CN117050017A - Axis chiral alkenyl-sulfur ylide compound and preparation method thereof - Google Patents
Axis chiral alkenyl-sulfur ylide compound and preparation method thereof Download PDFInfo
- Publication number
- CN117050017A CN117050017A CN202310873667.1A CN202310873667A CN117050017A CN 117050017 A CN117050017 A CN 117050017A CN 202310873667 A CN202310873667 A CN 202310873667A CN 117050017 A CN117050017 A CN 117050017A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- alkenyl
- aryl
- heteroaryl
- sulfur ylide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229910052717 sulfur Inorganic materials 0.000 title claims abstract description 80
- 150000001875 compounds Chemical class 0.000 title claims abstract description 72
- 239000011593 sulfur Substances 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 125000000217 alkyl group Chemical group 0.000 claims description 86
- 125000003118 aryl group Chemical group 0.000 claims description 52
- 125000001072 heteroaryl group Chemical group 0.000 claims description 49
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 38
- 239000003054 catalyst Substances 0.000 claims description 29
- 125000000304 alkynyl group Chemical group 0.000 claims description 19
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 16
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 15
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 14
- 238000007259 addition reaction Methods 0.000 claims description 12
- 125000004104 aryloxy group Chemical group 0.000 claims description 11
- 239000000654 additive Substances 0.000 claims description 10
- 230000000996 additive effect Effects 0.000 claims description 10
- 125000006735 (C1-C20) heteroalkyl group Chemical group 0.000 claims description 9
- 125000003860 C1-C20 alkoxy group Chemical group 0.000 claims description 9
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 9
- 239000002808 molecular sieve Substances 0.000 claims description 9
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 9
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 9
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 125000006738 (C6-C20) heteroaryl group Chemical group 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- FWFGVMYFCODZRD-UHFFFAOYSA-N oxidanium;hydrogen sulfate Chemical compound O.OS(O)(=O)=O FWFGVMYFCODZRD-UHFFFAOYSA-N 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 16
- 229940079593 drug Drugs 0.000 abstract description 13
- 239000000543 intermediate Substances 0.000 abstract description 13
- 239000008204 material by function Substances 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- -1 sulfur ion Chemical class 0.000 description 40
- 125000005842 heteroatom Chemical group 0.000 description 22
- 239000000047 product Substances 0.000 description 20
- 125000003545 alkoxy group Chemical group 0.000 description 17
- 125000001424 substituent group Chemical group 0.000 description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 13
- 229910052736 halogen Inorganic materials 0.000 description 12
- 150000002367 halogens Chemical class 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 125000003342 alkenyl group Chemical group 0.000 description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000010949 copper Substances 0.000 description 8
- 125000004404 heteroalkyl group Chemical group 0.000 description 8
- 125000002950 monocyclic group Chemical group 0.000 description 8
- 125000003367 polycyclic group Chemical group 0.000 description 8
- 230000003197 catalytic effect Effects 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 239000000376 reactant Substances 0.000 description 7
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 6
- 229910052802 copper Inorganic materials 0.000 description 6
- 150000002430 hydrocarbons Chemical group 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000011914 asymmetric synthesis Methods 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 125000004434 sulfur atom Chemical group 0.000 description 5
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 125000000547 substituted alkyl group Chemical group 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 239000000575 pesticide Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- CSCPPACGZOOCGX-MICDWDOJSA-N 1-deuteriopropan-2-one Chemical compound [2H]CC(C)=O CSCPPACGZOOCGX-MICDWDOJSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- GOIGHUHRYZUEOM-UHFFFAOYSA-N [S].[I] Chemical compound [S].[I] GOIGHUHRYZUEOM-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 229920001971 elastomer Polymers 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 150000002240 furans Chemical class 0.000 description 2
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000012434 nucleophilic reagent Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 125000005561 phenanthryl group Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 125000006000 trichloroethyl group Chemical group 0.000 description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 2
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
- 125000006649 (C2-C20) alkynyl group Chemical group 0.000 description 1
- 125000006717 (C3-C10) cycloalkenyl group Chemical group 0.000 description 1
- 125000006651 (C3-C20) cycloalkyl group Chemical group 0.000 description 1
- 125000006655 (C3-C8) heteroaryl group Chemical group 0.000 description 1
- PPWNCLVNXGCGAF-UHFFFAOYSA-N 3,3-dimethylbut-1-yne Chemical compound CC(C)(C)C#C PPWNCLVNXGCGAF-UHFFFAOYSA-N 0.000 description 1
- WVGCPEDBFHEHEZ-UHFFFAOYSA-N 4-bromo-1h-pyrazole Chemical compound BrC=1C=NNC=1 WVGCPEDBFHEHEZ-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000005109 alkynylthio group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 239000013626 chemical specie Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 1
- 229910000071 diazene Inorganic materials 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- RIKMMFOAQPJVMX-UHFFFAOYSA-N fomepizole Chemical compound CC=1C=NNC=1 RIKMMFOAQPJVMX-UHFFFAOYSA-N 0.000 description 1
- 229960004285 fomepizole Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000000623 heterocyclic 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
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004346 phenylpentyl group Chemical group C1(=CC=CC=C1)CCCCC* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005888 tetrahydroindolyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/16—Halogen atoms or nitro radicals
-
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application relates to the technical field of organic chemical synthesis, in particular to an axial chiral alkenyl-sulfur ylide compound and a preparation method thereof. The general molecular structural formula of the axial chiral alkenyl-sulfur ylide compound is shown as a formula I in the specification. The axial chiral alkenyl-sulfur ylide compound shown in the formula I has high functionality and can generate various chemical transformations, so that the axial chiral alkenyl-sulfur ylide compound is more diversified in the application of drug intermediate synthesis and functional materials, can be used for the synthesis of drug intermediates and the preparation of the functional materials, and can effectively reduce the economic cost of the drug intermediates and the preparation of the functional materials.
Description
Technical Field
The application belongs to the technical field of organic chemical synthesis, and particularly relates to an axial chiral alkenyl-sulfur ylide compound and a preparation method thereof.
Background
Sulfur ylides (s-ylides) have a carbanion structure stabilized by an adjacent positive sulfur ion; sulfur ylide is a functional group that can undergo multiple transformations, and due to its poor stability, it is generally introduced at the alpha position of the ketocarbonyl group to act to stabilize the functional group. As the interest of chemists on sulfur ylide increases, it has a significant impact on the fields of medicinal chemistry, material chemistry, chemical biology, biochemistry, etc.
Because rotation around a single bond is hindered, a group of conformational isomers can be separated from each other, forming new chemical species, which are atropisomers (atropimers) of each other. As atropisomers become more prevalent throughout drug discovery, there is an increasing opportunity to use atropisomers to modulate the potency, selectivity, and even pharmacokinetics of lead molecules in many classes of targets. Therefore, the novel atropisomer skeleton is developed, the asymmetric synthesis is realized, a more comprehensive axial chiral molecular library is established, and a wider visual field is very likely to be provided for the research and development of the atropisomer drugs.
Disclosure of Invention
The application aims to provide an axial chiral alkenyl-sulfur ylide compound and a preparation method thereof, and aims to solve the technical problem of how to provide a sulfur ylide compound containing a brand-new atropisomer skeleton of hexavalent sulfur center.
In order to achieve the purposes of the application, the technical scheme adopted by the application is as follows:
in a first aspect, the application provides an axial chiral alkenyl-sulfur ylide compound, wherein the molecular structural general formula of the axial chiral alkenyl-sulfur ylide compound is shown as formula I:
wherein R is 1 And R is 2 Independently include C 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Heterocycloalkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Heteroalkenyl, C 3 -C 20 Cycloalkenyl, C 3 -C 20 Heterocycloalkenyl, C 2 -C 20 Alkynyl, C 2 -C 20 Heteroalkynyl, C 3 -C 20 Cycloalkynyl radicals, C 3 -C 20 Heterocyclic alkynyl, C 1 -C 20 Alkoxy, C 6 -C 20 Aryl, substituted (C) 6 -C 20 ) Aryl, C 3 -C 20 Heteroaryl, substituted (C) 3 -C 20 ) Heteroaryl, C 6 -C 20 Aryloxy, C 3 -C 20 Heteroaryloxy, C 6 -C 20 Aryl (C) 1 -C 20 ) Alkyl, C 3 -C 20 Heteroaryl (C) 1 -C 20 ) Any one of alkyl groups;
R 3 comprising hydrogen, halogen atoms, C 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Heterocycloalkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Heteroalkenyl, C 3 -C 20 Cycloalkenyl, C 3 -C 20 Heterocycloalkenyl, C 2 -C 20 Alkynyl, C 2 -C 20 Heteroalkynyl, C 3 -C 20 Cycloalkynyl radicals, C 3 -C 20 Heterocyclic alkynyl, C 1 -C 20 Alkoxy, C 6 -C 20 Aryl, substituted (C) 6 -C 20 ) Aryl, C 3 -C 20 Heteroaryl, substituted (C) 3 -C 20 ) Heteroaryl, C 6 -C 20 Aryloxy, C 3 -C 20 Heteroaryloxy, C 6 -C 20 Aryl (C) 1 -C 20 ) Alkyl, C 3 -C 20 Heteroaryl (C) 1 -C 20 ) Any one of alkyl groups.
The axial chiral alkenyl-sulfur ylide compound provided by the first aspect of the application is an axial chiral alkenyl-sulfur ylide compound containing hexavalent sulfur center and having a brand new atropisomer skeleton. The axial chiral alkenyl-sulfur ylide compound shown in the formula I has high functionality and more active chemical property, and can generate various chemical transformations, so that the axial chiral alkenyl-sulfur ylide compound is more diversified in the application of drug intermediate synthesis and functional materials, can be used for the synthesis of drug intermediates and the preparation of the functional materials, can effectively reduce the economic cost of the preparation of the drug intermediates and the functional materials, and can be widely applied to the fields of organic synthetic chemistry, biochemistry, asymmetric catalysis, pesticides and medicine research.
In a second aspect, the application provides a method for preparing an axial chiral alkenyl-sulfur ylide compound, comprising the steps of:
carrying out addition reaction on a compound shown in a formula II and a compound shown in a formula III under the condition of a chiral phosphoric acid catalyst to obtain the axial chiral alkenyl-sulfur ylide compound;
in the preparation method of the axial chiral alkenyl-sulfur ylide compound provided by the second aspect of the application, the simple pyrazole compound shown in the formula III is used as a nucleophilic reagent to attack the alkynyl-sulfur ylide compound shown in the formula II, so that the target product precursor with high enantioselectivity and wide range is efficiently and greenly prepared, and the axial chiral alkenyl-sulfur ylide compound with potential application is obtained. According to the preparation method, the simple and easily obtained alkynyl-sulfur ylide and the commercial pyrazole compound are selected as reactants, raw materials are easy to obtain, the preparation method can be directly used for preparation and production without additional modification protection before synthesis, the operation steps are simplified, the reaction route is shortened, the chiral phosphoric acid catalyst is used, the atomic utilization rate of the reactants is high, the reaction rate is high, the production efficiency is obviously improved, and the designability and the application prospect of the axial chiral alkenyl-sulfur ylide compound shown in the formula I can be greatly expanded.
Detailed Description
In order to make the technical problems, technical schemes and beneficial effects to be solved more clear, the application is further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the application.
In the present application, the term "and/or" describes an association relationship of an association object, which means that three relationships may exist, for example, a and/or B may mean: a alone, a and B together, and B alone. Wherein A, B may be singular or plural. The character "/" generally indicates that the context-dependent object is an "or" relationship.
In the present application, "at least one" means one or more, and "a plurality" means two or more. "at least one of" or the like means any combination of these items, including any combination of single item(s) or plural items(s).
It should be understood that, in various embodiments of the present application, the sequence number of each process described above does not mean that the execution sequence of some or all of the steps may be executed in parallel or executed sequentially, and the execution sequence of each process should be determined by its functions and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.
The terminology used in the embodiments of the application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used in this application and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.
The weights of the relevant components mentioned in the description of the embodiments of the present application may refer not only to the specific contents of the components, but also to the proportional relationship between the weights of the components, so long as the contents of the relevant components in the description of the embodiments of the present application are scaled up or down within the scope of the disclosure of the embodiments of the present application. Specifically, the mass described in the specification of the embodiment of the application can be mass units known in the chemical industry field such as mu g, mg, g, kg.
The terms "first" and "second" are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implicitly indicating the number of technical features indicated for distinguishing between objects such as substances from each other. For example, a first XX may also be referred to as a second XX, and similarly, a second XX may also be referred to as a first XX, without departing from the scope of embodiments of the application. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature.
The compounds and derivatives thereof referred to in the examples of the present application are named according to the IUPAC (International Union of pure and applied chemistry) or CAS (chemical abstract service Co., columbus, ohio) naming system. Thus, the compound groups specifically referred to in the examples of the present application are described and illustrated as follows:
with respect to "hydrocarbon groups", the minimum and maximum values of the carbon atom content in the hydrocarbon groups are represented by prefixes, for example, prefixes (C a -C b ) Alkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, (C) 1 -C 6 ) Alkyl refers to alkyl groups containing one to six carbon atoms.
"alkoxy" refers to a straight or branched, monovalent, saturated aliphatic chain having an oxygen atom attached thereto and includes, but is not limited to, e.g., methoxy, ethoxy, propoxy, butoxy, isobutoxy, t-butoxy, and the like. (C) a -C b ) Alkoxy refers to any straight or branched, monovalent, saturated aliphatic chain having an alkyl group of "a" to "b" carbon atoms bonded to an oxygen atom.
"alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, and the like.
"heteroalkyl" refers to a straight or branched, monovalent, saturated fatty chain attached to at least one heteroatom, such as, but not limited to, methylaminoethyl or other similar group.
"alkenyl" refers to straight or branched chain hydrocarbons with one or more double bonds, including but not limited to, e.g., ethenyl, propenyl, and the like.
"heteroalkenyl" refers to a straight or branched chain hydrocarbon attached to at least one heteroatom with one or more double bonds, including but not limited to, e.g., vinylaminoethyl or other similar groups.
"alkynyl" refers to a straight or branched hydrocarbon bearing one or more triple bonds, including but not limited to, e.g., ethynyl, propynyl, and the like.
"heteroalkynyl" refers to a straight or branched chain hydrocarbon attached to at least one heteroatom with one or more triple bonds, including but not limited to, e.g., ethynyl, propynyl, and the like.
"aryl" refers to a cyclic aromatic hydrocarbon including, but not limited to, groups such as phenyl, naphthyl, anthryl, phenanthryl, and the like.
"heteroaryl" refers to a monocyclic or polycyclic or fused ring aromatic hydrocarbon in which one or more carbon atoms have been replaced by a heteroatom such as nitrogen, oxygen or sulfur. If the heteroaryl group contains more than one heteroatom, these heteroatoms may be the same or may be different. Heteroaryl groups include, but are not limited to, groups such as benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyranyl, furanyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazinyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridin [3,4-b ] indolyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolizinyl, quinolinyl, quinoxalinyl, thiadiazolyl, thiatriazolyl, thiazolyl, thienyl, triazinyl, triazolyl, xanthenyl, and the like.
"cycloalkyl" refers to a saturated monocyclic or polycyclic alkyl group, possibly fused to an aromatic hydrocarbon group. Cycloalkyl groups include, but are not limited to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl, tetrahydronaphthyl, and the like.
"Heterocyclyl" refers to a saturated mono-or polycyclic alkyl group, possibly fused to an aromatic hydrocarbon group, wherein at least one carbon atom has been replaced by a heteroatom such as nitrogen, oxygen or sulfur. If the heterocycloalkyl group contains more than one heteroatom, these heteroatoms may be the same or different. Heterocyclylalkyl groups include, but are not limited to, for example, azabicycloheptyl, azetidinyl, indolinyl, morpholinyl, pyrazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroindazolyl, tetrahydroindolyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinoxalinyl, tetrahydrothiopyranyl, thiazolidinyl, thiomorpholinyl, thioxanthyl, thiooxalkyl, and the like.
"cycloalkenyl" refers to an unsaturated, mono-or polycyclic alkenyl group with one or more double bonds, possibly fused to an aromatic hydrocarbon group, including but not limited to a cycloethenyl group, a cyclopropenyl group, or other similar groups.
"heterocycloalkenyl" refers to an unsaturated, monocyclic or polycyclic alkenyl group having one or more double bonds, possibly fused to an aromatic hydrocarbon group, in which at least one carbon atom is replaced by a heteroatom such as nitrogen, oxygen or sulfur. If the heterocycloalkyl group contains more than one heteroatom, these heteroatoms may be the same or different.
"cycloalkynyl" refers to an unsaturated, mono-or polycyclic alkynyl group with one or more triple bonds, possibly fused to an aromatic hydrocarbon group, including but not limited to cycloalkynyl, cyclopropynyl, or other like groups.
"heterocycloalkynyl" refers to an unsaturated, mono-or polycyclic alkynyl group with one or more triple bonds, possibly fused to an aromatic hydrocarbon group, in which at least one carbon atom is replaced with a heteroatom such as nitrogen, oxygen or sulfur. If the heterocycloalkyl group contains more than one heteroatom, these heteroatoms may be the same or different.
Asymmetric catalytic synthesis of atropisomers is mainly focused on the fields of biaryl-substituted atropisomers, aryl-olefin/amide atropisomers, asymmetric synthesis of arylamine atropisomers, and the like, while research on non-aryl-substituted atropisomers on both chiral axes is relatively poor. Therefore, the development of atropisomers of novel backbones and methods for developing asymmetric construction thereof are important and difficult to study in the field of axial chirality. In view of the above, the application develops a novel synthesis method to develop a brand-new atropisomer skeleton and complete the construction of an asymmetric synthesis methodology thereof, thereby providing a new idea for designing and synthesizing more axial chiral skeletons. The specific contents are as follows.
In a first aspect, an embodiment of the present application provides an axial chiral alkenyl-sulfur ylide compound, where the molecular structural general formula of the axial chiral alkenyl-sulfur ylide compound is shown in formula I:
wherein R is 1 And R is 2 Independently include C 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Heterocycloalkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Heteroalkenyl, C 3 -C 20 Cycloalkenyl, C 3 -C 20 Heterocycloalkenyl, C 2 -C 20 Alkynyl, C 2 -C 20 Heteroalkynyl, C 3 -C 20 Cycloalkynyl radicals, C 3 -C 20 Heterocyclic alkynyl, C 1 -C 20 Alkoxy, C 6 -C 20 Aryl, substituted (C) 6 -C 20 ) Aryl, C 3 -C 20 Heteroaryl, substituted (C) 3 -C 20 ) Heteroaryl, C 6 -C 20 Aryloxy, C 3 -C 20 Heteroaryloxy, C 6 -C 20 Aryl (C) 1 -C 20 ) Alkyl, C 3 -C 20 Heteroaryl (C) 1 -C 20 ) Any one of alkyl groups;
R 3 comprising hydrogen, halogen atoms, C 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Heterocycloalkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Heteroalkenyl, C 3 -C 20 Cycloalkenyl, C 3 -C 20 Heterocycloalkenyl, C 2 -C 20 Alkynyl, C 2 -C 20 Heteroalkynyl, C 3 -C 20 Cycloalkynyl radicals, C 3 -C 20 Heterocyclic alkynyl, C 1 -C 20 Alkoxy, C 6 -C 20 Aryl, substituted (C) 6 -C 20 ) Aryl, C 3 -C 20 Heteroaryl, substituted (C) 3 -C 20 ) Heteroaryl, C 6 -C 20 Aryloxy, C 3 -C 20 Heteroaryloxy, C 6 -C 20 Aryl (C) 1 -C 20 ) Alkyl, C 3 -C 20 Heteroaryl (C) 1 -C 20 ) Any one of alkyl groups.
The axial chiral alkenyl-sulfur ylide compound provided by the embodiment of the application is an axial chiral alkenyl-sulfur ylide compound containing hexavalent sulfur center and having a brand new atropisomer skeleton. The axial chiral alkenyl-sulfur ylide compound shown in the formula I has high functionality and more active chemical property, and can generate various chemical transformations, so that the axial chiral alkenyl-sulfur ylide compound is more diversified in the application of drug intermediate synthesis and functional materials, can be used for the synthesis of drug intermediates and the preparation of the functional materials, can effectively reduce the economic cost of the preparation of the drug intermediates and the functional materials, and can be widely applied to the fields of organic synthetic chemistry, biochemistry, asymmetric catalysis, pesticides and medicine research.
Wherein R is 1 And R is 2 Independently include C 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Heterocycloalkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Heteroalkenyl, C 3 -C 20 Cycloalkenyl, C 3 -C 20 Heterocycloalkenyl, C 2 -C 20 Alkynyl, C 2 -C 20 Heteroalkynyl, C 3 -C 20 Cycloalkynyl radicals, C 3 -C 20 Heterocyclic alkynyl, C 1 -C 20 Alkoxy, C 6 -C 20 Aryl, substituted (C) 6 -C 20 ) Aryl, C 3 -C 20 Heteroaryl, substituted (C) 3 -C 20 ) Heteroaryl, C 6 -C 20 Aryloxy, C 3 -C 20 Heteroaryloxy, C 6 -C 20 Aryl (C) 1 -C 20 ) Alkyl, C 3 -C 20 Heteroaryl (C) 1 -C 20 ) Any one of alkyl groups. R is R 3 Comprising hydrogen, halogen atoms, C 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Heterocycloalkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Heteroalkenyl, C 3 -C 20 Cycloalkenyl, C 3 -C 20 Heterocycloalkenyl, C 2 -C 20 Alkynyl, C 2 -C 20 Heteroalkynyl, C 3 -C 20 Cycloalkynyl radicals, C 3 -C 20 Heterocyclic alkynyl, C 1 -C 20 Alkoxy, C 6 -C 20 Aryl, substituted (C) 6 -C 20 ) Aryl, C 3 -C 20 Heteroaryl, substituted (C) 3 -C 20 ) Heteroaryl, C 6 -C 20 Aryloxy, C 3 -C 20 Heteroaryloxy, C 6 -C 20 Aryl (C) 1 -C 20 ) Alkyl, C 3 -C 20 Heteroaryl (C) 1 -C 20 ) Any one of alkyl groups.
Specifically, R 1 、R 2 、R 3 May include the same or different C 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Heterocycloalkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Heteroalkenyl, C 3 -C 20 Cycloalkenyl, C 3 -C 20 Heterocycloalkenyl, C 2 -C 20 Alkynyl, C 2 -C 20 Heteroalkynyl, C 3 -C 20 Cycloalkynyl radicals, C 3 -C 20 Heterocyclic alkynyl, C 1 -C 20 Alkoxy, C 6 -C 20 Aryl, substituted (C) 6 -C 20 ) Aryl, C 3 -C 20 Heteroaryl, substituted (C) 3 -C 20 ) Heteroaryl, C 6 -C 20 Aryloxy, C 3 -C 20 Heteroaryloxy, C 6 -C 20 Aryl (C) 1 -C 20 ) Alkyl, C 3 -C 20 Heteroaryl (C) 1 -C 20 ) Any one of alkyl groups.
When R is 1 、R 2 、R 3 Comprising identical or non-identical C 1 -C 20 When alkyl, in some embodiments, C 1 -C 20 The alkyl group may be (C 1 -C 10 ) Alkyl, (C) 1 -C 5 ) Alkyl, (C) 1 -C 4 ) Alkyl, (C) 1 -C 3 ) Alkyl, (C) 1 -C 2 ) Alkyl groups, and the like. In some embodiments, (C) 1 -C 20 ) The alkyl group may specifically be methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, and the like.
When R is 1 、R 2 、R 3 Comprising identical or non-identical (C 1 -C 20 ) In the case of heteroalkyl groups, in one embodiment, (C 1 -C 20 ) The heteroalkyl group may be (C) 1 -C 10 ) Heteroalkyl (C) 1 -C 5 ) Heteroalkyl (C) 1 -C 4 ) Heteroalkyl (C) 1 -C 3 ) Heteroalkyl (C) 1 -C 2 ) Heteroalkyl groups, and the like. In some embodiments, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is 1 、R 2 、R 3 Comprising identical or non-identical (C 3 -C 20 ) In the case of cycloalkyl, in one embodiment, (C 3 -C 20 ) Cycloalkyl groups may be (C) 3 -C 10 ) Cycloalkyl, (C) 3 -C 5 ) Cycloalkyl, (C) 3 -C 4 ) Cycloalkyl groups, and the like. In one embodiment, (C) 3 -C 20 ) Cycloalkyl groups may be cyclopropyl, cyclobutyl, cyclopentyl, and the like.
When R is 1 、R 2 、R 3 Comprising identical or non-identical (C 3 -C 20 ) When heterocycloalkyl, (C) in one embodiment 3 -C 20 ) Heterocyclylalkyl can be (C) 3 -C 10 ) Heterocycloalkyl, (C) 3 -C 10 ) Impurity(s)Cycloalkyl, (C) 3 -C 5 ) Heterocycloalkyl, (C) 3 -C 4 ) Heterocycloalkyl, and the like. In one embodiment, the heteroatom may be halogen, nitrogen, sulfur, or the like.
When R is 1 、R 2 、R 3 Comprising identical or non-identical (C 2 -C 20 ) Alkenyl groups, in one embodiment, (C 2 -C 20 ) Alkenyl groups may be (C) 3 -C 10 ) Alkenyl group (C) 3 -C 5 ) Alkenyl group (C) 3 -C 4 ) Alkenyl group (C) 2 -C 3 ) Alkenyl groups, and the like. In some embodiments, (C) 2 -C 20 ) Alkenyl groups may be ethenyl, propenyl, butenyl, pentenyl, and the like.
When R is 1 、R 2 、R 3 Comprising identical or non-identical (C 2 -C 20 ) In the case of heteroalkenyl groups, in one embodiment, (C 2 -C 20 ) The heteroalkenyl group may be (C) 2 -C 10 ) Heteroalkenyl, (C) 3 -C 10 ) Heteroalkenyl, (C) 3 -C 5 ) Heteroalkenyl, (C) 3 -C 4 ) Heteroalkenyl, (C) 2 -C 3 ) Heteroalkenyl groups, and the like. In some embodiments, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is 1 、R 2 、R 3 Comprising identical or non-identical (C 3 -C 20 ) In the case of cycloalkenyl, (C) 3 -C 20 ) Cycloalkenyl groups may be (C 3 -C 10 ) Cycloalkenyl, (C) 3 -C 5 ) Cycloalkenyl, (C) 3 -C 4 ) Cycloalkenyl groups, and the like. In some embodiments, (C) 3 -C 20 ) The cycloalkenyl group may be cyclopropenyl, cyclobutenyl, cyclopentenyl, and the like.
When R is 1 、R 2 、R 3 Comprising identical or non-identical (C 3 -C 20 ) In one embodiment, (C) 3 -C 20 ) The heterocycloalkenyl group may be (C 3 -C 10 ) Heterocycloalkenyl, (C) 3 -C 5 ) Heterocycloalkenyl, (C) 3 -C 4 ) Heterocycloalkenyl, and the like. In some embodimentsThe hetero atom may be halogen, nitrogen atom, sulfur atom, etc.
When R is 1 、R 2 、R 3 Comprising identical or non-identical (C 2 -C 20 ) Alkynyl groups, in one embodiment, (C) 2 -C 20 ) Alkynyl groups may be (C) 2 -C 10 ) Alkynyl, (C) 3 -C 10 ) Alkynyl, (C) 3 -C 5 ) Alkynyl, (C) 3 -C 4 ) Alkynyl, (C) 2 -C 3 ) Alkynyl groups, and the like. In some embodiments, (C) 2 -C 20 ) Alkynyl groups may be ethynyl, propynyl, butynyl, pentynyl, and the like.
When R is 1 、R 2 、R 3 Comprising identical or non-identical (C 2 -C 20 ) In the case of heteroalkynyl, (C) 2 -C 20 ) The heteroalkynyl group may be (C) 2 -C 10 ) Heteroalkynyl, (C) 3 -C 10 ) Heteroalkynyl, (C) 3 -C 5 ) Heteroalkynyl, (C) 3 -C 4 ) Heteroalkynyl, (C) 2 -C 3 ) Heteroalkynyl, and the like. In some embodiments, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is 1 、R 2 、R 3 Comprising identical or non-identical (C 3 -C 20 ) In the case of cycloalkynyl, in one embodiment, (C 3 -C 20 ) The cycloalkynyl group may be (C) 3 -C 10 ) Cycloalkynyl, (C) 3 -C 5 ) Cycloalkynyl, (C) 3 -C 4 ) Cycloalkynyl, and the like. In some embodiments, (C) 2 -C 20 ) The cycloalkynyl group may be cyclopropynyl group, cyclobutynyl group, cyclopentynyl group or the like.
When R is 1 、R 2 、R 3 Comprising identical or non-identical (C 3 -C 20 ) In one embodiment, (C) 3 -C 20 ) The heterocycloalkynyl group may be (C) 3 -C 10 ) Heterocycloalkynyl, (C) 3 -C 5 ) Heterocycloalkynyl, (C) 3 -C 4 ) Heterocycloalkynyl, and the like. In some embodiments, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is 1 、R 2 、R 3 Comprising identical or non-identical (C 1 -C 20 ) In the case of alkoxy groups, in one embodiment, (C 1 -C 20 ) Alkoxy groups may be (C) 1 -C 10 ) Alkoxy, (C) 1 -C 8 ) Alkoxy, (C) 1 -C 6 ) Alkoxy, (C) 1 -C 4 ) Alkoxy, (C) 1 -C 3 ) Alkoxy, (C) 1 -C 2 ) An alkoxy group. In some embodiments, (C) 1 -C 20 ) Alkoxy groups may be, but are not limited to, methyl, ethyl, propyl, etc.
When R is 1 、R 2 、R 3 Comprising identical or non-identical (C 6 -C 20 ) When aryl, the aryl may be, but is not limited to, monocyclic aryl, polycyclic aryl, fused ring aryl. In one embodiment, the aryl is a monocyclic aryl. In some embodiments, the aryl is phenyl.
When R is 1 、R 2 、R 3 Comprising identical or different substituents (C 6 -C 20 ) When aryl, the substituted aryl may be, but is not limited to, ortho, meta, para substituted phenyl, singly or multiply. Substituents include, but are not limited to, C 1 -C 10 Alkyl, substituted C 1 -C 10 Alkyl, halogen, C 1 -C 10 An alkylamino group, a nitro group. Where the substituents are alkyl groups, alkyl groups such as, but not limited to, methyl, ethyl, propyl, butyl, isobutyl; when the substituent is a substituted alkyl group, the substituted alkyl group is such as, but not limited to, trifluoromethyl, trichloromethyl, trifluoroethyl, trichloroethyl; when the substituent is halogen, halogen such as, but not limited to, fluorine, chlorine, bromine, iodine; when the substituent is an alkoxy group, the alkoxy group is, for example, but not limited to, a methyloxy group, an ethyloxy group, a propyloxy group. In one embodiment, the substituted aryl group may also be cyano (C 1 -C 10 ) Alkyl (C) 3 -C 8 ) Aryl, substituted (C) 3 -C 8 ) Aryl groups.
When R is 1 、R 2 、R 3 Comprising identical or non-identical C 3 -C 20 In the case of heteroaryl groups, in one embodiment, the heteroaryl group may be (C 3 -C 10 ) Heteroaryl, furan, thiophene.
When R is 1 、R 2 、R 3 Comprising identical or different substituents C 3 -C 20 In the case of heteroaryl groups, in one embodiment, the substituted heteroaryl groups may be substituted (C 3 -C 10 ) Heteroaryl, alkoxy substituted furans, (C) 3 -C 8 ) Heteroaryl substituted furans, fatty chain substituted thiophenes. Substituents include, but are not limited to, C 1 -C 10 Alkyl, substituted C 1 -C 10 Alkyl, halogen, C 1 -C 10 An alkylamino group, a nitro group. Where the substituents are alkyl groups, alkyl groups such as, but not limited to, methyl, ethyl, propyl, butyl, isobutyl; when the substituent is a substituted alkyl group, the substituted alkyl group is such as, but not limited to, trifluoromethyl, trichloromethyl, trifluoroethyl, trichloroethyl; when the substituent is halogen, halogen such as, but not limited to, fluorine, chlorine, bromine, iodine; when the substituent is an alkoxy group, the alkoxy group is, for example, but not limited to, a methyloxy group, an ethyloxy group, a propyloxy group.
When R is 1 、R 2 、R 3 Comprising identical or non-identical C 6 -C 20 When aryloxy, in one embodiment, the aryloxy may be phenoxy, naphthoxy, anthracenoxy, phenanthroxy.
When R is 1 、R 2 、R 3 Comprising identical or non-identical C 6 -C 20 Aryl (C) 1 -C 20 ) In the case of alkyl, in one embodiment, the aryl group (C 1 -C 20 ) The alkyl group may be aryl (C) 1 -C 10 ) Alkyl, phenyl (C) 1 -C 10 ) Alkyl, phenyl (C) 1 -C 5 ) Alkyl, phenyl (C) 1 -C 4 ) Alkyl, phenyl (C) 1 -C 3 ) Alkyl, phenyl (C) 1 -C 2 ) Alkyl groups, and the like. In some embodiments, aryl (C 1 -C 20 ) The alkyl group may be phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, phenylisobutyl, phenylpentyl, phenylisopentyl, phenylneopentyl.
When R is 1 、R 2 、R 3 Comprising identical or non-identical C 3 -C 20 Heteroaryl (C) 1 -C 20 ) In the case of alkyl, in one embodiment, the heteroaryl (C 1 -C 20 ) The alkyl group may be heteroaryl (C) 1 -C 10 ) Alkyl, heteroaryl (C) 1 -C 10 ) Alkyl, heteroaryl (C) 1 -C 5 ) Alkyl, heteroaryl (C) 1 -C 4 ) Alkyl, heteroaryl (C) 1 -C 3 ) Alkyl, heteroaryl (C) 1 -C 2 ) Alkyl groups, and the like. Wherein the heteroaryl group may be (C 3 -C 8 ) Heteroaryl, furan, pyridine, and the like.
In some embodiments, R 1 、R 2 、R 3 In (C) substituted (C) 6 -C 20 ) Aryl, C 3 -C 20 Heteroaryl, substituted (C) 3 -C 20 ) Heteroaryl groups, the substituents being independently selected from halogen atoms, C 1 -C 5 Alkyl, C 1 -C 5 At least one of an alkoxy group, a phenyl group, a phenoxy group, a nitro group, and an acyl group.
In some embodiments, R 1 Comprises C 1 -C 10 Alkyl, R 2 Comprises C 1 -C 10 An alkyl group. Further, R 1 Is C 4 -C 10 Tertiary alkyl, R 2 Is C 4 -C 10 And a tertiary alkyl group.
In some embodiments, R 3 Comprising hydrogen, halogen atoms, C 1 -C 10 At least one of the alkyl groups.
In some embodiments, the axial chiral alkenyl-sulfur ylide compound comprises at least one of:
in a second aspect, an embodiment of the present application provides a method for preparing an axial chiral alkenyl-sulfur ylide compound, including the steps of:
carrying out addition reaction on a compound shown in a formula II and a compound shown in a formula III under the condition of a chiral phosphoric acid catalyst to obtain the axial chiral alkenyl-sulfur ylide compound;
the preparation method of the axial chiral alkenyl-sulfur ylide compound provided by the second aspect of the application is a method for synthesizing a novel axial chiral alkenyl-sulfur ylide compound of atropisomer by utilizing an asymmetric addition method, and has the following advantages: (1) The application adopts an organic micromolecule asymmetric chiral phosphoric acid catalytic system, realizes the asymmetric synthesis of the axial chiral alkenyl-sulfur ylide compound, has simple preparation method and process, low requirements on reaction conditions, safe and controllable reaction process and simplifies the operation in the preparation and production processes. (2) According to the asymmetric addition method, a simple pyrazole compound shown in a formula III is used as a nucleophilic reagent to attack the alkynyl-sulfur ylide compound shown in a formula II, so that a target product precursor with high enantioselectivity and extremely wide range is efficiently and greenly prepared, and the axially chiral alkenyl-sulfur ylide compound shown in the formula I with potential application is obtained. (3) The asymmetric synthesis of the axial chiral alkenyl-sulfur ylide compound in the asymmetric addition process has higher atom utilization rate and high reaction efficiency, and is beneficial to improving the generation yield of reaction products. (4) The method provided by the application greatly expands the designability and application prospect of the compounds. The axial chiral alkenyl-sulfur ylide compound shown in the formula I obtained by the method has high enantioselectivity and high functional group, so that the axial chiral alkenyl-sulfur ylide compound is more diversified in application of drug intermediate synthesis and functional materials, can be widely used for synthesis of drug intermediates and preparation of functional materials, can effectively reduce economic cost of drug intermediates and functional materials preparation, and can be widely used in the fields of organic synthetic chemistry, biochemistry, asymmetric catalysis, pesticides and medicine research.
Specifically, R in the molecular structural formula of the alkynyl-sulfolobus-ylide compound shown in the formula II 1 And R is 2 The represented group is R in the molecular structure of the axial chiral alkenyl-sulfur ylide compound shown in the formula I in the example 1 And R is 2 The groups represented are the same. R in the molecular structural formula of pyrazole compound shown in formula III 3 The represented group is R in the molecular structure of the axial chiral alkenyl-sulfur ylide compound shown in the formula I 3 The groups represented are the same. For the sake of space saving, the description is omitted here.
The compound shown in the formula II is alkynyl-sulfolobus-ylide compound and can be prepared by containing R 1 Iodine-sulfur She Li de compound and R-containing 2 The alkyne compound is prepared by coupling reaction under the conditions of a copper catalyst and an alkali reagent, and the specific process is as follows:
by containing R as described above 1 Iodine-sulfur ylide reagent for hypervalent iodine and hexavalent sulfur and R-containing reagent 2 The alkyne compound of (2) is used as a substrate, and a commercially available copper catalyst is adopted to carry out a Sonogashira-like coupling reaction to obtain the corresponding alkyne-sulfur ylide compound. The copper catalyst system realizes the synthesis of the alkynyl-sulfur (VI) ylide compound of hexavalent (expressed by VI) sulfur, the coupling reaction catalyzed by copper metal has high atomic utilization rate and high reaction efficiency of reactants, is favorable for improving the yield of the product, and the reaction process is safe and controllable.
Further, the copper-based catalyst includes Cu (MeCN) 4 PF 6 And at least one of L-Cu-X; wherein X is a halogen atom, and L is a diimine-containing ligand. The alkali agent comprises lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate,At least one of sodium bicarbonate, potassium bicarbonate, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, triethylamine, diisopropylethylamine, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium diisopropylamide, n-butyllithium, t-butyllithium, methyllithium, sodium methoxide, sodium ethoxide, and sodium ethylthiolate.
Specifically, the pyrazole compound shown in the formula III plays a role of a nucleophile, and performs an addition reaction with the alkynyl-sulfur ylide compound shown in the formula II, wherein the alkynyl-sulfur ylide compound shown in the formula II is an alkynyl-sulfur (VI) ylide compound containing hexavalent (shown by VI) sulfur. Therefore, the atomic utilization rate of the reactant is effectively improved, the limitation of the substrate is widened, the target product precursor with high enantioselectivity and extremely wide range is efficiently and greenly prepared, and the axial chiral alkenyl-sulfur She Li German compound with potential application value is obtained through simple addition reaction.
In one embodiment, the water absorbing additive is added into the reaction system of the addition reaction, and the water absorbing additive comprises anhydrous sodium sulfate, anhydrous magnesium sulfate, 13X molecular sieve,Molecular sieves, & gt>Molecular sieves, & gt>At least one of the molecular sieves. The existence of water molecules easily disturbs a highly ordered transition state intermediate through hydrogen bond interaction, so that the water absorption additive is introduced into the reaction system to remove water in the reaction system, and the enantioselectivity of a target product is effectively improved; meanwhile, the water absorption additive can ensure that the reaction system is in a non-water state. Since the water-absorbing additive is mainly used for controlling the anhydrous requirement of the reaction system, the water-absorbing additive can be used according to the requirementsThe reaction time, solvent characteristics, etc. of the bulk reaction system are added, for example, in an amount sufficient to achieve the anhydrous nature of the reaction system. In one embodiment, the ratio of the water-absorbing additive to the solvent of the reactants recited above is controlled to be 100mg/mL.
In one embodiment, the preparation method has the following addition reaction formula:
in the chemical reaction formula, the chiral phosphoric acid catalyst and the water-absorbing additive act synergistically, so that the catalytic system has low toxicity, the atomic utilization rate and the reaction efficiency are improved, and the byproducts are few; meanwhile, the reaction process is safe and controllable, and the operation in the preparation and production processes is simplified. Wherein, the chiral phosphoric acid catalyst can provide better hydrogen bond interaction, thereby improving the enantiomeric excess (enantiomeric excess, ee) value of the product in the catalytic reaction process; under the condition that the contents of the three are in a certain range and in proportion, the reaction has high catalytic efficiency, and the target product with nearly single absolute configuration is obtained.
In one embodiment, the molar ratio of chiral phosphoric acid catalyst, alkynyl-thio ylide compound shown in formula II and pyrazole compound shown in formula III is (0.1-20): 1-100. In order to make the synergistic catalytic system exert more effective catalytic action, the molar ratio of chiral phosphoric acid catalyst to alkynyl-sulfur ylide compound is (0.1-20): 0.2-40. In this case, the reaction has high catalytic efficiency, which is advantageous in increasing the ee value of the reaction product. In some embodiments, the molar ratio of chiral phosphoric acid catalyst to alkynyl-sulfur ylide compound A is (0.2-20): 1-10.
In some embodiments, the chiral phosphoric acid catalyst comprises at least one of a catalyst of formula IV and a catalyst of formula V:
wherein R is 4 Comprises C 1 -C 20 Alkyl, C 6 -C 20 Aryl, substituted C 6 -C 20 Aryl, C 6 -C 20 Aryl (C) 1 -C 20 ) Alkyl, C 6 -C 20 Heteroaryl (C) 1 -C 20 ) Any one of alkyl groups.
In particular experiments, it was found that chiral phosphoric acid catalysts of formula IV can catalyze the above reaction more efficiently, but different chiral phosphoric acid catalysts result in products with different enantioselectivities. In one embodiment, R 4 Is C 1 -C 20 Alkyl, C 6 -C 20 Aryl, substituted C 6 -C 20 Aryl, C 6 -C 20 Aryl (C) 1 -C 20 ) Alkyl, C 6 -C 20 Heteroaryl (C) 1 -C 20 ) Any one of alkyl groups. Wherein aryl may be phenyl, naphthyl, anthryl, phenanthryl and the like, heteroaryl may be a monocyclic or polycyclic or fused ring aromatic hydrocarbon in which one or more carbon atoms have been replaced by heteroatoms such as nitrogen, oxygen or sulfur. Substituted C 6 -C 20 In the aryl group, the substituent may be a halogen atom, C 1 -C 5 Alkyl, perhalogen substituted C 1 -C 5 Alkyl groups, and the like. For example, R 4 May be (2, 6-diisopropyl-4-adamantyl) phenyl, 3, 5-bis (trifluoromethyl) phenyl, pyrenyl (1-pyrenyl), or the like.
In one embodiment, the temperature of the addition reaction is-60 ℃ to-45 ℃ and the time of the addition reaction is 10 to 48 hours. The reaction system of the embodiment of the application can be smoothly carried out even at a lower temperature, and the applicable reaction temperature range is-60 ℃ to-45 ℃. In order to further increase the reaction efficiency and increase the enantioselectivity of the reaction product, in one embodiment, the reaction temperature of the reaction system is between-60 ℃ and-50 ℃. In another embodiment, the reaction temperature of the reaction system is-50 ℃ to-45 ℃. The reaction time in the environment of each preferred reaction temperature should be such that the above reactants react sufficiently, e.g., the reaction time may be 12 to 48 hours, or longer.
In the above reaction system, a certain amount of solvent may be optionally added. The solvent includes, but is not limited to, diethyl ether, tetrahydrofuran, methylene chloride, toluene. In one embodiment, the solvent may be added in a molar ratio of solvent to catalyst such that (1000-1000000): 1.
in conclusion, the synergistic effect of the chiral phosphoric acid catalyst and the water removal agent in the preparation process of the axial chiral alkenyl-sulfur ylide compound ensures that the catalytic system has low toxicity, high atom utilization rate and production efficiency, safe and controllable reaction process and simplified operation in the preparation and production processes. Meanwhile, in a reaction system containing the chiral phosphoric acid catalyst and the water removal reagent, the toxicity of the residues in the reaction is reduced to the minimum, the pollution to the environment in the production process is reduced, and the steps and the operation for removing the residues after the reaction are simplified. In addition, by flexibly adjusting the proportion and the addition amount between the chiral phosphoric acid catalyst and the reactant, the high atom utilization rate and the production efficiency are further provided, and the production of byproducts is reduced.
The following description is made with reference to specific embodiments.
Example 1
The present embodiment provides a (R a ) - (E) -4- (dimethyloxo) -L6-sulfanylidene) -2, 7-tetramethyl-5- (1H-pyrazol-1-yl) oct-5-en-3-one and a process for preparing the same. The (R) a ) The structural formula of the- (E) -4- (dimethyloxo) -L6-sulfanylidene) -2, 7-tetramethyl-5- (1H-pyrazol-1-yl) oct-5-en-3-one is shown as a molecular structural formula I1, and the catalyst used for preparation is shown as a molecular structural formula IV (R) 4 Is (2, 6-diisopropyl-4-adamantyl) phenyl):
the preparation method comprises the following steps:
(1)R 1 and R is 2 Preparation of alkynyl-thioylide reagent, 4- (dimethyloxo) -L6-sulfonylidene-2, 7-tetramethyloct-5-yn-3-one, both of which correspond to tert-butyl group:
copper catalyst Cu (MeCN) was added in 10ml tubes 4 PF 6 (0.01 mmol,0.1 eq (equiv.)) and the corresponding iodo-thio ylide reagent (0.2 mmol,1.0 equiv.)) were dissolved in 1.0mL of pretreated dichloromethane, sealed with a rubber stopper, then replaced with gas under argon atmosphere (3 times), triethylamine (Et 3 N) (28. Mu.L, 1.0 equiv.) and R 2 3, 3-dimethyl-1-butyne (25 μl,1.0 equiv.) corresponding to tert-butyl group was replaced with the gas again under argon atmosphere (3 times). The test tube was sealed with a sealing film and stirred at 0℃for 1 hour. The mixture was directly separated and purified using neutral alumina column chromatography (dichloromethane and acetone as eluent) to give the target product as a white solid in 89% yield.
And (3) relevant characterization analysis, wherein the result is as follows: 1 H NMR(400MHz,Acetone-d 6 )δ3.55(s,6H),1.25(s,9H),1.23(s,9H). 13 C NMR(101MHz,Acetone-d 6 )δ196.22,105.00,76.49,72.86,41.03,40.01,29.89,27.86,25.67.HRMS(ESI-TOF)calculated for C 14 H 24 O 2 S(M+H + ) 257.1570, found:257.1578. This result further confirms that the product molecular structure is as described above.
(2) Preparation of formula I1
4 molecular sieves (100 mg) and the above alkynyl-thioylide reagent 4- (dimethyloxo) -L6-sulfonylidene-2, 7-tetramethyloct-5-yn-3-one (0.1 mmol,1.0 equiv.) were dissolved in 1.0mL of pretreated chloroform in 10mL of a tube, sealed with a rubber stopper, and then replaced with gas (3 times) under argon atmosphere, R of formula IV was added 4 A chloroform solution (0.1 mL) of a chiral phosphoric acid catalyst (0.01 mmol,0.1 equivalent (equiv.)) for (2, 6-diisopropyl-4-adamantyl) phenyl and pyrazole (0.20 mmol,2.0 equiv.)) was prepared, and after completion of the sample introduction, the mixture was reacted at-60℃for 12 hours. The mixture is directly separated and purified by silica gel column chromatography (ethyl acetate and normal hexane are used as eluent) to obtain the target product, and chiral HPL is usedThe enantioselectivity of the product was determined to give the desired product I1 in 92% yield, 97% ee.
And (3) relevant characterization analysis, wherein the result is as follows: 1 H NMR(400MHz,CDCl 3 )δ7.68(d,J＝2.4Hz,1H),7.52(d,J＝1.7Hz,1H),6.30(s,1H),6.10(s,1H),3.63(s,3H),3.55(s,3H),1.28(s,9H),0.98(s,9H). 13 C NMR(101MHz,CDCl 3 )δ194.78,139.57,139.41,127.76,127.23,106.15,77.23,43.51,41.92,40.86,33.83,30.35,27.77.HRMS(ESI-TOF)calculated for C 17 H 28 N 2 O 2 S(M+Na + ):347.1764,found:347.1767.Specific Rotation[α] 22 D ＝-127.2(c＝1,CH 2 Cl 2 ).HPLC：Daicel Chiralpak IB(4.6mm × 250 mmL), n-hexane/EtOH ＝ 90/10, v ＝ 1.0 mL·min –1 λ=254 nm. T (major) =9.31 min, t (minor) =6.00 min. This result further confirms that the product molecular structure is as described above for molecular structure I1.
Example 2
The present embodiment provides a (R a ) - (E) -4- (dimethyloxo) -L6-sulfanylidene) -2, 7-tetramethyl-5- (4-methyl-1H-pyrazol-1-yl) oct-5-en-3-one and a process for preparing the same. The (R) a ) The structural formula of the- (E) -4- (dimethyloxo) -L6-sulfanylidene) -2, 7-tetramethyl-5- (4-methyl-1H-pyrazol-1-yl) oct-5-en-3-one is shown as the following molecular structural formula I2:
the preparation method is described in example 1 (R) a ) - (E) -4- (dimethyloxo) -L6-sulfanylidene) -2, 7-tetramethyl-5- (1H-pyrazol-1-yl) oct-5-en-3-one, except that 4-methylpyrazole (0.2 mmol) was used instead of pyrazole. The reaction solution is directly separated and purified by silica gel column chromatography (ethyl acetate and normal hexane are used as eluent) to obtain a target product, colorless liquid, the yield is 98%, and the ee value is 93%.
The characterization data analysis of the prepared product I2 is carried out, and the result is that 1 H NMR(400MHz,Chloroform-d)δ7.44(s,1H),7.29(s,1H),5.99(s,1H),3.61(s,3H),3.48(s,3H),2.07(s,3H),1.24(s,9H),0.97(s,9H). 13 C NMR(101MHz,Chloroform-d)δ194.80,140.16,138.21,127.82,125.84,116.83,80.91,43.28,41.96,40.63,33.76,30.44,27.84,9.01.HRMS(ESI-TOF)calculated for C 18 H 30 N 2 O 2 S(M+Na + ):361.1920,found:361.1921.Specific Rotation：[α] 20 D ＝-85.2°(c＝1.00,CH 2 Cl 2 ).HPLC：Daicel Chiralpak IA(4.6mm×250mmL),n-hexane/ i PrOH＝95/5,v＝1.0mL·min –1 ,λ＝254nm.t(major)＝9.77min,t(minor)＝11.14min.]This result further confirms that the molecular structure of the product is as described above for molecular structure I2.
Example 3
This example provides (R) - (E) -5- (4-bromo-1H-pyrazol-1-yl) -4-dimethyl-L6-sulfa-ylidene-2, 7-tetramethyloct-5-en-3-one and methods of making the same. The structural formula of (R) - (E) -5- (4-bromo-1H-pyrazol-1-yl) -4-dimethyl-L6-sulfanylidene-2, 7-tetramethyloct-5-en-3-one is shown as the following molecular structural formula I3:
the preparation method is described in example 1 (R) a ) - (E) -4- (dimethyloxo) -L6-sulfanylidene) -2, 7-tetramethyl-5- (1H-pyrazol-1-yl) oct-5-en-3-one, except that 4-bromopyrazole (0.2 mmol) was used in place of pyrazole. The reaction solution is directly separated and purified by silica gel column chromatography (ethyl acetate and normal hexane are used as eluent) to obtain a target product, colorless liquid, the yield is 93%, and the ee value is 93%.
The prepared product I3 is subjected to characterization data analysis, and the result is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.71(s,1H),7.45(s,1H),6.04–5.96(m,1H),3.59(s,3H),3.54(s,3H),1.27–1.21(m,9H),0.97(d,J＝1.1Hz,9H). 13 C NMR(101MHz,Chloroform-d)δ194.63,139.94,139.89,127.66,127.23,93.89,79.92,43.68,41.89,41.07,33.89,30.25,27.82.HRMS(ESI-TOF)calculated for C 17 H 27 BrN 2 O 2 S(M+H + ):403.1049,found:403.1048.Specific Rotation：[α] 20 D ＝-16.6°(c＝0.68,CH 2 Cl 2 ).HPLC：[Daicel Chiralpak IB(4.6mm×250mmL),n-hexane/ i PrOH＝90/10,v＝1.0mL·min –1 ,λ＝254nm.t(major)＝7.06min,t(minor)＝6.26min.]this result further confirms that the molecular structure of the product is as described above for molecular structure I3.
The foregoing description of the preferred embodiments of the application is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the application.
Claims (10)
1. The axial chiral alkenyl-sulfur ylide compound is characterized in that the molecular structural general formula of the axial chiral alkenyl-sulfur ylide compound is shown as formula I:
wherein R is 1 And R is 2 Independently include C 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Heterocycloalkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Heteroalkenyl, C 3 -C 20 Cycloalkenyl, C 3 -C 20 Heterocycloalkenyl, C 2 -C 20 Alkynyl, C 2 -C 20 Heteroalkynyl, C 3 -C 20 Cycloalkynyl radicals, C 3 -C 20 Heterocyclic alkynyl, C 1 -C 20 Alkoxy, C 6 -C 20 Aryl, substituted (C) 6 -C 20 ) Aryl, C 3 -C 20 Heteroaryl, substituted (C) 3 -C 20 ) Heteroaryl, C 6 -C 20 Aryloxy, C 3 -C 20 Heteroaryloxy, C 6 -C 20 Aryl (C) 1 -C 20 ) Alkyl, C 3 -C 20 Heteroaryl (C) 1 -C 20 ) Any one of alkyl groups;
R 3 comprising hydrogen, halogen atoms, C 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Heterocycloalkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Heteroalkenyl, C 3 -C 20 Cycloalkenyl, C 3 -C 20 Heterocycloalkenyl, C 2 -C 20 Alkynyl, C 2 -C 20 Heteroalkynyl, C 3 -C 20 Cycloalkynyl radicals, C 3 -C 20 Heterocyclic alkynyl, C 1 -C 20 Alkoxy, C 6 -C 20 Aryl, substituted (C) 6 -C 20 ) Aryl, C 3 -C 20 Heteroaryl, substituted (C) 3 -C 20 ) Heteroaryl, C 6 -C 20 Aryloxy, C 3 -C 20 Heteroaryloxy, C 6 -C 20 Aryl (C) 1 -C 20 ) Alkyl, C 3 -C 20 Heteroaryl (C) 1 -C 20 ) Any one of alkyl groups.
2. The axial chiral alkenyl-sulfur ylide compound of claim 1, wherein R 1 Comprises C 1 -C 10 Alkyl, R 2 Comprises C 1 -C 10 An alkyl group.
3. The axial chiral alkenyl-sulfur ylide compound of claim 2, wherein R 1 Is C 4 -C 10 Tertiary alkyl, R 2 Is C 4 -C 10 And a tertiary alkyl group.
4. The axial chiral alkenyl-sulfur ylide compound of claim 1, wherein R 3 Comprising hydrogen, halogen atoms, C 1 -C 10 At least one of the alkyl groups.
5. The axial chiral alkenyl-sulfur ylide compound of any of claims 1-4, wherein the axial chiral alkenyl-sulfur ylide compound comprises at least one of:
6. the preparation method of the axial chiral alkenyl-sulfur ylide compound is characterized by comprising the following steps:
carrying out addition reaction on a compound shown in a formula II and a compound shown in a formula III under the condition of a chiral phosphoric acid catalyst to obtain the axial chiral alkenyl-sulfur ylide compound as claimed in any one of claims 1-5;
7. the method of preparing according to claim 6, wherein the chiral phosphoric acid catalyst comprises at least one of a catalyst of formula IV and a catalyst of formula V:
wherein R is 4 Comprises C 1 -C 20 Alkyl, C 6 -C 20 Aryl, substituted C 6 -C 20 Aryl, C 6 -C 20 Aryl (C) 1 -C 20 ) Alkyl, C 6 -C 20 Heteroaryl (C) 1 -C 20 ) Any one of alkyl groups.
8. The method according to claim 6, wherein a water-absorbing additive is added to the reaction system of the addition reaction, and the water-absorbing additive comprises no waterSodium sulfate hydrate, anhydrous magnesium sulfate, 13 x molecular sieve,Molecular sieves, & gt>Molecular sieves, & gt>At least one of the molecular sieves.
9. The process according to claim 6, wherein the molar ratio of the chiral phosphoric acid catalyst, the compound of formula II and the compound of formula III is (0.1-20): 1-100.
10. The preparation method according to any one of claims 6 to 9, wherein the temperature of the addition reaction is-60 ℃ to-45 ℃ and the time of the addition reaction is 10 to 48 hours.
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