CN114478362A - Preparation method of chiral pyridinol derivative - Google Patents
Preparation method of chiral pyridinol derivative Download PDFInfo
- Publication number
- CN114478362A CN114478362A CN202011167070.8A CN202011167070A CN114478362A CN 114478362 A CN114478362 A CN 114478362A CN 202011167070 A CN202011167070 A CN 202011167070A CN 114478362 A CN114478362 A CN 114478362A
- Authority
- CN
- China
- Prior art keywords
- chiral
- cod
- tert
- diphosphine
- pyridinol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 26
- -1 pyridine alcohol compounds Chemical class 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 12
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical group [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 32
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 claims description 30
- 239000003446 ligand Substances 0.000 claims description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 21
- 229910052751 metal Inorganic materials 0.000 claims description 19
- 239000002184 metal Substances 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 12
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- 239000002243 precursor Substances 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 229910052786 argon Inorganic materials 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 229910052703 rhodium Inorganic materials 0.000 claims description 5
- 229910052707 ruthenium Inorganic materials 0.000 claims description 5
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 4
- 239000005977 Ethylene Substances 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- DHCWLIOIJZJFJE-UHFFFAOYSA-L dichlororuthenium Chemical compound Cl[Ru]Cl DHCWLIOIJZJFJE-UHFFFAOYSA-L 0.000 claims description 4
- 229910052741 iridium Inorganic materials 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 3
- JRTIUDXYIUKIIE-KZUMESAESA-N (1z,5z)-cycloocta-1,5-diene;nickel Chemical compound [Ni].C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 JRTIUDXYIUKIIE-KZUMESAESA-N 0.000 claims description 2
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 2
- VNNDVNZCGCCIPA-FDGPNNRMSA-N (z)-4-hydroxypent-3-en-2-one;manganese Chemical compound [Mn].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O VNNDVNZCGCCIPA-FDGPNNRMSA-N 0.000 claims description 2
- SJBBXFLOLUTGCW-UHFFFAOYSA-N 1,3-bis(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC=CC(C(F)(F)F)=C1 SJBBXFLOLUTGCW-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 2
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 2
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 239000012298 atmosphere Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- GGRQQHADVSXBQN-FGSKAQBVSA-N carbon monoxide;(z)-4-hydroxypent-3-en-2-one;rhodium Chemical compound [Rh].[O+]#[C-].[O+]#[C-].C\C(O)=C\C(C)=O GGRQQHADVSXBQN-FGSKAQBVSA-N 0.000 claims description 2
- 229910001914 chlorine tetroxide Inorganic materials 0.000 claims description 2
- 229930007927 cymene Natural products 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 2
- 125000005394 methallyl group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
- BMGNSKKZFQMGDH-FDGPNNRMSA-L nickel(2+);(z)-4-oxopent-2-en-2-olate Chemical compound [Ni+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O BMGNSKKZFQMGDH-FDGPNNRMSA-L 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052723 transition metal Inorganic materials 0.000 claims description 2
- 150000003624 transition metals Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 10
- 239000000758 substrate Substances 0.000 abstract description 9
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 abstract description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 abstract 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 abstract 1
- 239000007789 gas Substances 0.000 description 10
- 239000010948 rhodium Substances 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 6
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 5
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000012300 argon atmosphere Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000009905 homogeneous catalytic hydrogenation reaction Methods 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 229940122236 Histamine receptor antagonist Drugs 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- UDGHXQPQKQPSBB-UHFFFAOYSA-N benzenesulfonic acid;4-[4-[(4-chlorophenyl)-pyridin-2-ylmethoxy]piperidin-1-yl]butanoic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1.C1CN(CCCC(=O)O)CCC1OC(C=1N=CC=CC=1)C1=CC=C(Cl)C=C1 UDGHXQPQKQPSBB-UHFFFAOYSA-N 0.000 description 1
- 229960001105 bepotastine besilate Drugs 0.000 description 1
- 230000002210 biocatalytic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000002894 chemical waste Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- GGOZGYRTNQBSSA-UHFFFAOYSA-N pyridine-2,3-diol Chemical compound OC1=CC=CN=C1O GGOZGYRTNQBSSA-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen 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
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon 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
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
- B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
-
- 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
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0225—Complexes comprising pentahapto-cyclopentadienyl analogues
- B01J2531/023—Phospholyl ligands, i.e. [CnP(5-n)Rn]- in which n is 0-4 and R is H or hydrocarbyl, or analogous condensed ring systems
-
- 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
- B01J2531/82—Metals of the platinum group
- B01J2531/827—Iridium
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pyridine Compounds (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a preparation method of a chiral pyridinol derivative, in particular to a method for preparing pyridinol by catalyzing asymmetric hydrogenation of pyridone through a chiral ferrocene skeleton phosphine ligand-metal complex. The method has the advantages of simple steps, simple and convenient operation, mild conditions and wide substrate application range, can efficiently and asymmetrically synthesize a series of pyridine alcohol compounds, can use the catalyst only in an amount of 0.002 mol% (S/C-50000), and has huge industrial application value.
Description
Technical Field
The invention belongs to the technical field of organic synthesis preparation, relates to asymmetric catalysis of compounds, and particularly relates to a preparation method of a chiral pyridinol derivative.
Background
The chiral pyridinol structure widely exists in natural products, novel functional materials and other substances and is also an important skeleton of various medicaments, for example, carbaxamine containing the chiral pyridinol structure and bepotastine besilate are two common histamine receptor antagonists; the compound A with a chiral pyridine alkyl alcohol structure as a framework is an anticancer drug in research; in addition, various chiral pyridine alkyl alcohols are intermediate components of catalyst ligands for part of industrial applications.
How to simply, cheaply and efficiently obtain chiral pyridine secondary alcohol is a problem which needs to be solved urgently. At present, asymmetric synthesis methods of chiral pyridinol derivatives can be divided into three major classes: (1) asymmetric addition of aryl organometallic reagents to heteroaromatic aldehydes; (2) biocatalytic techniques; (3) asymmetric catalytic hydrogenation. Among them, the chiral pyridinol product obtained by homogeneous asymmetric catalysis has a single configuration, the chemical waste generated in the reaction process is less, and the by-product is not generated basically, so that the asymmetric catalytic hydrogenation method is most attractive from the viewpoint of practical application and atom economy.
In 2000, the Noyori group (Pure appl. chem.,2001,73(2):227-2-BINAP-diamine was used as a catalyst, and the asymmetric hydrogenation of 2,3, 4-pyridylalkyl ketone and pyridyldiketone was studied. The system is found in the aspect of B [ OCH (CH)3)3]Under the condition of using the pyridine diketone as an additive, the efficient reduction of the pyridone substrate can be realized (the ee value of the product is more than 94 percent under the condition that S/C is 2000), and the pyridine diketone with the best reaction effect can obtain 100 percent of conversion and chiral pyridine diol with the ee value of more than 99.9 percent under the condition that S/C is 10000.
Ru (II) X in 2003 and 2008, groups of Cheng-yi Chen (Organic Letters,2003,5(26):5039-2Asymmetric catalysis of pyridine aryl ketones by BINAP-diamine catalytic system. The experimental result shows that the system can realize high-efficiency asymmetric hydrogenation reduction of pyridine aryl ketone with substituent at the ortho-position of aromatic ring under proper conditions, and the ee value of the product reaches 99% (S/C ═ 1000). However, when there is no substituent on the benzene ring or the substituent is at other positions, the selectivity of the system is greatly reduced.
In 2012, The Journal of Organic Chemistry,2012,77(1): 612-. The system exhibits greater catalytic capacity than the Noyori bisphosphine diamine catalyst in the catalytic reduction of such substrates, but, similar to previous experimental results, the high selectivity of the system to the substrate is dependent on the presence of aromatic ring ortho substituents on the substrate.
Despite the great progress made in the preparation of pyridinol derivatives by transition metal-catalyzed asymmetric hydrogenation, several important problems remain unsolved: (1) the conversion number (TON) is too low, and the TON is less than or equal to 2000, so that the requirement of industrial production cannot be met; (2) the catalytic system is single and is limited to diphosphine ligand and ruthenium or rhodium metal salt; (3) the substrate universality is poor, and the position of a substituent on a pyridine ring has a large influence on the ee value. These are problems to be solved urgently in the industrial synthesis of pyridinol derivatives. Therefore, the method for asymmetric catalytic hydrogenation with high efficiency, high stereoselectivity and wide substrate applicability has important practical significance.
Disclosure of Invention
In view of the above problems in the prior art, the present invention aims to provide a method for preparing chiral pyridinol derivatives, which has high atom economy, is suitable for industrial production and application, and can conveniently prepare chiral pyridinol derivatives with high purity and high enantioselectivity in large quantities.
The invention is realized by the following technical scheme, and the preparation method of the chiral pyridinol derivative is characterized by comprising the following steps of:
in the formulae (I) and (II), the substituent R1And a substituent R2Each independently selected from hydrogen, halogen, C1-C12 alkyl, aryl or heteroatom-containing substituted alkyl and aryl.
Wherein [ M ]/L is a catalyst formed by coordination bonding of a metal M complex and a chiral ligand L, wherein the metal M is Ru, Rh, Ir, Pd or the like, and the structure of the chiral ligand L is a ferrocene ligand shown in a general formula (III), (IV), (V) or (VI):
in the general formula, R represents methyl, isopropyl, tert-butyl, phenyl, benzyl or other optional linear, branched or cyclic substituent of C1-C6; ar represents phenyl, 4-methylphenyl, 4-methoxyphenyl, 3, 5-dimethylphenyl, 3, 5-dimethyl-4-methoxyphenyl, 3,4, 5-trimethylphenyl, 3, 5-di-tert-butylphenyl, 3, 5-di-tert-butyl-4-methoxyphenyl or 3, 5-di-tert-butyl-4-methylphenyl.
As a preferred embodiment of the present invention, the method includes:
1) sequentially adding a metal M complex and a chiral ligand L into a protic organic solvent under the atmosphere of argon at the temperature of 10-40 ℃, and stirring for reaction for 0.5-6 hours to prepare a catalyst [ M ]/L ] in which the metal M complex and the chiral ligand L are coordinately bound, wherein the metal M is Ru, Rh, Ir, Pd or the like;
2) adding the pyridone derivative shown in the formula (I), the catalyst [ M ]/L obtained in the step 1), a solvent and an alkali into an autoclave in sequence, carrying out asymmetric hydrogenation reaction at 10-60 ℃ and 0.1-10 MPa of hydrogen pressure for 2-24 hours, and obtaining the chiral pyridinol derivative shown in the formula (II) after the reaction is finished.
Wherein, after the reaction is finished, the reaction solution is decompressed and concentrated, after a proper amount of water is added, ethyl acetate is used for extraction, and the organic phase is remained after liquid separation. And then drying and concentrating the organic phase to obtain the chiral pyridine alcohol derivative shown in the formula (II).
As a preferred technical scheme of the invention, the chemical structure of the chiral ligand L includes but is not limited to chiral ligands shown as any one of formulas III-1 to III-6, IV-1, IV-2, V-1, V-2, VI-1 or VI-2:
as a preferred embodiment of the present invention, the metal M complex is [ Rh (NBD) ]2]+BF4 -;[Rh(NBD)Cl]2;[Rh(COD)Cl]2;[Rh(COD)2]+X-;Rh(acac)(CO)2;Rh(ethylene)2(acac);[Rh(ethylene)2Cl]2;RhCl(PPh3)3;Rh(CO)2Cl2;Ru(arylgroup)X2;RuHX(L)2(diphosphine);RuX2(L)2(diphosphine);Ru(arene)X2(diphosphine);Ru(RCOO)2(diphosphine);Ru(methallyl)2(diphosphine);Ru(aryl group)X2(PPh3)3;Ru(COD)(COT);Ru(COD)(COT)X;RuX2(cymene);Ru(COD)n;RuCl2(=CHR)(PR'3)2;Ru(arylgroup)X2(diphosphine);RuCl2(COD);[Ru(COD)2]X;RuX2(diphosphine);Ru(ArH)Cl2;Ru(COD)(methallyl)2;Ir(NBD)Cl]2;[Ir(NBD)2]X;[Ir(COD)Cl]2;[Ir(COD)2]X;[Ni(allyl)X]2;Ni(acac)2;Ni(COD)2;NiX2;MnX2;Mn(acac)2;CoX2;FeX2;CuX;CuX2;AgX;[Pd(allyl)Cl]2;PdCl2;Pd(OAc)2;Pd(CF3COO)2. In the above transition metal precursors, R and R' may be independently alkyl, alkoxy or substituted alkyl, aryl is aryl, and X is a negative anion, such as Cl-、Br-、BF4 -、ClO4 -、SbF6 -、PF6 -、CF3SO3 -、RCOO-、B(Ar)4 -Wherein Ar can be 3, 5-bis (trifluoromethyl) benzene or fluorobenzene. L is a solvent molecule, such as CH3CN, and the like.
Further, the solvent in step 1) and step 2) is independently selected from one or more mixed solvents of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, methanol, ethanol, n-propanol, isopropanol and tert-butanol.
Further, in the step 2), the molar ratio of the catalyst [ M ]/L, the base and the pyridone derivative is 1:10 to 200:100 to 50000.
Further, in the step 2), the reaction temperature for carrying out the asymmetric hydrogenation is 10 ℃ to 60 ℃.
Further, in the step 2), the pressure of hydrogen for performing the asymmetric hydrogenation reaction is 0.1-10 MPa.
Further, in the step 2), the reaction time for performing the asymmetric hydrogenation reaction is 2 to 24 hours.
Further, in the step 2), the base is one of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium methoxide or a mixture of sodium methoxide in any proportion.
Compared with the prior art, the invention has the following beneficial effects:
(1) the catalyst composed of chiral ferrocene tridentate ligand and metal complex is adopted, and due to high stability and reaction activity of the catalyst, inactivation caused by coordination of pyridine to the metal center of the catalyst is overcome. Compared with the prior art, the process is more advanced.
(2) Through a large number of experiments, the technology of the invention can obtain the enantioselectivity of more than 99 percent and the catalyst conversion number of 50000 which is far higher than that reported in the prior known public.
(3) The method has the characteristics of simple operation, mild reaction conditions, wide substrate application range, high atom economy, environmental friendliness and the like, and has great implementation value and social and economic benefits.
Detailed Description
The present invention will be further described with reference to specific examples, but the present invention is not limited thereto.
The experimental methods in the examples, in which specific conditions are not specified, are generally performed under the conditions described in the manual and the conventional conditions, or under the conditions recommended by the manufacturer; the materials, reagents and the like used are commercially available unless otherwise specified.
Example 1 (ligand examination)
In an argon-protected glove box, 0.021mmol chiral ligand L and metal M precursor [ Ir (COD) Cl ] were weighed]2(0.01mmol, 6.7mg) was added to a 10mL volumetric flask, 2mL of isopropanol solution was added, and the mixture was stirred at room temperature for 1 hour until it was completely dissolved, and the catalyst solution was directly used in the homogeneous catalytic hydrogenation reaction.
Under argon atmosphere, compound 1a (0.1mmol, 15mg), potassium carbonate (0.01mmol, 1.4mg) and the prepared catalyst solution (100uL, 0.001mmol) were added in this order to a 5mL hydrogenation tube, 0.9mL isopropanol was added, the reaction tube was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 50atm hydrogen was charged and reacted in a constant temperature oil bath at 50 ℃ for 12 hours. After the reaction, the gas in the autoclave was slowly released, the reaction mixture was purified by a silica gel column, the concentrated filtrate was vacuum-dried to obtain a white solid, i.e., compound 1b, and the conversion and ee values were measured by HPLC, and the results are shown in table 1 below.
Table 1.
Example 2 (solvent examination)
In a glove box protected by argon, 0.021mmol of chiral ligand III-3 and metal M precursor [ Ir (COD) Cl ] are weighed]2(0.01mmol, 6.7mg) was added to a 10mL volumetric flask, 2mL of isopropanol solution was added, and the mixture was stirred at room temperature for 1 hour until it was completely dissolved, and the catalyst solution was directly used in the homogeneous catalytic hydrogenation reaction.
Under argon atmosphere, compound 1a (0.1mmol, 15mg), potassium carbonate (0.01mmol, 1.4mg) and the prepared catalyst solution (100 μ L, 0.001mmol) were added in this order to a 5mL hydrogenation tube, then 0.9mL of solvent was added, the reaction tube was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, finally 50atm hydrogen was charged, and the reaction was carried out in a constant temperature oil bath at 50 ℃ for 12 hours. After the reaction, the gas in the autoclave was slowly released, the reaction mixture was purified by a silica gel column, the concentrated filtrate was vacuum-dried to obtain a white solid, i.e., compound 1b, and the conversion and ee values were measured by HPLC, and the results are shown in table 2 below.
Table 2.
Example 3 (examination of base)
In a glove box protected by argon, 0.021mmol of chiral ligand III-3 and metal M precursor are weighed[Ir(COD)Cl]2(0.01mmol, 6.7mg) was added to a 10mL volumetric flask, 2mL of isopropanol solution was added, and the mixture was stirred at room temperature for 1 hour until it was completely dissolved, and the catalyst solution was directly used in the homogeneous catalytic hydrogenation reaction.
Under argon atmosphere, compound 1a (0.1mmol, 15mg), a base (0.001mmol) and a prepared catalyst solution (10 μ L, 0.0001mmol) were sequentially added to a 5mL hydrogenation tube, 1mL isopropyl alcohol was further added, the reaction tube was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 50atm hydrogen was charged, and the reaction was carried out in a constant temperature oil bath at 50 ℃ for 12 hours. After the reaction, the gas in the autoclave was slowly released, the reaction mixture was purified by a silica gel column, the concentrated filtrate was vacuum-dried to obtain a white solid, i.e., compound 1b, and the conversion and ee values were measured by HPLC, and the results are shown in table 3 below.
Table 3.
Examples 4 to 19 (investigation of substrate Range)
In a glove box protected by argon, 0.021mmol of chiral ligand III-3 and metal M precursor [ Ir (COD) Cl ] are weighed]2(0.01mmol, 6.7mg) was added to a 10mL volumetric flask, 2mL of isopropanol solution was added and stirred at room temperature for 1 hour until it was completely dissolved, and the catalyst solution was directly used for homogeneous catalytic hydrogenation.
Under argon atmosphere, compound 1a (0.1mmol, 15mg), sodium methoxide (0.001mmol, 0.05mg) and the prepared catalyst solution (10 μ L, 0.0001mmol) were sequentially added to a 5mL hydrogenation tube, 1mL of a solvent was further added, the reaction tube was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 50atm hydrogen was charged and reacted in a constant temperature oil bath at 50 ℃ for 12 hours. After the reaction, the gas in the autoclave was slowly released, the reaction mixture was purified by a silica gel column, the concentrated filtrate was vacuum-dried to obtain a white solid, i.e., compound 1b, and the conversion and ee values were measured by HPLC, and the results are shown in table 4 below.
Table 4.
Example 20 (enlargement, S/C50000)
In a glove box protected by argon, 0.021mmol of chiral ligand III-3 and metal M precursor [ Ir (COD) Cl ] are weighed]2(0.01mmol, 6.7mg) was added to a 10mL volumetric flask, 2mL of isopropanol solution was added, and the mixture was stirred at room temperature for 1 hour until it was completely dissolved, and the catalyst solution was directly used in the homogeneous catalytic hydrogenation reaction.
Under argon atmosphere, compound 1a (40mmol, 6g), sodium methoxide (0.4mmol, 21.6mg) and the prepared catalyst solution (80 μ L, 0.0008mmol) were sequentially added to a 5mL hydrogenation tube, 1mL of isopropanol was further added, the reaction tube was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 50atm hydrogen was charged and reacted in a constant temperature oil bath at 50 ℃ for 12 hours. After the reaction is finished, slowly releasing the gas in the autoclave, purifying the reaction mixture by using a silica gel short column, concentrating the filtrate, and drying the filtrate in vacuum to obtain a white solid, namely the compound 1b, wherein the reaction yield is 97 percent, and the ee value is 99 percent by HPLC.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A preparation method of chiral pyridinol derivatives is characterized by comprising the following steps:
in the formulae (I) and (II), the substituent R1And a substituent R2Each independently selected from hydrogen, halogen, C1-C12 alkyl, aryl or heteroatom-containing substituted alkyl, aryl;
wherein [ M ]/L is a catalyst formed by coordination bonding of a metal M complex and a chiral ligand L, wherein the metal M is Ru, Rh, Ir, Pd or the like, and the structure of the chiral ligand L is a ferrocene ligand shown in a general formula (III), (IV), (V) or (VI):
in the general formula, R represents methyl, isopropyl, tert-butyl, phenyl, benzyl or other optional linear, branched or cyclic substituent of C1-C6; ar represents phenyl, 4-methylphenyl, 4-methoxyphenyl, 3, 5-dimethylphenyl, 3, 5-dimethyl-4-methoxyphenyl, 3,4, 5-trimethylphenyl, 3, 5-di-tert-butylphenyl, 3, 5-di-tert-butyl-4-methoxyphenyl or 3, 5-di-tert-butyl-4-methylphenyl.
2. The method for preparing a chiral pyridinol derivative according to claim 1, characterized by comprising:
1) sequentially adding a metal M complex and a chiral ligand L into a protic organic solvent under the atmosphere of argon at the temperature of 10-40 ℃, and stirring for reaction for 0.5-6 hours to prepare a catalyst [ M ]/L ] in which the metal M complex and the chiral ligand L are coordinately bound, wherein the metal M is Ru, Rh, Ir, Pd or the like;
2) adding the pyridone derivative shown in the formula (I), the catalyst [ M ]/L obtained in the step 1), a solvent and an alkali into an autoclave in sequence, carrying out asymmetric hydrogenation reaction at 10-60 ℃ and 0.1-10 MPa of hydrogen pressure for 2-24 hours, and obtaining the chiral pyridinol derivative shown in the formula (II) after the reaction is finished.
4. the process for preparing a chiral pyridinol derivative according to claim 1, wherein the metal M complex is [ Rh (NBD) ]2]+BF4 -;[Rh(NBD)Cl]2;[Rh(COD)Cl]2;[Rh(COD)2]+X-;Rh(acac)(CO)2;Rh(ethylene)2(acac);[Rh(ethylene)2Cl]2;RhCl(PPh3)3;Rh(CO)2Cl2;Ru(arylgroup)X2;RuHX(L)2(diphosphine);RuX2(L)2(diphosphine);Ru(arene)X2(diphosphine);Ru(RCOO)2(diphosphine);Ru(methallyl)2(diphosphine);Ru(aryl group)X2(PPh3)3;Ru(COD)(COT);Ru(COD)(COT)X;RuX2(cymene);Ru(COD)n;RuCl2(=CHR)(PR'3)2;Ru(arylgroup)X2(diphosphine);RuCl2(COD);[Ru(COD)2]X;RuX2(diphosphine);Ru(ArH)Cl2;Ru(COD)(methallyl)2;Ir(NBD)Cl]2;[Ir(NBD)2]X;[Ir(COD)Cl]2;[Ir(COD)2]X;[Ni(allyl)X]2;Ni(acac)2;Ni(COD)2;NiX2;MnX2;Mn(acac)2;CoX2;FeX2;CuX;CuX2;AgX;[Pd(allyl)Cl]2;PdCl2;Pd(OAc)2;Pd(CF3COO)2(ii) a In the above transition metal precursors, R and R' may be independently alkyl, alkoxy or substituted alkyl, aryl is aryl, and X is a negative anion, such as Cl-、Br-、BF4 -、ClO4 -、SbF6 -、PF6 -、CF3SO3 -、RCOO-、B(Ar)4 -Wherein Ar can be 3, 5-bis (trifluoromethyl) benzene or fluorobenzene; l is a solvent molecule, such as CH3CN, and the like.
5. The method according to claim 1, wherein the solvent in step 1) and step 2) is one or more selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, methanol, ethanol, n-propanol, isopropanol, and tert-butanol.
6. The method according to claim 1, wherein in step 2), the molar ratio of the catalyst [ M ]/L ] to the base to the pyridone derivative is 1:10 to 200:100 to 50000.
7. The method for preparing chiral pyridinol derivative according to claim 1, wherein the asymmetric hydrogenation is carried out at a reaction temperature of 10 to 60 ℃ in step 2).
8. The method for preparing chiral pyridinol derivative according to claim 1, wherein the hydrogen pressure for the asymmetric hydrogenation in step 2) is 0.1 to 10 MPa.
9. The method for preparing chiral pyridinol derivative according to claim 1, wherein the reaction time for the asymmetric hydrogenation in step 2) is 2-24 hours.
10. The method for preparing chiral pyridinol derivative according to claim 1, wherein in step 2), the base is one or a mixture of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium methoxide in any proportion.
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