CN108976241B - Synthesis method of chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound - Google Patents
Synthesis method of chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound Download PDFInfo
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- CN108976241B CN108976241B CN201710406149.3A CN201710406149A CN108976241B CN 108976241 B CN108976241 B CN 108976241B CN 201710406149 A CN201710406149 A CN 201710406149A CN 108976241 B CN108976241 B CN 108976241B
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- chiral
- compound
- dihydropyrano
- pyrazole
- propargyl
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- -1 1, 4-dihydropyrano [2,3-c ] pyrazole compound Chemical class 0.000 title claims abstract description 64
- 238000001308 synthesis method Methods 0.000 title description 3
- 239000010949 copper Substances 0.000 claims abstract description 27
- 239000003054 catalyst Substances 0.000 claims abstract description 18
- 239000003446 ligand Substances 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 17
- 229910052802 copper Inorganic materials 0.000 claims abstract description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 13
- 125000001424 substituent group Chemical group 0.000 claims abstract description 13
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000001879 copper Chemical class 0.000 claims abstract description 8
- HZKPKAKLGRSCJS-UHFFFAOYSA-N 1,4-dihydropyrano[2,3-c]pyrazole Chemical class C1C=COC2=C1C=NN2 HZKPKAKLGRSCJS-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000010189 synthetic method Methods 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000000654 additive Substances 0.000 claims description 14
- 230000000996 additive effect Effects 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 239000012429 reaction media Substances 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 7
- XBYRMPXUBGMOJC-UHFFFAOYSA-N 1,2-dihydropyrazol-3-one Chemical class OC=1C=CNN=1 XBYRMPXUBGMOJC-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- 238000006352 cycloaddition reaction Methods 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims 2
- 239000012141 concentrate Substances 0.000 claims 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000001544 thienyl group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 14
- 239000000758 substrate Substances 0.000 abstract description 9
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000011065 in-situ storage Methods 0.000 abstract 1
- 239000012454 non-polar solvent Substances 0.000 abstract 1
- 239000002798 polar solvent Substances 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 238000001228 spectrum Methods 0.000 description 10
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 125000004185 ester group Chemical group 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical class [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 2
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- ROORDVPLFPIABK-UHFFFAOYSA-N diphenyl carbonate Chemical class C=1C=CC=CC=1OC(=O)OC1=CC=CC=C1 ROORDVPLFPIABK-UHFFFAOYSA-N 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- CMPQUABWPXYYSH-UHFFFAOYSA-N phenyl phosphate Chemical class OP(O)(=O)OC1=CC=CC=C1 CMPQUABWPXYYSH-UHFFFAOYSA-N 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- ZRHUHDUEXWHZMA-UHFFFAOYSA-N 1,4-dihydropyrazol-5-one Chemical class O=C1CC=NN1 ZRHUHDUEXWHZMA-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 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
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Cs2CO3 Substances [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 241000565675 Oncomelania Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Chemical compound OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- XOLBLPGZBRYERU-UHFFFAOYSA-N SnO2 Inorganic materials O=[Sn]=O XOLBLPGZBRYERU-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 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
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- WOWHHFRSBJGXCM-UHFFFAOYSA-M cetyltrimethylammonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)C WOWHHFRSBJGXCM-UHFFFAOYSA-M 0.000 description 1
- 101150113535 chek1 gene Proteins 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910001914 chlorine tetroxide Inorganic materials 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000006452 multicomponent reaction Methods 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 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
- 239000010452 phosphate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- DKAHKEKMRSHQLY-UHFFFAOYSA-N pyrano[3,2-c]pyrazole Chemical class C1=COC2=CN=NC2=C1 DKAHKEKMRSHQLY-UHFFFAOYSA-N 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 239000002096 quantum dot Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010490 three component reaction Methods 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a synthetic method of a chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound. The chiral copper catalyst adopted by the method is generated in situ by copper salt and chiral P, N, N-tridentate ligand in various polar and nonpolar solvents. The invention can conveniently synthesize various chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compounds with substituent groups, and the enantiomeric excess percentage of the compounds is up to 96%. The method has the characteristics of simple operation, easily obtained raw materials, wide application range of the substrate, high enantioselectivity and the like.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthetic method of a chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound.
Background
The pyranopyrazole heterocyclic compound is an important structural unit in the nitrogen-containing heterocyclic compound, and has various biological activities and pharmacological activities, such as anticancer, anti-inflammatory, analgesic, antibacterial, insecticidal and the like; in addition, the protein also has oncomelania killing activity and is a potential human Chk1 enzyme inhibitor. Therefore, the synthesis of the compounds has been receiving wide attention from researchers, and is one of the hot spots in the field of organic synthesis [ (a).
Chem.Rev.2006,106,17–89.(b)N.Foloppe,L.M.Fisher,R.Howes,A.Potter,A.G.S.Robertson,A.E.Surgenor,Bioorg.Med.Chem.2006,14,4792–4802.(c)J.L.Wang,D.X.Liu,Z.J.Zhang,S.M.Shan,X.B.Han,S.M.Srinivasula,C.M.Croce,E.S.Alnemri,Z.W.Huang,Proc.Natl.Acad.Sci.U.S.A.2000,97,7124–7129.(d)S.C.Kuo,L.J.Huang,H.Nakamura,J.Med.Chem.1984,27,539–544.(e)S.R.Mandha,S.Siliveri,M.Alla,V.R.Bommena,M.R.Bommineni,S.Balasubramanian,Bioorg.Med.Chem.Lett.2012,22,5272–5278.(f)M.E.A.Zaki,H.A.Soliman,O.A.Hiekal,A.E.Rashad,Z.Naturforsch C2006,61,1–5.(g)X.T.Huang,Z.P.Li,D.Y.Wang,Y.Q.Li,Chinese Journal of Catalysis 2016,37,1461–1468.(h)Abdelrazek,F.M.；Metz,P.；Metwally,N.H.；El-Mahrouky,S.F.Arch.Pharm.2006,339,456.]. Such compounds are synthesized primarily by "one-pot" Multicomponent Reactions, with two common reaction pathways: 1) three-component reactions (3CRs) using carbonyl compounds, malononitrile and the corresponding 5-pyrazolones are commonly used as catalysts such as triethylamine, triethanolamine, piperidine, N-methylmorpholine, D, L-proline, bovine serum albumin [ (a) A.M.Shostopalov, Y.M.Emeliyanova, A.A.Shostopalov, L.A.Rodinovskaya, Z.I.Niazimbetova, D.H.Evans, Tetrahedron 2003,59, 7491-Strobenzin 7496 (b) R.Gr.Redkin, L.A.Shemchuk, V.P.Chernykh, O.V.Shishkin, S.V.Shekia, Tetrahedron 2007,63, 11444-Strobenzin 11450 (c) H.G.Kathroya, R.V.Shishkin, S.V.S.S.S.S.S.S.Sohrub.201.P.P.J.S.2,77,983–991.(d)F.Lehmann,M.Holm,S.Laufer,J.Comb.Chem.2008,10,364–367.(e)S.B.Guo,S.X.Wang,J.T.Li,Synth.Commun.2007,37,2111–2120.(f)K.Eskandari,B.Karami,S.Khodabakhshi,Catal.Commun.2014,54,124–130.(g)A.M.Shestopalov,Y.M.Emeliyanova,A.A.Shestopalov,L.A.Rodinovskaya,Z.I.Niazimbetova,D.H.Evans,Org.Lett.2002,4,423–425.](ii) a 2) The four-component reaction (4CRs) is carried out by using aldehyde, malononitrile, hydrazine hydrate and ethyl acetoacetate, and the commonly used catalysts comprise triethylamine, macroporous resin A21, hexadecyltrimethylammonium chloride, molecular sieve and magnetic Fe3O4Nanoparticles, SnO2Quantum dots, L-proline, glycine, etc., (a) Y.M.Litvinov, A.A.Shestopalov, L.A.Rodinovskaya, A.M.Shestopalov, J.Comb.Chem.2009,11, 914-919 (b) M.Bihani, P.P.Bora, G.Bez, H.Askari, ACS Sustain.Chem.Eng.2013,1, 440-conk. C) M.S.Wu, Q.Q.Feng, D.H.Wan, J.Y.Ma, Synth.Comun.2013, 43, 1721-1726-d. J.B.Gujar, M.A.Chaudi, D.S.Kawai, M.S.Shiaree, Teng.Shi, Ten-Shi, Ten.H.S.70, K.Shih.Shih.S.70, K.Shih.J.H.J.J.M.J.M.H.J.M.J.J.M.J.J.M.J.J.M.J.J.J.H.J.J.J.J.J.J.J.J.H.J.J.J.70, J.70, J.H.H.H.S.70, D.J.D.H.H.H.70, D.D.D.S.H.H.70, D.S.S.J.S.J.H.D.D.H.H.H.J.J.H.70, D.70, D.S.S.70, D.D.D.D.D.D.D.D.S.S.D.D.H.S.H.H.H.H.70, K.70, D.70, D.D.D.D.D.D.D.D.D.H.D.H.H.H.D.H.S.S.J.H.S.D.D.H.D.H.70, D.D.S.H.H.H.H.H.H.D.D.D.J.S.S.J.S.H.H.J.J.J.J.S.H.H.H.H.S.S.S.S.S.H.70, D.S.70, D.H.H.70, D.S.H.S.S.70, K.D.70, D.H.70, D.70, K.70, K.D.D.D.D.D.D.J.D.D.70, K.S.S.70, K.S.S.S.S.S.S.S.S.S.S.S.S.70, D.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.70, D.S.S.S.S.S.S.S.S.S.S.S.S.H.H.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.H.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S..]. Recently, a method for preparing pyrazolopyrans using a Suzuki coupling reaction with 4-bromobenzaldehyde and phenylboronic acid followed by five-component (5CRs) reaction with malononitrile, hydrazine hydrate and ethyl acetoacetate [ Z.X.Lu, J.L.Xiao, D.Y.Wang, Y.Q.Li, Asian J.org.Chem.2015,4, 487-one 492 ] has also been reported.]. However, the method is accompanied with the defects of harsh reaction conditions, expensive part of raw materials, large catalyst dosage, long reaction time, low reaction yield and the like, and more importantly, the pyrazolopyran compounds prepared by the method have no optical activity. Therefore, a new asymmetric catalytic process was developed to simply and efficiently construct chiral 1, 4-dihydropyrano [2,3-c ]]The pyrazole compounds are very importantThe significance of (1).
Disclosure of Invention
The invention aims to provide a method for synthesizing a chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound, which is a method for synthesizing the chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound by carrying out asymmetric [3+3] cycloaddition reaction on a copper-catalyzed 5-hydroxypyrazole compound and a propargyl compound. The method has the characteristics of easily obtained raw materials, simple operation, mild reaction conditions, high enantioselectivity and the like.
The invention provides a synthesis method of a chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound, which is characterized in that a chiral copper catalyst is used for catalyzing a 5-hydroxypyrazole compound and a propargyl compound to synthesize the chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound through an asymmetric [3+3] cycloaddition reaction.
The method comprises the following specific steps:
(1) preparation of chiral copper catalyst: under the protection of nitrogen, copper salt and P, N, N-ligand are stirred in a reaction medium for 1-2 hours according to the molar ratio of 1: 0.1-10 to prepare a chiral copper catalyst;
(2) preparation of 1, 4-dihydropyrano [2,3-c ] pyrazole compounds: dissolving a propargyl compound, a 5-hydroxypyrazole compound and an alkali additive in a reaction medium, adding the solution into the stirred solution of the chiral copper catalyst under the protection of nitrogen, and stirring and reacting for 24 hours at 10 ℃; after the reaction is finished, concentrating under reduced pressure until no solvent exists basically, separating by silica gel column chromatography, concentrating under reduced pressure, and drying in vacuum to obtain a target product;
the molar ratio of the chiral copper catalyst to the propargyl compound is 0.01-100% to 1,
the molar ratio of the alkali additive to the propargyl compound is 0.5-10: 1;
the molar ratio of the 5-hydroxypyrazole compound to the propargyl compound is 1: 1-2.
The reaction medium is at least one of methanol, ethanol, toluene, benzene, xylene, dichloromethane, 1, 2-dichloroethane, diethyl ether, tetrahydrofuran, dimethyl sulfoxide or N, N-dimethylformamide, and preferably at least one of methanol, ethanol or tetrahydrofuran.
The chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound has one of the following structures:
i and II are enantiomers of each other, wherein: r1，R2，R3Is one or more than two of C1-C40 alkyl, C3-C12 cycloalkyl or C3-C12 cycloalkyl with substituent, phenyl and substituted phenyl, benzyl and substituted benzyl, five-membered or six-membered heterocyclic aromatic group containing one or more than two oxygen, sulfur and nitrogen atoms and ester group; the substituent on the C3-C12 naphthenic base, the substituent on the phenyl and the substituent on the benzyl are respectively one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano.
The 5-hydroxypyrazole compound has the following structure:
in the formula: r1，R2Is represented by formula I, II1，R2The same groups.
The propargyl compound has the following structure:
in the formula: r3Is represented by formula I, II3The same group; x is one or more than two of fluorine, chlorine, bromine, iodine, C1-C10 alkyl carboxylic ester, C1-C10 alkyl carbonate, C1-C10 alkyl sulfonate, C1-C10 alkyl phosphate, phenyl carboxylic ester and substituted phenyl carboxylic ester, phenyl carbonate and substituted phenyl carbonate, phenyl sulfonate and substituted phenyl sulfonate or phenyl phosphate and substituted phenyl phosphate; substituents on substituted phenylIs one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent groups is 1-5.
Said copper salt is a divalent copper salt such as Cu (OAc)2·H2O、CuSO4·H2O、Cu(OAc)2、CuSO4、Cu(OTf)2、CuCl2And various monovalent copper salts such as CuOAc, CuCl, CuI, CuClO4、CuOTf·0.5C6H6、Cu(CH3CN)4BF4Or Cu (CH)3CN)4ClO4Preferably Cu (OAc)2·H2O、Cu(CH3CN)4BF4、Cu(OTf)2。
The chiral P, N, N-ligand has the following structural characteristics:
in the formula: r3，R4H, alkyl in C1-C10, cycloalkyl in C3-C8, phenyl and substituted phenyl, benzyl and substituted benzyl; the substituent on the substituted phenyl or the substituted benzyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5;
R5，R6is H, halogen, alkyl and cycloalkyl, phenyl and substituted phenyl, alkoxy, phenoxy, acyl, nitro;
R7is C1-C40 alkyl, C3-C12 cycloalkyl, phenyl and substituted phenyl, naphthyl and substituted naphthyl, and contains one or more than two five-membered or six-membered heterocyclic aromatic groups of oxygen, sulfur and nitrogen atoms; the substituent on the substituted phenyl or the substituted naphthyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5.
The alkaline additive is various inorganic bases or organic bases; preferably K2CO3、Cs2CO3Or K3PO4。
The catalytic reaction conditions are preferably as follows:
temperature: 10 ℃;
reaction medium: methanol;
pressure: normal pressure;
time: for 24 hours.
The mol ratio of the chiral copper catalyst to the propargyl compound is preferably 1-10% to 1,
the molar ratio of the alkali additive to the propargyl compound is preferably 1: 1;
the molar ratio of the 5-hydroxypyrazole compound to the propargyl compound is preferably 1: 1.2.
The reaction equation of the invention is as follows:
the invention has the following advantages:
1. high reaction activity, good stereoselectivity and mild reaction conditions.
2. The starting materials are cheap and easy to obtain.
3. The chiral ligand is simple and convenient to synthesize, the catalyst is cheap and easy to obtain, and the dosage is small.
4. Compared with the traditional method, the method can conveniently synthesize various substituted 1, 4-dihydropyrano [2,3-c ] pyrazole compounds.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of 1,3, 4-triphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-1 prepared in example 1;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of 1,3, 4-triphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-1 prepared in example 1;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of 3- (4-methoxyphenyl) -1, 4-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazolII-2 prepared in example 11;
FIG. 4 is a nuclear magnetic resonance carbon spectrum of 3- (4-methoxyphenyl) -1, 4-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole prepared in example 11;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of 3- (2-naphthyl) -1, 4-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-3 prepared in example 12;
FIG. 6 is a nuclear magnetic resonance carbon spectrum of 3- (2-naphthyl) -1, 4-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazolII-3 prepared in example 12;
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of 3, 4-diphenyl-1- (4-methylphenyl) -1, 4-dihydropyrano [2,3-c ] pyrazolII-4 prepared in example 13;
FIG. 8 is a NMR carbon spectrum of 3, 4-diphenyl-1- (4-methylphenyl) -1, 4-dihydropyrano [2,3-c ] pyrazolII-4 prepared in example 13;
FIG. 9 is a NMR spectrum of 4- (3-chlorophenyl) -1, 3-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-5 prepared in example 15;
FIG. 10 is a carbon nuclear magnetic resonance spectrum of 4- (3-chlorophenyl) -1, 3-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-5 prepared in example 15;
FIG. 11 is a NMR spectrum of 4- (4-chlorophenyl) -1, 3-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-6 prepared in example 16;
FIG. 12 is a carbon nuclear magnetic resonance spectrum of 4- (4-chlorophenyl) -1, 3-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-6 prepared in example 16;
Detailed Description
The following examples further illustrate the invention but are not intended to limit the invention thereto. NMR was measured by Bruker NMR and High Performance Liquid Chromatography (HPLC) was measured by Agilent1100 series HPLC.
Example 1
Cu(OAc)2·H2The complexation of O and L-1-1 is used as a catalyst to catalyze the reaction to generate 1, 4-dihydropyrano [2,3-c ]]Pyrazole cycloaddition product 1,3, 4-triphenyl-1, 4-dihydropyrano [2,3-c]Pyrazole II-1.
The metal precursor Cu (OAc) was added to the reaction flask2·H2O (0.015mmol, 5 mol%) and chiral ligand L-1-1(0.0165mmol, 5.5 mol%), adding under nitrogen protection1.0mL of anhydrous methanol was added thereto, and the mixture was stirred at room temperature for 1 hour. Then the reaction tube was moved to a 10 ℃ constant temperature reaction freezer, and propargyl alcohol ester IV-1 (0.36mmol, 1.2equiv), 5-hydroxypyrazole-based compound III-1 (0.3mmol, 1.0equiv) and Cs were added2CO3(0.36mmol, 1.2equiv) was dissolved in 2.0mL of anhydrous methanol, and the solution was added to the stirred catalyst solution under nitrogen protection, and the reaction was stirred at 10 ℃ for 24 h. After the reaction, the mixture was concentrated under reduced pressure until the mixture was substantially free of solvent, separated by silica gel column chromatography, concentrated under reduced pressure, and dried under vacuum to obtain a reddish brown oily substance with 87% yield and 94% ee. The hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance of the product II-1 are shown in the figures 1 and 2:
1H NMR(400MHz,DMSO)δ7.87–7.84(m,2H),7.62–7.55(m,4H),7.41–7.37(m,1H),7.29–7.21(m,7H),7.16–7.10(m,1H),6.87(dd,J＝6.0,1.5Hz,1H),5.26(dd,J＝6.0,4.2Hz,1H),5.12(dd,J＝4.1,1.5Hz,1H)；13C NMR(101MHz,DMSO)δ147.5,145.1,138.2,138.0,133.1,129.9,129.0,128.7,128.4,128.1,127.2,127.1,126.9,121.3,108.9,97.6,37.1.HPLC(Chiralcel OJ-H,n-hexane/i-PrOH＝50/50,0.8ml/min,254nm,40℃):tR(major)＝9.0min,tR(minor)＝17.4min。
the structural formula of III-1, IV-1, II-1, L-1-1 is as follows:
example 2
L-1-2 is used as ligand to react to generate a product II-1
The ligand L-1-1 in example 1 was replaced with the ligand L-1-2, and the base additive wasiPr2NEt, room temperature, the rest of example 1. The reaction gave compound II-1 in 20% yield and 11% ee.
The structural formula of L-1-2 is as follows:
example 3
L-2-1 is used as ligand to react to generate a product II-1
The ligand L-1-1 in example 1 was replaced with ligand L-2-1, and the base additive wasiPr2NEt, room temperature, the rest of example 1. The reaction gave compound II-1 in 69% yield and 83% ee.
The structural formula of L-2-1 is as follows:
example 4
L-3 as ligand reacts to generate a product II-1
The ligand L-1-1 in example 1 was replaced with ligand L-3, and the base additive wasiPr2NEt, room temperature, the rest of example 1. The reaction gave compound II-1 in 57% yield and 42% ee.
Example 5
Cu(OTf)2Catalytically reacting with L-1-1 to produce a product II-1
Cu (OAc) in example 12·H2Cu (OTf) for O2Instead, the base additive isiPr2NEt, room temperature, the rest of example 1. Compound II-1 was obtained in 59% yield and 86% ee.
Example 6
Cu(CH3CN)4BF4Catalytically reacting with L-1-1 to produce a product II-1
Cu (OAc) in example 12·H2Cu (CH) for O3CN)4BF4Instead, the base additive isiPr2NEt, at room temperature, as in example 1 gave compound II-1 in 77% yield and 87% ee.
Example 7
iPr2NEt as base additionAdding agent to react to generate a product II-1
Cs in example 12CO3Is replaced byiPr2NEt, room temperature, the rest of example 1. Compound II-1 was obtained in 66% yield and 90% ee.
Example 8
III-2 is used as a substrate to react to generate a product 3- (4-methoxyphenyl) -1, 4-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-2
The same procedure used in example 1 except for replacing 5-hydroxypyrazole III-1 with III-2 in example 1 gave compound II-2 in 97% yield and 94% ee. The hydrogen and carbon nuclear magnetic resonance spectra of the product II-2 are shown in FIGS. 3 and 4:1H NMR(400MHz,CDCl3)δ7.89–7.87(m,2H),7.48–7.44(m,4H),7.30–7.21(m,5H),7.19–7.14(m,1H),6.75–6.72(m,2H),6.56(dd,J＝6.0,1.5Hz,1H),5.15(dd,J＝6.0,4.1Hz,1H),4.89(dd,J＝4.0,1.4Hz,1H),3.74(s,3H)；13C NMR(101MHz,CDCl3)δ159.3,148.0,147.4,144.8,138.4,137.3,129.1,128.8,128.3,127.7,126.8,126.2,125.8,121.0,113.6,108.5,96.9,55.2,38.0.HPLC(Chiralcel AS-H,n-hexane/i-PrOH＝95/5,0.8ml/min,254nm,40℃):tR(major)＝8.8min,tR(minor)＝13.7min.
the structural formula of III-2 and II-2 is as follows:
example 9
III-3 is used as a substrate to react to generate a product 3- (2-naphthyl) -1, 4-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-3
The same procedure used in example 1 except for substituting 5-hydroxypyrazole III-1 with III-3 in example 1 gave compound II-3 in 96% yield and 95% ee. The hydrogen and carbon nuclear magnetic resonance spectra of the product II-3 are shown in FIGS. 5 and 6:1H NMR(400MHz,CDCl3)δ7.94–7.87(m,3H),7.79–7.71(m,3H),7.58–7.47(m,3H),7.41–7.37(m,2H),7.33–7.22(m,5H),7.18–7.14(m,1H),6.57(dd,J＝6.0,1.4Hz,1H),5.18(dd,J＝6.0,4.1Hz,1H),5.00(dd,J＝3.9,1.3Hz,1H)；13C NMR(101MHz,CDCl3)δ148.0,147.6,145.0,138.4,137.3,133.1,132.9,130.6,129.2,128.9,128.2,127.9,127.8,127.6,127.0,126.5,126.4,126.0,124.9,121.2,108.6,97.6,38.2.HPLC(Chiralcel OJ-H,n-hexane/i-PrOH＝50/50,0.8ml/min,254nm,40℃):tR(minor)＝14.1min,tR(major)＝19.6min.
the structural formula of III-3 and II-3 is as follows:
example 10
III-4 is used as a substrate to react to generate a product 3, 4-diphenyl-1- (4-methylphenyl) -1, 4-dihydropyrano [2,3-c ] pyrazole II-4
The same procedure used in example 1 except for substituting 5-hydroxypyrazole III-1 with III-4 in example 1 gave compound II-4 in 89% yield and 94% ee. The hydrogen and carbon nuclear magnetic resonance spectra of the product II-4 are shown in FIGS. 7 and 8:1H NMR(400MHz,CDCl3)δ7.76–7.74(m,2H),7.54–7.51(m,2H),7.28–7.17(m,9H),7.16–7.12(m,1H),6.55(dd,J＝6.0,1.4Hz,1H),5.14(dd,J＝6.0,4.1Hz,1H),4.92(dd,J＝4.0,1.3Hz,1H),2.39(s,3H)；13C NMR(101MHz,CDCl3)δ147.9,147.3,144.8,137.4,136.2,135.9,133.2,129.7,128.7,128.1,127.8,127.7,127.0,126.8,121.2,108.5,97.2,38.0,21.1.HPLC(Chiralcel OJ-H,n-hexane/i-PrOH＝50/50,0.8ml/min,254nm,40℃):tR(major)＝9.2min,tR(minor)＝18.9min.
the structural formula of III-4 and II-4 is as follows:
example 11
IV-2 is used as a substrate to react to generate a product 4- (3-chlorphenyl) -1, 3-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-5
The propargyl alcohol ester IV-1 in example 1 was replaced by IV-2, the remainder being as in example 1, givingCompound II-5, 91% yield, 96% ee. The hydrogen and carbon nuclear magnetic resonance spectra of the product II-5 are shown in FIGS. 9 and 10:1H NMR(400MHz,DMSO):δ7.95-7.85(m,6H),7.59-7.44(m,6H),5.35(t,J＝2.5Hz,1H),4.81(t,J＝2.8Hz,1H),4.27(t,J＝2.6Hz,1H),3.42(s,1H)；13CNMR(101MHz,DMSO):δ163.9,163.7,162.7,140.3,133.6,132.7,131.6,129.7,129.0,128.7,128.5,128.2,128.0,126.7,126.5,126.3,125.9,108.6,88.8,52.5,51.5.HPLC(Chiralcel OJ-H,n-hexane/i-PrOH＝50/50,0.8ml/min,254nm,40℃):tR(major)＝8.8min,tR(minor)＝16.7min.
the structural formula of IV-2 and II-5 is as follows:
example 12
IV-3 is used as a substrate to react to generate a product 4- (4-chlorphenyl) -1, 3-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-6
The propargyl alcohol ester IV-1 from example 1 was replaced by IV-3 and the remainder of the procedure is as in example 1 to give compound II-5 in 96% yield and 92% ee. The hydrogen and carbon nuclear magnetic resonance spectra of the product II-6 are shown in FIGS. 11 and 12:1H NMR(400MHz,DMSO):δ7.95-7.85(m,6H),7.59-7.44(m,6H),5.35(t,J＝2.5Hz,1H),4.81(t,J＝2.8Hz,1H),4.27(t,J＝2.6Hz,1H),3.42(s,1H)；13CNMR(101MHz,DMSO):δ163.9,163.7,162.7,140.3,133.6,132.7,131.6,129.7,129.0,128.7,128.5,128.2,128.0,126.7,126.5,126.3,125.9,108.6,88.8,52.5,51.5.HPLC(Chiralcel OJ-H,n-hexane/i-PrOH＝50/50,0.8ml/min,254nm,40℃):tR(major)＝9.5min,tR(minor)＝11.1min.
the structural formula of IV-3 and II-6 is as follows:
examples 13 to 26
Reaction substrate suitability
The present invention has wide substrate applicability, and many substrates can participate in the reaction according to the reaction conditions in example 1, and chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compounds can be obtained with high yield and high stereoselectivity, as shown in table 1:
TABLE 1
| entry | Ⅲ(R1) | Ⅲ(R2) | Ⅲ(R3) | Yield(％) | ee(％) | |
| 1 | | Ph | Ph | 87 | 94 | |
| 13 | 2-ClC6H4 | Ph | Ph | 39 | 70 | |
| 14 | 3-ClC6H4 | Ph | Ph | 83 | 93 | |
| 15 | 4-FC6H4 | Ph | Ph | 69 | 94 | |
| 16 | 4-ClC6H4 | Ph | Ph | 74 | 91 | |
| 17 | 4-BrC6H4 | Ph | Ph | 61 | 92 | |
| 18 | 4-MeC6H4 | Ph | Ph | 92 | 93 | |
| 19 | 2-thienyl | Ph | Ph | 72 | 91 | |
| 20 | Ph | 4-BrC6H4 | Ph | 81 | 94 | |
| 21 | Ph | 2-EtC6H4 | Ph | 49 | 93 | |
| 22 | Ph | 4-MeOC6H4 | Ph | 86 | 90 | |
| 23 | Ph | Ph | 4-FC6H4 | 86 | 90 | |
| 24 | Ph | Ph | 4-MeC6H4 | 95 | 87 | |
| 25 | Ph | Ph | 4-MeOC6H4 | 92 | 79 | |
| 26 | Ph | Ph | 4-CF3C6H4 | 85 | 94 |
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