CN112142773A - 一类四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物及其制备方法 - Google Patents
一类四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物及其制备方法 Download PDFInfo
- Publication number
- CN112142773A CN112142773A CN201910558646.4A CN201910558646A CN112142773A CN 112142773 A CN112142773 A CN 112142773A CN 201910558646 A CN201910558646 A CN 201910558646A CN 112142773 A CN112142773 A CN 112142773A
- Authority
- CN
- China
- Prior art keywords
- compound
- aqueous solution
- room temperature
- compounds
- reacting
- 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.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- INVNXZDHIJBAAM-UHFFFAOYSA-N 4,4a,5,6-tetrahydropyrrolo[2,3-e]oxazin-3-one Chemical compound O1NC(CC2C1=CCN2)=O INVNXZDHIJBAAM-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 96
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 52
- 239000007864 aqueous solution Substances 0.000 claims description 44
- 239000000243 solution Substances 0.000 claims description 31
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 23
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 18
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 claims description 18
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 9
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 claims description 8
- AQDDOANPLYUVEC-UHFFFAOYSA-N N1(CCCCC1)C1C(NOC=C1)=O Chemical class N1(CCCCC1)C1C(NOC=C1)=O AQDDOANPLYUVEC-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- -1 aromatic alkyne Chemical class 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 6
- 150000001345 alkine derivatives Chemical class 0.000 claims description 5
- 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 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- UCYRAEIHXSVXPV-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)indiganyl trifluoromethanesulfonate Chemical compound [In+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F UCYRAEIHXSVXPV-UHFFFAOYSA-K 0.000 claims description 3
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- 238000000605 extraction Methods 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 34
- 239000000575 pesticide Substances 0.000 abstract description 11
- FBXGQDUVJBKEAJ-UHFFFAOYSA-N 4h-oxazin-3-one Chemical group O=C1CC=CON1 FBXGQDUVJBKEAJ-UHFFFAOYSA-N 0.000 abstract description 7
- 230000004071 biological effect Effects 0.000 abstract description 4
- 241000238631 Hexapoda Species 0.000 abstract description 3
- 206010061218 Inflammation Diseases 0.000 abstract description 2
- 102100034343 Integrase Human genes 0.000 abstract description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 abstract description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 abstract description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 abstract description 2
- 230000003467 diminishing effect Effects 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 230000004054 inflammatory process Effects 0.000 abstract description 2
- 230000002147 killing effect Effects 0.000 abstract description 2
- 239000002777 nucleoside Substances 0.000 abstract description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 abstract description 2
- 230000036407 pain Effects 0.000 abstract description 2
- 230000001954 sterilising effect Effects 0.000 abstract description 2
- 238000009333 weeding Methods 0.000 abstract description 2
- 230000005764 inhibitory process Effects 0.000 abstract 2
- 230000001093 anti-cancer Effects 0.000 abstract 1
- 230000000078 anti-malarial effect Effects 0.000 abstract 1
- 230000002785 anti-thrombosis Effects 0.000 abstract 1
- 239000003430 antimalarial agent Substances 0.000 abstract 1
- LVASCWIMLIKXLA-LSDHHAIUSA-N halofuginone Chemical compound O[C@@H]1CCCN[C@H]1CC(=O)CN1C(=O)C2=CC(Cl)=C(Br)C=C2N=C1 LVASCWIMLIKXLA-LSDHHAIUSA-N 0.000 abstract 1
- 229950010152 halofuginone Drugs 0.000 abstract 1
- 238000004659 sterilization and disinfection Methods 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 56
- 230000015572 biosynthetic process Effects 0.000 description 32
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
- 229910052757 nitrogen Inorganic materials 0.000 description 28
- 239000000741 silica gel Substances 0.000 description 28
- 229910002027 silica gel Inorganic materials 0.000 description 28
- 239000007787 solid Substances 0.000 description 28
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
- 238000001035 drying Methods 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- 238000001914 filtration Methods 0.000 description 23
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- RENYIDZOAFFNHC-UHFFFAOYSA-N 1-ethynyl-3-methylbenzene Chemical group CC1=CC=CC(C#C)=C1 RENYIDZOAFFNHC-UHFFFAOYSA-N 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- KSZVOXHGCKKOLL-UHFFFAOYSA-N 4-Ethynyltoluene Chemical group CC1=CC=C(C#C)C=C1 KSZVOXHGCKKOLL-UHFFFAOYSA-N 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 4
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 4
- 241000607479 Yersinia pestis Species 0.000 description 4
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- TZDXNFAAJNEYIO-UHFFFAOYSA-N 1-bromo-3-ethynylbenzene Chemical group BrC1=CC=CC(C#C)=C1 TZDXNFAAJNEYIO-UHFFFAOYSA-N 0.000 description 2
- LTLVZQZDXQWLHU-UHFFFAOYSA-N 1-bromo-4-ethynylbenzene Chemical group BrC1=CC=C(C#C)C=C1 LTLVZQZDXQWLHU-UHFFFAOYSA-N 0.000 description 2
- DGLHLIWXYSGYBI-UHFFFAOYSA-N 1-chloro-2-ethynylbenzene Chemical group ClC1=CC=CC=C1C#C DGLHLIWXYSGYBI-UHFFFAOYSA-N 0.000 description 2
- LFZJRTMTKGYJRS-UHFFFAOYSA-N 1-chloro-4-ethynylbenzene Chemical group ClC1=CC=C(C#C)C=C1 LFZJRTMTKGYJRS-UHFFFAOYSA-N 0.000 description 2
- PPWNCLVNXGCGAF-UHFFFAOYSA-N 3,3-dimethylbut-1-yne Chemical compound CC(C)(C)C#C PPWNCLVNXGCGAF-UHFFFAOYSA-N 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940095731 candida albicans Drugs 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- QMGHHBHPDDAGGO-IIWOMYBWSA-N (2S,4R)-1-[(2S)-2-[[2-[3-[4-[3-[4-[[5-bromo-4-[3-[cyclobutanecarbonyl(methyl)amino]propylamino]pyrimidin-2-yl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide Chemical compound CN(CCCNC1=NC(NC2=CC=C(OCCCOCCCCOCCCOCC(=O)N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)NCC3=CC=C(C=C3)C3=C(C)N=CS3)C(C)(C)C)C=C2)=NC=C1Br)C(=O)C1CCC1 QMGHHBHPDDAGGO-IIWOMYBWSA-N 0.000 description 1
- IZGDXVLRMHXOJV-SFHVURJKSA-N (3s)-4-[2-[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]ethyl-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1CCP(O)(=O)C[C@@H](O)CC(O)=O IZGDXVLRMHXOJV-SFHVURJKSA-N 0.000 description 1
- RTTUBUXMNUJHRR-DXRVJIQQSA-N (3s)-4-[[(e)-2-[1-(4-fluorophenyl)-3-propan-2-ylindol-2-yl]ethenyl]-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound C12=CC=CC=C2C(C(C)C)=C(\C=C\P(O)(=O)C[C@@H](O)CC(O)=O)N1C1=CC=C(F)C=C1 RTTUBUXMNUJHRR-DXRVJIQQSA-N 0.000 description 1
- AOSODOHQJJPEAM-VUVZNRFTSA-N (3s)-4-[[(e)-2-[3'-(4-fluorophenyl)spiro[cyclopentane-1,1'-indene]-2'-yl]ethenyl]-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound OC(=O)C[C@H](O)CP(O)(=O)\C=C\C1=C(C=2C=CC(F)=CC=2)C2=CC=CC=C2C11CCCC1 AOSODOHQJJPEAM-VUVZNRFTSA-N 0.000 description 1
- WHQUHTXULUACFD-KRWDZBQOSA-N (3s)-4-[[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]methoxy-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1COP(O)(=O)C[C@@H](O)CC(O)=O WHQUHTXULUACFD-KRWDZBQOSA-N 0.000 description 1
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 1
- KBIAVTUACPKPFJ-UHFFFAOYSA-N 1-ethynyl-4-methoxybenzene Chemical group COC1=CC=C(C#C)C=C1 KBIAVTUACPKPFJ-UHFFFAOYSA-N 0.000 description 1
- BOOYHBPHFVNWNH-OAHLLOKOSA-N 1-tert-butyl-6-[[(1R)-1-(4-chlorophenyl)ethyl]amino]-5-[(4-fluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C[C@H](C1=CC=C(C=C1)Cl)NC2=NC3=C(C=NN3C(C)(C)C)C(=O)N2CC4=CC=C(C=C4)F BOOYHBPHFVNWNH-OAHLLOKOSA-N 0.000 description 1
- JWHYSEDOYMYMNM-QGZVFWFLSA-N 2-[4-[(2r)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]sulfanyl-2-methylphenoxy]acetic acid Chemical compound C([C@@H](OCC)CSC=1C=C(C)C(OCC(O)=O)=CC=1)OC1=CC=C(C(F)(F)F)C=C1 JWHYSEDOYMYMNM-QGZVFWFLSA-N 0.000 description 1
- 241000207965 Acanthaceae Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000195649 Chlorella <Chlorellales> Species 0.000 description 1
- 229940126650 Compound 3f Drugs 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- KGPGFQWBCSZGEL-ZDUSSCGKSA-N GSK690693 Chemical compound C=12N(CC)C(C=3C(=NON=3)N)=NC2=C(C#CC(C)(C)O)N=CC=1OC[C@H]1CCCNC1 KGPGFQWBCSZGEL-ZDUSSCGKSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000013557 Plantaginaceae Species 0.000 description 1
- 241000209504 Poaceae Species 0.000 description 1
- 241000218201 Ranunculaceae Species 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- HFIVLLBFACNAFN-UHFFFAOYSA-N [1-amino-2-[2-(4-methoxyphenyl)ethylamino]ethyl]phosphonic acid Chemical compound COc1ccc(CCNCC(N)P(O)(O)=O)cc1 HFIVLLBFACNAFN-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- NPTDXPDGUHAFKC-UHFFFAOYSA-N ethynylcyclopropane Chemical group C#CC1CC1 NPTDXPDGUHAFKC-UHFFFAOYSA-N 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- MUTCAPXLKRYEPR-ITWZMISCSA-N methyl (e,3r,5s)-7-[4-bromo-2,3-bis(4-fluorophenyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\N1C(C(C)C)=C(Br)C(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 MUTCAPXLKRYEPR-ITWZMISCSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- UMIPWJGWASORKV-UHFFFAOYSA-N oct-1-yne Chemical compound CCCCCCC#C UMIPWJGWASORKV-UHFFFAOYSA-N 0.000 description 1
- HUPKWBBKMAGWFY-UHFFFAOYSA-N octa-1,6-diyne Chemical compound CC#CCCCC#C HUPKWBBKMAGWFY-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属化学合成技术领域，涉及一类四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物及其制备方法，本发明制备了含有噁嗪酮骨架的化合物，具有广泛的生物活性，例如除草、杀虫、杀菌、消炎、抑制非核苷逆转录酶性、抑制磷酸二酯酶性、抗血栓性、镇痛等生物活性，同时，也是制备具有抗疟、抗癌等活性的常山酮、常山碱的核心骨架化合物，所述的化合物对研制和开发新型农药具有重要意义；本发明的制备方法具有反应条件简单，选择性高，可以进行大量制备的特点。
Description
技术领域
本发明属于化学合成领域，涉及一类四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物及其制备方法，对研制和开发新型农药具有重要意义。
背景技术
报道公开了我国是人口大国，粮食生产关乎国计民生；在生产和储存粮食的过程中，每年因病虫害将造成不小的损失，农药成为粮食生产中的刚性需求，但农药的使用不当会对人类健康和环境产生不良效应，因此，开发低毒、高效、选择性好、结构新颖、环境相容性好的“绿色”农药已刻不容缓[1]。
近年来，具有广泛生物活性的含氮杂环化合物成为新农药研制的热点，其中，含有噁嗪酮骨架的化合物具有广泛的生物活性，例如除草、杀虫、杀菌、消炎、抑制非核苷逆转录酶性、抑制磷酸二酯酶性、抗血栓性、镇痛等生物活性[2-3]，因此，研究含有噁嗪酮骨架的化合物对研制和开发新型农药具有重要意义。
现有技术公开了有关报道，如：1982年，N. Latif等人报道了一系列噁嗪酮类化合物(Figure 1, 4a)的合成及抗菌活性，测试结果表明其对目标化合物表现出广泛的抗菌活性[4]。1996年，He’ctor R. Bravo等报道了23种噁嗪酮类化合物(Figure 1, 4b)，对它们进行了抗白色念球菌和抗藻类的生物活性测试，结果显示大多数化合物均有抗白色念球菌和抗球形小藻的活性[5]。2002年，Sicker D. 等报道，骨架含有噁嗪酮的缩醛苷一般存在于爵床科、禾本科、毛茛科、玄参科，作为植物自身抵抗微生物疾病、害虫和真菌的物质，当遇到害虫袭击时，植物本身所含的糖苷配基转化为噁嗪酮类衍生物(Figure 1, 4c)，通过植物根部分泌到周围环境以抵抗害虫的侵袭[6]。
Figure
综上，合成四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物将为未来开发和研究新型绿色农药提供新的思路和方向。
基于现有技术的现状，本申请的发明人拟提供一类四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物及其制备方法
于本发明相关的现有技术有：
[1]王正权,王大翔.新世纪的农药发展趋势[J].农药市场信息, 2001, 5, 21.
[2]Agirbas H. et al. J. Mole. Stru.,2007, 830, 116.
[3]Waisser K. et al. Eur. J. Med. Chem., 2010, 45, 2719.
[4]N. Latif et al. Aust. J. Chem., 1982, 35, 1037.
[5]Waldo L. et al. J. Agric. Food Chem., 1996, 44, 1569.
[6]Sicker D. et al. stud. nat. prod. Chem., 2002, 27, 185。
发明内容
本发明的目的在于基于现有技术的现状，提供一类四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物及其制备方法，本发明的制备方法路线的特点是:反应条件简单，选择性高，可以进行大量制备，对未来新型农药的研制和开发具有重要意义。
本发明合成的一类四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物具有式（I）的化学结构：
（3a-3x）
其中，取代基R1代表烷基或芳香基。
进一步地，取代基R1可以为苯基、3-甲基苯基、4-甲基苯基、3-溴苯基、4-溴苯基、2-氯苯基、4-氯苯基、4-甲氧基苯基、正己基、环丙基、叔丁基。下面给出24种四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物具体化学结构，具体编号依次为3a、3b、3c、3d、3e、3f、3g、3h、3i、3j、3k、3l、3m、3n、3o、3p、3q、3r、3s、3t、3u、3v、3w和3x。
为了详实的描述式（I）化合物的结构，本发明定义上下文中的术语。
术语“烷基”应指从烷烃的任一碳原子上除去氢原子而衍生的一价基团，“烷基”的碳原子形成直链或支链的骨架，因此，“烷基”可分为“直链烷基”和“支链烷基”。该术语包括伯、仲、叔烷基子类，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、正己基、异己基。特别地，术语“烷烃”是指仅仅含有碳、氢的饱和烃化合物。
术语“芳香基”又可以称为“芳基”，应包括碳环芳环基团，碳原子数为C6-C10芳环基团，比如苯基（C6）、萘基（C10）和C8芳环基团。
为了合成具有式（I）结构的四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物，本发明的具体技术路线如下，在下文的陈述实施例中，中间体通式是根据结构式中的编号，用阿拉伯数字表示，其中化合物2a和2b是根据文献报道的方法制备，具体见文献(Ref. 1: Mark C.-E. Synlett. 2008, 13, 2028; Ref. 2: Huang P.-Q. J. Heterocyclic. Chem.2007,44, 499.）。
上述合成路线包括以下合成步骤：
-50oC氮气保护下将一种酸缓慢滴入化合物2a或2b与一种炔烃的一种极性溶剂溶液反应0.5-5小时后自然升至室温，加入一种碱的水溶液室温反应5－10分钟，经萃取、浓缩、纯化得化合物3a-3x。所说的一种酸是指盐酸、三氟乙酸、三氟化硼乙醚、三氟甲磺酸铜、三氟甲磺酸钪、三氟甲磺酸铟或三氟甲磺酸酐，特别是指三氟化硼乙醚、三氟甲磺酸铜和三氟甲磺酸钪; 所说的一种炔烃是指芳香炔烃、链状炔烃或环烷基炔烃; 所说的一种极性溶剂是指乙腈、1，2-二氯乙烷、二氯甲烷、甲醇，特别是指乙腈和二氯甲烷; 所说的一种碱的水溶液是指氢氧化钾的水溶液、氢氧化钠的水溶液、碳酸钾的水溶液、碳酸钠的水溶液、碳酸氢钠的水溶液、醋酸钾的水溶液、醋酸钠的水溶液、三乙胺，特别是指碳酸氢钠的水溶液。
本发明所述制备四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物的技术路线，操作简单，路线简洁，收率较高，所用的试剂均为常用试剂，而且，可适合大规模制备，所得目标产物可用于多个具有重要生理活性天然产物的多样性合成研究，对未来新型农药的研制和开发具有重要意义。
具体实施方式
实施例1
合成化合物3a
(4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-p-tolyl-5,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one（3a）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2b与对甲基苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3a（78 mg，72%）。1H NMR (400 MHz,CDCl3) δ 7.53-7.46 (m, 2H), 7.20-7.12 (m, 2H), 5.31-5.22 (m, 1H), 4.46 (d, J=13.2 Hz, 1H), 4.01-3.95 (m, 1H), 3.76-3.69 (m, 1H), 2.82-2.71 (m, 1H), 2.34(s, 3H), 2.16-2.04 (m, 1H), 1.94-1.86 (m, 1H), 1.69-1.60 (m, 1H), 1.47-1.40(m, 1H), 0.79 (s, 9H), 0.01 (s, 3H), -0.11 (s, 3H) ppm.
合成化合物3b
(4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-m-tolyl-5,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one（3b）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2b与间甲基苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3b（83mg, 77%）。1H NMR (400 MHz,CDCl3) δ 7.23-7.17 (m, 1H), 7.09-7.02 (m, 1H), 7.00-6.94 (m, 1H), 5.12 (d, J=4.4Hz, 1H), 4.29 (d, J=11.6 Hz, 1H), 3.82-3.74 (m, 1H), 3.64-3.56 (m, 1H),2.64-2.53 (m,1H), 2.17 (s, 3H), 2.00-1.87 (m, 1H), 1.77-1.69 (m, 1H), 1.54-1.41 (m, 1H), 1.33-1.21 (m, 1H), 0.61 (s, 9H), -0.17 (s, 3H), -0.28 (s, 3H)ppm.
合成化合物3c
(4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-phenyl-5,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one（3c）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2b与苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3c（73mg, 70%）。1H NMR (400 MHz, CDCl3) δ7.65-7.58 (m, 2H), 7.40-7.32 (m,3H), 5.33 (d, J=4.4 Hz, 1H), 4.48 (d, J=12.8Hz, 1H), 4.01 (d, J=4.0 Hz, 1H), 3.78-3.74 (m, 1H), 2.83-2.73 (m, 1H), 2.19-2.04 (m, 1H), 1.97-1.88 (m, 1H), 1.71-1.61 (m, 1H), 1.48-1.42 (m, 1H), 0.80(s, 9H), 0.03 (s, 3H), -0.10 (s, 3H) ppm.
合成化合物3e
(4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-cyclopropyl-5,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one（3e）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2b与环丙乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3e（65mg, 69%）。1H NMR (400 MHz, CDCl3) δ4.67-4.55 (m, 1H), 4.37 (d, J=13.2 Hz, 1H), 3.83-3.71 (m, 1H), 3.67-3.52 (m,1H), 2.73-2.62 (m, 1H), 2.09-1.94 (m, 1H), 1.88-1.80 (m, 1H), 1.62-1.51 (m,1H), 1.43-1.34 (m, 2H), 0.86 (s, 9H), 0.81-0.75 (m, 2H), 0.70-0.55 (m, 2H),0.01 (s, 6H) ppm.
合成化合物3f
(4aS,5S)-3-(4-Bromophenyl)-5-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one（3f）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2b与对溴苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3f（72mg, 57%）。1H NMR (400 MHz, CDCl3)δ 7.50-7.43 (m, 4H), 5.32 (d, J= 4.4 Hz, 1H), 4.45 (d, J= 13.2 Hz, 1H), 3.99(d, J= 4.4 Hz, 1H), 3.76-3.70 (m, 1H), 2.81-2.71 (m, 1H), 2.17-2.02 (m, 1H),1.95-1.86 (m, 1H), 1.74-1.59 (m, 1H), 1.47-1.41 (m, 1H), 0.78 (s, 9H), 0.01(s, 3H), -0.12 (s, 3H) ppm.
合成化合物3g
(4aS,5S)-3-(3-Bromophenyl)-5-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one（3g）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2b与间溴苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3g（80mg, 63%）。1H NMR (400 MHz, CDCl3)δ 7.79-7.75 (m, 1H), 7.55-7.45 (m, 2H), 7.26-7.20 (m, 1H), 5.35 (d, J=4.0 Hz,1H), 4.47 (d, J=13.2 Hz, 1H), 4.02 (d, J=4.0 Hz, 1H), 3.77-3.74 (m, 1H),2.83-2.74 (m, 1H), 2.20-2.04 (m, 1H), 1.96-1.89 (m, 1H), 1.72-1.61 (m, 1H),1.49-1.43 (m, 1H), 0.80 (s, 9H), 0.03 (m, 3H), -0.09 (s, 3H) ppm.
合成化合物3h
(4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-(2-chlorophenyl)-5,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one（3h）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2b与邻氯苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3h（43mg, 38%）。1H NMR (400 MHz, CDCl3)δ 7.70-7.35 (m, 3H), 5.54-5.44 (m, 1H), 4.48 (d, J= 12.4 Hz, 1H), 4.08-4.04(m, 1H), 3.80-3.76 (m, 1H), 2.83-2.75 (m, 1H), 2.16-2.06 (m, 1H), 1.96-1.89(m, 1H), 1.69-1.63 (m, 1H), 1.54-1.38 (m, 2H), 0.86 (s, 9H), 0.05 (s, 3H), -0.03 (s, 3H) ppm.
合成化合物3i
(4aS,5S)-3-tert-Butyl-5-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one（3i）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2b与3,3-二甲基-1-丁炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3i（62mg, 63%）。1H NMR (400MHz, CD3OD) δ 4.78 (d, J= 4.0 Hz, 1H), 4.27-4.19 (m, 1H), 3.89 (d, J= 4.0 Hz,1H), 3.74-3.68 (m, 1H), 2.80-2.71 (m, 1H), 2.01-1.88 (m, 1H), 1.86-1.78 (m,1H), 1.68-1.59 (m, 1H), 1.42-1.34 (m, 1H), 1.08 (s, 9H), 0.85 (s, 9H), 0.03(s, 3H), 0.01 (s, 3H) ppm.
合成化合物3j
(4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-(4-chlorophenyl)-5,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one（3j）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2b与对氯苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3j（74mg, 65%）。1H NMR (400 MHz, CD3OD)δ 7.55-7.50 (m, 2H), 7.43-7.31 (m, 2H), 5.85 (d, J= 3.6 Hz, 1H), 4.28 (d, J=13.6 Hz, 1H), 3.76 (dd, J= 9.6, 3.6 Hz, 1H), 3.53-3.43 (m, 1H), 2.80-2.70 (m,1H), 2.10-1.99 (m, 1H), 1.77-1.67 (m, 1H), 1.66-1.46 (m, 1H), 0.89 (s, 9H),0.06 (s, 3H), 0.05 (s,3H) ppm.
合成化合物3k
(4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-(4-((4aS,5S)-5-(tert-butyldimethylsilyloxy)-1-oxo-1,4a,5,6,7,8-hexahydropyrido[1,2-c][1,3]oxazin-3-yl)butyl)-5,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one（3k）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2b与1,6乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3k（92mg, 51%）。1H NMR (400 MHz, CDCl3) δ4.57 (d, J= 4.0 Hz, 1H), 4.44-4.36 (m, 1H), 3.79 (d, J= 3.2 Hz, 1H), 3.64-3.58 (m, 1H), 2.21-2.16 (m, 2H), 2.15-1.99 (m, 3H), 1.98-1.89(m, 1H), 1.88-1.82 (m, 1H), 1.70-1.60 (m, 6H), 0.86 (s, 9H), 0.02 (s, 3H), 0.01 (m, 3H)ppm.
合成化合物3l
(4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-(3-((4aS,5S)-5-(tert-butyldimethylsilyloxy)-1-oxo-1,4a,5,6,7,8-hexahydropyrido[1,2-c][1,3]oxazin-3-yl)propyl)-5,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one（3l）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2b与1,6乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3l（95mg, 54%）。1H NMR (400 MHz, CD3OD) δ4.81 (d, J= 4.4 Hz, 1H), 4.27-4.21 (m, 1H), 3.92 (d, J= 4.4 Hz, 1H), 3.73-3.70 (m, 1H), 2.83-2.76 (m, 1H), 2.24-2.21(m, 3H), 2.21-2.13 (m, 2H), 2.03-1.93 (m, 1H), 1.87-1.82 (m, 1H), 1.72-1.63 (m, 3H), 1.43-1.37 (m, 1H), 0.88(s, 9H), 0.05 (s, 3H), 0.03 (s, 3H) ppm.
合成化合物3m
(4aS,5S)-5-Hydroxy-3-phenyl-4a,5,6,7-tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one（3m）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2a与苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3m（48mg, 69%）。1H NMR (400 MHz, CD3OD) δ7.68-7.62 (m, 2H), 7.41-7.38 (m, 3H), 5.87-5.83 (m, 1H), 4.12-4.03 (m, 2H),3.84-3.76 (m, 1H), 3.68-3.61 (m, 1H), 2.38-2.30 (m, 1H), 2.22 (s, 1H), 1.92-1.82 (m, 1H) ppm.
合成化合物3n
(4aS,5S)-3-Hexyl-5-hydroxy-4a,5,6,7-tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one（3n）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2a与1-辛炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3n（55mg, 77%）。1H NMR (400 MHz, CD3OD) δ5.04-4.99 (m, 1H), 4.26-4.17 (m, 1H), 4.10-4.04 (m, 1H), 3.79-3.71 (m, 1H),3.46-3.38 (m, 1H), 2.20-2.15 (m, 2H), 2.10-2.01 (m, 1H), 1.94-1.87(m, 1H),1.58-1.50 (m, 2H) ppm.
合成化合物3o
(4aS,5S)-3-(4-Chlorophenyl)-5-hydroxy-4a,5,6,7-tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one（3o）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2a与对氯苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3o（43mg, 54%）。1H NMR (400 MHz, CD3OD)δ 7.66-7.58 (m, 2H), 7.42-7.33 (m, 2H), 5.89-5.81 (m, 1H), 4.34-4.28 (m, 1H),4.27-4.21 (m, 1H), 3.82-3.72 (m, 1H), 3.50-3.42 (m, 1H), 2.13-2.03 (m, 1H),1.96-1.88 (m, 1H) ppm.
合成化合物3p
(4aS,5S)-3-(3-Bromophenyl)-5-hydroxy-4a,5,6,7-tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one（3p）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2a与间溴苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3p（49mg, 53%）。1H NMR (400 MHz, CD3OD)δ 7.88-7.77 (m, 1H), 7.66-7.59 (m, 1H), 7.57-7.45 (m, 1H), 7.33-7.26 (m, 1H),5.92-5.87 (m, 1H), 4.34-4.29 (m, 1H), 4.27-4.23 (m, 1H), 3.80-3.72 (m, 1H),3.50-3.43 (m, 1H), 2.12-2.04 (m, 1H), 2.00-1.82 (m, 2H) ppm.
合成化合物3q
(4aS,5S)-5-Hydroxy-3-m-tolyl-4a,5,6,7-tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one（3q）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2a与间甲基苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3q（54mg, 73%）。1H NMR (400 MHz,CD3OD) δ 7.53-7.50 (m, 1H), 7.49-7.45 (m, 1H), 7.30-7.26 (m, 1H), 7.22-7.18(m, 1H), 5.84 (d, J= 2.0 Hz, 1H), 4.37-4.34 (m, 1H), 4.30-4.27 (m, 1H), 3.87-3.78 (m, 1H), 3.55-3.50 (m, 1H), 2.37 (s, 3H), 2.18-2.10 (m, 1H), 2.00-1.95(m, 1H) ppm.
合成化合物3r
(4aS,5S)-5-Hydroxy-3-p-tolyl-4a,5,6,7-tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one（3r）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2a与对甲基苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3r（53mg, 72%）。1H NMR (400 MHz,CD3OD) δ 7.57-7.53 (m, 1H), 7.23-7.21 (m, 1H), 5.95 (d, J= 1.2 Hz, 1H), 4.01-3.94 (m, 2H), 3.73-3.67 (m, 1H), 3.61-3.56 (m, 1H), 2.36 (s, 3H), 2.30-2.24(m, 1H), 1.86-1.79 (m, 1H) ppm.
合成化合物3s
(4aS,5S)-3-(2-Chlorophenyl)-5-hydroxy-4a,5,6,7-tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one（3s）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2a与邻氯苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3s（39mg, 49%）。1H NMR (400 MHz, CD3OD)δ 7.46-7.44 (m, 1H), 7.42-7.39 (m, 1H), 7.24-7.20 (m, 1H), 7.16-7.12 (m, 1H),5.80-5.77 (m, 1H), 4.31-4.27 (m, 1H), 4.24-4.21 (m, 1H), 3.76 (dd, J= 19.2,9.2 Hz, 1H), 3.49-3.43 (m, 1H), 2.31 (s, 3H), 2.10-2.02 (m, 1H), 1.95-1.88(m, 1H) ppm.
合成化合物3t
(4aS,5S)-3-tert-Butyl-5-hydroxy-4a,5,6,7-tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one（3t）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2a与3,3-二甲基-1-丁炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3t（48mg, 76%）。1H NMR (400MHz, CD3OD) δ 5.05 (d, J= 2.0 Hz, 1H), 4.26-4.18 (m, 1H), 4.09-4.05 (m, 1H),3.77-3.69 (m, 1H), 3.45-3.38 (m, 1H), 2.10-2.01 (m, 1H), 1.93-1.86 (m, 1H),1.14 (s, 9H) ppm.
合成化合物3u
(4aS,5S)-3-(4-Bromophenyl)-5-hydroxy-4a,5,6,7-tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one（3u）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2a与对溴苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3u（47mg, 65%）。1H NMR (400 MHz, CD3OD)δ 7.52-7.50 (m, 4H), 5.86-5.84 (m, 1H), 4.14-4.07 (m, 1H), 4.05-4.02 (m, 1H),3.84-3.75 (m, 1H), 3.69-3.61 (m, 1H), 2.40-2.31 (m, 1H), 2.21 (d, J=4.0 Hz,1H), 1.93-1.80 (m, 1H) ppm.
合成化合物3v
(4aS,5S)-5-Hydroxy-3-(4-methoxyphenyl)-4a,5,6,7-tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one（3v）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2a与对甲氧基苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体 3v（42mg, 54%）。1H NMR (400 MHz,CD3OD) δ 7.60-7.54 (m, 2H), 6.92-6.84 (m, 2H), 5.75-5.71 (m, 1H), 4.10-4.01(m, 2H), 3.82 (s, 3H), 3.80-3.73 (m, 1H), 3.67-3.59 (m, 1H), 2.59 (s, 1H),2.37-2.28 (m, 1H), 1.91-1.80 (m, 1H) ppm.
合成化合物3w
(4aS,5S)-5-Hydroxy-3-(4-((4aS,5S)-5-hydroxy-1-oxo-4a,5,6,7-tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazin-4-yl)butyl)-4a,5,6,7-tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one（3w）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2a与1,6-辛二炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体 3w（57mg, 51%）。1H NMR (400 MHz,CD3OD) δ 5.10-5.02 (m, 1H), 4.25-4.22 (m, 1H), 4.11-4.08 (m, 1H), 3.82-3.75(m, 1H), 3.47-3.41 (m, 1H), 2.25-2.20 (m, 6H), 2.12-2.05 (m, 1H), 1.96-1.90(m, 1H), 1.78-1.65 (m, 3H), 1.64-1.53 (m, 3H) ppm.
合成化合物3x
(4aS,5S)-5-Hydroxy-3-(3-((4aS,5S)-5-hydroxy-1-oxo-4a,5,6,7-tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazin-4-yl)propyl)-4a,5,6,7-tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one（3x）
-50oC氮气保护下将三氟化硼乙醚缓慢滴入化合物2a与1,7-庚二炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体 3x（56mg, 53%）。1H NMR (400 MHz,CD3OD) δ 5.07-5.01 (m, 1H), 4.22-4.17 (m, 1H), 4.08-4.04 (m, 1H), 3.78-3.69(m, 1H), 3.45-3.36 (m, 1H), 2.32-2.27 (m, 2H), 2.25-2.20 (m, 2H), 2.10-1.99(m, 1H), 1.92-1.86 (m, 1H), 1.77-1.70 (m, 2H) ppm。
实施例2
合成化合物3a
(4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-p-tolyl-5,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one（3a）
-50oC氮气保护下将三氟甲磺酸铜缓慢加入化合物2b与对甲基苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3a（52 mg, 48%）。
实施例3
合成化合物3a
(4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-p-tolyl-5,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one（3a）
-50oC氮气保护下将三氟乙酸缓慢加入化合物2b与对甲基苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3a（11mg, 10%）。
实施例4
合成化合物3b
(4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-m-tolyl-5,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one（3b）
-50oC氮气保护下将三氟甲磺酸钪缓慢加入化合物2b与间甲基苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3b（53mg, 49%）。
实施例5
合成化合物3b
(4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-m-tolyl-5,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one（3b）
-50oC氮气保护下将三氟甲磺酸铟缓慢加入化合物2b与间甲基苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3b（35mg, 32%）。
实施例6
合成化合物3b
(4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-m-tolyl-5,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one（3b）
-50oC氮气保护下将三氟甲磺酸酐缓慢加入化合物2b与间甲基苯乙炔的二氯甲烷溶液反应0.5-5小时后自然升至室温，加入碳酸氢钠的水溶液，室温反应5－10分钟，经萃取、无水硫酸钠干燥，抽滤，浓缩，硅胶柱纯化得白色固体3b（22mg，20%）。
Claims (7)
1.式（I）结构的四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物，
（I）
其中，取代基R1代表烷基或芳香基。
2.根据权利要求1所述的式（I）结构的四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物，其特征在于，所述取代基R1代表苯基、3-甲基苯基、4-甲基苯基、3-溴苯基、4-溴苯基、2-氯苯基、4-氯苯基、4-甲氧基苯基、正己基、环丙基或叔丁基。
3.根据权利要求1所述的式（I）结构的四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物，其特征在于，所述的化合物具有下述结构：
4.式（I）结构的四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物的制备方法，其特征在于，采用下述反应路线：
其中，取代基R1代表烷基或芳香基；
按下述步骤：
-50oC氮气保护下将一种酸如盐酸、三氟乙酸、三氟化硼乙醚、三氟甲磺酸铜、三氟甲磺酸钪、三氟甲磺酸铟或三氟甲磺酸酐缓慢滴入化合物2a或2b与一种炔烃如芳香炔烃、链状炔烃或环烷基炔烃的一种极性溶剂如乙腈、1，2-二氯乙烷、二氯甲烷或甲醇溶液反应0.5-5小时后自然升至室温，加入一种碱如氢氧化钾的水溶液、氢氧化钠的水溶液、碳酸钾的水溶液、碳酸钠的水溶液、碳酸氢钠的水溶液、醋酸钾的水溶液、醋酸钠的水溶液或三乙胺，室温反应5－10分钟，经萃取、浓缩、纯化得化合物3a-3x。
5.按权利要求4所述的制备方法，其特征在于，所述步骤中的一种酸是指三氟化硼乙醚、三氟甲磺酸铜或三氟甲磺酸钪。
6.按权利要求4所述的制备方法，其特征在于，所述步骤中的一种极性溶剂是指乙腈或二氯甲烷。
7.按权利要求4所述的制备方法，其特征在于，所述步骤中的一种碱的水溶液是指碳酸钾的水溶液、碳酸钠的水溶液或碳酸氢钠的水溶液。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910558646.4A CN112142773A (zh) | 2019-06-26 | 2019-06-26 | 一类四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物及其制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910558646.4A CN112142773A (zh) | 2019-06-26 | 2019-06-26 | 一类四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物及其制备方法 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112142773A true CN112142773A (zh) | 2020-12-29 |
Family
ID=73868460
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910558646.4A Pending CN112142773A (zh) | 2019-06-26 | 2019-06-26 | 一类四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物及其制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112142773A (zh) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100298309A1 (en) * | 2007-12-07 | 2010-11-25 | Miguel Angel Pericas-Brondo | Tricyclic triazolic compounds |
| CN109836451A (zh) * | 2017-11-28 | 2019-06-04 | 复旦大学 | 3-羟基2-哌啶酰胺骨架常山碱（酮）及其制备方法 |
-
2019
- 2019-06-26 CN CN201910558646.4A patent/CN112142773A/zh active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100298309A1 (en) * | 2007-12-07 | 2010-11-25 | Miguel Angel Pericas-Brondo | Tricyclic triazolic compounds |
| CN109836451A (zh) * | 2017-11-28 | 2019-06-04 | 复旦大学 | 3-羟基2-哌啶酰胺骨架常山碱（酮）及其制备方法 |
Non-Patent Citations (9)
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0011928B1 (en) | 3,5-dihydroxypentanoic ester derivatives having antihyperlipaemic activity, their manufacture and pharmaceutical compositions containing them | |
| JPS6289685A (ja) | １３−ハロゲンミルベマイシン誘導体 | |
| US4189571A (en) | Esters of cromoglycates | |
| Chiu et al. | Model studies examining the application of allyliminium salt photospirocyclization methodologies in synthetic approaches to the harringtonine alkaloids | |
| CN112142773A (zh) | 一类四氢吡咯并噁嗪酮和哌啶并噁嗪酮化合物及其制备方法 | |
| CS195677B2 (en) | Method of producing new derivatives of alkyl-n-acyl-6,7-aziridino-6-deamino-7-deoxy-alfa-thiolincosaminide | |
| US3223585A (en) | Pesticidal monosulfur heterocyclic compositions | |
| EP0188502B1 (en) | Etherified 2-hydroxy-ethyl-phosphonic acid derivatives and plant growth regulating agents containing same as active ingredient | |
| DE2416054A1 (de) | Verfahren und praeparate zur schaedlingsbekaempfung | |
| NZ206293A (en) | (n-(2-chloroethyl)-n-nitrosoureido)-methyl phosphonic acid derivatives and pharmaceutical compositions | |
| US3183148A (en) | Combating nematodes with carbamate hetero-sulfur compounds | |
| DE3520104C2 (de) | Naphthoxazine, ihre Herstellung und Verwendung | |
| US4534785A (en) | Herbicidal 5-deoxy-3-O-arylmethyl or substituted arylmethyl-1,2-O-ethylene-alpha-D-xylofuranose derivatives | |
| NO157421B (no) | Analogifremgangsmaate ved fremstilling av terapeutisk aktive 3,7-diazabicyclo-(3.3.1)-nonan-derivater. | |
| SU1282821A3 (ru) | Способ получени тилозиновых производных | |
| US3171778A (en) | Biologically active applications of hexachloro-trithiane-tetroxide and trimethyl-tritiane-dioxide | |
| CN110754474B (zh) | 奎尼定或奎尼定类衍生物的应用、植物源杀虫剂、奎尼定类衍生物及其制备方法 | |
| US3535386A (en) | Novel diethynylcarbinols | |
| FI58631C (fi) | Foerfarande foer 11a-dehalogenering av 11a-halo-6-metylentetracykliner | |
| CN115724729B (zh) | 一类1-芳基-α,β-不饱和酮类化合物及其合成方法和在制备杀根结线虫药物中的应用 | |
| US2904557A (en) | N-phthalidyl carbamic acid esters | |
| JP3619265B2 (ja) | アスコルビン酸−イノシトール結合体またはその塩、ならびにその製造方法 | |
| SE442297B (sv) | 13-oxa-prostaglandin, forfarande for framstellning derav samt en komposition med inhiberande effekt pa blodplettaggregering och/eller en bronkodilaterande verkan | |
| EP0317416A1 (fr) | Procédé de préparation de chloro-1 alkyl-5 isoquinoleines condensées avec des groupes aromatiques, les nouveaux produits obtenus, et leur application comme médicaments | |
| US5264559A (en) | Azoxy compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |