C1-C2-alkanes, di-(C1-C4-alkyl)-ethers, benzene, toluene, trifluoro toluene, the xylenes, chlorobenzene, dichlorobenzene, anisole and mixtures of the aforementioned solvents.

[0081] In one embodiment, said solvent is selected from 2-methyltetrahydrofuran, 1 ,4-dioxane, DMSO, DMF, Ci-Cs-alkanols, 2,2,2-trifluoroethanol, ethyl acetate, chlorinated Ci-C2-alkanes, di-(C1-C4- alkyl)-ethers, toluene, anisole, dimethoxy ethane, monochloro benzene, cyclopentyl methyl ether, N,N-dimethyl acetamide and mixtures of the aforementioned solvents.

[0082] In one embodiment, said solvent is selected from toluene, xylene, dioxane, 2-methyltetrahydro- furan, monochloro benzene, dimethoxy ethane, cyclopentyl methyl ether, N,N-dimethyl acetamide, or mixtures thereof.

[0083] Typically, the inventive processes are carried out at a temperature from -78 to 120°C.

[0084] In one embodiment, the inventive processes are carried out at a temperature of from 10 to 80°C.

[0085] In one embodiment, the inventive processes are carried out at a temperature of from 30 to 60°C.

[0086] The inventive process can typically be carried under acidic, neutral or basic conditions. However, strongly acidic , e.g. a pH below 5, or strongly basic conditions, e.g. pH above 9, are normally avoided. In one embodiment, the inventive process is carried out at a pH of 5 to 9.

[0087] The reaction is generally carried out by mixing the starting compound II, the chiral organoborane, optionally the solvent, the reducing agent different from the organoborane and optionally any further additives at the desired reaction, or mixing the components, and bringing then the temperature to the desired range. Typically, the chiral organoborane is added prior to the reducing agent, yet the order of addition is normally not particularly critical.

[0088] For instance,

[0089] (i) the starting compound (II) is dissolved in a solvent, the chiral organoborane, optionally dissolved in a solvent, is added, and reducing agent is added; or

[0090] (ii) the starting compound (II), optionally dissolved in a solvent, is added to the chiral organoborane, dissolved in a solvent, and reducing agent is added.

[0091] After completion of the reaction, excess borane is typically quenched, for example with an alcohol like methanol or other quenching agents. Normally this is done under cooling, for example below 25 °C. After completion of the reaction, the pyrimidinone of the formula (I) in enantiomeri- cally enriched form can be isolated from the reaction mixture. When the inventive processes are carried out on a commercial scale, workup of compound (I) is not always necessary. Rather Compound (I) can be used in the next synthesis step without further purification. If compound (I) is to be isolated and purified, isolation typically comprises adding water to the reaction mixture, isolating and optionally purifying the pyrimidinone of the formula (I) precipitated upon addition of water. Alternatively, isolation comprises setting the pH of the reaction mixture acidic; removing at least a part of the solvent, if any, to obtain a concentrate; adding water and a solvent which has low or no miscibility with water to the concentrate; extracting the pyrimidinone of the formula (I) into the solvent which has low or no miscibility with water; and isolating the pyrimidinone of the formula (I) from the extract. The solvent which has low or no miscibility with water is preferably selected from the group consisting of 2-methyltetrahydrofuran, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl isopropyl ketone, and chlorobenzene.

[0092] In one embodiment, processes of the invention allow the preparation of enantiomerically enriched compound (I) with S configuration (compound (l-S) with an enantiomeric excess (EE) of at least 55 %ee, preferably at least 60 %ee, more preferably at least 70 %ee, even more preferably at least 80%ee, or at least 90 %ee or at least 95%ee.

[0093] In one embodiment, processes of the invention allow the preparation of enantiomerically enriched compound (I) with R configuration (compound (l-R) with an enantiomeric excess (EE) of at least 55 %ee, preferably at least 60 %ee, more preferably at least 70 %ee, even more preferably at least 80%ee, or at least 90 %ee or at least 95%ee.

[0094] The starting compound (II) is obtainable by reaction of N-methylthiourea with an alkyl 2-phe- nylmalonate to 6-hydroxy-3-methyl-5-phenyl-2-sulfanyl-pyrimidin-4-one or the corresponding thiolate and reaction thereof with 2-chloro-1-(2-chlorothiazol-5-yl)ethanone to the compound (II). These reactions are known.

[0095] N-methylthiourea and alkyl 2-phenylmalonates are commercially available. 2-Chloro-1-(2-chloro- thiazol-5-yl)ethanone can be prepared, for example, as described in WO 2018 / 197541 or WO 2018 / 202654 by reaction of 2-chlorothiazole with a Grignard reagent to the corresponding chloro-(2-chlorothiazol-5-yl) magnesium species and reaction thereof with 2-chloro-N-methoxy- N-metyl-acetamide. Alternatively, the compound 3 can be prepared from thiourea according the method described by T. Chalopin et al. in Org. Biomol. Chem., 2016, 14, 3913-3925.

[0096] The present method leads to the compound (I) in high yields and stereoselectivity.

[0097] The compound (I) can be converted in just one further step into 3-(2-chlorothiazol-5-yl)-8-me- thyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate, and especially into enantiomerically enriched forms thereof. For this purpose, the compound (I) is subjected to an internal cyclization by a nucleophilic attack of the unsubstituted nitrogen atom of the pyrimidine ring on the carbon atom carrying the aliphatic OH group. This reaction is described under separate cover, e.g. in PCT / EP2022 / 051368.

[0098] While the compound (I) can be converted in just one step into 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, it can also be first subjected to some modifications, such as etherification of the hydroxyl group on the pyrimidine ring, substitution of the Cl atom on the thiazole ring or introduction of substituents on the phenyl ring, so as to allow formation of 2,3-dihydrothiazolo[3,2- a]pyrimidinium compounds other than 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5- olate.

[0099] The present invention inter alia offers the following advantages: Processes of the invention are easy and economical to carry out. Processes of the invention are environmentally friendly.

[0100] Processes of the invention yield compound (I) in high yields.

[0101] Processes of the invention yield compound (I) with high purity.

[0102] Processes of the invention allow the preparation of enantiomerically enriched compound (I) with an enantiomeric excess (EE) of at least 55 %ee, preferably at least 60 %ee, more preferably at least 70 %ee, even more preferably at least 80%ee, or at least 90 %ee or at least 95%ee.

[0103] The present invention is further illustrated in the following examples.

[0104] Examples

[0105] Abbreviations: catecholborane n,n- (-)-DIP-CI

[0106] (R)-Me-CBS (S)-Butyl-CBS Borane THF Borane DMS diethylanilineborane

[0107] OMe-indanol OiPr-indanol

[0108] Methods: The compounds were characterized by coupled High Performance Liquid Chromatography.

[0109] Achiral HPLC for conversion and chemoselectivity:

[0110] Software: Agilent Series 1100

[0111] Column: Dr. Maisch Retrospher 100 C18, 4.6x75 mm, 3.0 pm Eluent: -A: H2O with 0.1 vol% TFA

[0112] -B: MeCN with 0.1 vol % TFA

[0113] Detector: UV detector = 220 nm, band width = 4 nm Inject, vol.: 2 pL

[0114] Temperature: 30°C Analysis time: 15 min

[0115] Chiral HPLC for %ee:

[0116] Software: Agilent Series 1260

[0117] Column: Chiralpak AD-RH 5 pm 150*4.6 mm from Daicel

[0118] Eluent: - A: H2O with 0.1 vol% H3PO4

[0119] - B: MeCN / 2-Propanol (1 :1)

[0120] Detector: UV detector = 216 nm, band width = 4 nm

[0121] Inject, vol.: 3 pL

[0122] Temperature: 40°C

[0123] Analysis time: 22 min

[0124] Pressure: ca. 95 bar

[0125] Examples 1 to 10: Screening of Reducing Agents

[0126] Compound (II) (50 mg, 0.13 mmol) were suspended in THF (1 mL) under inert atmosphere at room temperature under stirring. Then the chiral organoborane compound (1 eq) was added turning the suspension into a solution, followed by dropwise addition of the reducing agent. Reaction sampling was done by taking 20 pL and dissolving it in MeOH (1 mL). All reactions were monitored by HPLC (“PAL A %” denotes the yield of compound (I)).

[0127] Examples 12 to 24: Screening of Chiral Organoboranes

[0128] Compound (II) (50 mg, 0.13 mmol) were suspended in THF (1 mL) under inert atmosphere at room temperature under stirring. Then the chiral organoborane compound (1 eq) was added turn- ing the suspension into a solution, followed by dropwise addition of the reducing agent. Reaction sampling was done by taking 20 pL and dissolving it in MeOH (1 mL). All reactions were monitored by HPLC (“PAL A %” denotes the yield of compound (I)).

[0129] Experiments 34 to 49: Screening of Solvent and Conditions

[0130] Compound (II) (50 mg, 0.13 mmol) were suspended in THF (1 mL) under inert atmosphere at the temperature given in the table under stirring. Then the chiral organoborane compound (1 eq) was added turning the suspension into a solution, followed by dropwise addition of the reducing agent.

[0131] Reaction sampling was done by taking 20 pL and dissolving it in MeOH (1 mL). All reactions were monitored by HPLC (“PAL A %” denotes the yield of compound (I)).

Claims

Claims1. Process for preparing an enantiomerically enriched form of 2-[2-(2-chlorothiazol-5-yl)-2-hy- droxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one (compound (I)) or a tautomer thereof which comprises reducing 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6- hydroxy-3-methyl-5-phenyl-pyrimidin-4-one (compound (II)) with a reducing agent in the presence of a chiral organoborane compound, where said reducing agent can be different from or identical to said chiral organoborane reagent.

2. Process according claim 1 , where said reducing agent is a borane compound comprising one or more boron-hydrogen bonds.

3. Process according to any of claims 1 to 2, where said reducing agent is a dialkoxy borane, a cyclic dialkoxy borane or an adduct of monoborane with a lewis base.

4. Process according to any of claims 1 to 3, where said reducing agent is selected from cat- echolborane or of adducts of monoborane with ethers such as tetrahydrofurane, sulfoethers such as dimethylsulfide, or tertiary amines.

5. Process according to any of claims 1 to 4, where said chiral organoborane compound is different from the reducing agent and said chiral organoborane reagent comprises a moiety having the following structure:where R is an alkyl, cycloalkyl, alkoxy, aryl or aralkyl group that may optionally be further substituted;R1is an aryl group that may optionally be further substituted.

6. Process according to any of claims 1 to 5, where said chiral organoborane compound is different from the reducing agent and said chiral organoborane reagent comprises a moiety having one of the following structures:where R is an alkyl, cycloalkyl, alkoxy, aryl or aralkyl group that may optionally be further substituted.

7. Process according to any of claims 1 to 6, where said chiral organoborane compound is selected fromProcess according to any of claims 1 to 7, where said chiral organoborane compound is selected from organoborane compounds being capable of reducing compound (II) in the absence of further reducing agents, said chiral organoborane compound being selected9. Process according to any of claims 1 to 8, where said chiral organoborane compound is used in at least stoichiometric amounts relative to compound (II).

10. Process according to any of claims 1 to 9, where the chiral organoborane compound, is used in an amount of from 1.0 to 5 mol per mol of compound (II).

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