CN111574487A - Preparation method of chiral dihydroisoflavone compound and product thereof - Google Patents
Preparation method of chiral dihydroisoflavone compound and product thereof Download PDFInfo
- Publication number
- CN111574487A CN111574487A CN202010488025.6A CN202010488025A CN111574487A CN 111574487 A CN111574487 A CN 111574487A CN 202010488025 A CN202010488025 A CN 202010488025A CN 111574487 A CN111574487 A CN 111574487A
- Authority
- CN
- China
- Prior art keywords
- chiral
- compound
- formula
- dihydroisoflavone
- reaction
- Prior art date
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- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- -1 isoflavanone compound Chemical class 0.000 claims abstract description 33
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 29
- 238000005984 hydrogenation reaction Methods 0.000 claims description 19
- 238000006722 reduction reaction Methods 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 229910052741 iridium Inorganic materials 0.000 claims description 15
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 15
- 239000003446 ligand Substances 0.000 claims description 13
- 239000010948 rhodium Substances 0.000 claims description 12
- 239000005977 Ethylene Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 150000001450 anions Chemical class 0.000 claims description 7
- 150000002736 metal compounds Chemical class 0.000 claims description 7
- 229910052703 rhodium Inorganic materials 0.000 claims description 7
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 5
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 229910001914 chlorine tetroxide Inorganic materials 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- XXZOEDQFGXTEAD-UHFFFAOYSA-N 1,2-bis(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC=CC=C1C(F)(F)F XXZOEDQFGXTEAD-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical group FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 4
- 239000000758 substrate Substances 0.000 abstract description 12
- 238000006243 chemical reaction Methods 0.000 description 73
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 34
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 19
- 229910052786 argon Inorganic materials 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 14
- 238000004809 thin layer chromatography Methods 0.000 description 13
- 239000001257 hydrogen Substances 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 229910001220 stainless steel Inorganic materials 0.000 description 8
- 239000010935 stainless steel Substances 0.000 description 8
- 150000002431 hydrogen Chemical class 0.000 description 7
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 description 7
- 235000008696 isoflavones Nutrition 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 241000196324 Embryophyta Species 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 150000002515 isoflavone derivatives Chemical class 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- RTRZOHKLISMNRD-UHFFFAOYSA-N isoflavanone Chemical compound C1OC2=CC=CC=C2C(=O)C1C1=CC=CC=C1 RTRZOHKLISMNRD-UHFFFAOYSA-N 0.000 description 3
- 229930013032 isoflavonoid Natural products 0.000 description 3
- 235000012891 isoflavonoids Nutrition 0.000 description 3
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical class OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 235000007627 Caesalpinia Nutrition 0.000 description 2
- 241000522234 Caesalpinia Species 0.000 description 2
- 244000306301 Caesalpinia sappan Species 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241000756100 Muscari Species 0.000 description 2
- 241001448424 Ophiopogon Species 0.000 description 2
- 229930195210 Ophiopogon Natural products 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Chemical group 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- GOMNOOKGLZYEJT-UHFFFAOYSA-N isoflavone Chemical class C=1OC2=CC=CC=C2C(=O)C=1C1=CC=CC=C1 GOMNOOKGLZYEJT-UHFFFAOYSA-N 0.000 description 2
- 150000003817 isoflavonoid derivatives Chemical class 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 description 1
- SJBBXFLOLUTGCW-UHFFFAOYSA-N 1,3-bis(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(C(F)(F)F)=C1 SJBBXFLOLUTGCW-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 1
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 241000722818 Aralia Species 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- VLTIBPLPLITYPK-UHFFFAOYSA-N C=C.C=C.[Ir+] Chemical compound C=C.C=C.[Ir+] VLTIBPLPLITYPK-UHFFFAOYSA-N 0.000 description 1
- 241000522220 Caesalpinia pulcherrima Species 0.000 description 1
- 235000015162 Caesalpinia sappan Nutrition 0.000 description 1
- KHJXEDCZDBSVBE-UHFFFAOYSA-M Cl[Ir].C1CC=CCCC=C1.C1CC=CCCC=C1 Chemical class Cl[Ir].C1CC=CCCC=C1.C1CC=CCCC=C1 KHJXEDCZDBSVBE-UHFFFAOYSA-M 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 241001609537 Eucomis Species 0.000 description 1
- 241000220485 Fabaceae Species 0.000 description 1
- 230000005526 G1 to G0 transition Effects 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
- 241000282596 Hylobatidae Species 0.000 description 1
- 241000234280 Liliaceae Species 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 241000187473 Mycobacterium aurum Species 0.000 description 1
- 241000186365 Mycobacterium fortuitum Species 0.000 description 1
- 241000187481 Mycobacterium phlei Species 0.000 description 1
- 241000187480 Mycobacterium smegmatis Species 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 235000007637 Poinciana pulcherrima Nutrition 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- ADUXGJUMXBHABJ-UHFFFAOYSA-N [Ir+].[Ir+].C=C Chemical compound [Ir+].[Ir+].C=C ADUXGJUMXBHABJ-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 150000001336 alkenes Chemical group 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229910052787 antimony Inorganic materials 0.000 description 1
- WATWJIUSRGPENY-UHFFFAOYSA-N antimony atom Chemical compound [Sb] WATWJIUSRGPENY-UHFFFAOYSA-N 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000007294 asymmetric addition reaction Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 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 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- 230000003749 cleanliness Effects 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- ADFCQWZHKCXPAJ-GFCCVEGCSA-N equol Chemical compound C1=CC(O)=CC=C1[C@@H]1CC2=CC=C(O)C=C2OC1 ADFCQWZHKCXPAJ-GFCCVEGCSA-N 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000002443 hepatoprotective effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- ADFCQWZHKCXPAJ-UHFFFAOYSA-N indofine Natural products C1=CC(O)=CC=C1C1CC2=CC=C(O)C=C2OC1 ADFCQWZHKCXPAJ-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- KAVKNHPXAMTURG-UHFFFAOYSA-N n-(4-bromonaphthalen-1-yl)acetamide Chemical compound C1=CC=C2C(NC(=O)C)=CC=C(Br)C2=C1 KAVKNHPXAMTURG-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 230000036281 parasite infection Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000028070 sporulation Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- 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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a preparation method of chiral isoflavanone compound, which adopts a specific catalyst and takes a compound conjugated outside a ring as a substrate to prepare the chiral isoflavanone compound.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a preparation method of a chiral dihydroisoflavone compound and a product thereof.
Background
Isoflavones are a class of compounds derived from isoflavones (3-phenylchromones). The C ═ C double bond in the isoflavone molecule is hydrogenated and is called isoflavanone or isoflavanone. Homoisoflavonoids (homoisoids) are a special class of flavonoids, the parent structure of which is one carbon atom more than that of isoflavones. Such compounds are rare in plants, and are mainly distributed in plants of the genus Ophiopogon (Ophiopogon), Sciula (Sciua), Polo (Eucomis) and Muscari (Muscari) of the family Liliaceae, and are also found in a small amount in plants of the genus Caesalpinia (Caesalpinia pulcherrima), Caesalpinia sappan (C.sappan), Aralia oleracea (C.bonduceta) and the like of the genus Caesalpinia of the family Leguminosae.
The isoflavone compound is not only from plants, but also has wide biological activity. Such as: the following compound A has the effects of inhibiting growth, promoting sporulation, promoting the formation of enzymes involved in the plant parasite infection mechanism, and broad-spectrum antibacterial activity.
The dihydro-homoisoflavone compound is a compound in which double bonds at 2, 3 positions of homoisoflavone are reduced into single bonds, and has various activities of inhibiting angiogenesis COX-l, COX-2 and the like. In 2006, the Gibbons group isolated the natural compound (S) -7, 8-methylenedioxy-4' -methoxydihydrohomoisoflavone (compound C above) from Chlorophytin and demonstrated that this compound has inhibitory effect on four rapidly proliferating mycobacteria M.fortuitum, M.smegmatis, M.phlei, M.aurum, with the lowest inhibitory concentration being 16-256. mu.g/mL. Compound B having R configuration, (R) -dihydrodaidzein is a hepatoprotective agent; the compound D with S configuration, (S) -equol can be obtained by reducing corresponding dihydro homoisoflavone, is a selective estrogen receptor regulator, and is a strong antioxidant.
The synthesis method of the chiral dihydroisoflavone compound comprises the following steps: the method of hydrogen transfer is utilized to realize the resolution of racemic isoflavonoid compounds Peter Metz (org. Lett.2017, 19, 11, 2981-2984); asymmetric hydrogenation of isoflavones to Haifeng Du (ANGEW CHEM INT ED, 2019, 59, 4498-4504); intramolecular asymmetric hydroacylation reaction of hydroxyalkylated salicylaldehyde Frank Glorius (ANGEW CHEM INT ED, 2011, 50, 4983-4987); asymmetric alkylation reaction of isoflavone compounds Karl A.Scheidt (org.Lett.2009, 11, 17, 4010-; asymmetric addition reaction of mercaptan to isoflavone compound with exocyclic conjugated alkene structure Qi-Lin Zhou (org. Lett.2019, 21, 23, 9391-9395); hydroacylation of salicylaldehyde to alkynes in tandem with intramolecular oxamichael addition reactions levim.stanley (org.lett.2015, 17, 3276-3279), and so on.
These asymmetric hydrogenation reactions are widely studied because of their advantages of high reactivity, high selectivity, high enantioselectivity, cleanliness, atom economy, etc. Asymmetric reduction of isoflavonoids with intra-cyclic conjugation has been reported, but no preparation method for producing chiral isoflavanone compounds from isoflavonoids with extra-cyclic conjugation is available.
Disclosure of Invention
In order to solve the above problems, a first aspect of the present invention provides a method for preparing a chiral dihydroisoflavone compound, comprising the steps of: carrying out hydrogenation reduction reaction on a compound with a structure shown as a formula 1 under the action of a chiral catalyst to obtain a chiral isoflavanone compound;
wherein R is1、R2Each independently selected from one of hydrogen atom, alkyl, aryl, alkoxy, ester group, nitro, halogen, cyano and heterocyclic substituent;
the preparation raw material of the chiral catalyst comprises a chiral ligand and a metal compound.
As a preferable embodiment, the metal compound is an iridium-containing compound and/or a rhodium-containing compound.
As a preferred technical scheme, the iridium-containing compound is selected from [ Ir (COD) Cl]2、[Ir(COD)2]X、Ir(ethylene)2(acac)、[Ir(η2-ethylene)2Cl]2A mixture of one or more of; wherein X is a monovalent anion.
As a preferred embodiment, the monovalent anion is selected from BF4 -、ClO4 -、SbF6 -、PF6 -、OTf-、B(Y)4 -A mixture of one or more of; wherein Y is bis (trifluoromethyl) benzene or fluorobenzene.
As a preferred embodiment, the rhodium-containing compound is [ Rh (acac) (CO) ]]2。
As a preferred technical scheme, the chiral ligand is selected from one of formula 2, formula 3 and formula 4,
wherein Ar is selected from one of phenyl, 4-methylphenyl, 3, 5-dimethylphenyl, 2,4, 6-trimethylphenyl, 3, 5-di (trifluoromethyl) phenyl, 4-methoxy-3, 5-dimethylphenyl and 4-methoxy-3, 5-di-tert-butylphenyl, and R is selected from one of isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl and benzyl.
As a preferred technical scheme, the hydrogenation reduction reaction is carried out in a solvent; the solvent is selected from one or more of 1, 4-dioxane, tetrahydrofuran, acetonitrile, toluene and dichloromethane.
As a preferable technical scheme, the hydrogenation reduction reaction is carried out at the temperature of minus 40-120 ℃.
As a preferable technical scheme, the hydrogenation reduction reaction is carried out under the pressure of 2-100 bar.
In a second aspect of the present invention, there is provided a chiral dihydroisoflavone compound prepared according to the preparation method as described above.
Has the advantages that: the invention provides a preparation method of chiral isoflavanone compound, which adopts a specific catalyst and takes a compound conjugated outside a ring as a substrate to prepare the chiral isoflavanone compound.
Detailed Description
The invention will be further understood by reference to the following detailed description of preferred embodiments of the invention and the examples included therein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. To the extent that a definition of a particular term disclosed in the prior art is inconsistent with any definitions provided herein, the definition of the term provided herein controls.
As used herein, a feature that does not define a singular or plural form is also intended to include a plural form of the feature unless the context clearly indicates otherwise. It will be further understood that the term "prepared from …," as used herein, is synonymous with "comprising," including, "comprising," "having," "including," and/or "containing," when used in this specification means that the recited composition, step, method, article, or device is present, but does not preclude the presence or addition of one or more other compositions, steps, methods, articles, or devices. Furthermore, the use of "preferred," "preferably," "more preferred," etc., when describing embodiments of the present application, is meant to refer to embodiments of the invention that may provide certain benefits, under certain circumstances. However, other embodiments may be preferred, under the same or other circumstances. In addition, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention.
In order to solve the above problems, a first aspect of the present invention provides a method for preparing a chiral dihydroisoflavone compound, comprising the steps of: carrying out hydrogenation reduction reaction on a compound with a structure shown as a formula 1 under the action of a chiral catalyst to obtain a chiral isoflavanone compound;
wherein R is1、R2Are respectively independentThe substituent is selected from one of hydrogen atom, alkyl, aryl, alkoxy, ester group, nitro, halogen, cyano and heterocyclic substituent.
The term "hydrogenation reduction reaction" herein refers to a reaction in which a reactant reacts with hydrogen to convert an unsaturated bond into a saturated bond.
The carbonyl and carbon-carbon double bond in the structure shown in the formula 1 form an exocyclic conjugated structure, and the carbon-carbon double bond is reduced by hydrogen to prepare the isoflavanone compound.
In some preferred embodiments, R is1One selected from hydrogen atom, alkyl and aryl; further preferably, R is1Is an aryl group.
In some preferred embodiments, R is2One selected from hydrogen atom, alkyl group and heterocyclic substituent.
Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, and a pentyl group.
The aryl group in the present application is a substituted aryl group or an unsubstituted aryl group, and in some preferred embodiments, the aryl group is selected from one of phenyl, 4-methoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-tolyl, 3-tolyl, 2-tolyl, 4-ethylphenyl, 3-ethylphenyl, 2-ethylphenyl; more preferably, the aryl group is selected from one of phenyl, 4-methoxyphenyl, 4-fluorophenyl and 4-tolyl.
Examples of the heterocyclic substituent include 1, 3-dioxolane, furan, tetrahydrofuran, ethylene oxide, propylene oxide, pyran, pyridine, imidazole, pyrrole, and the like.
As examples of the compound having the structure shown in formula 1, formula 5 to formula 12, formula 5:
in some preferred embodiments, the starting materials for the preparation of the chiral catalyst comprise a chiral ligand and a metal compound.
The term "chiral" in this context means that an object does not coincide with its mirror image.
The term "chiral catalyst" herein is a metal complex of a chiral ligand and a metal ion.
In some preferred embodiments, the metal compound is an iridium-containing compound and/or a rhodium-containing compound.
In some preferred embodiments, the iridium-containing compound is selected from [ Ir (COD) Cl]2、[Ir(COD)2]X、Ir(ethylene)2(acac)、[Ir(η2-ethylene)2Cl]2A mixture of one or more of; wherein X is a monovalent anion.
COD in the compound is 1, 5-cyclooctadiene, ethylene is ethylene, acac is acetylacetone; among the above compounds, [ Ir (COD) Cl]2Is bis (1, 5-cyclooctadiene) iridium (I) chloride dimer (CAS number: 12112-67-3), Ir (ethylene)2(acac) is iridium (I) bis (ethylene) acetylacetonate, [ Ir (η)2-ethylene)2Cl]2Is dichlorotetra (ethylene) diiridium (I) (CAS number: 39722-81-1).
In some preferred embodiments, the monovalent anion is selected from BF4 -、ClO4 -、SbF6 -、PF6 -、OTf-、B(Y)4 -A mixture of one or more of; wherein Y is bis (trifluoromethyl) benzene or fluorobenzene.
Among the above anions, BF4 -Is boron tetrafluoride ion, ClO4 -Is perchlorate ion, SbF6 -Is antimony hexafluoride ion, PF6 -Is phosphorus hexafluoride ion, OTf-Is trifluoromethanesulfonic acid ion, B (Y)4 -Is tetra [3, 5-bis (trifluoromethyl) benzene]Boron ion (abbreviated as BARF)-) Or tetrakis (4-fluorobenzene) boron ion.
In some preferred embodiments, the rhodium-containing compound is [ Rh (acac) (CO) ]]2(rhodium (I) dicarbonylacetylacetonate, CAS number: 14874-82-9).
In some preferred embodiments, the chiral ligand is selected from one of formula 2, formula 3, formula 4,
wherein Ar is selected from one of phenyl, 4-methylphenyl, 3, 5-dimethylphenyl, 2,4, 6-trimethylphenyl, 3, 5-di (trifluoromethyl) phenyl, 4-methoxy-3, 5-dimethylphenyl and 4-methoxy-3, 5-di-tert-butylphenyl, and R is selected from one of isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl and benzyl.
In some preferred embodiments, R is selected from one of isopropyl, sec-butyl, tert-butyl.
As examples of chiral ligands, mention may be made of those of the formulae 13 to 17,
wherein Ph represents phenyl, tBu represents tert-butyl, Tol represents tolyl, and sBu represents sec-butyl.
As examples of the chiral catalyst, there can be exemplified those of the formulae 18 to 22,
the preparation method of the chiral catalyst comprises the following steps: under the protection of inert gas, the molar ratio of 1: adding the chiral ligand of 1 and a metal compound into a proper amount of solvent, reacting at normal temperature for 2-4 h, and purifying to obtain the chiral ligand.
Taking the preparation method of the chiral catalyst of formula 18 as an example, the method comprises the following steps: in a glove box filled with argon, 0.25mmol of chiral ligand of formula 13, [ Ir (COD) Cl]2(amount of Ir substance: 0.25mmol), NaBARF (0.375mmol, chemical name: sodium tetrakis (3, 5-bis (trifluoromethyl) phenyl) borate, CAS number: 79060-88-1) were added to a Schlenk tube with a magnetic stirrer, and 3mL of dichloromethane were added, the reaction was reacted at room temperature for 3 hours, completion of the ligand-free reaction was confirmed by thin layer chromatography, the catalyst was further purified by column chromatography, and the mobile phase was dichloromethane/petroleum ether.
The term "thin layer chromatography" as used herein refers to a method in which a suitable stationary phase is applied to a glass plate, plastic or aluminum substrate to form a uniform thin layer, and after spotting and development, the resulting thin layer is compared with a chromatogram obtained by the same method based on a specific shift value (Rf) of a suitable reference substance to identify the drug, check impurities or measure the content of the drug. Thin layer chromatography is an important experimental technique for rapid separation and qualitative analysis of small amounts of substances, and is also used to follow the progress of the reaction. The specific method of monitoring the reaction by thin layer chromatography in the present application may be a procedure well known to those skilled in the art.
The term "column chromatography" as used herein is a technique for separating components of a sample mixture by repeated distribution of the components over a number of cycles, depending on the distribution coefficients of the components in the stationary and mobile phases. The specific method of column chromatography in the present application may be a procedure well known to those skilled in the art.
The inventor finds that, in a careful study, iridium element and rhodium element are easy to lose electrons due to weak constraint of atomic nucleus to outer layer electrons, and corresponding complexes can be used as electrophiles to catalyze hydrogenation reaction; when the chiral ligand has nitrogen and phosphorus, the bonding force with metal is enhanced, the performance of the catalyst is more stable, and the steric hindrance brought by the cyclic group and the branched alkyl enables reactants to be easier to generate interaction with metal ions, the reaction rate is obviously accelerated, and the yield and the product purity are also improved; in addition, the chiral ligand is combined with reactants to form an intermediate product with chirality, and hydrogen can only interact with the reactants from a specific position, so that the final product also has chirality.
In some preferred embodiments, the hydrogenation reduction reaction is carried out in a solvent; the solvent is selected from one or more of 1, 4-dioxane, tetrahydrofuran, acetonitrile, toluene and dichloromethane.
In some preferred embodiments, the hydrogenation reduction reaction is carried out at-40 to 120 ℃; preferably, the hydrogenation reduction reaction is carried out at the temperature of-20 to 80 ℃; furthermore, the hydrogenation reduction reaction is carried out at the temperature of-10 to 50 ℃.
In some preferred embodiments, the hydrogenation reduction reaction is carried out at a pressure of 2 to 100 bar; further preferably, the hydrogenation reduction reaction is carried out at a pressure of 2-50 bar; furthermore, the hydrogenation reduction reaction is carried out under the pressure of 2-10 bar.
The reaction progress of the hydrogenation reduction reaction is monitored by thin-layer chromatography to judge the reaction end point, and the reaction is separated by column chromatography after the reaction is completed.
In some preferred embodiments, the silica gel used in the column chromatography has a mesh size of 200 to 300 mesh.
In some preferred embodiments, the mobile phase petroleum ether/ethyl acetate used in the column chromatography is (2-10): 1.
in a second aspect of the present invention, there is provided a chiral dihydroisoflavone compound prepared according to the preparation method as described above.
Examples
The present invention will be specifically described below by way of examples. It should be noted that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention, and that the insubstantial modifications and adaptations of the present invention by those skilled in the art based on the above disclosure are still within the scope of the present invention.
Example 1
Example 1 provides a method for preparing a chiral dihydroisoflavone compound, comprising the steps of:
in a glove box filled with argon, formula 5:
(0.25mmol, 1equiv), chiral catalyst formula 18:
(iridium content was equivalent to 2.5 wt% of substrate) was charged into a 5mL reaction tube, and 1mL of toluene was added, this tube was charged into a stainless steel reaction vessel filled with argon, the reaction vessel was replaced three times with hydrogen, the pressure was charged to 2bar for the last time, the reaction tube was sealed and then heated to 25 ℃ for reaction, the end point of the reaction was judged by thin layer chromatography, the reaction was completely separated by column chromatography, silica gel was 200 mesh, and the mobile phase was petroleum ether: ethyl acetate ═ 6: 1, obtaining a product 1. The yield was 94% and the enantioselectivity 98%.
The reaction formula is as follows:
the structure of product 1 is confirmed as follows:
1H NMR(500MHz,CDCl3)7.90(dd,1H,J＝1.8,8.3Hz,Ar-H),7.46(ddd,1H,J＝1.7,7.2,8.3Hz,Ar-H),7.01(dt,1H,J＝1.2,7.6Hz,Ar-H),6.96(dd,1H,J＝0.6,8.3Hz,Ar-H),4.50(dd,1H,J＝5.2,11.5Hz,C-H),4.15(t,1H,J＝11.2Hz,C-H),2.83-2.90(m,1H,C-H),1.22(d,3H,J＝7.2Hz,C-H)；13C NMR(125MHz,CDCl3)194.8,161.7,135.6,127.3,121.3,120.5,117.7,72.2,40.7,10.6；
HRMS(ESI+):m/z(％)calcd for C10H11O2([M+H]+):163.0754,found:163.0753；
HPLC(Daicel Chiralcel OJ-H,hexane/i-PrOH＝95/5,flow rate＝1.0mL/min)t1＝8.8min(major),t2＝10.4min.
example 2
Embodiment 2 provides a method for preparing a chiral dihydroisoflavone compound, comprising the following steps:
in a glove box filled with argon, formula 6:
(0.25mmol, 1equiv), chiral catalyst formula 19:
(iridium content was equivalent to 2.5 wt% of substrate) was charged into a 5mL reaction tube, and 1mL of toluene was added, this tube was charged into a stainless steel reaction vessel filled with argon, the reaction vessel was replaced three times with hydrogen, the pressure was charged to 2bar for the last time, the reaction tube was sealed and then heated to 25 ℃ for reaction, the end point of the reaction was judged by thin layer chromatography, the reaction was completely separated by column chromatography, silica gel was 200 mesh, and the mobile phase was petroleum ether: ethyl acetate ═ 6: 1, obtaining a product 2. The yield was 92% and the enantioselectivity 96%.
The reaction formula is as follows:
the structure of product 2 was confirmed as follows:
1H NMR(500MHz,CDCl3)7.94(dd,1H,J＝1.4,7.7Hz,Ar-H),7.49(ddd,1H,J＝1.7,7.2,8.3Hz,Ar-H),7.32-7.35(m,2H,Ar-H),7.24-7.26(m,3H,Ar-H),7.04(dt,1H,J＝1.2,7.6Hz,Ar-H),6.97(d,1H,J＝8.3Hz,Ar-H),4.38(dd,1H,J＝4.3,11.5Hz,C-H),4.18(dd,1H,J＝8.3,11.5Hz,C-H),3.30(dd,1H,J＝4.6,14.1Hz,C-H),2.91-2.96(m,1H,C-H),2.72(dd,1H,J＝10.3,13.8Hz,C-H)；13C NMR(125MHz,CDCl3)193.8,161.5,138.2,135.9,129.1(2C),128.7(2C),127.5,126.6,121.4,120.5,117.8,69.4,47.6,32.4；
HRMS(ESI+):m/z(％)calcd for C16H15O2([M+H]+):239.1067,found:239.1065；
HPLC(Daicel Chiralcel OD-H,hexane/i-PrOH＝150/1,flow rate＝1.0mL/min)t1＝26.4min,t2＝29.0min(major).
example 3
Embodiment 3 provides a method for preparing a chiral dihydroisoflavone compound, comprising the following steps:
in a glove box filled with argon, formula 7:
(0.25mmol, 1equiv), chiral catalystThe chemical formula is 20:
(iridium content was equivalent to 2.5 wt% of substrate) was charged into a 5mL reaction tube, and 1mL of toluene was added, this tube was charged into a stainless steel reaction vessel filled with argon, the reaction vessel was replaced three times with hydrogen, the pressure was charged to 2bar for the last time, the reaction tube was sealed and then heated to 25 ℃ for reaction, the end point of the reaction was judged by thin layer chromatography, the reaction was completely separated by column chromatography, silica gel was 200 mesh, and the mobile phase was petroleum ether: ethyl acetate ═ 6: 1 to obtain a product 3. The yield was 96% and the enantioselectivity 98%.
The reaction formula is as follows:
the structure of product 3 is confirmed as follows:
1H NMR(500MHz,CDCl3)7.84(dd,J＝14.9,3.0Hz,1H),7.45(td,J＝15.0,3.0Hz,1H),7.30–7.07(m,2H),7.07–6.71(m,4H),4.35–3.99(m,2H),3.92–3.60(m,4H),3.00(dd,J＝24.8,15.5Hz,1H),2.75(dd,J＝24.8,15.5Hz,1H).13C NMR(125MHz,CDCl3)194.79(s),160.31(s),159.28(s),135.49(s),131.57(s),129.78(s),127.77(s),121.62(s),121.33(s),116.44(s),114.74(s),70.22(s),56.08(s),44.81(s),33.57(s)；
HRMS(ESI+):m/z(％)calcd for C17H17O3([M+H]+):268.1099,found:268.1101.
example 4
Embodiment 4 provides a method for preparing a chiral dihydroisoflavone compound, comprising the steps of:
in a glove box filled with argon, formula 8:
(0.25mmol, 1equiv), chiral catalyst formula 21:
(Iridium content corresponds to 2.5% by weight of the substrate) is addedAdding 1mL of toluene into a 5mL reaction tube, placing the tube into a stainless steel reaction kettle filled with argon, replacing the reaction kettle with hydrogen for three times, filling the pressure to 2bar for the last time, sealing the reaction tube, heating to 40 ℃ for reaction, judging the reaction endpoint by thin layer chromatography, and separating by column chromatography when the reaction is completely carried out, wherein the silica gel is 200 meshes, and the mobile phase is petroleum ether: ethyl acetate ═ 6: 1 to obtain a product 4. The yield was 96% and the enantioselectivity 97%.
The reaction formula is as follows:
the structure of product 4 is confirmed as follows:
1H NMR(500MHz,CDCl3)7.84(dd,J＝14.9,3.0Hz,1H),7.45(td,J＝15.0,3.0Hz,1H),7.34–7.07(m,4H),7.07–6.80(m,2H),4.11(ddd,J＝38.4,26.1,14.0Hz,2H),3.82(dd,J＝24.2,13.9Hz,1H),3.00(dd,J＝24.7,13.7Hz,1H),2.75(dd,J＝24.8,13.8Hz,1H).13CNMR(125MHz,CDCl3)194.79(s),163.53(s),161.51(s),160.31(s),135.49(s),134.96(d,J＝2.7Hz),130.51(d,J＝7.6Hz),127.77(s),121.62(s),121.33(s),116.44(s),115.96(s),115.80(s),70.22(s),44.81(s),33.57(s).19F NMR(472MHz,Chloroform)-115.50(s)；
HRMS(ESI+):m/z(％)calcd for C17H14FO2([M+H]+):256.0900,found:256.0903.
example 5
Example 5 provides a method for preparing a chiral dihydroisoflavone compound comprising the steps of:
in a glove box filled with argon, formula 9:
(0.25mmol, 1equiv), chiral catalyst formula 22:
(Iridium content was equivalent to 2.5% by weight of the substrate) was charged into a 5mL reaction tube, and 1mL of toluene was added, and the tube was charged with an argon-filled stainless steel tubeSteel reation kettle, this reation kettle replaces the cubic with hydrogen, lets pressure fill to 2bar for the last time, seals the reaction tube and then heats to 40 ℃ reaction, judges the reaction endpoint through thin layer chromatography, treats that the reaction is totally separated through the column chromatography, and silica gel is 200 meshes, and the mobile phase is petroleum ether: ethyl acetate ═ 6: 1 to obtain a product 5. The yield was 97% and the enantioselectivity was 99%.
The reaction formula is as follows:
the structure of product 5 was confirmed as follows:
1H NMR(500MHz,CDCl3)7.84(dd,J＝14.9,3.0Hz,1H),7.45(td,J＝15.0,3.0Hz,1H),7.15–6.74(m,6H),4.35–3.97(m,2H),3.82(dd,J＝24.2,14.0Hz,1H),3.00(dd,J＝24.8,15.2Hz,1H),2.75(dd,J＝24.8,15.3Hz,1H),2.19(s,3H).13C NMR(125MHz,CDCl3)194.79(s),160.31(s),136.54(s),135.49(s),135.24(s),129.67(s),129.06(s),127.77(s),121.62(s),121.33(s),116.44(s),70.22(s),44.81(s),33.57(s),21.12(s)；
HRMS(ESI+):m/z(％)calcd for C17H17O2([M+H]+):252.1150,found:252.1148.
example 6
Example 6 provides a method for preparing a chiral dihydroisoflavone compound comprising the steps of:
in a glove box filled with argon, formula 10:
(0.25mmol, 1equiv), chiral catalyst formula 18:
(Iridium content is equivalent to 2.5 wt% of substrate) into a 5mL reaction tube, adding 1mL of toluene, charging the tube into a stainless steel reaction vessel filled with argon, replacing the reaction vessel with hydrogen three times, charging pressure to 2bar for the last time, sealing the reaction vessel, heating to 40 deg.C for reaction, determining the end point of the reaction by thin layer chromatography, and waiting for the reaction to be completedThe separation is carried out by column chromatography, silica gel is 200 meshes, and the mobile phase is petroleum ether: ethyl acetate ═ 6: 1 to obtain a product 6. The yield was 93% and the enantioselectivity was 99%.
The reaction formula is as follows:
the structure of product 6 was confirmed as follows:
1H NMR(500MHz,CDCl3)7.75(d,J＝2.9Hz,1H),7.46–7.09(m,6H),6.96(d,J＝15.0Hz,1H),4.34–3.96(m,2H),3.82(dd,J＝24.2,14.0Hz,1H),3.00(dd,J＝24.8,15.2Hz,1H),2.75(dd,J＝24.8,15.3Hz,1H),2.42(s,3H).13C NMR(125MHz,CDCl3)195.09(s),160.22(s),139.00(s),137.61(s),130.25(s),129.07(d,J＝3.7Hz),127.23(s),126.80(s),119.91(s),116.95(s),70.22(s),44.81(s),33.57(s),21.21(s)；
HRMS(ESI+):m/z(％)calcd for C17H17O2([M+H]+):252.1150,found:252.1151.
example 7
Example 7 provides a method for preparing a chiral dihydroisoflavone compound comprising the steps of:
in a glove box filled with argon, formula 11:
(0.25mmol, 1equiv), chiral catalyst formula 19:
(iridium content was equivalent to 2.5 wt% of substrate) was charged into a 5mL reaction tube, and 1mL of toluene was added, the tube was charged into a stainless steel reaction vessel filled with argon, the reaction vessel was replaced three times with hydrogen, the pressure was charged to 2bar for the last time, the reaction tube was sealed and then heated to 40 ℃ for reaction, the end point of the reaction was judged by thin layer chromatography, the reaction was completely separated by column chromatography, silica gel was 200 mesh, and the mobile phase was petroleum ether: ethyl acetate ═ 6: 1 to obtain a product 7. The yield was 94% and the enantioselectivity 98%.
Reaction ofFormula (II):
the structure of product 7 was confirmed as follows:
1H NMR(500MHz,CDCl3)7.75(d,J＝2.9Hz,1H),7.35(dd,J＝15.0,2.9Hz,1H),6.96(d,J＝15.0Hz,1H),4.07(dd,J＝24.5,12.8Hz,1H),3.82(dd,J＝24.6,12.8Hz,1H),3.69(p,J＝12.6Hz,1H),2.42(s,3H),1.62–1.49(m,2H),1.45–1.18(m,4H),0.89(t,J＝12.7Hz,3H).13C NMR(125MHz,CDCl3)196.95(s),160.22(s),137.61(s),130.25(s),127.23(s),119.91(s),116.95(s),70.07(s),44.47(s),32.21(s),30.17(s),23.62(s),21.21(s),14.00(s)；
HRMS(ESI+):m/z(％)calcd for C14H19O2([M+H]+):218.1307,found:218.1309.
example 8
Embodiment 8 provides a method for preparing a chiral dihydroisoflavone compound, comprising the steps of:
in a glove box filled with argon, formula 12:
(0.25mmol, 1equiv), chiral catalyst formula 20:
(iridium content was equivalent to 2.5 wt% of substrate) was charged into a 5mL reaction tube, and 1mL of toluene was added, this tube was charged into a stainless steel reaction vessel filled with argon, the reaction vessel was replaced three times with hydrogen, the pressure was charged to 2bar for the last time, the reaction tube was sealed and then heated to 25 ℃ for reaction, the end point of the reaction was judged by thin layer chromatography, the reaction was completely separated by column chromatography, silica gel was 200 mesh, and the mobile phase was petroleum ether: ethyl acetate ═ 6: 1 to obtain a product 8. The yield was 90% and the enantioselectivity 98%.
The reaction formula is as follows:
the structure of product 8 was confirmed as follows:
1H NMR(500MHz,CDCl3)7.43(s,1H),7.35–7.23(m,4H),7.19(dt,J＝8.9,4.4Hz,1H),6.65(s,1H),6.06(s,2H),4.17(p,J＝7.5Hz,1H),4.07(dd,J＝12.3,7.2Hz,1H),3.82(dd,J＝12.3,7.1Hz,1H),3.00(dd,J＝12.4,7.7Hz,1H),2.75(dd,J＝12.4,7.7Hz,1H).13CNMR(125MHz,CDCl3)197.08(s),154.92(s),150.22(s),146.28(s),139.00(s),129.07(d,J＝3.7Hz),126.80(s),116.61(s),106.98(s),101.66(s),96.25(s),68.93(s),46.76(s),34.08(s)；
HRMS(ESI+):m/z(％)calcd for C17H15O4([M+H]+):282.0892,found:282.0893.
according to the embodiments 1 to 8, the chiral isoflavanone compound is prepared by using the extracyclic conjugated compound as the substrate and adopting the specific catalyst, and the method is simple, convenient and feasible, is suitable for large-scale industrial production and has popularization value.
The foregoing examples are merely illustrative and serve to explain some of the features of the method of the present invention. The appended claims are intended to claim as broad a scope as is contemplated, and the examples presented herein are merely illustrative of selected implementations in accordance with all possible combinations of examples. Accordingly, it is applicants' intention that the appended claims are not to be limited by the choice of examples illustrating features of the invention. Also, where numerical ranges are used in the claims, subranges therein are included, and variations in these ranges are also to be construed as possible being covered by the appended claims.
Claims (10)
1. A method for preparing a chiral dihydroisoflavone compound is characterized by comprising the following steps: carrying out hydrogenation reduction reaction on a compound with a structure shown as a formula 1 under the action of a chiral catalyst to obtain a chiral isoflavanone compound;
formula 1:
wherein R is1、R2Each independently selected from one of hydrogen atom, alkyl, aryl, alkoxy, ester group, nitro, halogen, cyano and heterocyclic substituent;
the preparation raw material of the chiral catalyst comprises a chiral ligand and a metal compound.
2. The process for producing chiral dihydroisoflavone compound according to claim 1, wherein the metal compound is an iridium-containing compound and/or a rhodium-containing compound.
3. The process for preparing chiral dihydroisoflavone compounds according to claim 2, wherein the iridium-containing compounds are selected from [ Ir (COD) Cl]2、[Ir(COD)2]X、Ir(ethylene)2(acac)、[Ir(η2-ethylene)2Cl]2A mixture of one or more of; wherein X is a monovalent anion.
4. The process for the preparation of chiral dihydroisoflavone compounds as claimed in claim 3, wherein the monovalent anion is selected from BF4 -、ClO4 -、SbF6 -、PF6 -、OTf-、B(Y)4 -A mixture of one or more of; wherein Y is bis (trifluoromethyl) benzene or fluorobenzene.
5. The process for preparing chiral dihydroisoflavone compounds as claimed in claim 2, wherein the rhodium-containing compounds are [ Rh (acac) (CO)]2、[Rh(COD)Cl]2、Rh(ethylene)2(acac) mixtures of one or more of (a), (b), (c), (d.
6. The method for preparing chiral dihydroisoflavone compound according to any of claims 1 to 5, wherein the chiral ligand is selected from one of formula 2, formula 3, and formula 4, formula 2:
formula 3:
formula 4:
wherein Ar is selected from one of phenyl, 4-methylphenyl, 3, 5-dimethylphenyl, 2,4, 6-trimethylphenyl, 3, 5-di (trifluoromethyl) phenyl, 4-methoxy-3, 5-dimethylphenyl and 4-methoxy-3, 5-di-tert-butylphenyl, and R is selected from one of isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl and benzyl.
7. The process for preparing chiral dihydroisoflavone compounds according to claim 1, wherein the hydrogenation reduction is carried out in a solvent; the solvent is selected from one or more of 1, 4-dioxane, tetrahydrofuran, acetonitrile, toluene and dichloromethane.
8. The method for preparing chiral isoflavanone compound according to claim 1, wherein the hydrogenation reduction reaction is carried out at-40 to 120 ℃.
9. The method for preparing chiral dihydroisoflavone compound according to claim 1, wherein the hydrogenation reduction is carried out at a pressure of 2 to 100 bar.
10. A chiral dihydroisoflavone compound characterized by being produced by the production method according to any one of claims 1 to 9.
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