CN113979982A - Preparation method and application of chiral dihydrochromone-2-carboxylic acid compound and derivative thereof - Google Patents
Preparation method and application of chiral dihydrochromone-2-carboxylic acid compound and derivative thereof Download PDFInfo
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- CN113979982A CN113979982A CN202111292465.5A CN202111292465A CN113979982A CN 113979982 A CN113979982 A CN 113979982A CN 202111292465 A CN202111292465 A CN 202111292465A CN 113979982 A CN113979982 A CN 113979982A
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- chiral
- dihydrochromone
- carboxylic acid
- derivatives
- acid compounds
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Links
- 238000002360 preparation method Methods 0.000 title claims description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 239000003054 catalyst Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 20
- 150000004696 coordination complex Chemical class 0.000 claims abstract description 9
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- -1 allyloxycarbonyl Chemical group 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 27
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 239000002184 metal Substances 0.000 claims description 19
- 229910052751 metal Inorganic materials 0.000 claims description 19
- 239000003446 ligand Substances 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 11
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 10
- 235000019253 formic acid Nutrition 0.000 claims description 10
- 239000003208 petroleum Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000004440 column chromatography Methods 0.000 claims description 9
- 125000001624 naphthyl group Chemical group 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 125000004185 ester group Chemical group 0.000 claims description 8
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229930014626 natural product Natural products 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 238000010668 complexation reaction Methods 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 2
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 2
- JMRDSOGPCPPHML-UHFFFAOYSA-N 2-(2,6-diisopropylphenyl)-3,3-dimethyl-2-azaspiro[4.5]dec-1-en-2-ium-1-ide Chemical compound CC(C)C1=CC=CC(C(C)C)=C1N1C(C)(C)CC2(CCCCC2)[C]1 JMRDSOGPCPPHML-UHFFFAOYSA-N 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- TZOYXRMEFDYWDQ-UHFFFAOYSA-N 3,4-dihydro-1h-quinolin-2-one Chemical class C1=CC=C2NC(=O)CCC2=C1 TZOYXRMEFDYWDQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 230000000536 complexating effect Effects 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 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
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 238000004809 thin layer chromatography Methods 0.000 claims description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- RVMGXWBCQGAWBR-UHFFFAOYSA-N 4-oxo-1-benzopyran-2-carboxylic acid Chemical class C1=CC=C2OC(C(=O)O)=CC(=O)C2=C1 RVMGXWBCQGAWBR-UHFFFAOYSA-N 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 abstract description 16
- 239000000126 substance Substances 0.000 abstract description 8
- 239000000758 substrate Substances 0.000 abstract description 4
- 239000000654 additive Substances 0.000 abstract 1
- 230000000996 additive effect Effects 0.000 abstract 1
- 238000005984 hydrogenation reaction Methods 0.000 description 27
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 23
- MSTDXOZUKAQDRL-UHFFFAOYSA-N 4-Chromanone Chemical compound C1=CC=C2C(=O)CCOC2=C1 MSTDXOZUKAQDRL-UHFFFAOYSA-N 0.000 description 15
- 239000010948 rhodium Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000003708 ampul Substances 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 6
- 150000004777 chromones Chemical class 0.000 description 6
- 238000011049 filling Methods 0.000 description 6
- 239000003517 fume Substances 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 238000002390 rotary evaporation Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- SEBPXHSZHLFWRL-UHFFFAOYSA-N 3,4-dihydro-2,2,5,7,8-pentamethyl-2h-1-benzopyran-6-ol Chemical compound O1C(C)(C)CCC2=C1C(C)=C(C)C(O)=C2C SEBPXHSZHLFWRL-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical group C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000006459 hydrosilylation reaction Methods 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- 229940042040 innovative drug Drugs 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical group CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001562 benzopyrans Chemical group 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 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
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 150000004699 copper complex Chemical class 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000004492 methyl ester group Chemical group 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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
- C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The method is to perform asymmetric hydrogenation on raw materials shown as I under the catalysis of a chiral metal complex catalyst to obtain chiral dihydrochromone-2-carboxylic acid compounds and derivatives thereof shown as II, and the method has high catalytic efficiency (up to 10000 conversion number), and excellent chemical selectivity and stereoselectivity (up to 100 percent of chemical selectivity and 99 percent of chemical selectivity)eeThe stereoselectivity), has the advantages of mild reaction conditions, no need of any additive, wide substrate application range and the like, and the prepared chiral dihydrochromone-2-carboxylic acid compound and the derivative thereof have wide application.
Description
Technical Field
The invention belongs to the technical field of compound synthesis, and particularly relates to a preparation method of chiral dihydrochromone-2-carboxylic acid compounds and derivatives thereof.
Background
The dihydrochromone compound and the derivative thereof are widely existed in natural products and medicinal active molecules, and have wide pharmacological activities of antitumor, antibacterial, antidiabetic, antioxidant, anti-inflammatory, neuroprotective and the like. In addition, the compounds can also construct compound molecules with novel structures through chemical reactions with rich carbonyl groups, such as reduction to alcohol to obtain chromogen alcohol, reduction to methylene to obtain benzopyran skeleton, oxime formation with hydroxylamine, and the like, and series reactions derived from substituent groups on the skeleton, provide chemical entities for innovative drug research, and have important values in the field of organic synthesis and pharmaceutical chemistry research. The following formula lists some representative bioactive dihydrochromones and natural products and drug molecules derived therefrom.
The thiodihydrochromone and dihydroquinolinone compounds are analogs of dihydrochromone, and although the content of the compounds in natural products is less than that of the dihydrochromone compounds, the compounds have been reported to have wide pharmacological activity and even higher activity compared with the dihydrochromone compounds.
At present, although there are a lot of reports related to the synthesis of dihydrochromone, the stereoselectivity example is relatively limited. Among the existing methods for synthesizing chiral dihydrochromone compounds, the method for obtaining optically pure dihydrochromone by asymmetric catalytic hydrogenation of C2 or/and C3 substituted chromone compounds is the most direct and efficient method. The asymmetric catalytic hydrogenation reaction catalyzed by the transition metal has the advantages of high atom economy, environmental protection, simple and convenient operation and the like, and occupies an important position in academia and industry. In 2013, Glorius et al reported asymmetric reduction of C2 substituted chromone compounds catalyzed by chiral ruthenium azacarbene complexes (Ru-NHC), wherein the chromone compounds are completely reduced into protophenol compounds under the catalytic system, and secondary alcohols are selectively oxidized by PCC to obtain optically pure dihydrochromone compounds at C2. The method has wide substrate applicability, high yield, and enantioselectivity up to 91%ee。
In the same year, Metz task group reports a method for preparing optically pure dihydrochromone compounds by dynamic resolution catalyzed by chiral metal complexes. Taking a rhodium (III)/diamine complex as a catalyst, and obtaining the dihydrochromone and the chromanol through asymmetric hydrogen transfer reaction in the presence of formic acid and triethylamine. They also utilize the catalytic system to synthesize a prenyl dihydrochromone with pharmacological activity.
In 2017, Wanjun task group realizes the asymmetric reduction reaction of a copper complex hydrosilation catalyst for catalyzing C2 substituted chromone compounds to obtain a series of chiral dihydrochromone compounds, the reaction takes hydrosilation as a hydrogen source, and a non-noble metal catalyst is adopted, so that the influence on the environment is small, and certain advantages are achieved. In addition, the catalytic system also obtains excellent reaction results in the synthesis of the thiodihydrochromone. However, the high amount of catalyst used (up to 20 mol%) limits its industrial application.
In 2018, zhangwan bin subject group adopts self-developed RuPHOX-Ru complex catalyst to catalyze asymmetric reduction of C2 substituted chromone, chiral chromanol is obtained with chemical yield as high as 99%, diastereoselectivity of >20:1 and stereoselectivity of 99%, and chiral dihydrochromone compounds are obtained by oxidation in the presence of PCC. Furthermore, they also showed by control experiments that the reaction underwent a continuous hydrogenation process of the C = C and C = O double bonds.
The above catalytic systems all achieve excellent catalytic effects, but have certain problems, for example, the catalytic systems reported by glorious and zhangwan bin do not have functional group selectivity for the reduction of chromone compounds, and all directly obtain chiral chromanol, and the dihydrochromone compounds can be obtained through oxidation reaction. In addition, in the reported examples of asymmetric reduction, the substituent at the C2 position is mainly alkyl or aryl, and only the catalytic system developed by the Wanjun subject group tries to reduce two cases of chromone compounds substituted by ester groups at the C2 position. In fact, however, the introduction of the C2 reactive functional group (such as carboxyl, ester group, cyano, etc.) is beneficial to the further derivation and enrichment of the chiral dihydrochromone skeleton, so as to be more widely used in organic synthesis and innovative drug research. Therefore, the catalytic system reported by the invention has obvious advantages in view of the above two problems of the existing catalytic system.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a preparation method and application of chiral dihydrochromone-2-carboxylic acid compounds and derivatives thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of chiral dihydrochromone-2-carboxylic acid compounds and derivatives thereof is characterized in that raw materials shown in the specification I are subjected to asymmetric catalytic hydrogenation reaction under the catalysis of a chiral metal complex catalyst to obtain chiral dihydrochromone-2-carboxylic acid compounds and derivatives thereof shown in the specification II, and the reaction formula is as follows:
wherein X is O, S, NH or N-R ', R' is a secondary amine protecting group; r1Is any one or the combination of at least two of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 perfluoroalkyl, halogen, phenyl, benzyl, naphthyl, ester group, heterocyclic substituent, amino or amine; r2Is hydroxy, alkoxy, aryloxy or amino; r3Is C1-C8 alkyl, phenyl, benzyl, naphthyl, heterocyclic substituent; the marked positions represent chiral carbon atoms, and n is an integer from 0 to 4.
The chiral dihydrochromone-2-carboxylic acid compound shown in II and the derivative thereof are obtained through one-step reaction by asymmetric hydrogenation reaction catalyzed by a chiral metal catalyst, so that the problem that the dihydrochromone is obtained by reducing to obtain the chromanol and oxidizing to obtain the dihydrochromone in the existing catalytic system is solved, and meanwhile, the catalytic system can be compatible with active functional groups, so that the chromone reaction substrates are effectively widened, and the construction and further enrichment of a chiral dihydrochromone compound library are promoted. The catalytic system also has high catalytic efficiency (up to 10000 conversion number) and outstanding selectivity (up to 100% chemical selectivity, 99%)eeStereoselectivity of (d), etc.
Preferably, the derivative is a chiral thiodihydrochromone compound and/or a chiral dihydroquinolinone compound.
Preferably, R' is any one of benzyloxycarbonyl, tert-butoxycarbonyl, fluorenyl methoxycarbonyl, allyloxycarbonyl, trimethylsiloxyethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, o-nitrobenzenesulfonyl, p-o-nitrobenzenesulfonyl, pivaloyl, benzoyl trityl, 2, 4-dimethoxybenzyl, p-methoxybenzyl or benzyl.
Preferably, the halogen is fluorine, chlorine, bromine and iodine.
In the present invention, R is as shown in I and II1Is a substituent on a benzene ring, the number of the substituent is n, n is an integer of 0-4, namely n can be 0, 1,2, 3 or 4. Said R1Is any one or the combination of at least two of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 perfluoroalkyl, halogen, phenyl, benzyl, naphthyl, ester group, heterocyclic substituent, amino or amine, wherein the combination refers to a plurality of groups (up to 4) substituted on the benzene ring, the groups can be the same or different, for example, when two positions on the benzene ring are substituted by the substituent, n =2, R1One or two of the above groups may be selected, such as methyl and phenyl.
In the present invention, the alkyl group having from C1 to C6 is an alkyl group having from 1 to 6 carbon atoms, and specifically, it may be a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, an isopentyl group, a hexyl group, or the like.
In the present invention, the C1-C6 alkoxy group is an alkoxy group having 1 to 6 carbon atoms, and specifically, it may be a methoxy group, an ethoxy group, a propoxy group, a butoxy group or the like.
In the invention, the C1-C6 perfluoroalkyl group is a C1-6 perfluoroalkyl group, such as trifluoromethyl, pentafluoroethyl and the like.
In the invention, the ester group is methyl ester group, ethyl ester group, propyl ester group and the like.
In the present invention, the heterocyclic substituent is a group containing O, S or N, preferably furyl, thienyl, pyridyl, pyrrolyl and the like.
Preferably, the chiral metal catalyst is prepared by in-situ complexing a metal salt with a chiral ligand.
Preferably, theThe metal salt is Rh (NBD)2BF4、Rh(NBD)2SbF6、Rh(NBD)2BARF、Rh(COD)2BF4、Rh(COD)2SbF6、Rh(COD)2BARF、[Rh(NBD)Cl]2、[Rh(COD)Cl]2、(CAAC-Cy)Rh(COD)Cl、[Ir(COD)Cl]2、[Ir(NBD)Cl]2、[Ir(COD)(OCH3)]2、Ru(PPh3)4Cl2Any one of them.
Preferably, the chiral ligand is a ligand with a structure shown as A-N or a ligand with a configuration opposite to any one of the ligands with the structures shown as A-N:
wherein, in A-H, Ar is phenyl, 4-methylphenyl, 3, 5-dimethylphenyl, 2,4, 6-trimethylphenyl, 3, 5-di (trifluoromethyl) phenyl, 4-methoxy-3, 5-dimethylphenyl, 4-methoxy-3, 5-di-tert-butylphenyl; in the I, R is methyl, ethyl, isopropyl, phenyl or benzyl; r in M-N1And R2Is tert-butyl, cyclohexyl, phenyl, 2-methylphenyl, 2-furyl, 3, 5-dimethylphenyl, 1-naphthyl, 4-methoxy-3, 5-dimethylphenyl, 4-trifluoromethylphenyl, 3, 5-bistrifluoromethylphenyl. t Bu represents a tert-butyl group, Me represents a methyl group, Cy represents a cyclohexyl group, and Ph represents a phenyl group.
Preferably, the chiral ligand is a ligand having a structure shown as H, K-N.
Preferably, the molar ratio of the metal salt to the chiral ligand in the chiral metal complex catalyst is 1:1.1 to 1:5, such as 1:1.1, 1:1.2, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, or 1: 5.
Preferably, the chiral metal catalyst complex reaction temperature is 0-60 ℃, such as 0 ℃,5 ℃, 10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃ or 60 ℃.
Preferably, the chiral metal catalyst is complexed for a time of 0.5 to 12 hours, such as 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours.
Preferably, the complexation of the metal salt with the chiral ligand is performed in an organic solvent, which is dichloromethane, 1, 2-dichloroethane, methanol, ethanol, isopropanol, tert-butanol, trifluoroethanol, hexafluoroisopropanol, toluene, n-hexane, carbon tetrachloride, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, acetone, preferably dichloromethane or methanol.
Preferably, the ratio of the chiral metal complex catalyst to the material of I is 0.0001:1 to 0.02:1, such as 0.0001:1, 0.000125:1, 0.0002:1, 0.00025:1, 0.0003:1, 0.001:1, 0.002:1, 0.01:1 or 0.02: 1.
Preferably, the asymmetric catalytic hydrogenation reaction is at a temperature of 0 ℃ to 100 ℃, such as 0 ℃,5 ℃, 10 ℃, 20 ℃, 25 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃ or 100 ℃.
Preferably, the hydrogen pressure of the asymmetric catalytic hydrogenation reaction is 5-100 atm, such as 5atm, 10atm, 20atm, 30atm, 40atm, 50atm, 60atm, 70atm, 80atm, 90atm, 100 atm.
Preferably, the asymmetric catalytic hydrogenation reaction is carried out for a period of time of 0.5 to 48 hours, such as 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 15 hours, 18 hours, 24 hours, 36 hours, or 48 hours.
Preferably, after the asymmetric catalytic hydrogenation reaction is finished, concentrating the organic solvent, and separating to obtain the chiral dihydrochromone-2-carboxylic acid compound and the derivative thereof.
Preferably, the separation method is column chromatography, thin layer chromatography or recrystallization;
preferably, the eluent used for the column chromatography is a mixed liquid of petroleum ether, ethyl acetate and formic acid.
Preferably, the volume ratio of petroleum ether to ethyl acetate is 5:1 to 80:1, such as 5:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1 or 80:1, and 2% formic acid is added according to the total volume at each ratio.
The preparation method of the chiral dihydrochromone-2-carboxylic acid compound and the derivative thereof specifically comprises the following steps:
(1) reacting a metal salt with a chiral ligand to form a chiral metal complex catalyst;
(2) the chiral dihydrochromone-2-carboxylic acid compound and the derivative thereof shown in the II are obtained by carrying out asymmetric catalytic hydrogenation on the raw material shown in the I under the catalysis of the chiral metal catalyst prepared in the step (1), and the reaction formula is as follows:
wherein X is O, S, NH or N-R ', R' is a secondary amine protecting group; r1Is any one or the combination of at least two of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 perfluoroalkyl, halogen, phenyl, benzyl, naphthyl, ester group, heterocyclic substituent, amino or amine; r2Is hydroxy, alkoxy, aryloxy or amino; r3Is C1-C8 alkyl, phenyl, benzyl, naphthyl, heterocyclic substituent; the marked positions represent chiral carbon atoms, and n is an integer from 0 to 4.
The invention provides the chiral dihydrochromone-2-carboxylic acid compound and the derivative thereof prepared by the preparation method, and the chiral dihydrochromone-2-carboxylic acid compound and the derivative thereof obtained by the method have high chemical yield and high optical purity.
The invention provides application of the chiral dihydrochromone-2-carboxylic acid compound and the derivative thereof in preparation of natural products and active intermediates of medicines.
Compared with the prior art, the invention has the following advantages:
in the invention, the chiral dihydrochromone-2-carboxylic acid compound and the derivative thereof are obtained through one-step reaction by asymmetric hydrogenation reaction catalyzed by a chiral metal catalyst, the catalytic efficiency is high (up to 10000 conversion numbers), and the selectivity is outstanding (up to 100 percent of chemical selectivity and 99 percent of chemical selectivity)eeStereoselectivity of (a). Meanwhile, the catalytic system can be compatible with active functional groups, so that chromone reaction substrates are effectively widened, and the prepared chiral dihydrochromone-2-carboxylic acid compounds and derivatives thereof have wide application and good application prospect.
Detailed Description
The technical solution of the present invention is further illustrated by the following specific embodiments. The examples are provided only to aid understanding of the invention and should not be construed as limiting the invention.
In the following experimental procedure, all reactions involving air-or moisture-sensitive compounds were carried out in a dry autoclave or glove box under an argon atmosphere. Unless otherwise indicated, all reagents and solvents were purchased from commercial suppliers without further purification, and anhydrous solvents were transferred using syringes.
Process for preparing compounds1H NMR, 13C NMR spectra were determined using Bruker ADVANCE II (400 MHz) using deuterated chloroform or deuterated dimethyl sulfoxide as solvent and Tetramethylsilane (TMS) as internal standard, and data are expressed as: diversity (s = singlet, d = doublet, t = triplet, m = multiplet). Enantiomeric excess was determined by using a chiral column in an Agilent 1200 series high performance liquid chromatography.
Example 1
In this example, a 4-oxo-dihydrochromone-2-carboxylic acid is prepared having the following structural formula:
the preparation method comprises the following steps:
a dry 5mL hydrogenation ampoule was taken and charged to a magnetic stirrer and 0.75 mg, 0.002 mmol Rh (NBD) was weighed into a glove box2BF4And 1.38 mg, 0.0022 mmol of JosiPhos (structure shown in formula M), adding into the above reaction flask, adding 1 ml of anhydrous tetrahydrofuran, stirring for 30 min, adding 38mg of 4-oxo-4H-chromone-2-carboxylic acid into the reaction flask, placing the hydrogenation reaction flask into a hydrogenation reaction kettle, and transferring outAnd (5) casing. And (3) exchanging hydrogen for 3-5 times, filling hydrogen until the pressure is 20atm, and stirring for 18 hours at room temperature. After releasing hydrogen in the reaction kettle in a fume hood, opening the reaction kettle, taking out a hydrogenation reaction bottle, removing the solvent by rotary evaporation to obtain a crude hydrogenation reaction product, separating by column chromatography, adopting 200-mesh 300-mesh silica gel, and using petroleum ether as a mobile phase in a volume ratio: ethyl acetate: formic acid =30:1: 0.5.
The product was a white solid (97% yield) with an optical purity of 99%ee。
The structural characterization data is as follows:
1H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 7.52 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 5.27 (dd, J = 7.3, 5.4 Hz, 1H), 3.07 (dd, J = 17.0, 5.2 Hz, 1H), 2.94 (dd, J = 17.0, 7.5 Hz, 1H), 2.27 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 189.89, 170.43, 158.07, 137.20, 130.60, 125.61, 120.27, 117.78, 74.47, 19.88.
example 2
In this example, 7-tert-butyl-4-oxo-dihydrochromone-2-carboxylic acid was prepared having the structural formula:
the preparation method comprises the following steps:
a dry 5mL hydrogenation ampoule was taken and charged to a magnetic stirrer and 0.46 mg, 0.002 mmol [ Rh (NBD) Cl ] was weighed into a glove box]2And 1.80mg, 0.0022 mmol MandyPhos (structure shown in formula H), adding into the above reaction flask, adding 2 ml of anhydrous dichloromethane, stirring for 1 hr, adding 49mg of 7-tert-butyl-4-oxo-4H-chromone-2-carboxylic acid into the reaction flask at one time, placing the hydrogenation reaction flask into a hydrogenation reaction kettle, and transferring out of a glove box. And (3) exchanging hydrogen for 3-5 times, filling hydrogen until the pressure is 30atm, and stirring for 48 hours at room temperature. Releasing hydrogen in the reaction kettle in a fume hood, opening the reaction kettle, taking out a hydrogenation reaction bottle, removing the solvent by rotary evaporation, and separating pure by column chromatographyAnd (2) adopting 200-mesh 300-mesh silica gel, wherein the volume ratio of the mobile phase is petroleum ether: ethyl acetate: formic acid =20:1: 0.5.
The product was an off-white solid (yield 93%) with an optical purity of 98%ee。
The structural characterization data is as follows:
1H NMR (400 MHz, DMSO-d6) δ 13.41 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 1.2 Hz, 1H), 5.29 (dd, J = 7.8, 5.2 Hz, 1H), 3.03 (dd, J = 16.9, 5.1 Hz, 1H), 2.93 (dd, J = 16.9, 8.0 Hz, 1H), 1.28 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 189.43, 170.37, 160.16, 159.94, 125.86, 119.16, 118.33, 114.22, 74.52, 35.06, 30.53.
example 3
In this example, 6-fluoro-4-oxo-dihydrochromone-2-carboxylic acid was prepared with the following structural formula:
the preparation method comprises the following steps:
a dry 5mL hydrogenation ampoule was taken and placed in a magnetic stirrer and 0.34 mg, 0.001 mmol [ Ir (COD) Cl ] was weighed in a glove box]2And 1.50mg, 0.002 mmol of ChenPhos (structure shown in formula L), adding into the above reaction bottle, adding 1 ml of anhydrous methanol, stirring for 1 hour, adding 63mg of 6-fluoro-4-oxo-dihydrochromone-2-carboxylic acid into the reaction bottle at one time, placing the hydrogenation reaction bottle into a hydrogenation reaction kettle, and transferring out of a glove box. And (3) exchanging hydrogen for 3-5 times, filling hydrogen until the pressure is 50atm, and stirring for 36 hours at room temperature. After releasing the hydrogen in the reaction kettle in a fume hood, opening the reaction kettle, taking out a hydrogenation reaction bottle, removing the solvent by rotary evaporation, separating and purifying by column chromatography, adopting 200-mesh and 300-mesh silica gel, and using petroleum ether as a mobile phase in a volume ratio: ethyl acetate: formic acid =15:1: 0.5.
The product was a white solid (yield 95%) with an optical purity of 99%ee。
The structural characterization data is as follows:
1H NMR (400 MHz, DMSO-d6) δ 13.50 (s, 1H), 7.49 (td, J = 8.6, 3.2 Hz, 1H), 7.43 (dd, J = 8.4, 3.1 Hz, 1H), 7.19 (dd, J = 9.0, 4.3 Hz, 1H), 5.34 (dd, J = 7.4, 5.3 Hz, 1H), 3.13 (dd, J = 17.1, 5.2 Hz, 1H), 2.99 (dd, J = 17.1, 7.5 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 189.31, 170.22, 157.79, 156.42, 155.41, 123.91, 123.66, 121.11, 120.17, 110.99, 110.76, 74.67; 19F NMR (100 MHz, DMSO-d6) δ-121.35.
example 4
In this example, 6, 8-dichloro-4-oxo-dihydrochromone-2-carboxylic acid was prepared having the structural formula:
the preparation method comprises the following steps:
a dry 5mL hydrogenation ampoule was taken and charged with a magnetic stirrer and 1.9 mg, 0.002 mmol Ru (PPh) was weighed in a glove box3)4Cl2And 1.86mg, 0.003 mmol (C: (M))R) BINAP (structure shown in formula A), adding into the above reaction flask, adding 2 ml anhydrous toluene, stirring for 2 hr, adding 52mg 6, 8-dichloro-4-oxo-chromone-2-carboxylic acid into the reaction flask, placing the hydrogenation reaction flask into hydrogenation reaction kettle, and transferring out of glove box. And (3) exchanging hydrogen for 3-5 times, filling hydrogen until the pressure is 30atm, and stirring for 36 hours at room temperature. After releasing the hydrogen in the reaction kettle in a fume hood, opening the reaction kettle, taking out a hydrogenation reaction bottle, removing the solvent by rotary evaporation, separating and purifying by column chromatography, adopting 200-mesh and 300-mesh silica gel, and using petroleum ether as a mobile phase in a volume ratio: ethyl acetate: formic acid =15:1: 0.5.
The product was a white solid (91% yield) with an optical purity of 98%ee。
The structural characterization data is as follows:
1H NMR (400 MHz, DMSO-d6) δ 13.70 (s, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.65 (d, J = 1.9 Hz, 1H), 5.54 (t, J = 5.7 Hz, 1H), 3.26 (dd, J = 17.2, 5.4 Hz, 1H), 3.04 (dd, J = 17.1, 6.3 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 188.25, 169.78, 154.56, 135.23, 125.50, 124.13, 123.23, 122.61, 75.28.
example 5
In this example, 7-fluoro-4-oxo-thiodihydrochromone-2-carboxylic acid was prepared with the following structural formula:
the preparation method comprises the following steps:
a dry 5mL hydrogenation ampoule was taken and charged with a magnetic stirrer and 0.98 mg, 0.004 mmol [ Rh (COD) Cl ] was weighed in a glove box]2And 4.70mg, 0.005 mmol of Walphos (structure shown by formula N), adding into the above reaction flask, adding 1 ml of anhydrous ethyl acetate, stirring for 2 hours, adding 45mg of 7-fluoro-4-oxo-thiodihydrochromone-2-carboxylic acid into the reaction flask at one time, placing the hydrogenation reaction flask into a hydrogenation reaction kettle, and transferring out of a glove box. And (3) exchanging hydrogen for 3-5 times, filling hydrogen until the pressure is 60atm, and stirring for 48 hours at room temperature. After releasing the hydrogen in the reaction kettle in a fume hood, opening the reaction kettle, taking out a hydrogenation reaction bottle, removing the solvent by rotary evaporation, separating and purifying by column chromatography, adopting 200-mesh and 300-mesh silica gel, and using petroleum ether as a mobile phase in a volume ratio: ethyl acetate: formic acid =40:1: 0.5.
The product was a pale yellow solid (yield 85%) with an optical purity of 93%ee。
The structural characterization data is as follows:
1H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 7.76-7.60 (m, 1H), 7.52-7.31 (m, 2H), 4.41 (t, J = 5.1 Hz, 1H), 3.22-2.97 (m, 2H). 13C NMR (100 MHz , DMSO-d 6 δ) 191.36, 171.51, 161.19, 158.77, 134.05, 131.55, 129.72, 121.51, 121.28, 113.73, 113.50, 41.18, 40.46.19F NMR (100 MHz, DMSO-d6) δ -116.24.
example 6
In this example, ethyl 4-oxo-dihydrochromone-2-carboxylate was prepared having the structural formula:
the preparation method comprises the following steps:
a dry 5mL hydrogenation ampoule was taken and charged to a magnetic stirrer and 1.04 mg, 0.002 mmol Rh (NBD) was weighed into a glove box2SbF6And 1.83 mg, 0.003 mmol of (R) SegPhos (structure shown in formula B), adding into the above reaction flask, adding 2 ml absolute ethyl alcohol, stirring for 1 hour, adding 44mg 4-oxo-chromone-2-carboxylic acid ethyl ester into the reaction flask, placing the hydrogenation reaction flask into a hydrogenation reaction kettle, and transferring out of a glove box. And (3) exchanging hydrogen for 3-5 times, filling hydrogen until the pressure is 50atm, and stirring for 24 hours at room temperature. After releasing the hydrogen in the reaction kettle in a fume hood, opening the reaction kettle, taking out a hydrogenation reaction bottle, removing the solvent by rotary evaporation to obtain a crude hydrogenation reaction product, separating and purifying by column chromatography, adopting 200-mesh silica gel with 300 meshes, and using petroleum ether as a mobile phase in volume ratio: ethyl acetate =10: 1.
The product was a white solid (yield 85%) with an optical purity of 98%ee。
The structural characterization data is as follows:
1H NMR (400 MHz, CDCl3) δ7.85 (d, J = 7.8 Hz, 1H), 7.51 (dd, J = 11.0, 4.0 Hz, 1H), 7.06 (dd, J = 16.5, 8.1 Hz, 2H), 5.11 (dd, J = 8.4, 5.9 Hz, 1H), 3.81 (s, 3H), 3.09-2.98 (m, 2H).
the present invention is illustrated by the above examples, but is not limited to the above detailed methods, i.e., it is not meant that the present invention must rely on the above detailed methods for its practice. It should be understood by those skilled in the art that any modification of the present invention, equivalent replacement of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (11)
1. A preparation method of chiral dihydrochromone-2-carboxylic acid compounds and derivatives thereof is characterized in that raw materials shown in the specification are subjected to asymmetric hydrogenation reaction under the catalysis of a chiral metal complex catalyst to obtain chiral dihydrochromone-2-carboxylic acid compounds and derivatives thereof shown in the specification, wherein the reaction formula is as follows:
wherein X is O, S, NH or N-R ', R' is a secondary amine protecting group; r1Is any one or the combination of at least two of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 perfluoroalkyl, halogen, phenyl, benzyl, naphthyl, ester group, heterocyclic substituent, amino or amine; r2Is hydroxy, alkoxy, aryloxy or amino; r3Is C1-C8 alkyl, phenyl, benzyl, naphthyl, heterocyclic substituent; the marked positions represent chiral carbon atoms, and n is an integer from 0 to 4.
2. The method for preparing chiral dihydrochromone-2-carboxylic acid compounds and derivatives thereof according to claim 1, wherein the derivatives are chiral thiodihydrochromone compounds and/or chiral dihydroquinolinone compounds.
3. The method for preparing chiral dihydro chromone-2-carboxylic acid compounds and their derivatives as claimed in claim 1 or 2, wherein R' is any one of benzyloxycarbonyl, tert-butoxycarbonyl, fluorenyl-methoxycarbonyl, allyloxycarbonyl, trimethylsiloxyethyl-carbonyl, methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, o-nitrobenzenesulfonyl, p-o-nitrobenzenesulfonyl, pivaloyl, benzoyl trityl, 2, 4-dimethoxybenzyl, p-methoxybenzyl or benzyl.
4. The method for preparing chiral dihydrochromone-2-carboxylic acid compounds and their derivatives as claimed in any one of claims 1 to 3, wherein the chiral metal catalyst is formed by in situ reaction and complexation of metal salts and chiral ligands.
5. The method for preparing chiral dihydrochromone-2-carboxylic acid compounds and derivatives thereof as claimed in claim 4, wherein the metal salt is Rh (NBD)2BF4、Rh(NBD)2SbF6、Rh(NBD)2BARF、Rh(COD)2BF4、Rh(COD)2SbF6、Rh(COD)2BARF、[Rh(NBD)Cl]2、[Rh(COD)Cl]2、[Ir(COD)Cl]2、(CAAC-Cy)Rh(COD)Cl、[Ir(NBD)Cl]2、[Ir(COD)(OCH3)]2、Ru(PPh3)4Cl2Any one of them.
6. The method for preparing chiral dihydrochromone-2-carboxylic acid compounds and derivatives thereof in claim 4 or 5, wherein the chiral ligand is a ligand with a structure shown as A-N or a ligand with a configuration opposite to any one of the ligands with the structures shown:
wherein, in A-H, Ar is phenyl, 4-methylphenyl, 3, 5-dimethylphenyl, 2,4, 6-trimethylphenyl, 3, 5-di (trifluoromethyl) phenyl, 4-methoxy-3, 5-dimethylphenyl, 4-methoxy-3, 5-di-tert-butylphenyl; in the I, R is methyl, ethyl, isopropyl, phenyl or benzyl; r in M-N1And R2Is tert-butyl, cyclohexyl, phenyl, 2-methylphenyl, 2-furyl, 3, 5-dimethylphenyl, 1-naphthyl, 4-methoxy-3, 5-dimethylphenyl, 4-trifluoromethylphenyl, 3, 5-bistrifluoromethylphenyl.
7. The method for preparing chiral dihydrochromone-2-carboxylic acid compounds and derivatives thereof according to any one of claims 4 to 6, wherein the molar ratio of the metal salt and the chiral ligand in the catalysis of the chiral metal complex is 1:1.1 to 1: 5; the temperature of the complexation reaction is 0-60 ℃; the complexing time is 0.5-12 hours.
8. The method for preparing chiral dihydrochromone-2 carboxylic acid compound and the derivative thereof in accordance with claim 7, wherein the complexation of the metal salt and the chiral ligand is performed in an organic solvent, and the organic solvent is dichloromethane, 1, 2-dichloroethane, methanol, ethanol, isopropanol, tert-butanol, trifluoroethanol, hexafluoroisopropanol, toluene, n-hexane, carbon tetrachloride, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, acetone, preferably dichloromethane or methanol.
9. The method for preparing chiral dihydrochromone-2-carboxylic acid compounds and derivatives thereof according to claims 4 to 8, wherein the ratio of the chiral metal complex catalyst to the material I is 0.0001:1 to 0.02: 1;
the temperature of the asymmetric catalytic hydrogenation reaction is 0-100 ℃;
the hydrogen pressure of the asymmetric catalytic hydrogenation reaction is 5-100 atm;
the time of the asymmetric catalytic hydrogenation reaction is 0.5-48 hours;
after the asymmetric catalytic hydrogenation reaction is finished, concentrating the organic solvent, and separating to obtain chiral dihydrochromone-2-carboxylic acid compounds and derivatives thereof;
the separation method is column chromatography, thin-layer chromatography or recrystallization;
the eluent used for the column chromatography is a mixed liquid of petroleum ether, ethyl acetate and formic acid;
the volume ratio of the petroleum ether to the ethyl acetate is 5: 1-80: 1, and then 2-5% of formic acid is added.
10. The method for preparing chiral dihydrochromone-2-carboxylic acid compounds and derivatives thereof according to claim 1, wherein the method for preparing chiral dihydrochromone-2-carboxylic acid compounds and derivatives thereof specifically comprises the following steps:
(1) reacting a metal salt with a chiral ligand to form a chiral metal complex catalyst;
(2) the chiral dihydrochromone-2-carboxylic acid compound and the derivative thereof shown in the II are obtained by carrying out asymmetric catalytic hydrogenation on the raw material shown in the I under the catalysis of the chiral metal catalyst prepared in the step (1), and the reaction formula is as follows:
wherein X is O, S, NH or N-R ', R' is a secondary amine protecting group; r1Is any one or the combination of at least two of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 perfluoroalkyl, halogen, phenyl, benzyl, naphthyl, ester group, heterocyclic substituent, amino or amine; r2Is hydroxy, alkoxy, aryloxy or amino; r3Is C1-C8 alkyl, phenyl, benzyl, naphthyl, heterocyclic substituent; the marked positions represent chiral carbon atoms, and n is an integer from 0 to 4.
11. The use of chiral dihydrochromone-2-carboxylic acid compounds and their derivatives according to claim 10 in the preparation of natural products, pharmaceuticals and biologically active compounds.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007123941A2 (en) * | 2006-04-18 | 2007-11-01 | Wyeth | Chromane and chromene derivatives and uses thereof |
| CN106977486A (en) * | 2017-05-25 | 2017-07-25 | 南方科技大学 | Preparation method and application of chiral flavanone compound and derivatives thereof |
| WO2021144814A1 (en) * | 2020-01-17 | 2021-07-22 | Lupin Limited | Methods, processes and intermediates for preparing chroman compounds |
-
2021
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007123941A2 (en) * | 2006-04-18 | 2007-11-01 | Wyeth | Chromane and chromene derivatives and uses thereof |
| CN106977486A (en) * | 2017-05-25 | 2017-07-25 | 南方科技大学 | Preparation method and application of chiral flavanone compound and derivatives thereof |
| WO2021144814A1 (en) * | 2020-01-17 | 2021-07-22 | Lupin Limited | Methods, processes and intermediates for preparing chroman compounds |
Non-Patent Citations (1)
| Title |
|---|
| XIONG, DONGLU,ET AL: "A highly enantioselective access to chiral chromanones and thiochromanones via copper-catalyzed asymmetric conjugated reduction of chromones and thiochromones", 《CHEMICAL COMMUNICATIONS》 * |
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|---|---|---|---|---|
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