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

1 . 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 formula (I):

where the asterisk * shows a stereogenic center; or of 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 formula 1

or a tautomer thereof with a reduction agent selected from the group consisting of formic acid HC(═O)OH, formates of the formula HC(═O) O M + , and mixtures of formic acid HC(═O)OH and one or more formates of the formula HC(═O)O − M + , where M + is a cation equivalent; in the presence of a chiral transition metal catalyst and optionally a base, where in the case that formic acid is used as reduction agent, the reaction is carried out in the presence of a base;

to obtain an enantiomerically enriched form of the pyrimidinone of the formula (I) or of a tautomer thereof.

2 . The method according to claim 1 , where M + is selected from the group consisting of alkali metal cations, ammonium cations of the formula [NHR 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, protonated 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 protonated 5- or 6-membered saturated heterocyclic rings containing one nitrogen atom as ring member and optionally one further heteroatom selected from N and O as ring member, where the ring may carry 1 to 6 C 1 -C 4 -alkyl groups and/or 1 or 2 OH groups.

3 . The method according to claim 1 , where the base is 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 may carry 1 to 6 C 1 -C 4 -alkyl groups and/or 1 or 2 OH groups, where the bases can be used in supported from.

4 . The method according to claim 1 , where the formic acid is used as reduction agent, where the formic acid and the base are used in a molar ratio of from 100:1 to 1:10.

5 . The method according to claim 1 , where the chiral transition metal catalyst is selected from group VIII metal catalysts.

6 . The method according to claim 5 , where the chiral transition metal catalyst is selected from Ru, Rh, and Ir catalysts.

7 . The method according to claim 1 , where the chiral transition metal catalyst, calculated on the basis of the transition metal content, is used in an amount of 0.01 to 10 mol % relative to 1 mol of the compound of formula 1.

8 . The method according to claim 7 , where the chiral transition metal catalyst, calculated on the basis of the transition metal content, is used in an amount of 0.1 to 5 mol-% relative to 1 mol of the compound of formula 1.

9 . The method according to claim 1 , where the chiral transition metal catalyst is either preformed and contains one or more chiral ligands coordinated to a transition metal; or is formed in situ by reaction of a transition metal precursor compound and one or more chiral ligands.

10 . The method according to claim 1 , where the chiral transition metal catalyst comprises one or more chiral ligands coordinated to a transition metal, where the chiral ligands are selected from the group consisting of bidentate amine-based chiral ligands.

11 . The method according to claim 10 , where the chiral transition metal catalyst comprises one or more chiral ligands coordinated to a transition metal, where the chiral ligands are selected from the group consisting of chiral forms of 1,2-diphenyl-ethylene-1,2-diamines of formula (II)

where

the asterisk shows the stereogenic centers;

R 5 and R 6 , independently of each other, are selected from the group consisting of OH, halogen, C 1 -C 4 -alkyl, and C 1 -C 4 -alkoxy;

R 7 and R 8 , independently of each other, are selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, -L-phenyl, where the phenyl ring may carry 1, 2, 3, 4, or 5 substituents selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, and C 1 -C 4 -alkoxy; and SO 2 R 9 ;

L is a linker selected from the group consisting of C 2 -C 6 -alkylene, C 1 -C 3 -alkylene-O—(CH 2 ) p , where p is 0, 1, or 2; and C 1 -C 3 -alkylene-(1,2-phenylene)-(CH 2 ) r , where r is 0, 1, or 2;

R 9 is selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, phenyl, phenyl-C 1 -C 3 -alkyl, where phenyl in the two aforementioned radicals optionally carry 1, 2, 3, 4, or 5 substituents selected from the group consisting of halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, and C 1 -C 4 -alkoxy; naphthyl, and NR 10 R 11 ;

R 10 is hydrogen or C 1 -C 4 -alkyl;

R 11 is phenyl-C 1 -C 3 -alkyl, where the phenyl ring may carry 1, 2, 3, 4, or 5 substituents selected from the group consisting of halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, and C 1 -C 4 -alkoxy; and

m and n, independently of each other, are 0, 1, 2, 3, 4, or 5.

12 . The method according to claim 11 , where the chiral transition metal catalyst comprises one or more chiral ligands coordinated to a transition metal, where the chiral ligands are selected from the group consisting of (1R,2R) or (1S,2S) forms of DPEN, TSDPEN, CF 3 TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, TripsMesityIDPEN, CsDPEN, MesityIDPEN, RsDPEN, TsDiOMeDPEN, and the compound of formula (II), wherein R 7 is SO 2 R 9 , where R 9 is C 1 -C 4 -alkyl or phenyl which optionally carry 1, 2, or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl, R 8 is —(CH 2 ) 3 -phenyl or —(CH 2 ) 4 -phenyl, where phenyl in the two last-mentioned radicals optionally carry 1, 2, or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, and C 1 -C 4 -alkoxy; and m and n are 0.

13 . The method according to claim 12 , where the chiral transition metal catalyst is selected from catalysts containing Ru, Rh, or Ir as central metal and at least one ligand selected from the group consisting of the (1R,2R) or (1S,2S) forms of DPEN, TsDPEN, CF 3 TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, TripsMesityIDPEN, CsDPEN, MesityIDPEN, RsDPEN, and TsDiOMeDPEN; and from catalysts containing Ru as central metal and at least one ligand selected from the (1R,2R) or (1S,2S) forms of the compound of formula (II), wherein R 7 is SO 2 R 9 , where R 9 is C 1 -C 4 -alkyl or phenyl which optionally carry 1, 2, or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl, R 8 is —(CH 2 ) 3 -phenyl or —(CH 2 ) 4 -phenyl, where phenyl in the two last-mentioned radicals optionally carry 1, 2, or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl and C 1 -C 4 -alkoxy; and m and n are 0.

14 . The method according to claim 11 , where in the case that none of R 7 and R 8 is -L-phenyl or SO 2 R 9 with R 9 being phenyl-C 1 -C 3 -alkyl or NR 10 R 11 , the catalyst contains additionally a ligand selected from Cp, Cp*, benzene, p-cymene, mesitylene and hexamethylbenzene.

15 . The method according to claim 11 , for preparing 2-sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of formula (I-S)

or a tautomer thereof

in an enantiomeric excess of at least 55% ee, where a chiral transition metal catalyst used comprises a chiral ligand selected from the group consisting of (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF 3 TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-FsDPEN, (1S,2S)-TripsMesityIDPEN, (1S,2S)-CsDPEN, (1S,2S)-MesityIDPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and the (1S,2S) form of a compound of the formula (II), wherein R 7 is SO 2 R 9 , where R 9 is C 1 -C 4 -alkyl or phenyl which optionally carry 1, 2, or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl, R 8 is —(CH 2 ) 3 -phenyl or —(CH 2 ) 4 -phenyl, where phenyl in the two last-mentioned radicals optionally carry 1, 2, or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, and C 1 -C 4 -alkoxy; and m and n are 0;

or

for preparing 2-sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of formula (I-R)

or a tautomer thereof

in an enantiomeric excess of at least 55% ee, where the chiral transition metal catalyst used comprises a chiral ligand selected from the group consisting of (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-CF 3 TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-FsDPEN, (1R,2R)-TripsMesityIDPEN, (1R,2R)-CsDPEN, (1R,2R)-MesityIDPEN, (1R,2R)-RsDPEN, (1R,2R)-TsDiOMeDPEN, and the (1R,2R) form of the compound of formula (II), wherein R 7 is SO 2 R 9 , where R 9 is C 1 -C 4 -alkyl or phenyl which optionally carry 1, 2, or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl, R 8 is —(CH 2 ) 3 -phenyl or —(CH 2 ) 4 -phenyl, where phenyl in the two last-mentioned radicals optionally carry 1, 2, or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, and C 1 -C 4 -alkoxy; and m and n are 0.

16 . The method according to claim 15 , for preparing 2-sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of the formula (I-S) or a tautomer thereof in an enantiomeric excess of at least 70% ee, where the chiral transition metal catalyst comprises as central metal Ru, Rh, or Ir, and comprises a chiral ligand selected from the group consisting of (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF 3 TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-FsDPEN, (1S,2S)-TripsMesityIDPEN, (1S,2S)-CsDPEN, (1S,2S)-MesityIDPEN, (1S,2S)-RsDPEN, and (1S,2S)-TsDiOMeDPEN; or is a catalyst containing Ru as central metal and at least one ligand selected from the (1S,2S) form of the compound of formula (II), wherein R 7 is SO 2 R 9 , where R 9 is C 1 -C 4 -alkyl or phenyl which optionally carry 1, 2, or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl, R 8 is —(CH 2 ) 3 -phenyl or —(CH 2 ) 4 -phenyl, where phenyl in the two last-mentioned radicals optionally carry 1, 2, or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, and C 1 -C 4 -alkoxy; and m and n are 0;

or

for preparing 2-sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of the formula (I-R) or a tautomer thereof

in an enantiomeric excess of at least 70% ee, where the chiral transition metal catalyst comprises as central metal Ru, Rh, or Ir, and comprises a chiral ligand selected from the group consisting of (1R,2R)-DPEN, (1R,2R)-TsDPEN, (1R,2R)-CF 3 TsDPEN, (1R,2R)-MsDPEN, (1R,2R)-MeMsDPEN, (1R,2R)-MeTsDPEN, (1R,2R)-FsDPEN, (1R,2R)-TripsMesityIDPEN, (1R,2R)-CsDPEN, (1R,2R)-MesityIDPEN, (1R,2R)-RsDPEN, and (1R,2R)-TsDiOMeDPEN; or is a catalyst containing Ru as central metal and at least one ligand selected from the (1R,2R) form of the compound of formula (II), wherein R 7 is SO 2 R 9 , where R 9 is C 1 -C 4 -alkyl or phenyl which optionally carry 1, 2, or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl, R 8 is —(CH 2 ) 3 -phenyl or —(CH 2 ) 4 -phenyl, where phenyl in the two last-mentioned radicals optionally carry 1, 2, or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, and C 1 -C 4 -alkoxy; and m and n are 0.

17 . The method according to claim 1 , where during the reaction a gas different from CO 2 is sparged through the reaction mixture; or where alternatively or additionally the reaction is carried out under reduced pressure.

18 . The method according claim 1 , where the reaction is carried out in the presence of an additive selected from the group consisting of diethyl phosphite, borate esters, and zinc salts; where the additive is used in an amount such that a molar ratio of the additive and the compound of formula 1 is in a range of from 1:10000 to 10:1.

19 . 2-sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of the formula (I) or an enatiomerically enriched form thereof

where the asterisk * shows the stereogenic center; or a tautomer thereof.

20 . The method according to claim 2 where M + is selected from the group consisting of Li + , Na + , K + , Cs + , NH 4 + , [NH 2 (C 2 H 5 ) 2 ] + , [NH(C 2 H 5 ) 3 ] + , [NH(CH 2 CH 2 CH 2 CH 3 ) 3 ] + , [NH(C 2 H 5 )(CH(CH 3 ) 2 ] + , [NH(CH 3 ) 2 (CH(CH 3 )] + , [NH 2 (C 2 H 5 )(C(CH 3 ) 3 ] + , [NH 2 (CH(CH 3 ) 2 )(C(CH 3 ) 3 ] + , [NH 2 (C 2 H 4 OCH 3 )(CH 3 )] + , [NH(cyclohexyl) 2 (CH 3 )] + , [NH(cyclohexyl)(CH 3 ) 2 ] + , protonated N,N,N′,N′-tetramethylethylenediamine, protonated N,N,N′,N′-tetramethylpropylene-1,3-diamine, protonated piperdine, protonated N-methylpiperidine, protonated 2,2,6,6-tetramethylpiperidine, protonated N-methyl-2,6,6-tetramethylpiperidine, protonated N-methyl-4-hydroxy-2,2,6,6-tetramethylpiperidine, protonated morpholine, and protonated N-methylmorpholine.

21 . The method according to claim 3 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.

22 . The method according to claim 10 where the chiral ligands are selected from the group consisting of chiral 1,2-diphenyl-ethylene-1,2-diamines, 1,2-cyclohexanediamines, and 1,2-bis(methylamino)cyclohexanes.

23 . The method according to claim 12 where the chiral transition metal catalyst is selected from catalysts containing Ru, Rh, or Ir as central metal and at least one chiral ligand selected from the group consisting of the (1R,2R) or (1S,2S) forms of DPEN, TSDPEN, CF 3 TSDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, FsDPEN, TripsMesityIDPEN, CsDPEN, MesityIDPEN, RsDPEN, TsDiOMeDPEN, and the compound of formula (II), wherein R 7 is SO 2 R 9 , where R 9 is C 1 -C 4 -alkyl or phenyl which optionally carry 1, 2, or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl, R 8 is —(CH 2 ) 3 -phenyl or —(CH 2 ) 4 -phenyl, where phenyl in the two last-mentioned radicals optionally carry 1, 2, or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, and C 1 -C 4 -alkoxy; and m and n are 0.

24 . The method according to claim 13 where the chiral transition metal catalyst is selected from catalysts containing Ru, Rh, or Ir as central metal and at least one ligand selected from the group consisting of the (1R,2R) or (1S,2S) forms of TsDPEN, CF 3 TsDPEN, MsDPEN, MeMsDPEN, MeTsDPEN, CsDPEN, MesityIDPEN, RsDPEN, and TsDiOMeDPEN; and from catalysts containing Ru as central metal and at least one ligand selected from the (1R,2R) or (1S,2S) forms of the compound of the formula (II), wherein R 7 is SO 2 R 9 , where R 9 is C 1 -C 4 -alkyl or phenyl which optionally carry 1, 2, or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl, R 8 is —(CH 2 ) 3 -phenyl or —(CH 2 ) 4 -phenyl; and m and n are 0.

25 . The method according to claim 15 where the chiral transition metal catalyst comprises as central metal Ru, Rh, or Ir, and comprises a chiral ligand selected from the group consisting of (1S,2S)-DPEN, (1S,2S)-TsDPEN, (1S,2S)-CF 3 TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-FsDPEN, (1S,2S)-TripsMesityIDPEN, (1S,2S)-CsDPEN, (1S,2S)-MesityIDPEN, (1S,2S)-RsDPEN, (1S,2S)-TsDiOMeDPEN, and the (1S,2S) form of the compound of formula (II), wherein R 7 is SO 2 R 9 , where R 9 is C 1 -C 4 -alkyl or phenyl which optionally carry 1, 2, or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl, R 8 is —(CH 2 ) 3 -phenyl or —(CH 2 ) 4 -phenyl, where phenyl in the two last-mentioned radicals optionally carry 1, 2, or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, and C 1 -C 4 -alkoxy; and m and n are 0.

26 . The method according to claim 16 where the chiral transition metal catalyst comprises as central metal Ru, Rh, or Ir, and comprises a chiral ligand selected from the group consisting of (1S,2S)-TsDPEN, (1S,2S)-CF 3 TsDPEN, (1S,2S)-MsDPEN, (1S,2S)-MeMsDPEN, (1S,2S)-MeTsDPEN, (1S,2S)-CsDPEN, (1S,2S)-MesityIDPEN, (1S,2S)-RsDPEN, and (1S,2S)-TsDiOMeDPEN; or is a catalyst containing Ru as central metal and at least one ligand selected from the (1S,2S) form of the compound of formula (II), wherein R 7 is SO 2 R 9 , where R 9 is C 1 -C 4 -alkyl or phenyl which optionally carry 1, 2, or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl, R 8 is —(CH 2 ) 3 -phenyl or —(CH 2 ) 4 -phenyl; and m and n are 0.