CN115594653B - Polysubstituted beta-alkenyl valerolactone compound, preparation method and application - Google Patents
Polysubstituted beta-alkenyl valerolactone compound, preparation method and application Download PDFInfo
- Publication number
- CN115594653B CN115594653B CN202211309200.6A CN202211309200A CN115594653B CN 115594653 B CN115594653 B CN 115594653B CN 202211309200 A CN202211309200 A CN 202211309200A CN 115594653 B CN115594653 B CN 115594653B
- Authority
- CN
- China
- Prior art keywords
- alkenyl
- polysubstituted
- beta
- valerolactone
- alkyl
- 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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- OZJPLYNZGCXSJM-UHFFFAOYSA-N delta-Valerolactone Natural products O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- 125000003118 aryl group Chemical group 0.000 claims abstract description 17
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract 3
- 150000002431 hydrogen Chemical class 0.000 claims abstract 3
- 150000002148 esters Chemical class 0.000 claims description 38
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- 229920001843 polymethylhydrosiloxane Polymers 0.000 claims description 4
- LZKLAOYSENRNKR-LNTINUHCSA-N iron;(z)-4-oxoniumylidenepent-2-en-2-olate Chemical compound [Fe].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O LZKLAOYSENRNKR-LNTINUHCSA-N 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 abstract description 23
- 239000003814 drug Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000004071 biological effect Effects 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
- 238000006243 chemical reaction Methods 0.000 description 30
- 238000010791 quenching Methods 0.000 description 30
- 230000000171 quenching effect Effects 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- 238000005303 weighing Methods 0.000 description 30
- 238000004519 manufacturing process Methods 0.000 description 23
- 239000007787 solid Substances 0.000 description 22
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- CDVAIHNNWWJFJW-UHFFFAOYSA-N 3,5-diethoxycarbonyl-1,4-dihydrocollidine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C CDVAIHNNWWJFJW-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- -1 amino, nitro, mercapto Chemical class 0.000 description 15
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 15
- 238000010992 reflux Methods 0.000 description 15
- BYDRTKVGBRTTIT-UHFFFAOYSA-N 2-methylprop-2-en-1-ol Chemical compound CC(=C)CO BYDRTKVGBRTTIT-UHFFFAOYSA-N 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 11
- VDCSGNNYCFPWFK-UHFFFAOYSA-N diphenylsilane Chemical compound C=1C=CC=CC=1[SiH2]C1=CC=CC=C1 VDCSGNNYCFPWFK-UHFFFAOYSA-N 0.000 description 11
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 9
- 239000012046 mixed solvent Substances 0.000 description 9
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical compound [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- 125000006165 cyclic alkyl group Chemical group 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- VEPSWGHMGZQCIN-UHFFFAOYSA-H ferric oxalate Chemical compound [Fe+3].[Fe+3].[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O VEPSWGHMGZQCIN-UHFFFAOYSA-H 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 229930014626 natural product Natural products 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- QQQSFSZALRVCSZ-UHFFFAOYSA-N triethoxysilane Chemical compound CCO[SiH](OCC)OCC QQQSFSZALRVCSZ-UHFFFAOYSA-N 0.000 description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 241000162439 Brontispa longissima Species 0.000 description 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 102000038030 PI3Ks Human genes 0.000 description 2
- 108091007960 PI3Ks Proteins 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- GPWHDDKQSYOYBF-UHFFFAOYSA-N ac1l2u0q Chemical compound Br[Br-]Br GPWHDDKQSYOYBF-UHFFFAOYSA-N 0.000 description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 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
- 201000011510 cancer Diseases 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 235000003891 ferrous sulphate Nutrition 0.000 description 2
- 239000011790 ferrous sulphate Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 2
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 2
- 201000004792 malaria Diseases 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
- 125000000962 organic group Chemical group 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- YNMZZHPSYMOGCI-UHFFFAOYSA-N undecan-3-one Chemical compound CCCCCCCCC(=O)CC YNMZZHPSYMOGCI-UHFFFAOYSA-N 0.000 description 2
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- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- 125000006736 (C6-C20) aryl group Chemical group 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- ZGYBYYJGIKPBFD-UHFFFAOYSA-N 2-methyl-1-phenylprop-2-en-1-ol Chemical compound CC(=C)C(O)C1=CC=CC=C1 ZGYBYYJGIKPBFD-UHFFFAOYSA-N 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
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- OVTKCGJIOHGDAN-HMQLAQMASA-N KHAYASIN Chemical compound C=1([C@@H]2OC(=O)CC3=C4C[C@H]5C(C([C@H](CC(=O)OC)[C@@](C)(C4CC[C@]32C)C5=O)(C)C)OC(=O)C(C)CC)C=COC=1 OVTKCGJIOHGDAN-HMQLAQMASA-N 0.000 description 1
- VHLJDTBGULNCGF-UHFFFAOYSA-N Limonin Natural products CC1(C)OC2CC(=O)OCC23C4CCC5(C)C(CC(=O)C6OC56C4(C)C(=O)CC13)c7cocc7 VHLJDTBGULNCGF-UHFFFAOYSA-N 0.000 description 1
- 241000158728 Meliaceae Species 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241001136485 Talaromyces wortmannii Species 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
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- 230000000843 anti-fungal effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
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- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
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- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
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- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
- SLLGVCUQYRMELA-UHFFFAOYSA-N chlorosilicon Chemical compound Cl[Si] SLLGVCUQYRMELA-UHFFFAOYSA-N 0.000 description 1
- BKFAZDGHFACXKY-UHFFFAOYSA-N cobalt(II) bis(acetylacetonate) Chemical compound [Co+2].CC(=O)[CH-]C(C)=O.CC(=O)[CH-]C(C)=O BKFAZDGHFACXKY-UHFFFAOYSA-N 0.000 description 1
- ZKXWKVVCCTZOLD-FDGPNNRMSA-N copper;(z)-4-hydroxypent-3-en-2-one Chemical compound [Cu].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O ZKXWKVVCCTZOLD-FDGPNNRMSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- QBJOHGAEIAUULA-UHFFFAOYSA-N cyclohexen-1-ylmethanol Chemical compound OCC1=CCCCC1 QBJOHGAEIAUULA-UHFFFAOYSA-N 0.000 description 1
- WJDFLCXFDSYKID-UHFFFAOYSA-N cyclopenten-1-ylmethanol Chemical compound OCC1=CCCC1 WJDFLCXFDSYKID-UHFFFAOYSA-N 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
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- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
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- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- OTIOLMDUPDTDHA-UHFFFAOYSA-N khayasin Natural products CC12CCC3C(C4=O)(C)C(CC(=O)OC)C(C)(C)C(OC(=O)C(C)C)C4CC3=C1CC(=O)OC2C=1C=COC=1 OTIOLMDUPDTDHA-UHFFFAOYSA-N 0.000 description 1
- KBDSLGBFQAGHBE-MSGMIQHVSA-N limonin Chemical compound C=1([C@H]2[C@]3(C)CC[C@H]4[C@@]([C@@]53O[C@@H]5C(=O)O2)(C)C(=O)C[C@@H]2[C@]34COC(=O)C[C@@H]3OC2(C)C)C=COC=1 KBDSLGBFQAGHBE-MSGMIQHVSA-N 0.000 description 1
- 150000002629 limonins Chemical class 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- DNFJSIPZGYBGON-JCLAUGGVSA-N mexicanolide Chemical compound C=1([C@@H]2OC(=O)CC3=C4C[C@H]5C(=O)C(C)(C)[C@@H]([C@]([C@H]4CC[C@]32C)(C)C5=O)CC(=O)OC)C=COC=1 DNFJSIPZGYBGON-JCLAUGGVSA-N 0.000 description 1
- SAKHPJFLERYVSP-UHFFFAOYSA-N mexicanolide Natural products COC(=O)CC1C(C)(C)C(=O)CCC2=C3C4OC1(C)C2CCC3(C)C(OC4=O)c5cocc5 SAKHPJFLERYVSP-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
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- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
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- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
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Abstract
The invention relates to the technical field of organic synthesis, in particular to a polysubstituted beta-alkenyl valerolactone compound, a preparation method and application thereof, wherein the structural formula of the compound is shown in a formula I,r is aryl or substituted aryl, R 1 Is hydrogen or alkyl or substituted alkyl, R 2 Is hydrogen, alkyl and substituted alkyl, aryl and substituted aryl, R 3 、R 4 、R 5 Is hydrogen or alkyl or substituted alkyl. The polysubstituted beta-alkenyl valerolactone compound has certain biological activity and can be used as a potential drug or a candidate drug; the preparation method disclosed by the invention is simple, easy to operate, simple in synthesis method, low in cost and good in yield, and the catalyst is cheap and easy to obtain and is environment-friendly.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a polysubstituted beta-alkenyl valerolactone compound, a preparation method and application thereof.
Background
Polysubstituted beta-alkenyl valerolactone is a parent nucleus structure of many natural products and drug molecules, and natural products with beta-alkenyl valerolactone as a parent nucleus show wide biological activity and pharmacological actions (such as insect resistance, food refusal, antibacterial, antitumor and anti-inflammatory). For example, the natural product, wortmannin, isolated from Penicillium Wortmannii was originally used as an anti-inflammatory and antibiotic agent and was subsequently widely used as a chemical probe to study biological processes associated with PI3Ks as an anti-tumor agent due to its excellent selectivity for phosphoinositide 3-kinases (PI 3 Ks). In addition, wortmannin has found application in the field of regenerative medicine.
Limonin compounds isolated from Meliaceae plants have a wide range of biological activities. Such as khayasin, appears as an effective selective insecticide for controlling destructive coconut leaf beetle pests; the limonin monomer moluccarinin a identified from the seed of the indian red tree fruit has in vitro selective cytotoxicity to tumor cells for use as an antitumor agent; the Mexicanolide natural products not only have excellent edibility, but also show poisoning activity on brontispa longissima larvae.
Currently, the synthesis of polysubstituted beta-alkenyl valerolactone compounds by systems is not reported. The reported literature only relates to the synthesis of a few compounds, and the reaction yields are low (J.org.chem.1995, 60,3065), the number of reaction steps (J.org.chem.2016, 11043) and the diversity of the products are not related.
In summary, the synthesis of polysubstituted β -alkenylvalerolactones still faces significant challenges.
Disclosure of Invention
< technical problem to be solved by the invention >
The current method for synthesizing beta-alkenyl valerolactone has the problems of low reaction yield, more reaction steps and poor product diversity.
< technical scheme adopted by the invention >
Aiming at the technical problems, the invention provides a polysubstituted beta-alkenyl valerolactone compound and a preparation method thereof.
First, the invention provides a polysubstituted beta-alkenyl valerolactone compound, the structural formula of which is shown as formula I,
wherein,
r is aryl or substituted aryl,
R 1 is hydrogen, alkyl and substituted alkyl,
R 2 hydrogen, alkyl and substituted alkyl, aryl and substituted aryl,
R 3 、R 4 、R 5 is hydrogen, alkyl, and substituted alkyl.
The invention provides a preparation method of a polysubstituted beta-alkenyl valerolactone compound, which comprises the following steps: mixing the dienyl ester derivative with allyl alcohol, a solvent, a catalyst and a reducing agent, and reacting to obtain a polysubstituted beta-alkenyl valerolactone compound;
the synthetic route of the synthetic route is as follows,
r is aryl or substituted aryl,
R 1 is hydrogen, alkyl and substituted alkyl,
R 2 hydrogen, alkyl and substituted alkyl, aryl and substituted aryl,
R 3 、R 4 、R 5 is hydrogen, alkyl, and substituted alkyl.
Third, the use of a compound of formula I, or a crystalline form thereof, or a pharmaceutically acceptable salt thereof, for anticancer, antimalarial, antiviral, antibacterial, antifungal, anti-inflammatory applications.
< beneficial effects achieved by the invention >
(1) The polysubstituted beta-alkenyl valerolactone compound has certain biological activity, can be used as a potential drug or candidate drug, and is a novel polysubstituted beta-alkenyl valerolactone compound for resisting cancer, malaria, viruses, bacteria, fungi and inflammation.
(2) The preparation method disclosed by the invention is simple, easy to operate, simple in synthesis method, low in cost and good in yield, and the catalyst is cheap and easy to obtain and is environment-friendly.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
First, the invention provides a polysubstituted beta-alkenyl valerolactone compound, which is characterized in that the structural formula of the compound is shown as a formula I,
wherein,
r is aryl or substituted aryl,
R 1 is hydrogen, alkyl and substituted alkyl,
R 2 hydrogen, alkyl and substituted alkyl, aryl and substituted aryl,
R 3 、R 4 、R 5 is hydrogen, alkyl, and substituted alkyl.
R, R as described above 1 -R 5 The number of carbon atoms in the "aryl group" is not limited herein, and may be preferably a C6-C20 aryl group, more preferably a C6-C10 aryl group. "aryl" refers to polyunsaturated aromatic hydrocarbon substituents which may be single or multiple rings fused together (i.e., fused ring aryl) or covalently linked single or multiple rings.
R, R as described above 1 -R 5 In the above, the "alkyl group" is a linear, branched or cyclic alkyl group, and the carbon atom is not limited thereto, and may be preferably a linear, branched or cyclic alkyl group of C1 to C10, more preferably a linear, branched or cyclic alkyl group of C1 to C8.
R, R as described above 1 -R 5 In "substituent in substituted aryl" and "The substituent "in the substituted alkyl group is selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, acyloxy, amino, nitro, mercapto. Wherein the substitution in the "substituted aryl" or "substituted alkyl" may be mono-substitution or poly-substitution. "substituted" refers to the aforementioned organic groups in which one or more bonds to a hydrogen atom contained in the organic group are replaced with one or more bonds to a non-hydrogen atom.
As the substituent "alkyl group", a C1-C10 linear, branched or cyclic alkyl group is specifically mentioned, and a C2-C10 linear, branched or cyclic alkyl group is preferable, and a C1-C8 linear, branched or cyclic alkyl group is further preferable.
For the substituent "haloalkyl", halogen may be selected from fluorine, chlorine, bromine, iodine; the alkyl group may be selected from linear, branched or cyclic alkyl groups of C1 to C10, preferably linear, branched or cyclic alkyl groups of C2 to C10. "haloalkyl" monohaloalkyl, polyhaloalkyl, and perhaloalkyl. For example, the term "halo (C1-C4) alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
As the substituent "alkenyl" there may be mentioned in particular C2-C10 linear, branched alkenyl. At least one double bond exists between two carbon atoms of an alkenyl group. Examples include, but are not limited to: vinyl, -ch=ch (CH 3), -ch=c (CH 3) 2, -C (CH 3) =ch2, -C (CH 3) =ch (CH 3), -C (CH 2CH 3) =ch2, butadienyl, pentadienyl, hexadienyl, and the like.
For the substituent "alkynyl" including linear, branched alkynyl groups, at least one triple bond exists between two carbon atoms. Examples include, but are not limited to: -C.ident.CH, -C.ident.C (CH 3), -C.ident.C (CH 2CH 3), -CH2 C.ident.CH, -CH2 C.ident.C (CH 3), and-CH 2 C.ident.C (CH 2CH 3), and the like.
For the substituent "halogen" is selected from fluorine, chlorine, bromine, iodine.
The substituent "alkoxy" is selected from alkoxy groups having 1 to 10 carbon atoms.
For the substituents "amino", -NH2, -NHR, -NR2, -NR3+ forms of the substituent. In particular, it may be a primary, secondary, tertiary or quaternary amino group.
As for each substituent mentioned above, it may be more preferable,
r is a C6-C10 aryl or substituted aryl,
R 1 is C1-C10 alkyl and substituted alkyl,
R 2 and R is R 3 Is C1-C8 alkyl and substituted alkyl,
R 4 and R is R 5 Aryl and substituted aryl groups of C6-C20, alkyl and substituted alkyl groups of C2-C10.
As for each substituent mentioned above, it may be more preferable,
r is aryl or substituted aryl,
R 1 is hydrogen, alkyl and substituted alkyl,
R 2 and R is R 3 Is C1-C8 alkyl and substituted alkyl,
R 4 and R is R 5 Is a C2-C10 alkyl group or a substituted alkyl group.
The invention provides a preparation method of a polysubstituted beta-alkenyl valerolactone compound, which is characterized by comprising the following steps:
the polydiene ester derivative is mixed with allyl alcohol, a solvent, a catalyst and a reducing agent to react to obtain the polysubstituted beta-alkenyl valerolactone compound.
The reaction route is as follows:
r is aryl or substituted aryl,
R 1 is hydrogen, alkyl and substituted alkyl,
R 2 hydrogen, alkyl and substituted alkyl, aryl and substituted aryl,
R 3 、R 4 、R 5 is hydrogen, alkyl, and substituted alkyl.
In the present invention, the solvent includes at least one of toluene, 1, 4-dioxane, ethylbenzene, benzene, ethylene glycol dimethyl ether, methylene chloride, ethanol, DMF, DMA, isopropanol, n-butanol, 1, 2-dichloroethane, methanol, tetrahydrofuran, diethyl ether, acetonitrile, or DMSO.
In the present invention, the catalyst comprises ZnCl 2 、CuSO 4 、Zn(OTf) 2 、Pd(OAc) 2 、FeSO 4 、Fe(acac) 3 、FeCl 3 、Fe(ox) 3 ·6H 2 O、FeBr 3 、Co(acac) 2 、Cu(acac) 2 、MnCl 2 ·4H 2 O, or La (OTf) 3 At least one of them.
In the invention, the reducing agent is HCOOH and NaBH 4 、NaCNBH 3 、Ph 2 SiH 2 、HSiCl 3 、(EtO) 3 SiH、Et 3 SiH、PhSiH 3 At least one of PhSiHMe, or PMHS.
In the present invention, the solvent includes at least one of toluene, 1, 4-dioxane, ethylbenzene, benzene, ethylene glycol dimethyl ether, methylene chloride, ethanol, DMF, DMA, isopropanol, n-butanol, 1, 2-dichloroethane, methanol, tetrahydrofuran, diethyl ether, acetonitrile, or DMSO.
In the invention, the mol ratio of the dienyl ester derivative to the allyl alcohol is 1:0.2-10.
In the invention, the mol ratio of the polydiene ester derivative to the catalyst is 1:0.05-2.
In the invention, the mol ratio of the polydiene ester derivative to the reducing agent is 1:0.5-7.
In the invention, the reaction time is 1-24 h; the reaction temperature is from room temperature to reflux; the product after the reaction is separated and purified to obtain the target product, and the target product is separated and purified by adopting a recrystallization or column chromatography separation mode.
Third, the compound shown in the formula I, or a crystal form or a pharmaceutically acceptable salt thereof, can be used for resisting cancer, malaria, viruses, bacteria, fungi and inflammation.
By "pharmaceutically acceptable salts" is meant non-toxic inorganic or organic acid and/or base addition salts.
Wherein the "salt" may be the hydrochloride, sulfate, citrate, besylate, hydrobromide, hydrofluoric, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate salt of the compound.
< example >
Example 1
A preparation method of polysubstituted beta-alkenyl valerolactone comprises the steps of sequentially adding 2.2g of dienyl ester and 1.2g of ferric oxalate into a reaction bottle, adding a mixed solvent of 6ml of acetonitrile and 1, 2-dichloroethane (the two are mixed according to any proportion), weighing 3.2g of 2-methallyl alcohol, 2.2g of phenylsilane, reacting for 4 hours at 50 ℃, adding water for quenching, extracting by ethyl acetate, and separating by column chromatography to obtain colorless liquid 3.0g with the yield of 82%. The product was (E) -4-benzolide-5, 5-dimethylethyl-2H-pyran-2-one (3 a)
137.7,136.0,128.5,128.2,126.9,125.1,77.0,36.2,33.7,25.4.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 14 H 17 O 2 217.1228；found 217.1230.
Example 2
A preparation method of polysubstituted beta-alkenyl valerolactone comprises the steps of sequentially adding 2.2g of dienyl ester and 1.0g of ferric acetylacetonate into a reaction bottle, adding 6ml of ethanol, weighing 2.1g of cyclohex-1-en-1-yl methanol, 1.0g of polymethyl hydrosiloxane, carrying out reflux reaction for 6h, adding water for quenching, extracting with ethyl acetate, and separating by column chromatography to obtain 2.1g of white solid with the yield of 75%.
The product is (E) -5-benzoidene-2-oxapiporo [5.5 ]]undecan-3-one(3b)
13.07,10.11Hz,3H),1.44(dd,J＝23.65,11.00Hz,3H). 13 C NMR(101MHz,CDCl 3 ):δ170.8,138.4,136.2,128.5,128.2,126.8,125.4,72.2,39.2,33.7,33.3,25.6,21.7.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 17 H 21 O 2 257.1541；found 257.1546.
Example 3
A preparation method of polysubstituted beta-alkenyl valerolactone comprises the steps of sequentially adding 2.2g of dienyl ester and 1.0g of ferric acetylacetonate into a reaction bottle, adding 6ml of methanol, weighing 2.0g of cyclopent-1-en-1-yl methanol and 1.2g of polymethyl hydrosiloxane, carrying out reflux reaction for 6h, adding water for quenching, extracting with ethyl acetate, and separating by column chromatography to obtain 1.8g of white solid with the yield of 74%.
The product was (E) -10-benzoidene-7-oxapiporo [4.5 ]]decan-8-one(3c)
1.75(m,4H). 13 C NMR(101MHz,CDCl 3 ):δ170.5,138.4,136.1,128.5,128.2,126.8,124.3,74.5,48.0,36.5,34.6,24.7.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 16 H 19 O 2 243.1385；found 243.1389.
Example 4
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.2g of dienyl ester, 1.5g of ferric acetylacetonate, adding 6ml of alcohol, weighing 2.6g of 2-methyl-1-phenylpropan-2-en-1-ol and 2.0g of diphenyl silane, reflux reaction for 4 hr, quenching with water, extracting with ethyl acetate, and separating by column chromatography to obtain white solid (1.5 g) with 50% of yield.
The product was (E) -4-benzoidene-5, 5-dimethyl-6-phenyl tetrahydro-2H-pyran-2-
one(3d)
(s,1H),5.23(s,1H),3.83–3.61(m,2H),1.23(s,3H),1.10(s,3H). 13 C NMR(101 MHz,CDCl 3 ):δ170.1,138.0,136.4,135.4,128.7,128.5,128.5,128.0,127.9,127.1,125.6,87.3,40.5,34.0,25.4,22.0.HRMS(ESI-TOF)m/z:[M+Na] + Calcd for C 20 H 20 O 2 Na 315.1361；found 315.1363.
Example 5
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.2g of dienyl ester, 1.6g of ferric acetylacetonate, adding 6ml of alcohol, weighing 1.6g of 1- (2-methylphenyl) -2-methylallyl-1-ol and 2.1g of diphenyl silane, reflux reaction for 8 hr, quenching with water, extracting with ethyl acetate, and separating by column chromatography to obtain white solid (1.7 g) with 45% yield.
The product was (E) -4-benzoyide-5- (o-tolyl) tetrahydroo-2H-pyran-2-one (3E)
1.21(s,3H). 13 C NMR(101MHz,CDCl 3 ):δ170.2,138.2,136.3,136.0,133.9,130.5,128.7,128.4,128.3,128.2,127.1,125.6,125.1,82.4,41.4,34.1,25.0,22.3,20.3.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 21 H 23 O 2 307.1698；found 307.1697.
Example 6
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.2g of dienyl ester, 1.2g of ferric acetylacetonate, adding 6ml of alcohol, weighing 1.8g of 1- (2-chlorophenyl) -2-methylallyl-1-ol and 2.0g of diphenyl silane, reflux reaction for 4 hr, quenching with water, extracting with ethyl acetate, and separating by column chromatography to obtain white solid (2.3 g) with 50% of yield.
The product was (E) -4-benzoidene-5- (2-chloropheny) tetrahydro-2H-pyran-2-one
(3f)
133.4,129.9,129.6,129.5,128.7,128.4,127.1,126.5,125.5,82.0,41.5,34.0,24.6,22.1.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 20 H 21 ClO 2 327.1151；found 327.1154.
Example 7
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.2g of dienyl ester, 1.5g of ferric acetylacetonate, adding 6ml of isopropanol, weighing 1.8g of 1- (3-methylphenyl) -2-methylallyl-1-ol and 2.1g of phenylsilane, reflux reaction for 8 hr, quenching with water, extracting with ethyl acetate, and recrystallizing to obtain white solid (2.7 g) with 58% of yield.
The product is
(E)-4-benzylidene-5,5-dimethyl-6-(m-tolyl)tetrahydro-2H-pyran-2-one
(3g)
1H),3.64(dd,J＝19.04,2.68Hz,1H),2.37(s,3H),1.23(s,3H),1.10(s,3H). 13 C NMR(101MHz,CDCl 3 ):δ169.9,137.9,137.4,136.3,135.2,129.0,128.5,128.5,128.3,127.5,126.9,125.3,125.1,87.2,87.2,40.3,33.8,25.3,21.9,21.3.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 21 H 23 O 2 307.1698；found 307.1697.
Example 8
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.2g of dienyl ester, 1.6g of ferric acetylacetonate, adding 6ml of isopropanol, weighing 2.2g of 1- (3-chlorophenyl) -2-methylallyl-1-ol and 2.0g of phenylsilane, reflux reaction for 8 hr, quenching with water, extracting with ethyl acetate, and recrystallizing to obtain white solid (2.4 g) with 50% of yield.
The product is
(E)-4-benzylidene-6-(3-chlorophenyl)-5,5-dimethyltetrahydro-2H-pyran-
2-one(3h)
137.3,137.3,136.0,133.8,129.0,128.6,128.5,128.3,128.0,127.1,126.1,125.7,86.3,86.3,40.3,33.7,25.2,21.8.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 20 H 21 ClO 2 327.1151；found 327.1154.
Example 9
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.2g of dienyl ester, 1.6g of ferric acetylacetonate, adding 6ml of methanol, weighing 2.5g of 1- (4-fluorophenyl) -2-methylallyl-1-ol and 2.0g of phenylsilane, reflux reaction for 8 hr, quenching with water, extracting with ethyl acetate, and recrystallizing to obtain white solid (2.3 g) with 60% yield.
The product is
(E)-4-benzylidene-6-(4-fluorophenyl)-5,5-dimethyltetrahydro-2H-pyran-
2-one(3i)
(s,3H). 13 C NMR(101MHz,CDCl 3 ):δ169.6,163.8,161.3,137.5,136.1,129.6,129.5,128.5,128.3,127.0,125.6,114.9,114.6,86.5,86.4,40.3,33.8,25.2,21.7. 19 F NMR(376MHz,CDCl 3 ):δ-113.31.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 20 H 21 FO 2 311.1447；found 311.1449.
Example 10
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.2g of dienyl ester and 1.5g of ferric acetylacetonate to a reactor, adding 6ml of ethylene glycol dimethyl ether, weighing 2.3g of 1- (4-chlorophenyl) -2-methylallyl-1-ol and 2.2g of phenylsilane, reflux reaction for 6 hr, quenching with water, extracting with ethyl acetate, and recrystallizing to obtain white solid (2.5 g) with 65% yield.
The product is
(E)-4-benzylidene-6-(4-chlorophenyl)-5,5-dimethyltetrahydro-2H-pyran-
2-one(3j)
MHz,CDCl 3 ):δ169.5,137.4,136.1,134.3,133.8,129.2,128.5,128.3,128.0,127.1,125.7,86.4,40.3,33.8,25.2,21.7.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 20 H 21 ClO 2 327.1151；found 327.1156.
Example 11
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.2g of dienyl ester and 2.3g of ferric trichloride in a reactor, adding 6ml of ethylene glycol dimethyl ether, weighing 2.5g of 1- (4-bromophenyl) -2-methylallyl-1-ol and 2.2g of phenylsilane, reflux reaction for 6 hr, quenching with water, extracting with ethyl acetate, and recrystallizing to obtain white solid (2.8 g) with 60% yield.
The product is
(E)-4-benzylidene-6-(4-bromophenyl)-5,5-dimethyltetrahydro-2H-pyran-
2-one(3k)
(101MHz,CDCl 3 ):δ169.5,137.3,136.0,134.3,130.9,129.5,128.5,128.3,127.0,125.6,122.4,86.3,40.2,33.7,25.1,21.7.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 20 H 21 BrO 2 371.0646；found 371.0649.
Example 12
A preparation method of polysubstituted beta-alkenyl valerolactone comprises the steps of sequentially adding 2.2g of dienyl ester and 2.3g of ferric oxalate into a reaction bottle, adding 6ml of ethylene glycol dimethyl ether, weighing 2.4g of 1- (4-methylphenyl) -2-methallyl-1-ol, 2.2g of diphenyl silane, reacting for 10 hours at 50 ℃, adding water for quenching, extracting with ethyl acetate, and recrystallizing to obtain 2.3g of white solid with the yield of 78%.
The product is
(E)-4-benzylidene-5,5-dimethyl-6-(p-tolyl)tetrahydro-2H-pyran-2-one
(3l)
NMR(101MHz,CDCl 3 ):δ170.0,138.1,137.9,136.3,132.3,128.5,128.4,128.3,127.8,126.9,125.3,87.1,87.1,40.3,33.8,25.3,21.9,21.0.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 21 H 23 O 2 307.1698；found 307.1693.
Example 13
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.2g of dienyl ester and 2.2g of iron oxalate to a reactor, adding 6ml of n-butanol, weighing 2.5g of 1- (4-methoxyphenyl) -2-methylallyl-1-ol, reacting at 60 deg.C for 8 hr, adding water, quenching, extracting with ethyl acetate, recrystallizing to obtain white solid (2.3 g) with yield of 70%.
The product is
(E)-4-benzylidene-6-(4-methoxyphenyl)-5,5-dimethyltetrahydro-2H-
pyran-2-one(3m)
3H). 13 C NMR(101MHz,CDCl 3 ):δ170.1,159.7,138.1,136.4,129.2,128.7,128.4,127.6,127.1,125.5,113.3,87.1,55.3,40.6,34.0,25.5,22.0.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 21 H 22 O 3 323.1647,found 323.1646.
Example 14
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.2g of dienyl ester and 2.1g of ferric trichloride in a reactor, adding 6ml of n-butanol, weighing 2.5g of 1- (3, 4-dimethylphenyl) -2-methylallyl-1-ol, reacting at 60 deg.C for 8 hr, quenching with water, extracting with ethyl acetate, and recrystallizing to obtain white solid (2.3 g) with 65% yield.
The product is
(E)-4-benzylidene-6-(3,4-dimethylphenyl)-5,5-dimethyltetrahydro-2H-
pyran-2-one(3n)
6H),1.22(s,3H),1.10(s,3H). 13 C NMR(101MHz,CDCl 3 ):δ170.3,138.2,136.9,136.5,136.1,132.9,129.2,129.1,128.7,128.5,127.1,125.6,125.5,87.4,40.5,34.0,25.5,22.1,19.9,19.5.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 22 H 25 O 2 321.1855,found 321.1855.
Example 15
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.2g of dienyl ester, 1.2g of ferric acetylacetonate, adding the mixed solvent of acetonitrile and 1, 2-dichloroethane (proportionally mixing them), weighing 2.3g of 1, 3-benzodioxol-2-methylpropan-2-en-1-ol and 2.1g of diphenyl silane, reflux reaction for 8 hr, quenching with water, extracting with ethyl acetate, and separating by column chromatography to obtain white solid (2.6 g) with 65% yield.
The product is
(E)-6-(benzo[d][1,3]dioxol-5-yl)-4-benzylidene-5,5-
dimethyltetrahydro-2H-pyran-2-one(3o)
Hz,1H),1.21(s,3H),1.11(s,3H). 13 C NMR(101MHz,CDCl 3 ):δ170.0,147.7,147.4,138.0,129.2,128.7,128.5,127.1,125.6,121.8,108.5,107.6,101.3,87.1,87.1,40.6,33.9,25.5,22.1.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 21 H 21 O 4 337.1440,found 337.1438.
Example 16
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.2g of dienyl ester and 1.5g of ferric acetylacetonate to a reaction bottle, adding 6ml of mixed solvent of tetrahydrofuran and 1, 2-dichloroethane (mixed proportionally), weighing 2.2g of 2-methylenyl cycloheptyl-2-en-1-ol and 2.1g of diphenyl silane, reflux reaction for 10 hr, quenching with water, extracting with ethyl acetate, and column chromatography to obtain white solid (1.5 g) with yield of 43%.
The product is
(E)-4-benzylidene-4a-methyloctahydrocyclohepta[b]pyran-2(3H)
2H),7.23(d,J＝7.45Hz,1H),7.19–7.11(m,2H),6.50(d,J＝2.52Hz,1H),4.27(dd,J＝10.45,2.79Hz,1H),3.64(dd,J＝18.64,1.53Hz,1H),3.47(dd,J＝18.59,2.84Hz,1H),2.04–1.89(m,3H),1.89–1.69(m,3H),1.68–1.56(m,4H),1.15(s,3H). 13 C NMR(101MHz,CDCl 3 ):δ171.3,139.9,136.6,128.7,128.4,126.9,85.2,43.1,37.1,34.2,28.6,27.6,24.0,22.0,20.4.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 18 H 23 O 2 271.1698,found 271.1697.
Example 17
A preparation method of polysubstituted beta-alkenyl valerolactone comprises the steps of sequentially adding 2.1g of 4-methyldienyl ester and 1.2g of ferric acetylacetonate into a reaction bottle, adding a mixed solvent of 6ml of tetrahydrofuran and diethyl ether (the two are mixed according to any proportion), weighing 2.3g of 2-methallyl alcohol and 2.1g of phenylsilane, carrying out reflux reaction for 10 hours, adding water for quenching, extracting with ethyl acetate, and separating by column chromatography to obtain 2.2g of white solid with the yield of 70%.
The product is
(E)-5,5-dimethyl-4-(4-methylbenzylidene)tetrahydro-2H-pyran-2-one(3q)
136.9,136.6,133.0,129.4,128.9,128.3,124.9,124.8,76.8,36.1,33.7,33.7,25.3,20.9.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 15 H 19 O 2 231.1385；found 231.1387.
Example 18
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.1g of 4-fluorodienyl ester and 1.2g of ferric acetylacetonate to a reactor, adding the mixed solvent of tetrahydrofuran and diethyl ether (proportionally mixing them), weighing 2.3g of 2-methallyl alcohol and 2.1g of phenylsilane, reflux reaction for 15 hr, quenching with water, extracting with ethyl acetate, and separating by column chromatography to obtain colorless liquid (2.1 g) with 65% yield. The product is(E)-4-(4-fluorobenzylidene)-5,5- dimethyltetrahydro-2H-pyran-2-one(3r)
115.5,115.3,76.9,36.4,33.8,25.6. 19 F NMR(376MHz,CDCl 3 ):δ-114.71.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 14 H 16 FO 2 235.1134；found235.1131.
Example 19
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.1g of 4-chlorodienyl ester and 2.0g of iron oxalate to a reactor, adding the mixed solvent of acetonitrile and 1, 2-dichloroethane (proportionally mixing them), weighing 2.1g of 2-methallyl alcohol, 2.2g of phenylsilane, reacting at 40 deg.C for 6 hr, quenching with water, extracting with ethyl acetate, and recrystallizing to obtain white solid (2.3 g) with 60% yield.
The product was (E) -4- (4-chlorobenzylidene) -5, 5-dimethylethy-2H-pyran-2-
one(3s)
129.9,128.6,124.1,36.5,76.9,33.8,25.5.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 14 H 16 ClO 2 251.0838；found 251.0835.
Example 20
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.1g of 4-bromodienolide and 2.0g of iron oxalate to a reactor, adding 6ml of mixed solvent of benzene and 1, 2-dichloroethane, proportionally mixing them, weighing 2.2g of 2-methallyl alcohol, 2.2g of diphenyl silane, reacting at 80 deg.C for 5 hr, quenching with water, extracting with ethyl acetate, and recrystallizing to obtain white solid (2.3 g) with yield of 63%.
The product was (E) -4- (4-bromoxynil) -5, 5-dimethylethy-2H-pyran-2-
one(3t)
138.9,135.1,131.6,130.3,124.2,121.0,76.8,36.5,33.8,25.5.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 20 H 21 BrO 2 295.0333；found295.0339.
Example 21
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.1g of 2-methyldienyl ester and 1.5g of ferric trichloride in a reactor, adding the mixed solvent of benzene and 1, 2-dichloroethane (proportionally mixing them), weighing 2.2g of 2-methylallyl alcohol, 2.2g of diphenyl silane, reacting at 80 deg.C for 6 hr, quenching with water, extracting with ethyl acetate, and recrystallizing to obtain colorless liquid (2.1 g) with 50% yield.
The product is
(Z)-5,5-dimethyl-4-(2-methylbenzylidene)tetrahydro-2H-pyran-2-one(3u)
135.2,130.1,128.7,127.4,125.7,124.8,77.2,36.3,33.6,25.8,19.7.HRMS(ESI-TOF)m/z:[M+Na] + Calcd for C 15 H 18 O 2 Na 253.1204；found 253.1208.
Example 22
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.1g of 3-trifluoromethyl biadienyl ester and 2.2g of ferric tribromide to a reactor, adding the mixed solvent of 6ml of alcohol and 1, 2-dichloroethane, proportionally mixing them, weighing 2.3g of 2-methylallyl alcohol, 1.8g of triethylsilane, reaction at 80 deg.C for 7 hr, quenching with water, extracting with ethyl acetate, and recrystallizing to obtain colorless liquid (2.1 g) with 45% yield.
The product is
(E)-5,5-dimethyl-4-(3-(trifluoromethyl)benzylidene)tetrahydro-2H-
pyran-2-one(3v)
129.4,125.9,125.9,124.5,124.3,124.3,77.3,37.0,34.3,26.0. 19 F NMR(376MHz,CDCl 3 ):δ-62.74.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 15 H 16 F 3 O 2 285.1102；found 285.1102.
Example 23
A preparation method of polysubstituted beta-alkenyl valerolactone comprises the steps of sequentially adding 2.1g of 2, 5-dimethyl dienyl ester and 2.2g of ferric tribromide into a reaction bottle, adding 6ml of ethanol, weighing 2.3g of 2-methallyl alcohol and 1.8g of triethoxysilane, reacting for 5 hours at 50 ℃, adding water for quenching, extracting with ethyl acetate, recrystallizing to obtain colorless liquid 1.6g, and obtaining the yield of 40%.
The product is
(E)-4-(2,5-dimethylbenzylidene)-5,5-dimethyltetrahydro-2H-pyran-2-one
(3w)
2H),2.30(s,3H),2.15(s,3H),1.29(s,6H). 13 C NMR(101MHz,CDCl 3 ):δ171.0,137.8,135.1,133.0,130.0,129.3,128.1,124.9,77.0,36.3,33.6,25.8,22.9,21.0,19.2.HRMS(ESI-TOF)m/z:[M+Na] + Calcd for C 16 H 20 O 2 Na267.1361；found 267.1367.
Example 24
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.1g of 2, 3-dichloro-dienyl ester and 1.2g of ferrous sulfate to reactor, adding 5ml of alcohol, weighing 2.3g of 2-methylallyl alcohol and 1.8g of triethoxysilane, reacting at 50 deg.C for 5 hr, quenching with water, extracting with ethyl acetate, recrystallizing to obtain colorless liquid 1.9g, and yield of 56%.
The product is
(E)-4-(2,3-dichlorobenzylidene)-5,5-dimethyltetrahydro-2H-pyran-2-one
(3x)
136.7,133.5,132.0,129.4,128.3,127.0,123.0,76.8,36.6,33.7,25.5.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 14 H 15 Cl 2 O 2 285.0449；found 285.0452.
Example 25
A preparation method of polysubstituted beta-alkenyl valerolactone comprises the steps of sequentially adding 2.1g of 1-methyldienyl ester and 1.8g of ferrous sulfate into a reaction bottle, adding 5ml of ethanol, weighing 2.3g of 2-methallyl alcohol and 1.8g of triethoxysilane, reacting for 10 hours at 50 ℃, adding water for quenching, extracting with ethyl acetate, and recrystallizing to obtain 2.0g of colorless liquid with the yield of 44%.
The product was (E) -4-benzolide-3, 5-trimethylethyl-hydro-2H-pyran-2-one (3 y)
MHz,CDCl 3 ):δ7.34(t,J＝7.49Hz,2H),7.25(d,J＝7.28Hz,1H),7.21(t,J＝7.59Hz,2H),6.49(s,1H),4.30(d,J＝11.26Hz,1H),3.99(d,J＝11.26Hz,1H),3.86(q,J＝7.64,7.22Hz,1H),1.38(d,J＝7.63Hz,3H),1.27(s,6H). 13 CNMR(101MHz,CDCl 3 ):δ174.1,144.2,136.4,128.6,128.2,127.1,125.5,76.1,38.0,36.3,27.4,25.2,19.1.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 15 H 19 O 2 231.1385；found 231.1385.
Example 26
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.1g of 1-benzyl dienyl ester and 1.2g of ferric acetylacetonate to reactor, adding 5ml of alcohol, weighing 2.3g of 2-methallyl alcohol and 1.8g of diphenyl silane, reacting at 50 deg.C for 5 hr, quenching with water, extracting with ethyl acetate, recrystallizing to obtain white solid (2.3 g) and yield (50%).
The product is(E)-3-benzyl-4-benzylidene-5,5-dimethyltetrahydro-2H-pyran-2- one(3z)
1H),3.78–3.70(m,2H),2.92(dd,J＝6.68,2.36Hz,2H),1.26(s,3H),1.18(s,3H). 13 C NMR(101MHz,CDCl 3 ):δ172.4,137.2,136.7,129.2,128.7,128.4,128.2,127.1,127.0,126.4,75.3,45.6,38.5,36.0,28.8,24.5.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 21 H 23 O 2 307.1698；found 307.1700.
Example 27
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.1g of 1- (4-trifluorobenzyl) dienyl ester and 1.8g of ferric acetylacetonate to a reactor, adding 5ml of alcohol, weighing 2.3g of 2-methylallyl alcohol and 1.8g of diphenyl silane, reacting at 75 deg.C for 2 hr, quenching with water, extracting with ethyl acetate, recrystallizing to obtain white solid (1.8 g) and yield (44%).
The product is
(E)-4-benzylidene-5,5-dimethyl-3-(4-(trifluoromethyl)benzyl)
tetrahydro-2H-pyran-2-one(3aa)
11.44Hz,1H),3.91(d,J＝11.38Hz,1H),2.95(dd,J＝7.06,3.56Hz,2H),1.29(s,3H),1.23(s,3H). 13 C NMR(101MHz,CDCl 3 ):δ172.0,142.1,141.3,136.4,129.5,128.8,128.1,127.2,127.0,125.2,125.2,75.8,45.1,38.4,36.2,28.5,24.7. 19 F NMR(376MHz,CDCl 3 ):-62.53.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 22 H 22 BF 3 O 2 375.15719；found 375.1570.
Example 28
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.1g of 1-allyl dienyl ester and 1.5g of ferric acetylacetonate to a reactor, adding 5ml of alcohol, weighing 2.3g of 2-methylallyl alcohol, reacting 2g of diphenyl silane at 75 deg.C for 4 hr, quenching with water, extracting with ethyl acetate, recrystallizing to obtain colorless liquid 2.1g, and yield 50%.
The product was (E) -3-all-4-benzoyleidene-5, 5-dimethylethyl-2H-pyran-2-one
(3ab)
11.42Hz,1H),3.93–3.87(m,1H),2.45(dt,J＝14.37,6.19Hz,2H),1.30(s,3H),1.27(s,3H). 13 C NMR(101MHz,CDCl 3 ):δ172.2,142.9,136.4,133.8,128.6,128.3,127.1,126.4,117.8,75.7,44.1,37.3,36.2,28.6,25.2.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 17 H 21 O 2 257.1541；found 257.1541.
Example 29
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.1g of 1-methyldienyl ester and 1.2g of ferric acetylacetonate to a reactor, adding 5ml of methanol, weighing 2.3g of 1- (4-methoxyphenyl) -2-methylallyl-1-ol, reacting at 50 deg.C for 5 hr, quenching with water, extracting with ethyl acetate, and recrystallizing to obtain white solid (1.9 g) with yield of 55%.
The product is
(E)-4-benzylidene-6-(4-methoxyphenyl)-3,5,5-trimethyltetrahydro-2H-
pyran-2-one(3ac)
(s,3H),1.06(s,3H). 13 C NMR(101MHz,CDCl 3 ):δ174.06,159.64,144.17,136.82,129.23,128.64,128.20,127.87,127.10,126.27,113.25,85.86,55.30,40.94,38.22,26.26,23.61,19.85.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 22 H 25 O 3 337.1803；found 337.1800
Examples30
A process for preparing polysubstituted beta-alkenyl valerolactone includes such steps as sequentially adding 2.1g of 4-methyldienyl ester and 1.9g of ferric acetylacetonate to a reactor, adding 5ml of alcohol, weighing 2.3g of 1- (4-chlorophenyl) -2-methylallyl-1-ol, reacting at 50 deg.C for 5 hr, quenching with water, extracting with ethyl acetate, and recrystallizing to obtain white solid (2.0 g) with 50% yield.
The product is
(E)-4-benzylidene-6-(4-chlorophenyl)-3,5,5-trimethyltetrahydro-2H-
pyran-2-one(3ad)
173.6,143.7,136.6,134.4,134.2,129.3,128.7,128.1,128.1,127.2,126.6,85.3,40.7,38.2,26.2,23.5,19.8.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 21 H 22 ClO 2 341.1308；found 341.1303.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (4)
1. The preparation method of the polysubstituted beta-alkenyl valerolactone compound is characterized by comprising the following steps:
mixing the dienyl ester derivative with allyl alcohol, a solvent, a catalyst and a reducing agent, and reacting to obtain a polysubstituted beta-alkenyl valerolactone compound;
the synthetic route of the synthetic route is as follows,
r is aryl or substituted aryl,
R 1 is hydrogen, alkyl, and is not limited by the formula,
R 2 is hydrogen, alkyl, aryl or substituted aryl,
R 3 、R 4 、R 5 is hydrogen or alkyl;
the catalyst is FeSO 4 、Fe(acac) 3 、FeCl 3 、Fe(ox) 3 ·6H 2 O、FeBr 3 At least one of (a) and (b);
the reducing agent is Et 3 SiH、(EtO) 3 SiH、PhSiH 3 、Ph 2 SiH 2 At least one of PMHS.
2. The process for producing a polysubstituted β -alkenylvalerolactone compound according to claim 1, wherein the molar ratio of the dienyl ester derivative to allyl alcohol is 1:0.2 to 10.
3. The process for producing a polysubstituted β -alkenylvalerolactone compound according to claim 1, wherein the molar ratio of the dienyl ester derivative to the catalyst is 1:0.05-2.
4. The process for producing a polysubstituted β -alkenylvalerolactone compound according to claim 1, wherein the molar ratio of the dienyl ester derivative to the reducing agent is 1:0.5 to 7.
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