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EP-4313978-B1 - METHOD FOR PREPARING ENANTIOMERICALLY ENRICHED 2-[2-(2-CHLOROTHIAZOL-5-YL)-2-HYDROXY-ETHYL]SULFANYL-6-HYDROXY-3-METHYL-5-PHENYL-PYRIMIDIN-4-ONE BY HYDROGENATION OF THE 2-OXO DERIVATIVE IN THE PRESENCE OF A CHIRAL TRANSITION METAL CATALYST

EP4313978B1EP 4313978 B1EP4313978 B1EP 4313978B1EP-4313978-B1

Inventors

  • MCLAUGHLIN, Martin John
  • KORADIN, CHRISTOPHER
  • KADUSKAR, RAHUL
  • SHINDE, Harish
  • GOETZ, ROLAND

Dates

Publication Date
20260506
Application Date
20220325

Claims (15)

  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 the formula (I): where the asterisk * shows the 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 the formula 1 or a tautomer thereof with hydrogen in the presence of a chiral transition metal catalyst 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 the chiral transition metal catalyst is selected from group VIII metal catalysts, preferably from group 8 or 9 metal catalysts, more preferably from Ru, Rh and Ir catalysts and even more preferably from Rh and Ir catalysts.
  3. The method according to any of the preceding claims, where the chiral transition metal catalyst, calculated on the basis of the transition metal content, is used in an amount of from 0.01 to 10 mol%, preferably from 0.05 to 5 mol-%, more preferably from 0.1 to 5 mol-%, in particular from 1 to 5 mol-%, relative to 1 mol of the compound of the formula 1.
  4. The method according to any of the preceding claims, 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.
  5. The method according to any of the preceding claims, where the chiral transition metal catalyst comprises one or more chiral ligands coordinated to a transition metal, where the chiral ligands are chiral phosphine ligands comprising one or more phosphino groups, where in case that the chiral ligands comprise just one phosphino group, they comprise additionally at least one of a phosphine oxide group, an amino group or an imino group.
  6. The method according to claim 5, 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 the chiral forms of the ligands of formulae L.1 to L.15: where in L.1: R 1 and R 2 , independently of each other and independently of each occurrence, are selected from the group consisting of C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, phenyl and naphthyl, where phenyl and naphthyl may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl; in L.2: R 1 and R 2 , independently of each other and independently of each occurrence, are selected from the group consisting of C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl; in L.3: R 1 and R 2 , independently of each other and independently of each occurrence, are selected from the group consisting of C 3 -C 6 -cycloalkyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy; and R 3 and R 4 are methyl; in L.4: R 1 and R 2 , independently of each other and independently of each occurrence, are selected from the group consisting of C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl; in L.5: R 1 is phenyl or naphthyl, where phenyl and naphthyl may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl; and R 2 is C 1 -C 4 -alkyl; in L.6: R 1 is selected from the group consisting of C 3 -C 6 -cycloalkyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy; R 2 is phenyl; and R 3 and R 4 , independently of each other, are C 1 -C 4 -alkyl; in L.7: R 1 is phenyl; in L.8: R 1 and R 2 are phenyl in L.9: R 1 is C 3 -C 6 -cycloalkyl; R 2 is phenyl; and R 3 and R 4 , independently of each other, are C 1 -C 4 -alkyl; in L.10: R 1 and R 2 are phenyl; and R 3 and R 4 , independently of each other, are C 1 -C 4 -alkyl; in L.11: each R 1 is independently selected from the group consisting of C 1 -C 6 -alkyl, phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, amino, C 1 -C 4 -alkylamino and di-(C 1 -C 4 -alkyl)-amino; and a 5- or 6-membered heteroaromatic ring having 1, 2 or 3 heteroatoms selected from C, N and S are ring members; R 2a and R 2d are hydrogen; and R 2b and R 2c are C 1 -C 4 -alkoxy; or R 2a and R 2b form together a bridging group -CH=CH-CH=CH- or -O-CH 2 -O-; and R 2c and R 2d form together a bridging group -CH=CH-CH=CH- or -O-CH 2 -O-; in L.12: each R 1 is independently phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy; in L.13: each R 1a is independently C 1 -C 6 -alkyl; each R 1b is independently C 1 -C 6 -alkyl; where R 1a and R 1b bound on the same P atom are not identical; in L.14.1 and L.14.2: R 1 is phenyl; in L.15: each R 1 is independently phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy; each R 5 is independently H or methyl; and n is 0, 1 or 2.
  7. The method according to claim 6, where the chiral ligands are selected from the group consisting of the ligands of formulae L.1.1 to L.15.2: where R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined in claim 6.
  8. The method according to claim 7, where: in L.1.1, L.1.2, L.1.3 and L.1.4: the two radicals R 1 are identical and selected from the group consisting of C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, phenyl and naphthyl, where phenyl and naphthyl may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl; and the two radicals R 2 are identical and selected from the group consisting of C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, phenyl and naphthyl, where phenyl and naphthyl may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl; in L.2.1, L.2.2, L.2.3, L.2.4, L.2.5, L.2.6, L.2.7 and L.2.8: R 1 is selected from the group consisting of C 1 -C 6 -alkyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl; and the two radicals R 2 are identical and selected from the group consisting of C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl; in L.3.1, L.3.2, L.3.3 and L.3.4: the two radicals R 1 are identical and selected from the group consisting of C 3 -C 6 -cycloalkyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy; the two radicals R 2 are identical and selected from the group consisting of C 3 -C 6 -cycloalkyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy; and R 3 and R 4 are methyl; in L.4.1, L.4.2, L.4.3 and L.4.4: the two radicals R 1 are identical and selected from the group consisting of C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl; the two radicals R 2 are identical and selected from the group consisting of C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl; in L.5.1, L.5.2, L.5.3 and L.5.4: the two radicals R 1 are identical and selected from the group consisting of phenyl or naphthyl, where phenyl and naphthyl may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl; and R 2 is C 1 -C 4 -alkyl; in L.6.1, L.6.2, L.6.3, L.6.4, L.6.5, L.6.6, L.6.7 and L.6.8: the two radicals R 1 are identical and selected from the group consisting of C 3 -C 6 -cycloalkyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy; R 2 is phenyl; and R 3 and R 4 are identical and are C 1 -C 4 -alkyl; in L.7.1, L.7.2, L.7.3 and L.7.4: R 1 is phenyl; in L.8.1, L.8.2, L.8.3 and L.8.4 R 1 and R 2 are phenyl; in L.9.1: the two radicals R 1 are identical and are C 3 -C 6 -cycloalkyl; R 2 is phenyl; and R 3 and R 4 are identical and are C 1 -C 4 -alkyl; in L.10.1: R 1 and R 2 are phenyl; and R 3 and R 4 are identical and are C 1 -C 4 -alkyl; in L.11.1 and L.11.2: the four radicals R 1 are identical and selected from the group consisting of C 1 -C 6 -alkyl, phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, amino, C 1 -C 4 -alkylamino and di-(C 1 -C 4 -alkyl)-amino; and a 5- or 6-membered heteroaromatic ring having 1, 2 or 3 heteroatoms selected from O, N and S are ring members; R 2a and R 2d are hydrogen; and R 2b and R 2c are identical and are C 1 -C 4 -alkoxy; or R 2a and R 2b form together a bridging group -CH=CH-CH=CH-; and simultaneously R 2c and R 2d form together a bridging group -CH=CH-CH=CH-; or R 2a and R 2b form together a bridging group -O-CH 2 -O-; and simultaneously R 2c and R 2d form together a bridging group -O-CH 2 -O-; in L.12.1 and L.12.2: the four radicals R 1 are identical and are phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy; in L.13.1 and L.13.2: the two radicals R 1a are identical and are C 1 -C 6 -alkyl; the two radicals R 1b are identical and are C 1 -C 6 -alkyl; where R 1a and R 1b bound on the same P atom are not identical; in L.14.1 and L.14.2: R 1 is phenyl; in L.15: the four radicals R 1 are identical and are phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy; each R 5 is independently H or methyl; and n is 0, 1 or 2.
  9. The method according to any of the preceding claims, for preparing 2-[(2S)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]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 50% ee, preferably at least 55% ee, more preferably at least 60% ee, even more preferably at least 70% ee, in particular at least 80% ee, where a chiral transition metal catalyst is used which comprises a chiral ligand selected from following ligands: - L.1.1, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.1.1.1 phenyl tert-butyl L.1.1.2 cyclohexyl phenyl L.1.1.3 3,5-di-(trifluoromethyl)-phenyl cyclohexyl L.1.1.4* 4-(trifluoromethyl)-phenyl tert-butyl L.1.1.5 1-naphthyl tert-butyl *with Ir - L.1.2, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.1.2.1 1-naphthyl tert-butyl L.1.2.2 tert-butyl 2-methylphenyl L.1.2.3 phenyl tert-butyl L.1.2.4 cyclohexyl cyclohexyl L.1.2.5** 4-(trifluoromethyl)-phenyl tert-butyl ** with Rh - L.2.1, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.2.1.1 tert-butyl phenyl L.2.1.2 phenyl tert-butyl L.2.1.3 phenyl phenyl L.2.1.4 tert-butyl 3,5-dimethylphenyl L.2.1.5 tert-butyl tert-butyl L.2.1.6 tert-butyl cyclohexyl - L.2.2, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.2.2.1 tert-butyl phenyl - L.2.3, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.2.3.1 tert-butyl phenyl L.2.3.2 phenyl phenyl L.2.3.3 tert-butyl 3,5-dimethylphenyl L.2.3.4 tert-butyl tert-butyl L.2.3.5 tert-butyl cyclohexyl - L.2.4, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.2.4.1 phenyl tert-butyl - L.3.1, wherein R 3 and R 4 are methyl and R 1 and R 2 have the following meanings: No. R 1 R 2 L.3.1.1 phenyl phenyl L.3.1.2* cyclohexyl cyclohexyl * with Ir - L.3.2, wherein R 3 and R 4 are methyl and R 1 and R 2 have the following meanings: No. R 1 R 2 L.3.2.1** cyclohexyl cyclohexyl ** with Rh - L.3.4, wherein R 3 and R 4 are methyl and R 1 and R 2 have the following meanings: No. R 1 R 2 L.3.4.1 3,5-dimethyl-4-methoxyphenyl 3,5-dimethyl-4-methoxyphenyl - L.4.1, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.4.1.1 phenyl tert-butyl L.4.1.2 tert-butyl tert-butyl L.4.1.3 cyclohexyl 3,5-di-(trifluoromethyl)-phenyl - L.4.2, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.4.2.1 phenyl cyclohexyl - L.5.2, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.5.2.1 1-naphthyl isopropyl - L.6.1, wherein R 3 and R 4 are methyl and R 1 and R 2 have the following meanings: No. R 1 R 2 L.6.1.1 cyclohexyl phenyl L.6.1.2 3,5-dimethyl-4-methoxyphenyl phenyl - L.7.1, wherein R 1 is phenyl - L.8.1, wherein R 1 and R 2 are phenyl - L.9.1, wherein R 1 is cyclohexyl, R 2 is phenyl and R 3 and R 4 are methyl - L.10.1, wherein R 1 is phenyl, R 2 is phenyl and R 3 and R 4 are methyl - L.11.1, wherein R 2a , R 2b , R 2c , R 2d and R 1 have the following meanings: No. R 2a R 2b R 2c R 2d R 1 L.11.1.1 H OCH 3 OCH 3 H 3,5-di-(tert-butyl)-4-methoxyphenyl L.11.1.2* H OCH 3 OCH 3 H 2-furyl * with Ru - L.11.2, wherein R 2a , R 2b , R 2c , R 2d and R 1 have the following meanings: No. R 2a R 2b R 2c R 2d R 1 L.11.2.1 H OCH 3 OCH 3 H isopropyl L.11.2.2 H OCH 3 OCH 3 H 3,5-diisopropyl-4-(dimethylamino)-phenyl L.11.2.3** H OCH 3 OCH 3 H 2-furyl L.11.2.4 -O-CH 2 -O- -O-CH 2 -O- xylyl L.11.2.5 -CH=CH- -CH=CH- phenyl CH=CH- CH=CH- ** with Ir - L.12.2, wherein R 1 is 3,5-dimethyl-4-methoxyphenyl - L.13.1, wherein R 1a is tert-butyl and R 1b is methyl - L.14.1, wherein R 1 is phenyl - L.15.2, wherein R 1 is phenyl, R 5 is methyl and n is 1.
  10. The method according to claim 9, where the chiral ligand is selected from following ligands: - L.2.1, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.2.1.2 phenyl tert-butyl - L.3.1, wherein R 3 and R 4 are methyl and R 1 and R 2 have the following meanings: No. R 1 R 2 L.3.1.1 phenyl phenyl - L.4.1, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.4.1.2 tert-butyl tert-butyl - L.10.1, wherein R 1 is phenyl, R 2 is phenyl and R 3 and R 4 are methyl - L.11.1, wherein R 2a , R 2b , R 2c , R 2d and R 1 have the following meanings: No. R 2a R 2b R 2c R 2d R 1 L.11.1.1 H OCH 3 OCH 3 H 3,5-di-(tert-butyl)-4-methoxyphenyl
  11. The method according to any of claims 1 to 8, for preparing 2-[(2R)-2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]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 50% ee, preferably at least 55% ee, more preferably at least 60% ee, even more preferably at least 70% ee, in particular at least 80% ee, where a chiral transition metal catalyst is used which comprises a chiral ligand selected from following ligands: - L.1.1, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.1.1.5 1-naphthyl tert-butyl L.1.1.6 tert-butyl 2-methylphenyl L.1.1.1 phenyl tert-butyl L.1.1.7 cyclohexyl cyclohexyl L.1.1.4* 4-(trifluoromethyl)-phenyl tert-butyl * with Rh - L.1.2, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.1.2.3 phenyl tert-butyl L.1.2.6 cyclohexyl phenyl L.1.2.7 3,5-di-(trifluoromethyl)-phenyl cyclohexyl L.1.2.5** 4-(trifluoromethyl)-phenyl tert-butyl L.1.2.1 1-naphthyl tert-butyl **with Ir - L.2.1, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.2.1.1 tert-butyl phenyl - L.2.2, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.2.2.1 tert-butyl phenyl L.2.2.2 phenyl tert-butyl L.2.2.3 phenyl phenyl L.2.2.4 tert-butyl 3,5-dimethylphenyl L.2.2.5 tert-butyl tert-butyl L.2.2.6 tert-butyl cyclohexyl - L.2.3, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.2.3.6 phenyl tert-butyl L.2.3.1 tert-butyl phenyl - L.2.4, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.2.4.2 tert-butyl phenyl L.2.4.3 phenyl phenyl L.2.4.4 tert-butyl 3,5-dimethylphenyl L.2.4.5 tert-butyl tert-butyl L.2.4.6 tert-butyl cyclohexyl - L.3.1, wherein R 3 and R 4 are methyl and R 1 and R 2 have the following meanings: No. R 1 R 2 L.3.1.2* cyclohexyl cyclohexyl * with Rh - L.3.2, wherein R 3 and R 4 are methyl and R 1 and R 2 have the following meanings: No. R 1 R 2 L.3.2.2 phenyl phenyl L.3.2.1** cyclohexyl cyclohexyl ** with Ir - L.3.3, wherein R 3 and R 4 are methyl and R 1 and R 2 have the following meanings: No. R 1 R 2 L.3.3.1 3,5-dimethyl-4-methoxyphenyl 3,5-dimethyl-4-methoxyphenyl - L.4.1, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.4.1.4 phenyl cyclohexyl - L.4.2, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.4.2.2 phenyl tert-butyl L.4.2.3 tert-butyl tert-butyl L.4.2.4 cyclohexyl 3,5-di-(trifluoromethyl)-phenyl - L.5.1, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.5.1.1 1-naphthyl isopropyl - L.6.2, wherein R 3 and R 4 are methyl and R 1 and R 2 have the following meanings: No. R 1 R 2 L.6.2.1 cyclohexyl phenyl L.6.2.2 3,5-dimethyl-4-methoxyphenyl phenyl - L.7.2, wherein R 1 is phenyl - L.8.2, wherein R 1 and R 2 are phenyl - L.11.1, wherein R 2a , R 2b , R 2c , R 2d and R 1 have the following meanings: No. R 2a R 2b R 2c R 2d R 1 L.11.1.3 H OCH 3 OCH 3 H isopropyl L.11.1.4 H OCH 3 OCH 3 H 3,5-diisopropyl-4-(dimethylamino)-phenyl L.11.1.2* H OCH 3 OCH 3 H 2-furyl L.11.1.5 -O-CH 2 -O- -O-CH 2 -O- xylyl L.11.1.6 -CH=CH-CH=CH- -CH=CH-CH=CH- phenyl * with Ir - L.11.2, wherein R 2a , R 2b , R 2c , R 2d and R 1 have the following meanings: No. R 2a R 2b R 2c R 2d R 1 L.11.2.6 H OCH 3 OCH 3 H 3,5-di-(tert-butyl)-4-methoxyphenyl L.11.2.3** H OCH 3 OCH 3 H 2-furyl ** with Ru - L.12.1, wherein R 1 is 3,5-dimethyl-4-methoxyphenyl - L.13.2, wherein R 1a is tert-butyl and R 1b is methyl - L.14.2, wherein R 1 is phenyl - L.15.1, wherein R 1 is phenyl, R 5 is methyl and n is 1 - L.15.2, wherein R 1 is phenyl, R 5 is methyl and n is 1; where in particular the chiral ligand is selected from: - L.2.3, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.2.3.6 phenyl tert-butyl - L.3.2, wherein R 3 and R 4 are methyl and R 1 and R 2 have the following meanings: No. R 1 R 2 L.3.2.2 phenyl phenyl - L.3.3, wherein R 3 and R 4 are methyl and R 1 and R 2 have the following meanings: No. R 1 R 2 L.3.3.1 3,5-dimethyl-4-methoxyphenyl 3,5-dimethyl-4-methoxyphenyl - L.4.2, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.4.2.4 cyclohexyl 3,5-di-(trifluoromethyl)-phenyl - L.5.1, wherein R 1 and R 2 have the following meanings: No. R 1 R 2 L.5.1.1 1-naphthyl isopropyl - L.11.1, wherein R 2a , R 2b , R 2c , R 2d and R 1 have the following meanings: No. R 2a R2b R 2c R 2d R 1 L.11.1.3 H OCH 3 OCH 3 H isopropyl - L.11.2, wherein R 2a , R 2b , R 2c , R 2d and R 1 have the following meanings: No. R 2a R 2b R 2c R 2d R 1 L.11.2.3** H OCH 3 OCH 3 H 2-furyl ** with Ru
  12. The method according to any of the preceding claims, where the reaction is carried out at a hydrogen pressure of from 1 to 100 bar, preferably from 2 to 80 bar, in particular from 10 to 60 bar, specifically from 40 to 60 bar; and/or where the reaction is carried out at a temperature of from -5 to 120°C; preferably from 10 to 80°C; in particular from 30 to 60°C.
  13. The method according to any of the preceding claims, where the reaction is carried out in the presence of a solvent, where the solvent is preferably selected from the group consisting of polar aprotic solvents, polar protic solvents, C 1 -C 4 -alkyl acetates, chlorinated alkanes, open-chained ethers, aromatic solvents and mixtures thereof; where the solvent is more preferably selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,3-dioxane, 1,4-dioxane, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, C 1 -C 4 -alkanols, fluorinated C 1 -C 4 -alkanols, C 1 -C 4 -alkyl acetates, chlorinated C 1 -C 2 -alkanes, di-(C 1 -C 4 -alkyl)-ethers, benzene, toluene, trifluorotoluene, the xylenes, chlorobenzene, dichlorobenzene, anisole and mixtures of the aforementioned solvents; in particular from 2-methyltetrahydrofuran, 1,4-dioxane, DMSO, DMF, C 1 -C 3 -alkanols, 2,2,2-trifluoroethanol, ethyl acetate, chlorinated C 1 -C 2 -alkanes, di-(C 1 -C 4 -alkyl)-ethers, toluene, anisole and mixtures of the aforementioned solvents; and specifically from 2-methyltetrahydrofuran, mixtures of 2-methyltetrahydrofuran and a C 1 -C 3 -alkanol; mixtures of 1,4-dioxane and a C 1 -C 3 -alkanol, 2,2,2-trifluoroethanol or DMSO; ethyl acetate, mixtures of ethyl acetate and a C 1 -C 3 -alkanol; mixtures of a di-(C 1 -C 4 -alkyl)-ether and a C 1 -C 3 -alkanol; and mixtures of anisole a C 1 -C 3 -alkanol.
  14. The method according to any of the preceding claims, where the reaction is carried out in the presence of an additive selected from the group consisting of organic bases, organic or inorganic Brønsted or Lewis acids, borate esters, zinc halides and zinc sulfonates; preferably in the presence of C 1 -C 6 -trialkylamines, BF 3 and adducts thereof, borate esters, zinc halides and zinc sulfonates; in particular in the presence of BF 3 , of adducts thereof, or of a borate ester; specifically in the presence of a BF 3 adduct or a tri-(C 1 -C 4 -alkyl)-borate ester.
  15. The method according to claim 14, where the additive is used in such an amount that the molar ratio of additive and the compound 1 is in the range of from 1:100 to 10:1, preferably from 1:10 to 5:1, specifically from 1:10 to 1:1.

Description

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. Technical background 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. The methods thus far known for the preparation of these pyriminidium compounds are cumbersome and not yet satisfactory. 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: RA is 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, R1 is a (cyclo)aliphatic group and R2 is 5- or 6-membered carbo- or heterocyclic ring. In WO 2018/177970 the amine VII is obtained via another reaction path from the corresponding sulfinylimine. 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 heteroarylmethyl 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: Het is optionally substituted pyridin-3-yl, thiazol-5-yl or pyrimidin-5-yl, W and LG are leaving groups, M2 is Li, Na, K, Al, Ba, Cs, Ca or Mg, RAC is alkylcarbonyl, X1 is halogen, R1 is a (cyclo)aliphatic group and R2 is 5- or 6-membered carbo- or heterocyclic ring. 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. Summary of the invention It was the object of the present invention to provide an economic process 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 1 or a tautomer thereofwith hydrogen in the presence of a chiral transition metal catalyst;to obtain an enantiomerically enriched form of the pyrimidinone of the formula (I) or of a tautomer thereof. Detailed description of the invention Definitions "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) 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 a single 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 member