CN108623581B - 一种制备哌尼诺安化合物的方法 - Google Patents
一种制备哌尼诺安化合物的方法 Download PDFInfo
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- CN108623581B CN108623581B CN201710180896.XA CN201710180896A CN108623581B CN 108623581 B CN108623581 B CN 108623581B CN 201710180896 A CN201710180896 A CN 201710180896A CN 108623581 B CN108623581 B CN 108623581B
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- acid
- reaction
- palladium
- compound
- carbonate
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- 150000001875 compounds Chemical class 0.000 title claims description 17
- 238000000034 method Methods 0.000 title abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- -1 penicinotam compound Chemical class 0.000 claims abstract description 10
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 4
- DERAACKMMNJAFU-UHFFFAOYSA-N 2-ethoxy-1,3-dioxane-4,6-dione Chemical compound CCOC1OC(=O)CC(=O)O1 DERAACKMMNJAFU-UHFFFAOYSA-N 0.000 claims abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 51
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 42
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 28
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 28
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 14
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 14
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 14
- 230000035484 reaction time Effects 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 238000009835 boiling Methods 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 230000002140 halogenating effect Effects 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 6
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- 125000000532 dioxanyl group Chemical group 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 4
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000001099 ammonium carbonate Substances 0.000 claims description 4
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 4
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 4
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 4
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 4
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 4
- 239000001095 magnesium carbonate Substances 0.000 claims description 4
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 4
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 4
- 239000000347 magnesium hydroxide Substances 0.000 claims description 4
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- UOURRHZRLGCVDA-UHFFFAOYSA-D pentazinc;dicarbonate;hexahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Zn+2].[Zn+2].[Zn+2].[Zn+2].[Zn+2].[O-]C([O-])=O.[O-]C([O-])=O UOURRHZRLGCVDA-UHFFFAOYSA-D 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- JIXDOBAQOWOUPA-UHFFFAOYSA-N 1-fluoro-2-methoxybenzene Chemical compound COC1=CC=CC=C1F JIXDOBAQOWOUPA-UHFFFAOYSA-N 0.000 claims description 3
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical compound NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000007848 Bronsted acid Substances 0.000 claims description 3
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 3
- 239000000920 calcium hydroxide Substances 0.000 claims description 3
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 3
- AXZAYXJCENRGIM-UHFFFAOYSA-J dipotassium;tetrabromoplatinum(2-) Chemical compound [K+].[K+].[Br-].[Br-].[Br-].[Br-].[Pt+2] AXZAYXJCENRGIM-UHFFFAOYSA-J 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 229940071870 hydroiodic acid Drugs 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 claims description 3
- 229910001487 potassium perchlorate Inorganic materials 0.000 claims description 3
- 229930185107 quinolinone Natural products 0.000 claims description 3
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 3
- PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 claims description 3
- MLIWQXBKMZNZNF-KUHOPJCQSA-N (2e)-2,6-bis[(4-azidophenyl)methylidene]-4-methylcyclohexan-1-one Chemical compound O=C1\C(=C\C=2C=CC(=CC=2)N=[N+]=[N-])CC(C)CC1=CC1=CC=C(N=[N+]=[N-])C=C1 MLIWQXBKMZNZNF-KUHOPJCQSA-N 0.000 claims description 2
- KZLMCDNAVVJKPX-UHFFFAOYSA-N 1,3-dichloro-2-methoxybenzene Chemical compound COC1=C(Cl)C=CC=C1Cl KZLMCDNAVVJKPX-UHFFFAOYSA-N 0.000 claims description 2
- HUDMAQLYMUKZOZ-UHFFFAOYSA-N 1,4-difluoro-2-methoxybenzene Chemical compound COC1=CC(F)=CC=C1F HUDMAQLYMUKZOZ-UHFFFAOYSA-N 0.000 claims description 2
- XTIGGAHUZJWQMD-UHFFFAOYSA-N 1-chloro-2-methoxyethane Chemical compound COCCCl XTIGGAHUZJWQMD-UHFFFAOYSA-N 0.000 claims description 2
- ULVPJKKERHMKLS-UHFFFAOYSA-N 1-chloro-4-fluoro-2-methoxybenzene Chemical compound COC1=CC(F)=CC=C1Cl ULVPJKKERHMKLS-UHFFFAOYSA-N 0.000 claims description 2
- XGXUGXPKRBQINS-UHFFFAOYSA-N 2,4-dibromo-1-methoxybenzene Chemical compound COC1=CC=C(Br)C=C1Br XGXUGXPKRBQINS-UHFFFAOYSA-N 0.000 claims description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
- JIQXVIJARQLCOY-UHFFFAOYSA-N 2-bromo-4-fluoro-1-methoxybenzene Chemical compound COC1=CC=C(F)C=C1Br JIQXVIJARQLCOY-UHFFFAOYSA-N 0.000 claims description 2
- RKCGJVGMRPKPNY-UHFFFAOYSA-N 2-chloro-4-fluoro-1-methoxybenzene Chemical compound COC1=CC=C(F)C=C1Cl RKCGJVGMRPKPNY-UHFFFAOYSA-N 0.000 claims description 2
- QDXIHHOPZFCEAP-UHFFFAOYSA-N 2-chloroethylsulfanylbenzene Chemical compound ClCCSC1=CC=CC=C1 QDXIHHOPZFCEAP-UHFFFAOYSA-N 0.000 claims description 2
- DGBISJKLNVVJGD-UHFFFAOYSA-N 2-phenylsulfanylaniline Chemical compound NC1=CC=CC=C1SC1=CC=CC=C1 DGBISJKLNVVJGD-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- SEVMQEIGENUPIE-UHFFFAOYSA-N 4-bromo-1-fluoro-2-methoxybenzene Chemical compound COC1=CC(Br)=CC=C1F SEVMQEIGENUPIE-UHFFFAOYSA-N 0.000 claims description 2
- 238000010766 Gould–Jacobs reaction Methods 0.000 claims description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 2
- 239000005662 Paraffin oil Substances 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 2
- JOSWYUNQBRPBDN-UHFFFAOYSA-P ammonium dichromate Chemical compound [NH4+].[NH4+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O JOSWYUNQBRPBDN-UHFFFAOYSA-P 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- AXSFFIVWTMWAEH-UHFFFAOYSA-N dibromo(tritert-butyl)-lambda5-phosphane palladium tritert-butylphosphane Chemical compound [Pd].[Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(Br)(Br)(C(C)(C)C)C(C)(C)C AXSFFIVWTMWAEH-UHFFFAOYSA-N 0.000 claims description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- QFWPJPIVLCBXFJ-UHFFFAOYSA-N glymidine Chemical compound N1=CC(OCCOC)=CN=C1NS(=O)(=O)C1=CC=CC=C1 QFWPJPIVLCBXFJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- JGJLWPGRMCADHB-UHFFFAOYSA-N hypobromite Inorganic materials Br[O-] JGJLWPGRMCADHB-UHFFFAOYSA-N 0.000 claims description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical group IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- KMFJVYMFCAIRAN-UHFFFAOYSA-N methyl 3-bromobenzoate Chemical compound COC(=O)C1=CC=CC(Br)=C1 KMFJVYMFCAIRAN-UHFFFAOYSA-N 0.000 claims description 2
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 claims description 2
- RHFUXPCCELGMFC-UHFFFAOYSA-N n-(6-cyano-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl)-n-phenylmethoxyacetamide Chemical compound OC1C(C)(C)OC2=CC=C(C#N)C=C2C1N(C(=O)C)OCC1=CC=CC=C1 RHFUXPCCELGMFC-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- HBEQXAKJSGXAIQ-UHFFFAOYSA-N oxopalladium Chemical compound [Pd]=O HBEQXAKJSGXAIQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910003445 palladium oxide Inorganic materials 0.000 claims description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 2
- INIOZDBICVTGEO-UHFFFAOYSA-L palladium(ii) bromide Chemical compound Br[Pd]Br INIOZDBICVTGEO-UHFFFAOYSA-L 0.000 claims description 2
- GPNDARIEYHPYAY-UHFFFAOYSA-N palladium(ii) nitrate Chemical compound [Pd+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O GPNDARIEYHPYAY-UHFFFAOYSA-N 0.000 claims description 2
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 claims description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 2
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 claims description 2
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 2
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 2
- 229940005657 pyrophosphoric acid Drugs 0.000 claims description 2
- CGFYHILWFSGVJS-UHFFFAOYSA-N silicic acid;trioxotungsten Chemical compound O[Si](O)(O)O.O=[W]1(=O)O[W](=O)(=O)O[W](=O)(=O)O1.O=[W]1(=O)O[W](=O)(=O)O[W](=O)(=O)O1.O=[W]1(=O)O[W](=O)(=O)O[W](=O)(=O)O1.O=[W]1(=O)O[W](=O)(=O)O[W](=O)(=O)O1 CGFYHILWFSGVJS-UHFFFAOYSA-N 0.000 claims description 2
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 claims 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims 2
- 239000011734 sodium Substances 0.000 claims 2
- 229910052708 sodium Inorganic materials 0.000 claims 2
- IOBWAHRFIPQEQL-UHFFFAOYSA-N 1,3-difluoro-2-methoxybenzene Chemical compound COC1=C(F)C=CC=C1F IOBWAHRFIPQEQL-UHFFFAOYSA-N 0.000 claims 1
- BEROAYCGKMZRLO-UHFFFAOYSA-N 1-bromo-3-(3-bromophenyl)sulfonylbenzene Chemical compound BrC1=CC=CC(S(=O)(=O)C=2C=C(Br)C=CC=2)=C1 BEROAYCGKMZRLO-UHFFFAOYSA-N 0.000 claims 1
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-UHFFFAOYSA-N 0.000 claims 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims 1
- RXXCIBALSKQCAE-UHFFFAOYSA-N 3-methylbutoxymethylbenzene Chemical compound CC(C)CCOCC1=CC=CC=C1 RXXCIBALSKQCAE-UHFFFAOYSA-N 0.000 claims 1
- TUXYZHVUPGXXQG-UHFFFAOYSA-N 4-bromobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1 TUXYZHVUPGXXQG-UHFFFAOYSA-N 0.000 claims 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000011575 calcium Substances 0.000 claims 1
- 229910052791 calcium Inorganic materials 0.000 claims 1
- LJSQFQKUNVCTIA-UHFFFAOYSA-N diethyl sulfide Chemical compound CCSCC LJSQFQKUNVCTIA-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 150000004702 methyl esters Chemical class 0.000 claims 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 claims 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims 1
- CHWRSCGUEQEHOH-UHFFFAOYSA-N potassium oxide Chemical compound [O-2].[K+].[K+] CHWRSCGUEQEHOH-UHFFFAOYSA-N 0.000 claims 1
- 229910001950 potassium oxide Inorganic materials 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- 150000003462 sulfoxides Chemical class 0.000 claims 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tert-butyl alcohol Substances CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims 1
- 238000006257 total synthesis reaction Methods 0.000 claims 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 230000031709 bromination Effects 0.000 abstract description 2
- 238000005893 bromination reaction Methods 0.000 abstract description 2
- 238000006482 condensation reaction Methods 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- QFTHRUCJNWMSRD-UHFFFAOYSA-N ctk2i4050 Chemical compound C1=CC=C2C(=O)C(C(N3C=CC=C33)=O)=C3NC2=C1 QFTHRUCJNWMSRD-UHFFFAOYSA-N 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 235000006538 Opuntia tuna Nutrition 0.000 description 3
- 244000237189 Opuntia tuna Species 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 2
- XSVGCAMLFRACNO-UHFFFAOYSA-N ethyl 2-bromo-4-chloroquinoline-3-carboxylate Chemical compound C1=CC=CC2=C(Cl)C(C(=O)OCC)=C(Br)N=C21 XSVGCAMLFRACNO-UHFFFAOYSA-N 0.000 description 2
- JWXOFLPYYXEDKZ-UHFFFAOYSA-N ethyl 4-chloro-2-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrol-2-yl]quinoline-3-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1C(=CC=C1)C1=NC2=CC=CC=C2C(=C1C(=O)OCC)Cl JWXOFLPYYXEDKZ-UHFFFAOYSA-N 0.000 description 2
- YBEOYBKKSWUSBR-UHFFFAOYSA-N ethyl 4-oxo-1h-quinoline-3-carboxylate Chemical compound C1=CC=C2C(=O)C(C(=O)OCC)=CNC2=C1 YBEOYBKKSWUSBR-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- YBFDBOCHDKHFSQ-UHFFFAOYSA-N penicinotam Chemical compound O=C1C2=CC=CC=C2N(C)C2=C1C(=O)N1C=CC=C12 YBFDBOCHDKHFSQ-UHFFFAOYSA-N 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- OGFAWKRXZLGJSK-UHFFFAOYSA-N 1-(2,4-dihydroxyphenyl)-2-(4-nitrophenyl)ethanone Chemical compound OC1=CC(O)=CC=C1C(=O)CC1=CC=C([N+]([O-])=O)C=C1 OGFAWKRXZLGJSK-UHFFFAOYSA-N 0.000 description 1
- BZQCDIOVYZYASY-UHFFFAOYSA-N 1-bromo-3-[(3-bromophenyl)methylsulfonylmethyl]benzene Chemical compound BrC1=CC=CC(CS(=O)(=O)CC=2C=C(Br)C=CC=2)=C1 BZQCDIOVYZYASY-UHFFFAOYSA-N 0.000 description 1
- GBNVXYXIRHSYEG-UHFFFAOYSA-N 1-chloro-2-ethylsulfanylethane Chemical compound CCSCCCl GBNVXYXIRHSYEG-UHFFFAOYSA-N 0.000 description 1
- QGRPVMLBTFGQDQ-UHFFFAOYSA-N 1-chloro-2-methoxybenzene Chemical compound COC1=CC=CC=C1Cl QGRPVMLBTFGQDQ-UHFFFAOYSA-N 0.000 description 1
- MWFMGBPGAXYFAR-UHFFFAOYSA-N 2-hydroxy-2-methylpropanenitrile Chemical compound CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- MYMLZSMMPSNRGR-UHFFFAOYSA-N [1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrol-2-yl]oxyboronic acid Chemical compound CC(C)(C)OC(=O)N1C=CC=C1OB(O)O MYMLZSMMPSNRGR-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- JJTZLLSJYIAJGC-UHFFFAOYSA-N bromo hypobromite;sodium Chemical compound [Na].BrOBr JJTZLLSJYIAJGC-UHFFFAOYSA-N 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 231100000481 chemical toxicant Toxicity 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- DWXQUAHMZWZXHP-UHFFFAOYSA-N ethyl 4-chloroquinoline-3-carboxylate Chemical compound C1=CC=CC2=C(Cl)C(C(=O)OCC)=CN=C21 DWXQUAHMZWZXHP-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- CZNGTXVOZOWWKM-UHFFFAOYSA-N methyl 4-bromobenzoate Chemical compound COC(=O)C1=CC=C(Br)C=C1 CZNGTXVOZOWWKM-UHFFFAOYSA-N 0.000 description 1
- UJNZOIKQAUQOCN-UHFFFAOYSA-N methyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C)C1=CC=CC=C1 UJNZOIKQAUQOCN-UHFFFAOYSA-N 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 1
- 230000000361 pesticidal effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- HQYNSFAFYFMRLG-UHFFFAOYSA-N tribromo phosphite Chemical compound BrOP(OBr)OBr HQYNSFAFYFMRLG-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于有机合成领域，具体涉及一种哌尼诺安(penicinotam)化合物的合成方法。本发明以苯胺和乙氧基甲叉丙二酸已二酯为起始原料经缩合反应，Gould‑Jacob反应形成喹啉母环，再经过溴代以及铃木反应制得2‑(1‑(叔丁氧羰基)‑1H‑吡咯‑2‑基)‑4‑氯喹啉‑3‑甲酸乙酯中间体，最后经过关环反应制备得到目标产物哌尼诺安。
Description
技术领域
本发明属于化学合成领域，具体涉及一种式I所示的哌尼诺安化合物的合成新方法。
背景技术
文献Shao, Chang-Lun; Wang, Chang-Yun; Gu, Yu-Cheng; Wei, Mei-Yan;Pan, Jia-Hui; Deng, Dong-Sheng; She, Zhi-Gang; Lin, Yong-Cheng. Bioorganic & Medicinal Chemistry Letters (2010), 20(11), 3284-3286.中公开了活性天然产物penicinotam的结构和杀虫活性。
中国专利CN 2009100183213公开了如下所示的化合物作为杀虫剂。
Abe, Masaki; Imai, Tetsuya; Ishii, Naoki; Usui, Makio. Synthesis ofquinolactacide via an acyl migration reaction and dehydrogenation withmanganese dioxide, and its insecticidal activities. Bioscience, Biotechnology, and Biochemistry (2006), 70(1), 303-306 中公开了如下化合物,一种quinolactacide的合成方法。
鉴于活性天然产物penicinotam独特的化学结构及生理活性，具有深入开展结构优化和药效学研究的重要意义结构优化和药效学研究的重要意义。目前，该类化合物的合成方法虽有报道，但是现有的方法步骤繁琐，过程复杂，成本高，反应所用试剂中用到的丙酮合氰化氢为剧毒化学品，对人体和环境危害极大。
为满足工业化需求，本发明开发了一条完全不同于已有合成方法的新路线，用于高收率，高纯度，低成本地制备式I结构化合物。本发明以苯胺乙氧基甲叉丙二酸已二酯为起始原料经缩合反应，Gould-Jacobs反应形成喹啉母环，再经过溴代以及铃木反应制得2-(1-(叔丁氧羰基)-1H-吡咯-2-基)-4-氯喹啉-3-甲酸乙酯中间体，最后经过酯交换以及简单取代反应制备得到目标产物哌尼诺安(penicinotam)。
发明内容
本发明目的在于提供式Ⅰ喹啉酮化合物的合成方法，包括以下步骤：
本发明目的在于提供式Ⅰ喹啉酮化合物哌尼诺安(penicinotam)的合成方法，包括以下步骤：
苯胺和乙氧基甲叉丙二酸乙二酯在高温下缩合，经Gould-Jacobs反应生成化合物2：
反应i所用溶剂选自二氧六环、四氢呋喃、苯、甲苯、甲醇、乙醇、己烷、辛烷、环己烷、环己酮、乙腈、吡啶、苯酚、DMF、DMSO，反应温度为所用溶剂沸腾温度，反应时间为0.5h～24h；反应ii所用溶剂选自乙二醇甲醚、二苯醚、苯甲醚、2,4-二溴苯甲醚、2,5-二氟苯甲醚、2,6-二氟苯甲醚、2,6-二氯苯甲醚、2-氟-5-溴苯甲醚、2-氟苯甲醚、2-氟茴香硫醚、2-氨基二苯硫醚、2-氯-4-氟苯甲醚、2-氯-5-氟苯甲醚、2-氯乙基乙基硫醚、2-氯乙基甲基醚、2-氯乙基苯硫醚、2-氯茴香硫醚、2-溴-4-氟苯甲醚、苯醚、石蜡油的一种或者几种反应温度为常温到回流，反应时间为0.5h～24h。
（2）化合物2在卤化剂作用下制备得到化合物3:
其中所用卤化剂选自二氯亚砜，草酰氯，三氯化磷，或五氯化磷中的一种或几种，溶剂为选自二氧六环、四氢呋喃、苯、甲苯、甲醇、乙醇、己烷、辛烷、环己烷、环己酮、乙腈、吡啶、苯酚、DMF、DMSO中的一种或几种，温度为所用溶剂的沸腾温度。
（3）化合物3在氧化剂和卤化剂作用下反应制备得到化合物4:
其中反应i和ii为一锅煮反应；反应i所用氧化剂选自双氧水、重铬酸铵、高氯酸钾、高碘酸钾、高氯酸、过硫酸钾、无水过氧化钠、次氯酸钠溶液、过甲酸、过乙酸、过氧苯甲酸、间氯过氧苯甲酸、过氧化叔丁醇、臭氧、戴斯马丁试剂中的一种或几种，溶剂为二氧六环、四氢呋喃、苯、甲苯、甲醇、乙醇、己烷、辛烷、环己烷、环己酮、乙腈、吡啶、苯酚、DMF、DMSO中一种或几种，温度为常温到回流，反应时间为0.5h～24h，反应ii所用卤化剂选自溴水、五溴氧磷中、三溴化磷、3-溴苯甲砜、3-溴苯甲酸甲酯、二溴亚砜、四溴化碳、对溴苯甲酸甲酯、氧溴化磷中的一种或几种，溶剂为二氧六环、四氢呋喃、苯、甲苯、甲醇、乙醇、己烷、辛烷、环己烷、环己酮、乙腈、吡啶、苯酚、DMF、DMSO中一种或几种，温度为常温到回流，反应时间为0.5h～24h。
（4）化合物4在碱性条件下与(1-(叔丁氧羰基)-1H-吡咯-2-基)硼酸经铃木耦合反应制备得到化合物5：
其中碱性试剂选自无水碳酸钠、碳酸钾、碳酸铯、碳酸锂、碳酸铵、氢氧化钙、氢氧化钠、氢氧化钾、氢氧化铯、氢氧化镁、氢氧化钡、氨水、碱式碳酸锌、碱式碳酸镁、甲醇钠、乙醇钠、叔丁醇钾/钠中的一种或几种；催化剂为钯粉、钯碳、醋酸钯、氧化钯、硝酸钯、硫酸钯、二溴化钯、氢氧化钯、氯化钯、醋酸钯、四三苯基膦钯、三苯基膦钯、双(三苯基膦)二氯化钯(Ⅱ)、二溴双(三叔丁基膦)二钯(I)、双(三邻甲苯膦)二氯化钯(II)、双(甲基二苯膦)二氯化钯(II)中的一种或几种，溶剂为二氧六环、四氢呋喃、苯、甲苯、甲醇、乙醇、己烷、辛烷、环己烷、环己酮、乙腈、吡啶、苯酚、DMF、DMSO、水中一种或几种，反应温度为常温到所选溶剂的沸腾温度，反应时间为0.5h～24h。
（5）化合物5在布朗斯特酸性高温条件下制备化合物6：
其中布朗斯特酸为溴化氢、亚硫酸、次磷酸、氟硼酸、氢氟酸、氢溴酸、氢碘酸、硅钨酸、硼酸、碘酸、磷酸、高碘酸、氢氟酸、盐酸、硫酸、硝酸、甲酸、乙酸、亚磷酸、多聚磷酸、氟硼酸、氟磷酸、氢氟酸、氢碘酸、氨基磺酸、焦磷酸、磷酸、磷钼酸溶液、对甲苯磺酸中的一种或几种，溶剂二氧六环、四氢呋喃、苯、甲苯、甲醇、乙醇、己烷、辛烷、环己烷、环己酮、乙腈、吡啶、苯酚、DMF、DMSO、水中一种或几种，反应温度为50℃～200℃之间，反应时间0.5h～48h。
（6）化合物6在碱性条件，高温下进行关环反应得到目标产物哌尼诺安(penicinotam):
其中碱性试剂选自无水碳酸钠、碳酸钾、碳酸铯、碳酸锂、碳酸铵、氢氧化钙、氢氧化钠、氢氧化钾、氢氧化铯、氢氧化镁、氢氧化钡、氨水、碱式碳酸锌、碱式碳酸镁、甲醇钠、乙醇钠、叔丁醇钾/钠中的一种或几种，溶剂为二氧六环、四氢呋喃、苯、甲苯、甲醇、乙醇、己烷、辛烷、环己烷、环己酮、乙腈、吡啶、苯酚、DMF、DMSO、水中一种或几种，反应温度为常温到所选溶剂的沸腾温度，时间为0.5h～24h。
具体实施方式
为了进一步探明本发明下面给出一些实例，这些实例完全是例证性的，他们知用来对本发明具体描述，不应当理解为对本发明的限制。
实施例
4-羟基喹啉-3-甲酸乙酯
称取苯胺(1.02 mL，0. 011 mol)和乙氧基甲叉丙二酸二乙酯（0.5-2 eq）加入乙醇中，在100-200℃加热三小时，冷却到室温，加入苯乙醚，在100-200℃加热30min，冷却至室温，反应结束后，加入冰水，乙酸乙酯萃取(100mL×2)，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，有机相浓缩，残留物经硅胶柱层析得产物为白色固体1.6g（76%产率）；
ESI-MS m/z 218.32 [M+H]+
1 H NMR (500 MHz， DMSO-d 6 ): 10.62 (brs, 1H), 8.80 (s, 1H), 8.46-7.78(m, 4H), 4.10 (q, J =7.1 Hz, 2H), 1.30 (t, J =7.1 Hz， 3H)。
4-氯喹啉-3-甲酸乙酯
称取4-羟基喹啉-3-甲酸乙酯（1.6g，7.3mmol）溶解于四氢呋喃中，然后加入三氯氧磷（0.5-10 eq）混合后，在100℃加热一小时，反应结束后将反应液倒入冰水中，用饱和碳酸氢钾溶液调节pH至中性，乙酸乙酯萃取(100mL×2)，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，有机相浓缩，残留物经硅胶柱层析得产物为白色固体1.1g（64%产率）；
ESI-MS m/z 237.42 [M+H]+
1H NMR (500 MHz, DMSO-d 6) δ12.56（s, 1H）, 8.57(s, 1H), 8.19 (d, J=8.0Hz, 1), 7.74(dd, J=8.0, 7.0Hz 1H), 7.68(d, J=8Hz，1H), 7.45(t, J=7Hz，1H),4.25(q，J=7Hz, 2H), 1.31(t, J=7Hz，3H) 。
2-溴-4-氯喹啉-3-甲酸乙酯
称取4-氯喹啉-3-甲酸乙酯(1.1 g， 4.7 mmol)溶于氯仿中(20 mL)，室温向其中加入85%的过氧苯甲酸(0.5-2 eq)后室温搅拌4小时，往反应液加入三溴氧磷(0.5-2 eq)后搅拌1小时，反应结束后将反应液倒入冰水中，用饱和碳酸钾溶液调pH值至8，乙酸乙酯萃取(100 mL×2)，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，有机相浓缩，残留物经柱层析得产物为白色固体(1.1 g，74% 收率)；
ESI-MS m/z: 316.0 [M+H]+
1H NMR (500 MHz， CDCl3) δ 8.32-8.19 (m, 1H), 8.15-8.04 (m， 1H), 7.91-7.81 (m， 1H), 7.78-7.68 (m, 1H), 4.56 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1Hz, 3H) 。
2-(1-(叔丁氧羰基)-1H-吡咯-2-基)-4-氯喹啉-3-甲酸乙酯
称取2-溴-4-氯喹啉-3-甲酸乙酯(1.1g， 3.2 mmol)和(1-(叔丁氧羰基)-1H-吡咯-2-基)硼酸(0.69 g， 3.3 mmol)溶于1，4-二氧六环 (15 mL)中，向其中加入碳酸铯(4.0g， 6.5 mmol)和醋酸钯(360 mg， 0.3 mmol)，反应液在75 oC下搅拌3小时，反应结束后将反应液倒入冰水中，用乙酸乙酯萃取(100 mL×2)。合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，有机相浓缩，残留物经柱层析得产物为无色油状物(734 mg，53% 收率)；
ESI-MS m/z: 345.2 [M+H]+
1H NMR (500 MHz， CDCl3 )，δ 11.65 (s, 1H), 11.59 (s, 1H), 8.07 (d, J =7.6 Hz， 1H)， 7.77-7.61 (m, 2H), 7.36 (t, J = 7.3 Hz, 1H), 7.13 (s, 1H), 6.49(d, J = 2.5 Hz， 1H), 6.33-6.18 (m， 1H), 4.14 (q, J = 7.1 Hz, 2H), 1.14 (t, J= 7.1 Hz, 3H) 。
4-氧代-2-(1H-吡咯-2-基)-1，4-二氢喹啉-3-甲酸乙酯
将2-(1-(叔丁氧羰基)-1H-吡咯-2-基)-4-氯喹啉-3-甲酸乙酯(643 mg， 1.7mmol)溶于乙酸(10 mL)，乙醇(6 mL)，水（5ml）后升温至80 oC反应18小时，减压蒸馏除去乙酸，乙醇，所得残留物加水稀释，用饱和碳酸钾溶液调至中性，乙酸乙酯萃取(100 mL×2)，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，有机相浓缩。残留物经柱层析得产物为淡黄色固物(258mg， 54% 收率)；
ESI-MS m/z 283.82 [M+H]+;
1H NMR (500 MHz， DMSO-d6) δ 16.12 (s, 1H)， 12.40 (s, 1H), 11.81 (s,1H)， 8.25 (d， J = 8.0 Hz, 1H), 7.95-7.78 (m, 2H), 7.60-7.48 (m, 1H), 7.15 (d,J = 1.4 Hz, 1H), 6.82 (s， 1H)， 6.33-6.24 (m, 1H) 。
哌尼诺安
将4-氧代-2-(1H-吡咯-2-基)-1,4-二氢喹啉-3-甲酸乙酯(50 mg,0.18 mmol)，碳酸钾(10 mg, 0.054 mmol)，溶于乙腈20mL，60℃搅拌12h，再加入碘甲烷（10 μL,0.20mmol）。反应结束后将反应液倒入冰水中，用稀盐酸溶液调pH值至中性，乙酸乙酯萃取（50mL×2），合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，有机相浓缩，残留物经硅胶柱层析得产物为黄色固体（34 mg，68%产率）,
1H NMR (500 MHz, DMSO-d 6) δ 8.20(dd, J=8.0,1.6Hz，1H), 7.89 (d, J=8.0,1.6Hz, 1H), 7.78(ddd, J = 8.0,8.0,1.6Hz ,1H), 7.51 (ddd, J = 8.0,8.0,1.6Hz ,1H),7.47（dd, J = 3.0,1.0Hz,1H）, 7.0 (dd, J = 3.5,1.0Hz, 1H), 6.45 (dd,J=3.0,1.0Hz，1H), 3.9（s,1H）。
Claims (7)
1.具有式I结构的喹啉酮类化合物哌尼诺安的全合成制备方法,
其特征在于，按下述合成路线制备式I所示化合物，其包括步骤：
步骤(1):苯胺和乙氧基甲叉丙二酸乙二酯缩合，经Gould-Jacobs反应形成化合物2；
步骤(2):化合物2在卤化剂作用下制备化合物3；
步骤(3):化合物3在氧化剂以及卤化剂作用下制备得到化合物4；
步骤(4):化合物4碱性条件下经铃木耦合反应制备得到化合物5；
步骤(5):化合物5在高温条件下与布朗斯特酸反应得到化合物6；
步骤(6):化合物6在碱性条件下反应得到式I化合物；
2.权利要求1所述的制备方法，其特征在于步骤(1)中反应i所用溶剂选自二氧六环、四氢呋喃、苯、甲苯、甲醇、乙醇、己烷、辛烷、环己烷、环己酮、乙腈、吡啶、苯酚、DMF、DMSO，反应温度为所用溶剂沸腾温度，反应时间为0.5h～24h；反应ii所用溶剂选自乙二醇甲醚、二苯醚、苯甲醚、2,4-二溴苯甲醚、2,5-二氟苯甲醚、2,6-二氟苯甲醚、2,6-二氯苯甲醚、2-氟-5-溴苯甲醚、2-氟苯甲醚、2-氟茴香硫醚、2-氨基二苯硫醚、2-氯-4-氟苯甲醚、2-氯-5-氟苯甲醚、2-氯乙基乙基硫醚、2-氯乙基甲基醚、2-氯乙基苯硫醚、2-氯茴香硫醚、2-溴-4-氟苯甲醚、苯醚、石蜡油的一种或者几种，反应温度为常温到回流，反应时间为0.5h～24h。
3.权利要求1所述的制备方法，其特征在于步骤(2)中所用卤化剂选自二氯亚砜，草酰氯，三氯化磷，或五氯化磷中的一种或几种，溶剂选自二氧六环、四氢呋喃、苯、甲苯、甲醇、乙醇、己烷、辛烷、环己烷、环己酮、乙腈、吡啶、苯酚、DMF、DMSO中的一种或几种，温度为所用溶剂的沸腾温度。
4.权利要求1所述的制备方法，其特征在于步骤(3)中反应i所用氧化剂选自双氧水、重铬酸铵、高氯酸钾、高碘酸钾、高氯酸、过硫酸钾、无水过氧化钠、次氯酸钠溶液、过甲酸、过乙酸、间氯过氧苯甲酸、过氧化叔丁醇、臭氧、戴斯马丁试剂中的一种或几种，溶剂为二氧六环、四氢呋喃、苯、甲苯、甲醇、乙醇、己烷、辛烷、环己烷、环己酮、乙腈、吡啶、苯酚、DMF、DMSO中一种或几种，温度为常温到回流，反应时间为0.5h～24h，反应ii所用卤化剂选自溴水、五溴氧磷、三溴化磷、3-溴苯甲砜、3-溴苯甲酸甲酯、二溴亚砜、四溴化碳、对溴苯甲酸甲酯、氧溴化磷中的一种或几种，溶剂为二氧六环、四氢呋喃、苯、甲苯、甲醇、乙醇、己烷、辛烷、环己烷、环己酮、乙腈、吡啶、苯酚、DMF、DMSO中一种或几种，温度为常温到回流，反应时间为0.5h～24h。
5.权利要求1所述的制备方法，其特征在于步骤(4)中碱性试剂选自无水碳酸钠、碳酸钾、碳酸铯、碳酸锂、碳酸铵、氢氧化钙、氢氧化钠、氢氧化钾、氢氧化铯、氢氧化镁、氢氧化钡、氨水、碱式碳酸锌、碱式碳酸镁、甲醇钠、乙醇钠、叔丁醇钾/钠中的一种或几种；催化剂为钯粉、钯碳、醋酸钯、氧化钯、硝酸钯、硫酸钯、二溴化钯、氢氧化钯、氯化钯、四三苯基膦钯、三苯基膦钯、双(三苯基膦)二氯化钯(Ⅱ)、二溴双(三叔丁基膦)二钯(I)、双(三邻甲苯膦)二氯化钯(II)、双(甲基二苯膦)二氯化钯(II)中的一种或几种，溶剂为二氧六环、四氢呋喃、苯、甲苯、甲醇、乙醇、己烷、辛烷、环己烷、环己酮、乙腈、吡啶、苯酚、DMF、DMSO、水中一种或几种，反应温度为常温到所选溶剂的沸腾温度，反应时间为0.5h～24h。
6.权利要求1所述的制备方法，其特征在于步骤(5)中布朗斯特酸为溴化氢、亚硫酸、次磷酸、氢氟酸、氢溴酸、氢碘酸、硅钨酸、硼酸、碘酸、高碘酸、盐酸、硫酸、硝酸、甲酸、乙酸、亚磷酸、多聚磷酸、氟硼酸、氟磷酸、氨基磺酸、焦磷酸、磷酸、磷钼酸、对甲苯磺酸中的一种或几种，溶剂选自二氧六环、四氢呋喃、苯、甲苯、甲醇、乙醇、己烷、辛烷、环己烷、环己酮、乙腈、吡啶、苯酚、DMF、DMSO、水中一种或几种，反应温度为50℃～200℃之间，反应时间0.5h～48h。
7.权利要求1所述的制备方法，其特征在于步骤(6)中反应试剂选自碘甲烷,碱性试剂选自无水碳酸钠、碳酸钾、碳酸铯、碳酸锂、碳酸铵、氢氧化钙、氢氧化钠、氢氧化钾、氢氧化铯、氢氧化镁、氢氧化钡、氨水、碱式碳酸锌、碱式碳酸镁、甲醇钠、乙醇钠、叔丁醇钾/钠中的一种或几种，溶剂为二氧六环、四氢呋喃、苯、甲苯、甲醇、乙醇、己烷、辛烷、环己烷、环己酮、乙腈、吡啶、苯酚、DMF、DMSO、水中一种或几种；反应温度为常温到所选溶剂的沸腾温度，时间为0.5h～24h。
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