CN114989121B - 一种3,4,6-三取代吡喃酮的制备方法和应用 - Google Patents
一种3,4,6-三取代吡喃酮的制备方法和应用 Download PDFInfo
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- -1 3,4, 6-trisubstituted pyrone Chemical class 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 239000003054 catalyst Substances 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 230000000844 anti-bacterial effect Effects 0.000 claims description 9
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 7
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 244000063299 Bacillus subtilis Species 0.000 claims description 6
- 235000014469 Bacillus subtilis Nutrition 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- UBOXGVDOUJQMTN-UHFFFAOYSA-N 1,1,2-trichloroethane Chemical compound ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- JHYKJJIJPWNOME-UHFFFAOYSA-N 1,4a,8-triazido-2,3,4,5,6,7-hexahydro-1H-naphthalene Chemical compound N(=[N+]=[N-])C12CCCC(=C2C(CCC1)N=[N+]=[N-])N=[N+]=[N-] JHYKJJIJPWNOME-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 8
- 125000003118 aryl group Chemical group 0.000 abstract description 7
- 125000003107 substituted aryl group Chemical group 0.000 abstract description 6
- 125000000217 alkyl group Chemical group 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 abstract description 4
- 125000000547 substituted alkyl group Chemical group 0.000 abstract description 4
- 239000000758 substrate Substances 0.000 abstract description 3
- 229940124350 antibacterial drug Drugs 0.000 abstract description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 2
- 229930192474 thiophene Natural products 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000007787 solid Substances 0.000 description 11
- 230000001580 bacterial effect Effects 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 5
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 4
- 230000000845 anti-microbial effect Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- OEBXWWBYZJNKRK-UHFFFAOYSA-N 1-methyl-2,3,4,6,7,8-hexahydropyrimido[1,2-a]pyrimidine Chemical compound C1CCN=C2N(C)CCCN21 OEBXWWBYZJNKRK-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical group 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- HOVMFCOUXZBNBX-UHFFFAOYSA-N 1,3-bis(4-bromophenyl)propane-1,3-dione Chemical compound C1=CC(Br)=CC=C1C(=O)CC(=O)C1=CC=C(Br)C=C1 HOVMFCOUXZBNBX-UHFFFAOYSA-N 0.000 description 1
- HXLJEXGLRWDMDB-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-(4-methoxyphenyl)propane-1,3-dione Chemical compound C1=CC(OC)=CC=C1C(=O)CC(=O)C1=CC=C(Cl)C=C1 HXLJEXGLRWDMDB-UHFFFAOYSA-N 0.000 description 1
- FVKFHMNJTHKMRX-UHFFFAOYSA-N 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine Chemical compound C1CCN2CCCNC2=N1 FVKFHMNJTHKMRX-UHFFFAOYSA-N 0.000 description 1
- 240000006439 Aspergillus oryzae Species 0.000 description 1
- 235000002247 Aspergillus oryzae Nutrition 0.000 description 1
- SRMXTNLYGIBPQJ-UHFFFAOYSA-N C(C)(C)(C)OC(C(=C=NCCC1=CC(=C(C=C1)OC)OC)C1=CC=CC=C1)=O Chemical compound C(C)(C)(C)OC(C(=C=NCCC1=CC(=C(C=C1)OC)OC)C1=CC=CC=C1)=O SRMXTNLYGIBPQJ-UHFFFAOYSA-N 0.000 description 1
- AYQNGRHXNAJBPJ-UHFFFAOYSA-N COC(C(=C=NC1CCCCC1)C1=CC=CC=C1)=O Chemical compound COC(C(=C=NC1CCCCC1)C1=CC=CC=C1)=O AYQNGRHXNAJBPJ-UHFFFAOYSA-N 0.000 description 1
- DYLFHHPICWOVOG-UHFFFAOYSA-N COC(C(=C=NCCC1=CC(=C(C=C1)OC)OC)C1=CC=CC=C1)=O Chemical compound COC(C(=C=NCCC1=CC(=C(C=C1)OC)OC)C1=CC=CC=C1)=O DYLFHHPICWOVOG-UHFFFAOYSA-N 0.000 description 1
- 241001081178 Cryptocarya Species 0.000 description 1
- 108010010369 HIV Protease Proteins 0.000 description 1
- 241000187654 Nocardia Species 0.000 description 1
- 241000203619 Nocardiopsis dassonvillei Species 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 241000760908 Stenoptera Species 0.000 description 1
- 241001052560 Thallis Species 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 125000002897 diene group Chemical group 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 230000008121 plant development Effects 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000006049 ring expansion reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000005829 trimerization reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
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- 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
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
- C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Nitrogen Condensed Heterocyclic Rings (AREA)
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Abstract
本发明公开了一种3,4,6‑三取代吡喃酮的制备方法和应用,其化学结构如下所示,其中,R选自烷基、取代烷基、芳基、取代芳基中的任意一种;R1和R2都选自烷基、取代烷基、芳基、取代芳基、萘、吡啶、呋喃和噻吩中的任意一种,R3选自芳基、取代芳基、萘中的任意一种。3,4,6‑三取代吡喃酮类化合物具有较好的药物活性,可用于制备抗菌药物,有望成为一类新型的药物中间体。本发明还公开了3,4,6‑三取代吡喃酮类化合物的制备方法,本发明所述3,4,6‑三取代吡喃酮类化合物的制备方法具有原料和催化剂便宜易得;反应条件温和,操作简单方便;底物的普适性广等优点,对一系列3,4,6‑三取代吡喃酮类化合物均可取得很高的产率。
Description
技术领域
本发明涉及化合物合成技术领域,具体为一种 3,4,6-三取代吡喃酮的制备方法和应用。
背景技术
α-吡喃酮是一类含有不饱和键的六元环内酯,在自然界分布极广的化合物。例如,在硬枝隐山核桃根材中提取出来的化合物1 (J. Nat. Prod. 2015, 78, 1330-1338),从海洋来源的放线菌Nocardiopsis dassonvillei HR10-5中分离得到的具有抗菌活性的化合物2和3 (J. Nat. Prod. 2011, 74, 2219-2223),米曲霉中分离出来的化合物4 (J.Nat. Prod. 2022, 85, 384-390),以及在海洋源诺卡菌菌株中分离出来的化合物5 (J.Nat. Prod. 2016, 79, 1610-1618)。同时,研究发现,α-吡喃酮衍生物具有广泛的生物活性,例如化合物6能调节植物发育(Org. Lett. 2003, 5, 1935-1938),化合物7具有抗植物毒性(Agric. Biol. Chem. 1981, 45, 1675),化合物8是艾滋病毒蛋白酶的抑制剂(Bioorg. Med. Chem. Lett. 2002, 12, 3509-3513),化合物9可以抑制胆固醇的合成(Med. chem. 1999, 42, 4250),化合物10已被应用于局部麻醉。
此外,α-吡喃酮具有的共轭二烯骨架和酯基结构使其成为有机合成中一类多功能的构建块。因此,开发高效的α-吡喃酮合成方法一直是有机合成领域追求的目标。迄今为止,虽然已经报道了几种合成策略,如环三聚、过渡金属催化环化和扩环等策略。但这些策略中,在α-吡喃酮上取代的官能团相对有限。例如,C4-位的取代基通常仅限于烷基或芳基,而酰胺取代基很少。因此,发展一种α-吡喃酮上C4-位酰胺取代的3,4,6-三取代吡喃酮合成策略可突破目前α-吡喃酮合成所面临的瓶颈,具有重要的理论价值和潜在的药用价值。
发明内容
(一)解决的技术问题
针对现有技术的不足,本发明提供了一种 3,4,6-三取代吡喃酮的制备方法和应用,具备原料和催化剂便宜易得等优点,解决了底物的普适性范围小的问题。
为实现上述原料和催化剂便宜易得目的,本发明提供如下技术方案:一种 3,4,6-三取代吡喃酮的制备方法和应用,包括以下步骤:
S1、原料选取
式I
R选自烷基、取代烷基、芳基、取代芳基中的任意一种;R1 和R2都选自烷基、取代烷基、芳基、取代芳基、萘、吡啶、呋喃和噻吩中的任意一种; R3选自芳基、取代芳基、萘中的任意一种。
S2、原料混合
将催化剂、式Ⅱ所示化合物、式Ⅲ所示化合物和溶剂混合均匀,在-60 ~ 150℃下搅拌至反应完成,分离得式Ⅰ所示化合物;
其中式Ⅱ所示化合物、式Ⅲ所示化合物以及式Ⅰ所示化合物的结构式如下所示:
S3、原料配比
选取催化剂为1,2,2,6,6-五甲基哌啶、1,8-二氮杂双环[5.4.0]十一碳-7-烯、碳酸铯、叔丁醇钾、1,5,7-三叠氮双环(4.4.0)癸-5-烯、三乙胺、7-甲基-1,5,7-三氮杂二环[4.4.0]癸-5-烯、三乙烯二胺、1,1,3,3-四甲基胍、碳酸钾、叔丁醇钠、氢氧化钠、甲醇钠、氢氧化钾中的任意一种。
优选的,所述在S1、步骤中,化学结构选自以下结构式中的一种:
优选的,所述在S1、步骤中,化学结构选自以下结构式中的一种:
优选的,所述在S2、步骤中,催化剂的量为式Ⅲ所示化合物物质的量的x%,x = 0.1~100。
优选的,所述在S2、步骤中,式Ⅱ所示化合物的物质的量为式Ⅲ所示化合物的物质的量的y倍,y = 0.1~50。
优选的,所述在S2、步骤中,溶剂为甲醇、乙醇、甲苯、乙酸乙酯、二氯甲烷、丙酮、乙腈、N,N-二甲基甲酰胺异丙醇、1,2-二氯乙烷、四氢呋喃、氯仿、1,1,2-三氯乙烷、1,1,2,2-四氯乙烷、乙醚、二甲基亚砜和硝基甲烷中的至少一种。
优选的,所述在S2、步骤中,原料的具体反应路线如下所示:
优选的,所述在S3、步骤中,3,4,6-三取代吡喃酮类化合物在制备抗菌药物中的应用。
优选的,所述在S3、步骤中,3,4,6-三取代吡喃酮类化合物在制备抗枯草芽孢杆菌药物中的应用。
与现有技术相比,本发明提供了一种一种 3,4,6-三取代吡喃酮的制备方法和应用,具备以下有益效果:
1、该 3,4,6-三取代吡喃酮的制备方法和应用,有望成为一类新型的药物中间体。本发明所述的3,4,6-三取代吡喃酮类化合物的制备方法具有以下优点:原料和催化剂便宜易得;反应条件温和,操作简单方便;底物的普适性广,对一系列3,4,6-三取代吡喃酮类化合物均可取得很高的产率。
附图说明
图1为本发明3,4,6-三取代吡喃酮类化合物的合成图示意图;
图2为本发明3,4,6-三取代吡喃酮类化合物的合成图示意图;
图3为本发明3,4,6-三取代吡喃酮类化合物的合成图示意图;
图4为本发明3,4,6-三取代吡喃酮类化合物的合成图示意图;
图5为本发明3,4,6-三取代吡喃酮类化合物的合成图示意图;
图6为本发明3,4,6-三取代吡喃酮类化合物的合成图示意图;
图7为本发明3,4,6-三取代吡喃酮类化合物的合成图示意图;
图8为本发明3,4,6-三取代吡喃酮类化合物的合成图示意图;
图9为本发明3,4,6-三取代吡喃酮类化合物的合成图示意图。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
式Ⅱ所示化合物为3-(苯乙亚胺基)-2-芳基-丙烯酸酯化合物,可按照以下文献方法中的任意一种合成 [(a) Z. Liu, S. Cao, J. Wu, G. Zanoni, P. Sivaguru, X. Bi,ACS Catalysis202010, 12881-12887; (b) J. Luo, G.-S. Chen, S.-J. Chen, Z.-D.Li, Y.-L. Zhao, Y.-L. Liu, Adv. Synth. Catal.2020, 362, 3635-3643. ]。
式Ⅲ所示化合物为1,3-二酮类化合物,购买自萨恩化学技术(上海)有限公司。
实施例1
式Ⅰ-1所示3,4,6-三取代吡喃酮类化合物的合成:
氮气保护下,在10 mL反应瓶中依次加入3-(环己基亚氨基)-2-苯丙烯酸甲酯III-1 (28.29 mg, 0.11 mmol)、1,3-二苯基-1,3-丙酮II-1 (22.4 mg, 0.10 mmol)、催化剂1,8-二氮杂双环[5.4.0]十一碳-7-烯[DBU](2.28 mg, 0.015 mmol)和溶剂乙腈[ACN](1.0mL)。将反应液在60℃下搅拌3h后,TLC检测原料基本已反应完,停止反应。反应液直接柱层析,淋洗剂(石油醚/乙酸乙酯=5/1),得产品I-1浅绿色固体42.2mg,产率94%。
式Ⅰ-1所示3,4,6-三取代吡喃酮类化合物的分析数据:1H NMR (400 MHz, CDCl3):δ 1.09-1.23 (m, 3H), 1.62-1.64 (m, 3H), 1.76-1.84 (m, 4H), 4.05 (brs, 1H),6.71 (s, 1H), 7.10 (d, J = 7.2 Hz, 2H), 7.16 (brs, 2H), 7.22 (t, J = 7.2 Hz,2H), 7.33-7.37 (m, 4H), 7.50-7.51 (m, 3H), 7.85-7.87 (m, 2H); 13C NMR (100MHz, CDCl3): δ 170.18, 162.50, 157.78, 151.03, 135.72, 131.70, 131.12,130.75, 130.52, 129.87, 129.01, 128.46, 128.15, 127.95, 127.45, 127.12,125.60, 104.68, 60.47, 31.81, 26.09, 25.35. HRMS (ESI): Exact mass calcd forC30H27NNaO3 [M+Na]+: 472.1883, Found: 472.1875.
实施例2
式Ⅰ-2所示3,4,6-三取代吡喃酮类化合物的合成:
氮气保护下,在10 mL反应瓶中依次加入((4-氯苯乙基)亚氨基)-2-苯丙烯酸甲酯III-2 (46.96 mg, 0.15 mmol)、1,3-二苯基-1,3-丙酮II-1 (22.4mg, 0.10 mmol)、催化剂三乙胺[Et3N] (5.05 mg, 0.05 mmol)和溶剂N,N-二甲基甲酰胺[DMF] (0.5 mL)。将反应液在20℃下搅拌7h后,TLC检测原料基本已反应完,停止反应。反应液直接柱层析,淋洗剂(石油醚/乙酸乙酯=6/1),得产品I-2白色固体48 mg,产率95%。
式Ⅰ-2所示3,4,6-三取代吡喃酮类化合物的分析数据:1H NMR (400 MHz, CDCl3):δ 3.05 (s, 2H), 3.86 (brs, 2H), 5.71 (s, 1H), 6.97 (d, J = 6.4 Hz, 2H), 7.07(d, J = 7.6 Hz, 2H), 7.17-7.23 (m, 4H), 7.30-7.35 (m, 3H), 7.38 (d, J = 8.4Hz, 3H), 7.46-7.49 (m, 3H), 7.51-7.55 (m, 2H); 13C NMR (100 MHz, CDCl3): δ169.75, 162.22, 158.79, 153.38, 137.90, 134.43, 133.02, 131.29, 131.22,131.17, 130.86, 130.35, 129.83, 129.03, 129.01, 128.56, 128.38, 128.01,127.95, 125.46, 120.96, 102.25, 52.90, 33.06. HRMS (ESI): Exact mass calcdfor C32H24ClNNaO3 [M+Na]+: 528.1337, Found: 528.1326.
实施例3
式Ⅰ-3所示3,4,6-三取代吡喃酮类化合物的合成:
氮气保护下,在10 mL反应瓶中依次加入((4-甲氧基苯乙基)亚氨基)-2-苯丙烯酸甲酯III-3 (61.82 mg, 0.20 mmol)、1,3-二苯基-1,3-丙酮II-1 (22.4mg, 0.10 mmol)、催化剂1,2,2,6,6-五甲基哌啶[PMP] (6.21 mg, 0.04 mmol)和溶剂四氢呋喃[THF] (1.0mL)。将反应液在80℃下搅拌3.5 h后,TLC检测原料基本已反应完,停止反应。反应液直接柱层析,淋洗剂(石油醚/乙酸乙酯=4/1),得产品I-3白色固体46.38 mg,产率93%。
式Ⅰ-3所示3,4,6-三取代吡喃酮类化合物的分析数据:1H NMR (400 MHz, CDCl3):δ 3.02 (brs, 2H), 3.51 (brs, 1H), 3.79 (s, 3H), 4.25 (brs, 1H), 5.74 (s, 1H),6.91-6.94 (m, 2H), 6.98-6.99 (m, 2H), 7.07 (d, J = 7.2 Hz, 2H), 7.16 (d, J =8.4 Hz, 2H), 7.20 (t, J = 8.0 Hz, 2H), 7.30-7.38 (m, 4H), 7.41-7.49 (m, 3H),7.54-7.56 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 169.77, 162.33, 158.68, 158.49,153.68, 134.67, 131.34, 131.28, 131.13, 131.03, 130.49, 129.88, 128.79,128.48, 128.35, 128.03, 127.88, 125.55, 120.86, 114.24, 102.59, 55.20, 53.36,32.80. HRMS (ESI): Exact mass calcd for C33H27NNaO4 [M+Na]+: 524.1832, Found:524.1824.
实施例4
式Ⅰ-4所示3,4,6-三取代吡喃酮类化合物的合成:
氮气保护下,在10 mL反应瓶中依次加入3-((3,4-二甲氧基苯乙基)亚氨基)-2-苯丙烯酸叔丁酯III-3 (101.74 mg, 0.30 mmol)、2,6-二甲基-3,5-二酮II-1 (15.61 mg,0.10 mmol)、催化剂碳酸钾[K2CO3] (4.15 mg, 0.03 mmol)和溶剂甲醇[MeOH] (5.0 mL)。将反应液在80℃下搅拌5h后,TLC检测原料基本已反应完,停止反应。反应液直接柱层析,淋洗剂(石油醚/乙酸乙酯=3/1),得产品I-4白色固体43.1 mg,产率93%。
式Ⅰ-4所示3,4,6-三取代吡喃酮类化合物的分析数据:1H NMR (400 MHz, CDCl3):δ 1.02 (d, J = 56.8 Hz, 6H), 1.19 (d, J = 6.8 Hz, 6H), 2.58-2.72 (m, 3H),2.89 (brs, 2H), 3.83 (s, 3H), 3.84 (s, 3H), 3.91 (brs, 1H), 5.33 (s, 1H),6.62 (d, J = 7.2 Hz, 2H), 6.76 (d, J = 8.0 Hz, 1H), 7.27-7.28 (m, 2H), 7.31-7.35 (m, 1H), 7.37-7.41 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 176.69, 169.12,163.34 153.19, 148.94, 147.75, 131.54, 129.32, 128.70, 128.64, 120.91,111.98, 111.10, 102.96, 55.80, 50.92, 33.50, 32.42, 20.54, 20.00, 19.75,19.01. HRMS (ESI): Exact mass calcd for C28H33NNaO5 [M+Na]+: 486.2251, Found:486.2258.
实施例
式Ⅰ-5所示3,4,6-三取代吡喃酮类化合物的合成:
氮气保护下,在10 mL反应瓶中依次加入3-((3,4-二甲氧基苯乙基)亚氨基)-2-苯丙烯酸叔丁酯III-3 (84.79 mg, 0.25 mmol)、1-(4-氯苯基)-3-(4-甲氧基苯基)丙烷-1,3-二酮II-2 (28.80 mg, 0.10 mmol)、催化剂三乙烯二胺[DABCO] (6.73 mg, 0.06 mmol)和溶剂二甲基亚砜[DMSO] (8.0 mL)。将反应液在80℃下搅拌6 h后,TLC检测原料基本已反应完,停止反应。反应液萃取后柱层析,淋洗剂(石油醚/乙酸乙酯=3/1),得产品I-5白色固体12.51 mg,产率21%。
式Ⅰ-5所示3,4,6-三取代吡喃酮类化合物的分析数据:1H NMR (400 MHz, CDCl3):δ 3.02 (brs, 2H), 3.64 (brs, 2H), 3.78 (s, 3H), 3.79 (s, 3H), 3.88 (s, 3H),5.66 (s, 1H), 6.68 (d, J = 8.4 Hz, 2H), 6.72-6.73 (m, 1H), 6.79 (dd, J = 6.8,1.2 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.94-6.96 (m, 2H), 7.01 (d, J = 8.8Hz, 2H), 7.28-7.33 (m, 3H), 7.41-7.43 (m, 2H), 7.46-7.48 (m, 2H); 13C NMR (100MHz, CDCl3): δ 169.27, 162.16, 162.01, 157.44, 153.98, 149.37, 148.09,137.25, 132.09, 131.30, 130.17, 129.84, 129.46, 129.18, 129.02, 128.49,128.34, 126.83, 126.70, 121.42, 120.73, 113.16, 112.55, 111.35, 102.60,55.94, 55.87, 55.35, 53.32, 33.15. HRMS (ESI): Exact mass calcd forC35H30ClNNaO6 [M+Na]+: 618.1654, Found: 618.1650.
实施例6
式Ⅰ-6所示3,4,6-三取代吡喃酮类化合物的合成:
氮气保护下,在10 mL反应瓶中依次加入3-((4-氟苯乙基)亚氨基)-2-苯丙烯酸甲酯III-5 (61.05 mg, 0.18 mmol)、1,3-二吡啶-2-丙烷-1,3-二酮II-4 (22.60 mg, 0.10mmol)、催化剂叔丁醇钾[tBuOK] (3.36 mg, 0.03 mmol)和溶剂乙酸乙酯[EA] (2.0 mL)。将反应液在65℃下搅拌3.5h后,TLC检测原料基本已反应完,停止反应。反应液直接柱层析,淋洗剂(石油醚/乙酸乙酯=8/1),得产品I-6白色固体48.45 mg,产率89%.
式Ⅰ-6所示3,4,6-三取代吡喃酮类化合物的分析数据:1H NMR (400 MHz, CDCl3):δ 2.96 (brs, 2H), 3.39 (brs, 1H), 3.76 (s, 3H), 3.83 (s, 3H), 4.11 (brs, 1H),6.69 (s, 1H), 6.72 (d, J = 3.2 Hz, 2H), 6.93 (s, 1H), 7.28-7.34 (m, 5H),7.38-7.42 (m, 2H), 7.59-7.61 (m, 1H), 7.68-7.72 (m, 1H), 7.77-7.81 (m, 1H),7.96 (d, J = 8.0 Hz, 1H), 8.39 (d, J = 4.0 Hz, 1H), 8.57-8.89 (m, 1H); 13C NMR(100 MHz, CDCl3): δ 167.66, 162.65, 156.01, 149.69, 148.93, 148.39, 147.69,147.55, 136.99, 136.83, 132.06, 130.79, 129.61, 129.00, 128.54, 128.50,128.26, 128.21, 125.71, 124.81, 124.70, 120.94, 120.32, 111.99, 111.16,105.87, 55.74, 51.53, 33.79. HRMS (ESI): Exact mass calcd for C32H27N3NaO5 [M+Na]+: 556.1843, Found: 556.1846.
实施例7
式I-7所示3,4,6-三取代吡喃酮类化合物的合成:
氮气保护下,在10 mL反应瓶中依次加入3-((3,4-二甲氧基苯乙基)亚氨基)-2-苯丙烯酸甲酯III-5 (135.66 mg, 0.40 mmol)、1,3-二呋喃-2-丙烷-1,3-二酮II-5 (20.40mg, 0.10 mmol)、催化剂叔丁醇钠[tBuONa] (4.8 mg, 0.05 mmol)和溶剂甲苯[Toluene](4.0 mL)。将反应液在100℃下搅拌5 h后,TLC检测原料基本已反应完,停止反应。反应液直接柱层析,淋洗剂(石油醚/乙酸乙酯=7/1),得产品I-7白色固体44.47 mg,产率87%。
式I-7所示3,4,6-三取代吡喃酮类化合物的分析数据:1H NMR (400 MHz, CDCl3):δ 2.83 (s, 2H), 3.64 (brs, 2H), 3.78 (s, 3H), 3.80 (s, 3H), 5.88 (s, 1H),6.43 (dd, J = 3.6, 1.6 Hz, 1H), 6.53 (dd, J = 3.2, 1.6 Hz, 1H), 6.64-6.67 (m,2H), 6.74 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 3.6 Hz, 1H), 6.99 (d, J = 3.6 Hz,1H), 7.25-7.27 (m, 2H), 7.32-7.37 (m, 3H), 7.41-7.42 (m, 1H), 7.49-7.50 (m,1H); 13C NMR (100 MHz, CDCl3): δ 161.94, 158.86, 153.35, 150.17, 149.01,147.85, 147.17, 145.82, 144.99, 144.96, 131.56, 130.75, 129.32, 128.70,128.54, 120.97, 119.74, 117.66, 112.52, 112.20, 112.03, 111.91, 111.14,101.72, 55.74, 55.72, 51.33, 33.56. HRMS (ESI): Exact mass calcd forC30H25NNaO7 [M+Na]+: 534.1523, Found: 534.1522.
实施例8
式I-8所示3,4,6-三取代吡喃酮类化合物的合成:
氮气保护下,在10 mL反应瓶中依次加入3-((3,4-二甲氧基苯乙基)亚氨基)-2-苯丙烯酸甲酯III-1 (203.49 mg, 0.60 mmol)、1,3-双(4-溴苯基)丙烷-1,3-二酮II-6(37.99 mg, 0.10 mmol)、催化剂1,5,7-三氮杂双环[4.4.0]癸-5-烯[TBD] (13.92 mg,0.1 mmol)和溶剂异丙醇[IPA] (3.0 mL)。将反应液在120℃下搅拌5h后,TLC检测原料基本已反应完,停止反应。反应液直接柱层析,淋洗剂(石油醚/乙酸乙酯=5/1),得产品I-8白色固体63.89 mg,产率93%。
式I-8所示3,4,6-三取代吡喃酮类化合物的分析数据:1H NMR NMR (400 MHz,CDCl3) 2.94 (brs, 2H), 3.41 (brs, 1H), 3.79 (s, 3H), 3.89 (s, 3H), 4.42 (brs,1H), 5.65 (s, 1H), 6.74 (s, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4Hz, 2H), 6.89 (d, J = 8.0 Hz, 1H), 6.92 (brs, 2H), 7.30-7.34 (m, 5H), 7.40(d, J = 8.4 Hz, 2H), 7.58-7.60 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 168.68,161.77, 157.89, 153.16, 149.47, 148.22, 133.33, 132.19, 131.83, 131.09,130.94, 129.86, 129.51, 129.25, 128.67, 128.42, 126.84, 125.91, 125.85,121.44, 121.33, 112.40, 111.39, 102.03, 55.94, 55.88, 53.62, 33.01. HRMS(ESI): Exact mass calcd for C34H27Br2NNaO5 [M+Na]+: 710.0148, Found: 710.0152.
实施例9
式I-9所示3,4,6-三取代吡喃酮类化合物的合成:
氮气保护下,在10 mL反应瓶中依次加入3-((3,4-二甲氧基苯乙基)亚氨基)-2-苯丙烯酸甲酯III-5 (118.70 mg, 0.35 mmol)、1,3-二苯基-1,3-丙酮II-1 (22.40 mg,0.10 mmol)、催化剂甲醇钠[MeONa] (2.7 mg, 0.05 mmol)和溶剂乙醇[EtOH] (0.5 mL)。将反应液在20℃下搅拌2h后,TLC检测原料基本已反应完,停止反应。反应液直接柱层析,淋洗剂(石油醚/乙酸乙酯=8/1),得到产品I-9白色固体49.38 mg,产率93%。
式I-9所示3,4,6-三取代吡喃酮类化合物的分析数据:1H NMR (400 MHz, CDCl3):δ 3.03 (brs, 2H), 3.68 (brs, 2H), 3.77 (s, 3H), 3.86 (s, 3H), 5.78 (s, 1H),6.72 (s, 1H), 6.79-6.82 (m, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 6.0Hz, 2H), 7.05 (d, J = 7.6 Hz, 2H), 7.19 (t, J = 7.6 Hz, 2H), 7.29-7.38 (m,4H), 7.42-7.46 (m, 3H), 7.55-7.56 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 169.79,162.33, 158.67, 153.62, 149.34, 148.09, 134.62, 131.33, 131.25, 131.11,130.53, 129.90, 128.89, 128.50, 128.37, 128.09, 127.90, 125.50, 121.33,120.83, 120.64, 112.46, 111.88, 111.35, 102.50, 55.87, 55.82, 53.23, 33.16.HRMS (ESI): Exact mass calcd for C34H29NNaO5 [M+Na]+: 554.1938, Found:554.1932.
实施例10
3,4,6-三取代吡喃酮类化合物的抗菌活性测试:
鉴于我们所合成的3,4,6-三取代吡喃酮类化合物具有药物开发的重要元素,我们接下来对以上实施例中所提及的化合物进行了抗菌活性测试。上述背景介绍了具有抗菌作用的化合物2,而利用本发明方法合成的化合物与其具有一定的相似性,因此本实施例以具有抗菌作用的化合物2为参照物,测试了下表1中所示化合物对枯草芽孢杆菌的抗菌活性。具体的实施过程如下:将冰箱保存的枯草芽孢杆菌移接到牛肉膏蛋白胨固体培养基上,置于37 ℃恒温培养箱中培养24 h,用接种环挑取少许菌体与装有无菌生理盐水的试管中,震荡均匀,制成菌悬液。具体为用接种环挑取一环(本实验是吸取50 μL菌悬液)于5 mL的无菌生理盐水中,每 10倍稀释一次地逐级稀释,取(10-9、10-10、10-11)的浓度50μL做涂布实验,每个梯度平行三组,加50 μL 药品溶剂(二甲基亚砜)的空白对照3个平板,完全不加任何样品即只是LB培养基的完全空白对照1个平板,调整菌悬液浓度,用平板菌落法测定其菌液浓度,使其含菌体数为10³ cfu/mL,即为供试菌悬液。随后将灭菌固体培养基加热至熔化,待冷却至25 ℃时,每10 mL培养基倒入无菌培养皿中。待平板自然晾干后,分别移取0.05 mL待测药品,0.05 mL供试菌悬液,均匀涂布于加药平板上,每个处理3次重复。(涂布1 h后再倒置)另设置对照组,涂菌,以等量无菌水(溶解药品物质)代替药液。上述操作在超净工作台内进行。将做好的细菌平板在37 ℃恒温培养48 h,统计菌落个数, 数据取自三个平行实验平均值。具体结果见表1。
表1 化合物2和实施例1~9所述3,4,6-三取代吡喃酮类化合物的抗菌活性测试数据
从上表中的数据可以看出,化合物I-1至I-9均对枯草芽孢杆菌具有一定的抗菌活性。其中大部分3,4,6-三取代吡喃酮类化合物的抗菌性比化合物2弱,但是化合物I-4和I-6对枯草芽孢杆菌的抗菌性比化合物2优越。总体上来说,表1中的抗菌性测试数据表明本发明所述的3,4,6-三取代吡喃酮类化合物对枯草芽孢杆菌具有一定的抗菌活性,有望发展成为一类新型的抗菌药物或药物前体尽管已经示出和描述了本发明的实施例,对于本领域的普通技术人员而言,可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由所附权利要求及其等同物限定。
Claims (7)
1.一种 3,4,6-三取代吡喃酮的制备方法,其特征在于,包括以下步骤:
将催化剂、式Ⅱ所示化合物、式Ⅲ所示化合物和
溶剂混合均匀,在-60 ~ 150℃下搅拌至反应完成,分离得式Ⅰ所示化合物;
其中式Ⅱ所示化合物、式Ⅲ所示化合物以及式Ⅰ所示化合物的结构式如下所示:
选取催化剂为1,2,2,6,6-五甲基哌啶、1,8-二氮杂双环[5.4.0]十一碳-7-烯、碳酸铯、叔丁醇钾、1,5,7-三叠氮双环(4.4.0)癸-5-烯、三乙胺、三乙烯二胺、叔丁醇钠、甲醇钠中的任意一种;
式 Ⅰ选自以下结构式中的一种:
。
2.根据权利要求1所述的一种 3,4,6-三取代吡喃酮的制备方法,其特征在于,式 Ⅰ 选自以下结构式中的一种:
。
3.根据权利要求1所述的一种 3,4,6-三取代吡喃酮的制备方法,其特征在于,所述催化剂的量为式Ⅲ所示化合物物质的量的x%,x = 0.1~100。
4.根据权利要求1所述的一种 3,4,6-三取代吡喃酮的制备方法,其特征在于,所述式Ⅱ所示化合物的物质的量为式Ⅲ所示化合物的物质的量的y倍,y = 0.1~50。
5.根据权利要求1所述的一种 3,4,6-三取代吡喃酮的制备方法,其特征在于,所述溶剂为甲醇、乙醇、甲苯、乙酸乙酯、二氯甲烷、丙酮、乙腈、N,N-二甲基甲酰胺异丙醇、1,2-二氯乙烷、四氢呋喃、氯仿、1,1,2-三氯乙烷、1,1,2,2-四氯乙烷、乙醚、二甲基亚砜和硝基甲烷中的至少一种。
6.根据权利要求1 所制备的 3,4,6-三取代吡喃酮式Ⅰ化合物在制备抗菌药物中的应用。
7.根据权利要求1所制备的 3,4,6-三取代吡喃酮式Ⅰ化合物在制备抗枯草芽孢杆菌药物中的应用。
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