Method for preparing an enantiomerically enriched form of 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate

1 . A method for preparing an enantiomerically enriched form of 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate of formula (I):

where the asterisk * shows the stereogenic center;

which method comprises reacting 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 formula 1

where the asterisk * shows the stereogenic center;

or of a tautomer thereof;

with an activating agent which enhances electrophilicity of the carbon atom marked with the asterisk in the compound of formula 1 without promoting racemization at said carbon atom;

to obtain an enantiomerically enriched form of the compound of formula (I).

2 . The method according to claim 1 , where the activating agent is selected from the group consisting of P(OR 1 ) 2 Cl, P(OR 1 )Cl 2 , P(═O)(OR 1 ) 2 Cl, P(═O)(OR 1 )Cl 2 , where each R 1 in the four aforementioned compounds is independently C 1 -C 4 -alkyl; PCl 3 , P(═O)Cl 3 , polyphosphoric acid, P 4 O 10 , Mitsunobu-type reagents, triphenylphosphine in combination with a halogenating agent, SO 3 complexes with Lewis bases selected from amines, carboxamides, and heteroaromatic compounds containing 1, 2, or 3 basic nitrogen ring atoms; S(O)Cl 2 , CH 3 S(O) 2 Cl, carbonyldiimidazole (CDI), Vilsmeier reagent, complexes of N,N-dimethylformamide and/or N,N-dimethylacetamide with a Lewis acid; and mixtures of two or more of the aforementioned activating agents.

3 . The method according to claim 2 , where the activating agent is selected from the group consisting of P(OR 1 ) 2 Cl, P(OR 1 )Cl 2 , P(═O)(OR 1 ) 2 Cl, where each R 1 in the three aforementioned compounds is independently C 1 -C 4 -alkyl; PCl 3 , P(O)Cl 3 , SO 3 /dimethyl formamide complex, SOCl 2 , CH 3 S(═O) 2 Cl, CDI, and Mitsunobu-type reagents.

4 . The method according to claim 3 , where the activating agent is selected from the group consisting of dimethyl chlorophosphite (P(OCH 3 ) 2 Cl), diethyl chlorophosphite (P(OCH 2 CH 3 ) 2 Cl), methyl dichlorophosphite (P(OCH 3 )Cl 2 ), ethyl dichlorophosphite (P(OCH 2 CH 3 )Cl 2 ), PCl 3 , P(O)Cl 3 , SO 3 /dimethyl formamide complex, CH 3 S(═O) 2 Cl, and CDI.

5 . The method according to claim 4 , where the activating agent is selected from the group consisting of dimethyl chlorophosphite (P(OCH 3 ) 2 Cl), diethyl chlorophosphite (P(OCH 2 CH 3 ) 2 Cl), and PCl 3 .

6 . The method according to claim 5 , where the activating agent is selected from the group consisting of dimethyl chlorophosphite (P(OCH 3 ) 2 Cl) and diethyl chlorophosphite (P(OCH 2 CH 3 ) 2 Cl).

7 . The method according to claim 1 , where the compound of the formula 1 and the activating agent are used in a molar ratio of from 10:1 to 1:10.

8 . The method according to claim 7 , where the compound of the formula 1 and the activating agent are used in a molar ratio of from 1:1 to 1:4.

9 . The method according to claim 1 , where the reaction is carried out at a temperature of from −80 to 120° C.

10 . The method according to claim 1 , where the reaction is carried out in the presence of a solvent, where the solvent is selected from the group consisting of polar aprotic solvents, mixtures of polar aprotic solvents and water, C 1 -C 4 -alkyl acetates, chlorinated alkanes, aromatic solvents, heterocyclic solvents, and mixtures thereof.

11 . The method according to claim 10 , where the solvent is selected from the group consisting of dimethylformamide, diethylformamide, dibutylformamide, dimethylacetamide, tetrahydrofuran, mixtures of tetrahydrofuran and water, 2-methyltetrahydrofuran, the dioxanes, dimethylsulfoxide, acetonitrile, N-methylpyrrolidone, N-(n-butyl)-pyrrolidone, N-(tert-butyl)-pyrrolidone, sulfolane, dimethylcarbonate, diethylcarbonate, propylene carbonate, γ-valerolactone, N,N,N′,N′-tetrabutyl urea, 1,3-dimethyl-2-imidazolinone, ethyl acetate, isopropyl acetate, dichloromethane, trichloromethane, dichloroethane, benzene, toluene, trifluorotoluene, the xylenes, chlorobenzene, dichlorobenzene, 4-formyl-morpholine, dihydrolevoglucosenone, and mixtures thereof.

12 . The method according to claim 11 , where the solvent is selected from the group consisting of dimethylformamide, diethylformamide, dibutylformamide, dimethylacetamide, tetrahydrofuran, mixtures of tetrahydrofuran and water, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate, dichloromethane, toluene, chlorobenzene and mixtures thereof.

13 . The method according to claim 1 , where the reaction is carried out in the presence of a base selected from the group consisting of alkali metal hydroxides, amines of the formula NR 1 R 2 R 3 , where R 1 , R 2 , and R 3 , independently of each other, are selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy, and C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, where at least one of R 1 , R 2 , and R 3 is not hydrogen; diamines of the formula NR 1 R 2 -A-NR 3 R 4 , where R 1 , R 2 , R 3 , and R 4 , independently of each other, are selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy, and C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, and A is (CH 2 ) 2 or (CH 2 ) 3 ; and a 5- or 6-membered saturated heterocyclic ring containing one nitrogen atom as ring member and optionally one further heteroatom selected from N and O as ring member, where the ring optionally carry 1 to 6 C 1 -C 4 -alkyl groups and/or 1 or 2 OH groups.

14 . The method according to claim 13 , where the base is selected from the group consisting of LiOH, NaOH, KOH, diethylamine, triethylamine, tributylamine, diisopropylethylamine, dimethylisopropylamine, ethyl-tert-butylamine, isopropyl-tert-butylamine, (2-methoxyethyl)methylamine, N,N-dicyclohexylmethylamine, N-cyclohexyldimethylamine, N,N,N′,N′-tetramethylethylenediamine, N,N,N′,N′-tetramethylpropylene-1,3-diamine, piperdine, N-methylpiperidine, 2,2,6,6-tetramethylpiperidine, N-methyl-2,6,6-tetramethylpiperidine, N-methyl-4-hydroxy-2,2,6,6-tetramethylpiperidine, morpholine, and N-methylmorpholine, where the bases can be used in supported from.

15 . The method according to claim 1 , for preparing (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate of formula (I-R)

in an enantiomeric excess of at least 55% ee;

which method comprises reacting 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of formula 1-S

or a tautomer thereof with an activating agent.

16 . The method according to claim 1 , for preparing (3S)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate of formula (I-S)

in an enantiomeric excess of at least 55% ee;

which method comprises reacting 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of formula 1-R

or a tautomer thereof with an activating agent.