WO2022200344A1 - Verfahren zur herstellung von enantiomeren-angereicherten (2z)-2-(phenylimino)-1,3-thiazolidin-4- on-sulfoxid-derivaten - Google Patents
Verfahren zur herstellung von enantiomeren-angereicherten (2z)-2-(phenylimino)-1,3-thiazolidin-4- on-sulfoxid-derivaten Download PDFInfo
- Publication number
- WO2022200344A1 WO2022200344A1 PCT/EP2022/057479 EP2022057479W WO2022200344A1 WO 2022200344 A1 WO2022200344 A1 WO 2022200344A1 EP 2022057479 W EP2022057479 W EP 2022057479W WO 2022200344 A1 WO2022200344 A1 WO 2022200344A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- hydrogen
- alkoxy
- cyano
- formula
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 120
- -1 2-(phenylimino)-1,3-thiazolidin-4-one sulfoxide Chemical class 0.000 claims description 75
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 72
- 238000000034 method Methods 0.000 claims description 61
- 229910052739 hydrogen Inorganic materials 0.000 claims description 50
- 239000001257 hydrogen Substances 0.000 claims description 50
- 125000003545 alkoxy group Chemical group 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 41
- 239000003446 ligand Substances 0.000 claims description 36
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 32
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 26
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 25
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 24
- 229910052731 fluorine Inorganic materials 0.000 claims description 24
- 239000011737 fluorine Substances 0.000 claims description 24
- 125000001188 haloalkyl group Chemical group 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 20
- 229910052801 chlorine Inorganic materials 0.000 claims description 20
- 239000000460 chlorine Substances 0.000 claims description 20
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 19
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 19
- 229910052723 transition metal Inorganic materials 0.000 claims description 18
- 150000003624 transition metals Chemical class 0.000 claims description 18
- 239000000654 additive Substances 0.000 claims description 17
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 16
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 15
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 14
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 14
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 14
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 12
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 10
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 10
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 10
- 229910052744 lithium Inorganic materials 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 9
- 230000000996 additive effect Effects 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 239000007800 oxidant agent Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 229910052700 potassium Inorganic materials 0.000 claims description 8
- 239000011591 potassium Substances 0.000 claims description 8
- 239000010936 titanium Substances 0.000 claims description 8
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 7
- 229910052742 iron Inorganic materials 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 229940078552 o-xylene Drugs 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 229910052719 titanium Inorganic materials 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 5
- 150000003608 titanium Chemical class 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 2
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims description 2
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 claims description 2
- 150000002505 iron Chemical class 0.000 claims description 2
- 229910052748 manganese Inorganic materials 0.000 claims description 2
- 239000011572 manganese Substances 0.000 claims description 2
- 229910052750 molybdenum Inorganic materials 0.000 claims description 2
- 239000011733 molybdenum Substances 0.000 claims description 2
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 2
- 150000002978 peroxides Chemical class 0.000 claims description 2
- 229910052726 zirconium Inorganic materials 0.000 claims description 2
- LZKLAOYSENRNKR-LNTINUHCSA-N iron;(z)-4-oxoniumylidenepent-2-en-2-olate Chemical compound [Fe].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O LZKLAOYSENRNKR-LNTINUHCSA-N 0.000 claims 1
- 150000002739 metals Chemical class 0.000 claims 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 abstract description 8
- 238000006243 chemical reaction Methods 0.000 description 27
- 238000003786 synthesis reaction Methods 0.000 description 20
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 17
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 16
- 230000003647 oxidation Effects 0.000 description 15
- 238000007254 oxidation reaction Methods 0.000 description 15
- AQBLLJNPHDIAPN-LNTINUHCSA-K iron(3+);(z)-4-oxopent-2-en-2-olate Chemical compound [Fe+3].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O AQBLLJNPHDIAPN-LNTINUHCSA-K 0.000 description 12
- 239000012071 phase Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- CQLPADBURXSAHN-VKGKTOGESA-N CC1=C(C=C(\N=C2/SCC(=O)N2CC(F)(F)F)C(F)=C1)[S@](=O)CC(F)(F)F Chemical compound CC1=C(C=C(\N=C2/SCC(=O)N2CC(F)(F)F)C(F)=C1)[S@](=O)CC(F)(F)F CQLPADBURXSAHN-VKGKTOGESA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 150000003462 sulfoxides Chemical class 0.000 description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 8
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 8
- ITQXLAAWOXWMOR-UUYOSTAYSA-N CC1=C(SCC(F)(F)F)C=C(\N=C2/SCC(=O)N2CC(F)(F)F)C(F)=C1 Chemical compound CC1=C(SCC(F)(F)F)C=C(\N=C2/SCC(=O)N2CC(F)(F)F)C(F)=C1 ITQXLAAWOXWMOR-UUYOSTAYSA-N 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- YDIYEOMDOWUDTJ-UHFFFAOYSA-N 4-(dimethylamino)benzoic acid Chemical compound CN(C)C1=CC=C(C(O)=O)C=C1 YDIYEOMDOWUDTJ-UHFFFAOYSA-N 0.000 description 5
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 5
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical class [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 5
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 5
- 235000010234 sodium benzoate Nutrition 0.000 description 5
- 239000004299 sodium benzoate Substances 0.000 description 5
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 5
- 239000008096 xylene Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 230000007812 deficiency Effects 0.000 description 4
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- YSAVZVORKRDODB-UHFFFAOYSA-N Diethyl tartrate Chemical compound CCOC(=O)C(O)C(O)C(=O)OCC YSAVZVORKRDODB-UHFFFAOYSA-N 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002262 Schiff base Substances 0.000 description 2
- 150000004753 Schiff bases Chemical class 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000005595 acetylacetonate group Chemical group 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 150000001559 benzoic acids Chemical class 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 238000003821 enantio-separation Methods 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 150000001451 organic peroxides Chemical class 0.000 description 2
- PGMYKACGEOXYJE-UHFFFAOYSA-N pentyl acetate Chemical compound CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- PSDQQCXQSWHCRN-UHFFFAOYSA-N vanadium(4+) Chemical compound [V+4] PSDQQCXQSWHCRN-UHFFFAOYSA-N 0.000 description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 1
- FSJSYDFBTIVUFD-SUKNRPLKSA-N (z)-4-hydroxypent-3-en-2-one;oxovanadium Chemical compound [V]=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FSJSYDFBTIVUFD-SUKNRPLKSA-N 0.000 description 1
- BOSAWIQFTJIYIS-UHFFFAOYSA-N 1,1,1-trichloro-2,2,2-trifluoroethane Chemical compound FC(F)(F)C(Cl)(Cl)Cl BOSAWIQFTJIYIS-UHFFFAOYSA-N 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- IDZVASMEIALXSV-UHFFFAOYSA-N 1,1,1-trifluoro-2-(2,2,2-trifluoroethylsulfinyl)ethane Chemical class FC(F)(F)CS(=O)CC(F)(F)F IDZVASMEIALXSV-UHFFFAOYSA-N 0.000 description 1
- SEQRDAAUNCRFIT-UHFFFAOYSA-N 1,1-dichlorobutane Chemical compound CCCC(Cl)Cl SEQRDAAUNCRFIT-UHFFFAOYSA-N 0.000 description 1
- 125000001607 1,2,3-triazol-1-yl group Chemical group [*]N1N=NC([H])=C1[H] 0.000 description 1
- RELMFMZEBKVZJC-UHFFFAOYSA-N 1,2,3-trichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1Cl RELMFMZEBKVZJC-UHFFFAOYSA-N 0.000 description 1
- 125000001766 1,2,4-oxadiazol-3-yl group Chemical group [H]C1=NC(*)=NO1 0.000 description 1
- 125000004505 1,2,4-oxadiazol-5-yl group Chemical group O1N=CN=C1* 0.000 description 1
- 125000004515 1,2,4-thiadiazol-3-yl group Chemical group S1N=C(N=C1)* 0.000 description 1
- 125000004516 1,2,4-thiadiazol-5-yl group Chemical group S1N=CN=C1* 0.000 description 1
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 1
- 125000001305 1,2,4-triazol-3-yl group Chemical group [H]N1N=C([*])N=C1[H] 0.000 description 1
- KNKRKFALVUDBJE-UHFFFAOYSA-N 1,2-dichloropropane Chemical compound CC(Cl)CCl KNKRKFALVUDBJE-UHFFFAOYSA-N 0.000 description 1
- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 description 1
- 125000004509 1,3,4-oxadiazol-2-yl group Chemical group O1C(=NN=C1)* 0.000 description 1
- 125000004521 1,3,4-thiadiazol-2-yl group Chemical group S1C(=NN=C1)* 0.000 description 1
- 125000004317 1,3,5-triazin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=N1 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- FFFIRKXTFQCCKJ-UHFFFAOYSA-N 2,4,6-trimethylbenzoic acid Chemical compound CC1=CC(C)=C(C(O)=O)C(C)=C1 FFFIRKXTFQCCKJ-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- CDVAIHNNWWJFJW-UHFFFAOYSA-N 3,5-diethoxycarbonyl-1,4-dihydrocollidine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C CDVAIHNNWWJFJW-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- WVBNUUNXQNMMOB-MTTUFYGSSA-N CC(C)(C)[C@H](CO)\[NH+]=C\c1cc(I)cc(I)c1[O-] Chemical compound CC(C)(C)[C@H](CO)\[NH+]=C\c1cc(I)cc(I)c1[O-] WVBNUUNXQNMMOB-MTTUFYGSSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- UAWABSHMGXMCRK-UHFFFAOYSA-L Kagan reagent Substances I[Sm]I UAWABSHMGXMCRK-UHFFFAOYSA-L 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 102000008109 Mixed Function Oxygenases Human genes 0.000 description 1
- 108010074633 Mixed Function Oxygenases Proteins 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical group ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 description 1
- 108700020962 Peroxidase Proteins 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 238000006202 Sharpless epoxidation reaction Methods 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 0.000 description 1
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VHILIAIEEYLJNA-UHFFFAOYSA-N methyl p-tolyl sulfide Chemical compound CSC1=CC=C(C)C=C1 VHILIAIEEYLJNA-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- QULYNCCPRWKEMF-UHFFFAOYSA-N parachlorobenzotrifluoride Chemical compound FC(F)(F)C1=CC=C(Cl)C=C1 QULYNCCPRWKEMF-UHFFFAOYSA-N 0.000 description 1
- BNIXVQGCZULYKV-UHFFFAOYSA-N pentachloroethane Chemical compound ClC(Cl)C(Cl)(Cl)Cl BNIXVQGCZULYKV-UHFFFAOYSA-N 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000003579 shift reagent Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 229950011008 tetrachloroethylene Drugs 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/54—Nitrogen and either oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/04—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing carboxylic acids or their salts
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2217—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/70—Oxidation reactions, e.g. epoxidation, (di)hydroxylation, dehydrogenation and analogues
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/40—Complexes comprising metals of Group IV (IVA or IVB) as the central metal
- B01J2531/46—Titanium
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/84—Metals of the iron group
- B01J2531/842—Iron
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the present invention relates to a catalytic process for preparing 2-(phenylimino)-1,3-thiazolidin-4-one sulfoxide derivatives in an enantiomerically pure form or in an enantiomerically enriched form.
- Chiral sulfoxides and corresponding derivatives are of great importance in the pharmaceutical and agrochemical industries.
- the preparation of enantiomerically pure chiral sulfoxides not only avoids waste in the manufacturing process, but also avoids potentially harmful side effects that can result from the undesired enantiomer (Nugent et al., Science 1993, 259, 479; Noyori et al, CHEMTECH 1992, 22, 360) .
- a frequently used method for the enantioselective oxidation of thioethers is the method of the well-known Sharpless epoxidation with chiral titanium complexes modified by Kagan (/. Am. Chem. Soc. 1984, 106, 8188-8193).
- the chiral titanium complex consisting of ThO'Pi E and (+)- or (-)-diethyl tartrate (DET) is "deactivated" with one equivalent of water and catalyzes the enantioselective sulfide oxidation of aryl alkyl sulfides.
- good results have only been obtained with the Kagan reagent with high proportions of DET (e.g.
- Pasini et al. were able to oxidize phenylmethyl sulfide with small amounts of chiral oxotitan(IV) complexes and hydrogen peroxide, but with poor enantiomeric excesses of ee ⁇ 20% (Gaz. Chim. Ital. 1986, 116, 35-40). Furthermore, titanium-catalyzed processes result in very complex work-up, which is very disadvantageous for an economical process on an industrial scale.
- Another method is based on vanadium(IV) or iron(III) complexes as efficient catalysts for the sulfide oxidation.
- the chiral catalysts are prepared in situ from VO(acac)2 ( Synlett 1998, 12, 1327-1328; Euro. J. Chem. 2009, 2607-2610) or Fe(acac)3 ( Angew . Chem. Int. Ed. 2003 , 42, 5487-5489; Angew Chem Int Ed 2004, 43, 4225-4228) as a precursor together with a Schiff base.
- this method is limited to simple and non-fluorinated aryl alkyl thioethers such as p-tolyl methyl sulfide.
- the subject matter of the present invention is therefore a process for preparing 2-(phenylimino)-1,3-thiazolidin-4-one sulfoxide derivatives of the formula (I) in enantiomerically pure or enantiomerically enriched form in which
- Y 1 and Y 2 are independently fluorine, chlorine or hydrogen, R 1 and R 2 are independently hydrogen, (Ci-Ci 2 ) alkyl, (Ci-Ci 2 ) haloalkyl, cyano, halogen or nitro, and
- R 3 is hydrogen or optionally substituted CYCio-aryl, (Ci-Ci 2 ) alkyl or (Ci-Ci 2 ) haloalkyl, where the substituents are selected from halogen, (Ci-C 6 ) alkyl, (C 3 - Cio) Cycloalkyl, cyano, nitro, hydroxy, (Ci-C 6 ) alkoxy, (Ci-C 6 ) haloalkyl and (Ci-C 6 ) haloalkoxy, in particular from fluorine, chlorine, (C1-C3) alkyl, (C 3 -C 6 ) cycloalkyl, cyclopropyl, cyano, (Ci-C 3 )alkoxy, (Ci-C 3 )haloalkyl and (Ci-C 3 )haloalkoxy, which is characterized in that a sulfide of the formula (II): in which Y 1 , Y 2
- the compounds of formulas (I) and (II) can exist as E or Z isomers or as a mixture of these isomers. This is illustrated by the crossed double bond in formulas (I) and (II).
- the E isomer is present in each case.
- the Z isomer is present in each case.
- Y 1 and Y 2 independently represent fluorine, chlorine or hydrogen
- R 1 and R 2 are independently fluorine, chlorine, (Ci-C 3 ) alkyl or hydrogen, and
- R 3 is hydrogen or optionally substituted phenyl, (Ci-C ö jalkyl or (Ci C6) haloalkyl, where the substituents are selected from halogen, (Ci-C ö jalkyl, (C 3 -Cio) cycloalkyl, cyano, nitro, hydroxy , (Ci-C6) alkoxy, (Ci-C6) haloalkyl and (Ci-C6) haloalkoxy, in particular from fluorine, chlorine, (Ci-C 3 ) alkyl, (C 3 -Ce) cycloalkyl, cyclopropyl, cyano, (Ci -C 3 )alkoxy, (Ci-C 3 )haloalkyl and (Ci-C 3 )haloalkoxy.
- Y 1 and Y 2 independently represent fluorine or hydrogen
- R 1 and R 2 independently represent fluorine, chlorine, hydrogen or methyl
- R 3 is hydrogen, (Ci-C ö jalkyl or (Ci C6) haloalkyl.
- Y 1 and Y 2 are very particularly preferably fluorine
- R 1 and R 2 independently represent fluorine or methyl
- R 3 is (Ci C6)haloalkyl.
- R1 is methyl
- R 2 is fluoro
- R 3 is CH2CF3.
- the chiral (2-(phenylimino)-1,3-thiazolidin-4-one sulfoxide derivatives of the formula (I) can be obtained with the process according to the invention with good yields and in high chemical and optical purity, and consequently high enantiomeric excesses ( preferably expressed as an ee value).Furthermore, the process according to the invention allows the use of industrial-scale solvents.Another advantage is that the process according to the invention enables the desired target compounds to be obtained without the need for complex purification methods such as chiral chromatography.
- compounds of the formula (I) are formed in the process according to the invention in an enantiomeric ratio of 50.5:49.5 to 100:0 (R):(S)-enantiomer or (S):(R)-enantiomer .
- the (R)-enantiomer of the compound of the formula (I) is preferred.
- the enantiomeric purity can be increased by various methods.
- Such methods include in particular the preferential crystallization from an organic solvent or a mixture of organic solvents with water or a mixture of organic solvents.
- the process according to the invention can be explained using the following scheme (I):
- halogens includes such elements selected from the group consisting of fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred and fluorine and chlorine being particularly preferred are preferably used.
- Optionally substituted groups can be substituted once or several times, where in the case of multiple substitutions the substituents can be identical or different.
- the substituents are selected from halogen, (CVGjalkyl, (C3-Cio)cycloalkyl, cyano, nitro, hydroxy, (CVOjalkoxy, (C 1 -G >) haloalkyl and (Ci-Ojhaloalkoxy, in particular from Fluorine, chlorine, (Ci-C3)alkyl, (C3-C6)cycloalkyl, cyclopropyl, cyano, (Ci-C3)alkoxy, (Ci-C3)haloalkyl and (Ci-C3)haloalkoxy.
- Alkyl groups substituted with one or more halogen atoms are selected, for example, from trifluoromethyl (CF 3 ), difluoromethyl (CHF 2 ), CF 3 CH 2 , CICH 2 , CF 3 CCI 2 .
- alkyl groups are linear, branched or cyclic saturated hydrocarbon groups.
- Ci-Ci2-alkyl includes the largest range defined herein for an alkyl group. Specifically, this definition includes, for example, the meanings methyl, ethyl, n-, iso-propyl, n-, iso-, sec- and t-butyl, n-pentyl, n-hexyl, 1,3-dimethylbutyl, 3,3- dimethylbutyl, n-heptyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl.
- aryl groups in connection with the present invention are aromatic hydrocarbon groups which can have one, two or more heteroatoms (selected from O, N, P and S).
- this definition includes, for example, the meanings cyclopentadienyl, phenyl, cycloheptatrienyl, cyclooctatetraenyl, naphthyl and anthracenyl; 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3- pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, 1,2,4-oxadiazol- 3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,
- alkylaryl groups are aryl groups which are substituted by alkyl groups and have an alkylene chain and one or more heteroatoms (selected from O, N, P and S) in the aryl skeleton.
- enantiomerically enriched is understood to mean the presence of a mixture of enantiomers of such a compound in which a certain enantiomer of this compound is present in a higher amount compared to the other enantiomer of this compound.
- enantiomerically enriched is understood to mean the presence of a mixture of enantiomers of such a compound in which a certain enantiomer of this compound is present in a higher amount compared to the other enantiomer of this compound.
- the proportion of one enantiomer in an enantiomerically enriched mixture is more than 50% and more preferably more than 60%, 65%, 70%, 75, 80%, 85%, 90%, 92.5%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7% and 99 .75%, in each case based on the total amount of both enantiomers of the compound.
- the presence of more than 99% of an enantiomer in an enantiomer mixture is also referred to as enantiomerically pure.
- the enantiomeric excess can be between 0% ee and 100% ee.
- Enantiomeric excess is an indirect measure of the enantiomeric purity of a compound and gives the proportion of a pure enantiomer in a mixture, the remainder of which is the racemate of the compound.
- the chiral catalyst of the process according to the invention is a chiral metal-ligand complex.
- This chiral metal-ligand complex is made from a chiral ligand and a transition metal or, preferably, a transition metal derivative.
- the transition metal derivative is preferably a molybdenum, zirconium, iron, manganese and titanium derivative and particularly preferably an iron derivative. These derivatives are very particularly preferred in the form of transition metal (II) or (III) halides, transition metal (II) or (III) carboxylates or transition metal (II) or (III) acetylacetonates deployed.
- the transition metal derivative is more preferably an iron or titanium derivative, in particular titanium and iron halides, carboxylates and acetylacetonates, iron(II) and iron(III) acetylacetonate being very particularly preferred.
- the chiral ligand is a compound capable of forming a chiral metal-ligand complex with the transition metal derivative.
- Such ligands are preferably selected from compounds having at least two heteroatoms suitable for complexing on the metal (for example O, N, P, S).
- Preferred chiral ligands are those of formula (III): where in formula (III)
- R 4 and R 5 are independently hydrogen, (Ci-C 6 ) alkyl, (Ci-C 6 ) haloalkyl, (Ci-C 6 ) alkylphenyl, phenyl, halogen, cyano, nitro, cyano (Ci-C 6 ) alkyl , Hydroxy (Ci-C 6 ) alkyl, (Ci-C 6 ) alkoxycarbonyl (Ci-C 6 ) alkyl, (Ci-C 6 ) alkoxy, (Ci-C 6 ) haloalkoxy or (Ci-C 6 ) alkoxy (Ci -C 6 )alkyl,
- R 6 is (Ci-C 6 )alkyl, (Ci-C 6 )alkyl substituted by halogen, cyano, nitro, amino, hydroxy or phenyl, carboxyl, carbonyl(Ci-C 6 ) alkyl, (Ci-C 6 )alkoxycarbonyl (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy(Ci-C 6 )alkyl, (Ci-C 6 )alkoxy or di(Ci-C 6 )alkoxy(Ci-C 6 )alkyl, R 7 represents hydrogen, (Ci-C 6 )alkyl, (Ci-C 6 )alkylphenyl, aryl or aryl(Ci-C 6 )alkyl, and chiral carbon atoms are marked with *.
- R 4 and R 5 are independently hydrogen, (Ci-C4) alkyl, (Ci-C4) alkylphenyl, phenyl, halogen, cyano, nitro, cyano (Ci-C4) alkyl, hydroxy (Ci-C4) alkyl, (Ci -C4) alkoxycarbonyl (Ci-C4) alkyl or (Ci- C 4 ) alkoxy (Ci-C 4 ) alkyl,
- R 6 is (Ci-C3)alkyl, (Ci-C3)alkyl substituted by halogen, cyano, nitro, amino, hydroxy or phenyl, carboxyl, carbonyl(Ci-C3)alkyl, (Ci-C3)alkoxycarbonyl(Ci-C3 )alkyl, (Ci-C3)alkoxy(Ci-C3)alkyl, (Ci-C3)alkoxy or di(Ci-C3)alkoxy(Ci-C3)alkyl, and
- R 7 is hydrogen, (Ci-C4)alkyl, (Ci-C4)alkylphenyl, aryl or aryl(Ci-C4)alkyl. Standing is particularly preferred
- R 4 and R 5 are each independently hydrogen, (Ci-C4)alkyl, phenyl, halogen, cyano, nitro, hydroxy(Ci-C4)alkyl, (Ci-C4)alkoxycarbonyl(Ci-C4)alkyl or (Ci-C4 )alkoxy(Ci-C4)alkyl,
- R 6 is halogen, cyano, nitro, amino, hydroxy or phenyl-substituted (Ci-C3)alkyl or carboxyl, and R 7 for terf. -butyl, ao-propyl, benzyl or phenyl.
- R 4 and R 5 independently represent hydrogen, chlorine, bromine, iodine or tert-butyl
- R 6 is hydroxy-substituted Ci-alkyl
- R 7 is tert. -butyl or / ' v - propyl.
- R 4 and R 5 are each independently hydrogen or chlorine, R 6 is hydroxy-substituted Ci-alkyl, and R 7 is tert. -butyl.
- the chiral ligands of the formula (III) are used as enantiomerically enriched compounds.
- More preferred chiral ligands are those of the formula (purple):
- R 4 and R 5 are independently hydrogen, (Ci-C 6 )alkyl, (Ci-C 6 )alkylphenyl, phenyl, halogen, cyano, nitro, cyano(Ci-C 6 )alkyl, hydroxy(Ci-C 6 ) alkyl, (Ci-C 6 )alkoxycarbonyl(Ci-C 6 )aIkyI or (Ci-C 6 )alkoxy(Ci-C 6 )aIkyI, R 6 is (Ci-C6)alkyl, (Ci-C6)alkyl substituted by halogen, cyano, nitro, amino, hydroxy or phenyl, carboxyl, carbonyl(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6 )alkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)alkoxy or di(Ci-C
- R 7 is hydrogen, (Ci-C6)alkyl, (Ci-C6)alkylphenyl, aryl or aryl(Ci-C6)alkyl, and chiral carbon atoms are marked with *.
- R 4 and R 5 are each independently hydrogen, (Ci-C 4 )alkyl, (Ci-C 4 )alkylphenyl, phenyl, halogen, cyano, nitro, cyano(Ci-C 4 )alkyl, hydroxy(Ci-C 4 ) alkyl, (Ci-C 4 )alkoxycarbonyl(Ci-C 4 )alkyl or (Ci-C 4 )alkoxy(Ci-C 4 )alkyl,
- R 6 is (Ci-C 3 )alkyl, (Ci-C 3 )alkyl substituted by halogen, cyano, nitro, amino, hydroxy or phenyl, carboxyl, carbonyl(Ci-C 3 ) alkyl, (Ci-C 3 )alkoxycarbonyl (Ci-C 3 )alkyl, (Ci-C 3 )alkoxy(Ci-C 3 )alkyl, (Ci-C 3 )alkoxy or di(Ci-C 3 )alkoxy(Ci-C 3 )alkyl, and
- R 7 is hydrogen, (Ci-C 4 ) alkyl, (Ci-C 4 ) alkylphenyl, aryl or aryl (Ci-C 4 ) alkyl.
- R 4 and R 5 are independently hydrogen, (Ci-C 4 ) alkyl, phenyl, halogen, cyano, nitro, hydroxy (Ci-C 4 ) alkyl, (Ci-C 4 ) alkoxycarbonyl (Ci-C 4 ) alkyl or (Ci-C 4 )alkoxy(Ci-C 4 )alkyl,
- R 6 is (Ci-C 3 )alkyl or carboxyl substituted by halogen, cyano, nitro, amino, hydroxy or phenyl, and
- R 7 is tert-butyl, ao-propyl, benzyl or phenyl.
- R 4 and R 5 independently represent hydrogen, chlorine, bromine, iodine or tert-butyl
- R 6 is hydroxy-substituted Ci-alkyl
- R 7 is tert. -butyl or ao-propyl.
- R 4 and R 5 independently represent hydrogen or chlorine
- R 6 is hydroxy-substituted Ci-alkyl, and R 7 for tert. -butyl.
- the chiral ligands of the formula (lila) are used as enantiomerically enriched compounds.
- the chiral ligand of formula (III) or of formula (IIIa) is employed in (R)-configuration to obtain the R-enantiomer of the compound of formula (I) enriched.
- the chiral ligand of the formula (III) or of the formula (IIIa) is used in the (S) configuration in order to obtain the S-enantiomer of the compound of the formula (I) in an enriched form.
- the chiral ligand of the formula (III) or of the formula (IIIa) is used in the (R) configuration in order to obtain the S-enantiomer of the compound of the formula (I) in an enriched form.
- the chiral ligand of formula (III) or of formula (IIIa) is used in (S) configuration in order to obtain the R-enantiomer of the compound of formula (I) enriched.
- the chiral metal-ligand complex is generated by reacting a transition metal derivative and a chiral ligand separately or in the presence of the sulfide.
- the ratio of transition metal derivative to chiral ligand is in the range from 10:1 to 1:10, preferably in the range from 1:1 to 1:10, particularly preferably in the range from 1:1 to 1:5 and very particularly preferably im Range 1:1 to 1:3.
- the ligands can be prepared by known methods (e.g. Adv. Synth. Catal. 2005, 347, 1933-1936).
- chiral metal-ligand complex based on the sulfide of the formula (II) is preferably in the range from 0.01 to 20 mol%, preferably from 0.1 to 10 mol%, particularly preferably from 0.5 to 7 mol % and most preferably from 0.5 to 5 mol%.
- a higher use of chiral metal-ligand complex is possible, but generally not economically viable.
- the chiral metal-ligand complex or its constituents can either already be present at the start of the reaction or else be partly added during the reaction until the intended total amount is reached.
- the additive is the salt of an organic acid.
- the salt is an alkali metal or ammonium salt, with lithium, sodium or potassium salts being preferred in turn.
- Preferred additives are those of the formula (IV): where in formula (IV)
- R 8 , R 9 , R 10 , R n and R 12 are independently hydrogen, (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, (Ci-C 6 )alkylphenyl , phenyl, halogen, cyano, nitro, (Ci-C 6 )alkoxy, cyano(Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, (Ci-C 6 )alkoxycarbonyl(Ci-C 6 )alkyl, (Ci-C 6 )alkoxy(Ci-C 6 )alkyl or aminodi(Ci-C 6 )alkyl, and
- A is lithium, sodium, potassium or a radical NR 13 R 14 R 15 R 16 , where
- R 13 , R 14 , R 15 and R 16 are independently hydrogen, benzyl or (Ci-C 6 ) alkyl. Preferred standing
- R 8 , R 9 , R n and R 12 are independently hydrogen, (Ci-C4) alkyl or (Ci-C4) alkoxy,
- R 10 is hydrogen, (Ci-C4) alkyl, (Ci-C4) alkoxy or amino-di (Ci-C4) alkyl, and A is lithium, sodium, potassium or ammonium.
- R 8 , R 9 , R n and R 12 independently represent hydrogen or methoxy
- R 10 is hydrogen, methoxy or dimethylamino, and A is lithium, sodium, potassium or ammonium.
- R 8 , R 9 , R n and R 12 are hydrogen, R i o for hydrogen or methoxy or dimethylamino, and
- a for lithium, sodium or potassium is lithium, sodium or potassium.
- additive based on the sulfide of the formula (II) is preferably in the range from 0.1 to 20 mol%, particularly preferably from 0.5 to 10 mol% and very particularly preferably from 1 to 8 mol%. A higher use of additive is possible, but generally not economically sensible.
- the conversion of the sulfide of the formula (II) into the compound of the formula (I) is preferably carried out in the presence of a solvent.
- Suitable solvents which should be mentioned in particular are: tetrahydrofuran (THF), dioxane, diethyl ether, diglyme, methyl tert-butyl ether (MTBE), tert-kmyl methyl ether (TAME), dimethyl ether (DME), 2-methyl-THF, acetonitrile (ACN), acetone , butyronitrile, toluene, anisole, o-xylene, m-xylene, p-xylene, ethylbenzene, mesitylene, ethyl acetate, isopropyl acetate, butyl acetate, pentyl acetate, methyl isobutyl ketone, alcohols such as methanol, ethanol, propanol, butanol
- Preferred solvents are methylene chloride, chloroform, 1,2-dichloroethane, chlorobenzene, 1,2-dichlorobenzene, acetonitrile, acetone, toluene, anisole, o-xylene, m-xylene, p-xylene, ethylbenzene, ethyl acetate, methyl tert-butyl ether (MTBE), Tetrahydrofuran (THF), N,N-dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), ethanol, or mixtures thereof.
- Particularly preferred solvents are methylene chloride, 1,2-dichloroethane, chlorobenzene, anisole, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, or mixtures thereof.
- solvents are toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, chlorobenzene, anisole and methylene chloride, or mixtures thereof.
- Particularly preferred solvents are toluene, o-xylene, m-xylene, p-xylene and methylene chloride, or a mixture of o-xylene, m-xylene, p-xylene and ethylbenzene (technical xylene).
- the oxidizing agents which can be used for this reaction are not particularly limited.
- an oxidizing agent for the preparation of the sulfoxides for example, inorganic peroxides such as. B. hydrogen peroxide or organic peroxides such as alkyl hydroperoxides and arylalkyl hydroperoxides are suitable.
- the preferred oxidizing agent is hydrogen peroxide.
- the molar ratio of oxidizing agent to the sulfide of the formula (II) is in the range from 0.9:1 to 5:1, preferably between 1.2:1 and 3.5:1.
- the reaction is generally carried out at a temperature between -80.degree. C. and 100.degree. C., preferably between -10.degree. C. and 60.degree. C., very particularly preferably between -5.degree. C. and 30.degree.
- the reaction is typically carried out at normal pressure, but can also be carried out at elevated or reduced pressure.
- Products obtained by the process according to the invention have an enantiomeric ratio of from 50.5:49.5 to 100:0, preferably from 75:25 to 100:0, particularly preferably from 90:10 to 100:0 (R):(S)- Enantiomer or (S):(R)-enantiomer, very particularly preferably (R):(S)-enantiomer. According to the invention, preference is given in each case to those enantiomeric ratios which have an excess of (R)-enantiomer.
- the desired compounds of the formula (I) can be isolated, for example, by subsequent extraction and crystallization. If necessary, the enantiomeric excess can be significantly increased by subsequent crystallization.
- Such methods are known to those skilled in the art and include in particular the preferential crystallization from an organic solvent or a mixture of organic solvents with water or a mixture of organic solvents.
- Preferred solvents for the crystallization are 3-methyl-1-butanol and 1-butanol or mixtures thereof with methylcyclohexane.
- the reaction mixture was diluted at 5°C to 10°C with 400 ml each of water and toluene and then stirred with 200 ml of a 39% aqueous sodium bisulfite solution. After phase separation, the aqueous phase was extracted with 400 ml of toluene. Concentration of the combined organic phases yielded 480.4 g of a dark oil. This was dissolved in 960 ml of methylene chloride and flash chromatographed over 3.5 kg of silica gel (28 l of methylene chloride, then 25 l of methylene chloride (95%) + methyl tert-butyl ether (MTBE) (5%). After removal of the solvent, 416 was obtained.
- Example 2 Synthesis of (2Z)-2-( ⁇ 2-Fluoro-4-methyl-5-[(R)-(2,2,2-trifluoroethyl)sulfinyl]phenyl ⁇ -imino)-3-(2, 2,2-trifluoroethyl)-1,3-thiazolidin-4-one 0.75 ml of methylene chloride and 10.3 mg (0.029 mmol) of iron(III) acetylacetonate were placed in the reaction vessel.
- Example 12 Synthesis of (2Z)-2-( ⁇ 2-Fluoro-4-methyl-5-[(R)-(2,2,2-trifluoroethyl)sulfinyl]phenyl ⁇ -imino)-3-(2, 2,2-trifluoroethyl)-1,3-thiazolidin-4-one 10 ml of toluene, 19.2 mg (0.8 mmol) of lithium hydroxide and 97.7 mg (0.8 mmol) of benzoic acid were placed in the reaction vessel and stirred at 20° C. for 10 minutes.
- Example 15 The synthesis described above in Example 15 was carried out using different proportions of ferric acetylacetonate, ligand and 4-dimethylaminobenzoic acid/LiOH, based on the amount of
- Table 3 Oxidation of (2Z)-2-( ⁇ 2-Fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]-phenyl ⁇ imino)-3-(2,2,2- trifluoroethyl)-1,3-thiazolidin-4-one according to Example 15 in the presence of different quantitative ratios of iron(III) acetylacetonate, ligand and 4-dimethylaminobenzoic acid/LiOH, based on the amount of starting compound.
- Example 18 Synthesis of (2Z)-2-( ⁇ 2-Fluoro-4-methyl-5-[(R)-(2,2,2-trifluoroethyl)sulfinyl]phenyl ⁇ -imino)-3-(2, 2,2-trifluoroethyl)-1,3-thiazolidin-4-one 265 mg (0.75 mmol) iron(III) acetylacetonate, 437 mg (1.50 mmol) 2,4-dichloro-6-[(E)- ⁇ [(2R)-l-hydroxy-3, Submitted 3-dimethylbutan-2-yl]imino ⁇ methyl]phenol and 216 mg (1.50 mmol) of sodium benzoate in 9 ml of technical xylene mixture and stirred at 15° C.
- Example 23 Synthesis of (2Z)-2-( ⁇ 4-Fluoro-2-methyl-5-[(R)-(2,2,2-trifluoroethyl)sulfinyl]phenyl ⁇ -imino)-3-(2, 2,2-trifluoroethyl)-1,3-thiazolidin-4-one 1000 ml of toluene, 3.335 g (11.5 mmol) of 2,4-dichloro-6-[(E)-[[(2R)-1-hydroxy-3,3- dimethylbutan-2-yl]imino ⁇ methyl]phenol, 1.656 g (11.5 mmol) of sodium benzoate and 2.03 g (5.75 mmol) of iron(III) acetylacetonate and stirred for 1 hour.
- the suspension was filtered and the reaction vessel rinsed out with some mother liquor.
- the filter cake obtained was washed with 215 g of a 3:1 mixture of methylcyclohexane and 3-methyl-1-butanol and with 215 g of pure methylcyclohexane. Both washes were at 20 °C performed as displacement washes.
- the filter cake was then dried at 50° C. and a reduced pressure of 20 mbar.
- Example 2 The synthesis described in principle in Example 2 was carried out under different conditions. The results are compiled in Table 5.
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MX2023011254A MX2023011254A (es) | 2021-03-26 | 2022-03-22 | Procedimiento para la preparacion de derivados de sulfoxido de (2z)-2-(fenilimino)-1,3-tiazolidin-4-ona enantiomericamente enriquecidos. |
KR1020237035357A KR20230163439A (ko) | 2021-03-26 | 2022-03-22 | (2z)-2-(페닐이미노)-1,3-티아졸리딘-4-온 술폭시드 유도체의 거울상이성질체적으로 풍부한 형태로의 제조 방법 |
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BR112023017032A BR112023017032A2 (pt) | 2021-03-26 | 2022-03-22 | Processo para preparar derivados de sulfóxido de (2z)-2-(fenilimino)-1,3-tiazolidin-4-ona enantiomericamente enriquecidos |
CN202280018238.XA CN116981659A (zh) | 2021-03-26 | 2022-03-22 | 制备对映体富集的(2z)-2-(苯基亚氨基)-1,3-噻唑烷-4-酮亚砜衍生物的方法 |
IL306031A IL306031A (en) | 2021-03-26 | 2022-03-22 | Process for the preparation of (2Z)-2-(phenylimino)-1, 3-thiazolidine-4-one-sulfoxide derivatives in an enantiomerically enriched form |
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