CN108546253A - The method that multistep synthesizes 2- benzyl -1,5- dihydrobenzos [e] [1,4] oxygen azatropylidene - Google Patents
The method that multistep synthesizes 2- benzyl -1,5- dihydrobenzos [e] [1,4] oxygen azatropylidene Download PDFInfo
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- CN108546253A CN108546253A CN201810655353.3A CN201810655353A CN108546253A CN 108546253 A CN108546253 A CN 108546253A CN 201810655353 A CN201810655353 A CN 201810655353A CN 108546253 A CN108546253 A CN 108546253A
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- China
- Prior art keywords
- reaction
- nitrae
- isosorbide
- oxygen azatropylidene
- benzyls
- 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.)
- Granted
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- 238000000034 method Methods 0.000 title claims abstract description 44
- 239000001301 oxygen Substances 0.000 title claims abstract description 35
- 229910052760 oxygen Inorganic materials 0.000 title claims abstract description 35
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 title claims abstract description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 17
- 150000007530 organic bases Chemical class 0.000 claims abstract description 15
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 14
- BWRBVBFLFQKBPT-UHFFFAOYSA-N (2-nitrophenyl)methanol Chemical compound OCC1=CC=CC=C1[N+]([O-])=O BWRBVBFLFQKBPT-UHFFFAOYSA-N 0.000 claims abstract description 13
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 13
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims abstract description 12
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims abstract description 10
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims abstract description 10
- 229910052796 boron Inorganic materials 0.000 claims abstract description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 claims abstract description 10
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims abstract description 10
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 claims abstract description 10
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 6
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 62
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 37
- 239000002994 raw material Substances 0.000 claims description 23
- -1 tetrabutyl ammonium halide Chemical class 0.000 claims description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 7
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical group [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- 230000005595 deprotonation Effects 0.000 claims description 3
- 238000010537 deprotonation reaction Methods 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- WZZMHOBVLAEJOD-UHFFFAOYSA-N methylsulfanylmethane;hydrobromide Chemical compound [Br-].C[SH+]C WZZMHOBVLAEJOD-UHFFFAOYSA-N 0.000 claims description 3
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- PURWQTAHOUPNBE-UHFFFAOYSA-N [N+](=O)([O-])BrCC1=CC=CC=C1 Chemical group [N+](=O)([O-])BrCC1=CC=CC=C1 PURWQTAHOUPNBE-UHFFFAOYSA-N 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 238000006073 displacement reaction Methods 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 claims description 2
- 238000007040 multi-step synthesis reaction Methods 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 229940125797 compound 12 Drugs 0.000 claims 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- 230000021736 acetylation Effects 0.000 claims 1
- 238000006640 acetylation reaction Methods 0.000 claims 1
- 229940125898 compound 5 Drugs 0.000 claims 1
- 229910000103 lithium hydride Inorganic materials 0.000 claims 1
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1h-pyrrole Chemical group C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 33
- 238000003786 synthesis reaction Methods 0.000 abstract description 18
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 abstract description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 9
- 229910021589 Copper(I) bromide Inorganic materials 0.000 abstract description 5
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 2
- 125000005133 alkynyloxy group Chemical group 0.000 abstract 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 29
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 238000000926 separation method Methods 0.000 description 21
- 239000000243 solution Substances 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 16
- 235000019441 ethanol Nutrition 0.000 description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- 238000001914 filtration Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 125000005605 benzo group Chemical group 0.000 description 7
- 229940049706 benzodiazepine Drugs 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000007792 addition Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- VAJVDSVGBWFCLW-UHFFFAOYSA-N 3-Phenyl-1-propanol Chemical compound OCCCC1=CC=CC=C1 VAJVDSVGBWFCLW-UHFFFAOYSA-N 0.000 description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 5
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropyl alcohol Natural products CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- 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 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 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 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- 125000003368 amide group Chemical group 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000005352 clarification Methods 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- GHUURDQYRGVEHX-UHFFFAOYSA-N prop-1-ynylbenzene Chemical compound CC#CC1=CC=CC=C1 GHUURDQYRGVEHX-UHFFFAOYSA-N 0.000 description 3
- 239000003223 protective agent Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 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 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical group C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 2
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- 150000002148 esters Chemical class 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
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- 238000012986 modification Methods 0.000 description 2
- 150000005181 nitrobenzenes Chemical class 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical class N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- KLYCPFXDDDMZNQ-UHFFFAOYSA-N Benzyne Chemical compound C1=CC#CC=C1 KLYCPFXDDDMZNQ-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- VHHPDZDTKZOHTB-UHFFFAOYSA-M [Br-].[Mg+]C.C1CCOC1 Chemical compound [Br-].[Mg+]C.C1CCOC1 VHHPDZDTKZOHTB-UHFFFAOYSA-M 0.000 description 1
- XYLXXNFYVQYJRZ-UHFFFAOYSA-M [Cl-].[Mg+]C.C1CCOC1 Chemical compound [Cl-].[Mg+]C.C1CCOC1 XYLXXNFYVQYJRZ-UHFFFAOYSA-M 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 description 1
- 125000005604 azodicarboxylate group Chemical group 0.000 description 1
- 150000005130 benzoxazines Chemical class 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 125000001309 chloro group Chemical class Cl* 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- SSZQNIRPDNESTG-UHFFFAOYSA-N cyclohex-2-en-1-ylmethylbenzene Chemical class C=1C=CC=CC=1CC1CCCC=C1 SSZQNIRPDNESTG-UHFFFAOYSA-N 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000012912 drug discovery process Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000005201 scrubbing Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of methods that multistep synthesizes 2 benzyl 1,5 dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, belong to technical field of organic synthesis.1 nitro 2 (propinyl oxygroup methyl) benzene is obtained at ether using o-nitro benzyl alcohol and propargyl bromide or propilolic alcohol, then iron powder/acetic acid or NiCl2 (dppp)/two boron of tetrahydroxy/organic base is used to restore to obtain 2 (propinyl oxygroup methyl) aniline, Sonogashira then occurs with iodobenzene to be coupled to obtain 2 [(3 phenyl, 2 alkynyloxy group) methyl] aniline, then after carrying out acetyl group protection to amino, by cuprous bromide/cesium carbonate cyclization, deprotection obtains 2 benzyls 1 under subsequent alkaline condition, 5 dihydrobenzos [e] [1, 4] oxygen azatropylidene.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of multistep synthesis (E) -2- benzals -1,2,3,5-
The method of tetrahydro benzo [e] [1,4] oxygen azatropylidene and 2- benzyl -1,5- dihydrobenzos [e] [1,4] oxygen azatropylidene.
Background technology
The organic compound of the benzoxazine derivative containing 1,4- causes in chemistry and medical research extensive in recent years
Concern, this may be the diversity due to its pharmacological action, especially heterocyclic compound containing N/O, and its some derivatives
Show extensive bioactivity such as anticancer, treating tuberculosis, anti-hypertension, antirheumatic, serotonin -3 (5-HT3) receptor antagonist
Agent, neuroprotective antioxidant etc..
Therefore, Isosorbide-5-Nitrae-benzoxazine is a kind of skeleton of high special efficacy in drug discovery process, potential anti-for developing
Tubercular drugs.In view of its medical value, in the past few decades it has been reported that 3,4- dihydros-Isosorbide-5-Nitrae-benzo oxygen azatropylidene
Several synthesis strategies and method.However, these methods have certain limitation to molecular diversity.There are many although
Report is about 2H-1, the synthesis of 4- benzo oxygen azatropylidenes, but few stereoselective syntheses (E) -2- benzals -1,2, and 3,5-
The method of tetrahydro benzo [e] [1,4] oxygen azatropylidene and 2- benzyl -1,5- dihydrobenzos [e] [1,4] oxygen azatropylidene.
Invention content
The present invention provides a kind of stabilization easy to operate, synthesis (E) -2- that yield is higher, environmental-friendly, route is relatively reasonable
Benzal -1,2,3,5- tetrahydro benzos [e] [1,4] oxygen azatropylidene and 2- benzyl -1,5- dihydrobenzos [e] [1,4] oxygen azatropylidene
Method.
Preparation method provided by the invention is completed from o-nitro benzyl alcohol by five steps or six steps.
Route one, the reaction of five steps, reaction equation are as follows：
The realization of technical scheme of the present invention, which is characterized in that including steps are as follows:
The first step：The synthesis of 2- (propinyl oxygroup methyl) nitrobenzene (4)
2- (propinyl oxygroup methyl) nitrobenzene is obtained by the reaction at ether in o-nitro benzyl alcohol 3, propargyl bromide by method one.Its
Middle agents useful for same is sodium hydride or methyl Grignard, and the solvent of selection is tetrahydrofuran, and wherein reaction temperature is selected from -20 DEG C extremely
25℃。
Sodium hydride method is used in this method, and 1-2 equivalents are added, in common reactant solvent THF, DMSO, DMF, reaction
Yield 20-30%.When using methyl Grignard, reacted at -20 DEG C to 0 DEG C, yield is improved to 65-70%.
However, being flowed back in acetone instead using o-nitro benzyl alcohol 3,1-1.2 equivalent potassium carbonates and 1-1.2 equivalents propargyl bromide
At once, no product generates.
Method two, by under the conditions of o-nitro benzyl alcohol 3, propilolic alcohol, triphenyl phosphorus and azodiformate anhydrous and oxygen-free at ether
Obtain 2- (propinyl oxygroup methyl) nitrobenzene.The solvent of selection is dichloromethane or toluene, and wherein reaction temperature is selected from 20 DEG C
To 25 DEG C.This method reaction condition is milder, and separation yield is 90% or more.
Further, in the above-mentioned technical solutions, in first step reaction, nitro alcohol 3 and propargyl bromide molar ratio
Example is 1:1.5-1.6；The nitro alcohol 3 is 1 with propargyl alcohol molar ratio:1.2-1.3.
Further, in the above-mentioned technical solutions, in first step reaction, nitro alcohol 3 is used with propargyl bromide at ether
To 1-2 equivalent methyl Grignard Reagent.It is preferred that equivalent is that 1.2-1.5 times of 3 equivalent of raw material is added.
Further, in the above-mentioned technical solutions, in first step reaction, nitro alcohol, triphenyl phosphorus and azo two
Formic acid esters molar ratio is selected from 1:1-2:1-2.Both triphenyl phosphorus and azodiformate are equimolar ratio simultaneously.
Further, in the above-mentioned technical solutions, in first step reaction, azodiformate is selected from azo-dicarboxylate
(vehicle economy AD) or azoformic acid isopropyl ester (abbreviation DIAD).
Second step：The synthesis of 2- (propinyl oxygroup methyl)-aniline (5)
Method one, raw material 4 back flow reaction in iron powder/acetic acid/ethanol system obtain 2- (propinyl oxygroup methyl)-aniline
5。
Wherein, iron powder uses after overactivation, and addition is the 2-5 equivalents of raw material 4, and preferably equivalent is 4-4.5 equivalents.
Method two, raw material 4 back flow reaction in NiCl2 (dppp)/two boron of tetrahydroxy/organic base/ethanol system obtain 2-
(propinyl oxygroup methyl)-aniline 5.
Wherein, wherein organic base is selected from triethylamine or diisopropyl ethyl amine；It is NiCl2 (dppp), two boron of tetrahydroxy, organic
Alkali equivalent ratio is 0.01-0.03:2-3:2.5-4.
Two methods of this step raw material can convert completely, and separation yield can be examined when 85% or more, TLC detects reaction process
Measure the intermediate product by partial reduction.In two schemes, from useless solid process angle, preferred method two.
Third walks：The synthesis of 2- [(3- phenyl -2- alkynyloxy groups) methyl]-aniline (6)
2- (propinyl oxygroup methyl)-aniline 5 and iodobenzene, under palladium catalyst and cuprous iodide catalysis, triethylamine condition
It is lower to be coupled to obtain 2- [(3- phenyl -2- alkynyloxy groups) methyl]-aniline 6 by Sonogashira.Wherein solvent is triethylamine, palladium
Catalyst is selected from Pd (PPh3) 2Cl2, corresponds to the 1.5-2.5% and 3-5% of raw material equivalent, and the two respectively with CuI additions
Holding ratio is 1:2.
Further, in the above-mentioned technical solutions, in three-step reaction, 2- (propinyl oxygroup methyl)-aniline 5 and Pd
(PPh3) 2Cl2, iodobenzene, triethylamine, iodate Asia ketone molar ratio be 1:0.025-0.03:1.05-1.2:1.5-1.7:
0.05-0.08。
4th step：The synthesis of 2- [(3- phenyl -2- alkynyloxy groups) methyl]-PG aniline (7)
PG (protecting group) is introduced on amido includes：Ac (acetyl group), Bz (benzoyl), Ts (p-toluenesulfonyl).
In the presence of an organic base, 2- [(3- phenyl -2- alkynyloxy groups) methyl]-aniline 6 and amido protecting agent, after reaction
To corresponding protection product 2- [(3- phenyl -2- alkynyloxy groups) methyl]-PG aniline 7.Wherein reaction temperature is selected from -10 DEG C to 25 DEG C,
The solvent of selection is tetrahydrofuran, dichloromethane.
Amido protecting agent is selected from：Chloroacetic chloride, acetic anhydride, chlorobenzoyl chloride or paratoluensulfonyl chloride.Organic base is selected from three second
Amine or pyridine, preferably triethylamine.
Further, in the above-mentioned technical solutions, in four-step reaction, 2- [(3- phenyl -2- alkynyloxy groups) methyl]-aniline
6, amido protecting agent and organic alkali equivalent ratio are 1:1-1.5:1.1-1.6.
This step Reaction Separation yield is usually between 83-95%.
5th step：(E) -2- benzals -1,2,3,5- tetrahydro benzos [e] [1,4] oxygen azatropylidene (1) and 2- benzyls -1,5-
The synthesis of dihydrobenzo [e] [1,4] oxygen azatropylidene (2)
2- [(3- phenyl -2- alkynyloxy groups) methyl]-PG aniline 7 and tetrabutylammonium iodide or tetrabutylammonium bromide, protobromide
Copper or cuprous bromide-dimethyl sulphide, the cyclization of cesium carbonate elder generation generate benzal -1,2,3 corresponding intermediate product N-PG- (E) -2-,
5- tetrahydro benzos [e] [Isosorbide-5-Nitrae] oxygen azatropylidene 8 and N-PG-2- benzyls -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene 9 are then logical
It crosses deprotection and obtains (E) -2- benzal -1,2,3,5- tetrahydro benzos [e] [1,4] oxygen azatropylidene 1 and 2- benzyl -1,5- dihydrobenzenes
And [e] [1,4] oxygen azatropylidene 2.Wherein reaction temperature is selected from 80 DEG C to 110 DEG C, and the solvent of selection is glycol dimethyl ether, second
Nitrile, 1,4- dioxane.
Further, in the above-mentioned technical solutions, in the reaction of the 5th step, described two kinds of reaction conditions are in alkaline condition
Under, and tetrabutylammonium iodide or tetrabutylammonium bromide, cuprous bromide or cuprous bromide-dimethyl sulphide, the cyclization of cesium carbonate elder generation, then
Acetyl group (Ac) or benzoyl (Bz) protection are by sodium hydroxide or potassium hydroxide/methanol aqueous systems deprotection, to toluene sulphur
Acyl group (Ts) is deprotected to obtain target product by sodium/naphthalene.
Further, in the above-mentioned technical solutions, in the 5th step, 2- [(3- phenyl -2- alkynyloxy groups) methyl]-PG aniline 7
Molar ratio with n-Bu4NI, cuprous bromide, cesium carbonate is 1:1.1-1.3:0.35-0.4:1.1-1.5.When ring closure reaction, adopt
It is nearly no detectable product when with the organic bases such as inorganic base K2CO3, Na2CO3, Li2CO3 and DBU, DBN, after being refluxed overnight, TLC
The new point estimation of observation is no more than 5%.
Further, in the above-mentioned technical solutions, the product that the 5th step obtains can be distinguished obviously on TLC, be passed through
After column chromatography, (E) -2- benzals -1,2,3,5- tetrahydro benzos [e] [Isosorbide-5-Nitrae] oxygen azatropylidene 1 and 2- benzyls can be easily separated
Base -1,5- dihydrobenzos [e] [1,4] oxygen azatropylidene 2.Final product, after differently protection group reaction, both 1 and 2 ratios
The two is in 1-3:1.
Further, in the above-mentioned technical solutions, when the 5th step product column chromatography, eluent petroleum ether and acetic acid second used
The eluting solvent volume ratio of ester mixed system is from 15:1 is gradually increased to 3:1.
For successive reaction separation yield usually between 55-73%, ring closure reaction supposition is in alkaline condition twice in this step
Under first pass through connection alkene process, then carry out cyclization again.Optimize by different alkali, in common alkaline reagent (inorganic base
K2CO3、KHCO3、Na2CO3、NaHCO3、Li2CO3、Cs2CO3；Organic base DBU, DBN, TMG), additive (such as KI, n-
Bu4NI, n-Bu4NBr) and after copper salt catalyst (CuBr, CuI, CuCl, CuBr-Me2S) optimizes screening, find best
It is combined as CuBr or CuBr-Me2S, n-Bu4NI or n-Bu4NBr and Cs2CO3 systems.
Route two, four-step reaction, reaction equation are as follows：
In the reaction route, o-nitro benzyl alcohol 3 or adjacent nitro benzyl bromine 10 are first obtained by the reaction 12 with phenyl alkynol 11, then pass through
It crosses iron powder/acetic acid or NiCl2 (dppp)/two boron of tetrahydroxy/organic base restores to obtain 6.Other reaction steps are identical as route one.
The first step：The synthesis of 2- (phenylpropyl alcohol ynyloxymethyl) nitrobenzenes (12)
Method one, by o-nitro benzyl alcohol 3, phenyl propyne alcohol 10, triphenyl phosphorus and azoformic acid diester, (Mitsunbo is anti-
Answer) 2- (phenylpropyl alcohol ynyloxymethyl) nitrobenzene 12 is obtained at ether under the conditions of anhydrous and oxygen-free.The solvent of selection is dichloromethane, first
Benzene or tetrahydrofuran, wherein reaction temperature are selected from 20 DEG C to 25 DEG C.This method Reaction Separation yield is 86% or more.
Method two obtains 12 after nucleophilic displacement of fluorine occurs using adjacent nitro bromobenzyl 10 and phenyl propyne alcohol 11.When operation, four
In hydrogen THF solvent, after phenyl propyne alcohol 11 and 1-1.1 equivalents butyl lithium or sodium hydride deprotonation, then in 40-60 DEG C of item
Under part, adjacent nitro bromobenzyl 10 is added dropwise and enters system reaction, separation yield is in 75-80%.
Second step：The synthesis of 2- (phenylpropyl alcohol ynyloxymethyl)-aniline (6)
The back flow reaction in iron powder/acetic acid/ethanol system of raw material 12 obtains 2- (phenylpropyl alcohol ynyloxymethyl)-aniline 6.
Wherein, iron powder uses after overactivation, and addition is the 2-5 equivalents of raw material 11, and preferably equivalent is 3.5-4 equivalents.
Method two, raw material 12 back flow reaction in NiCl2 (dppp)/two boron of tetrahydroxy/organic base/ethanol system obtain 2-
(propinyl oxygroup methyl)-aniline 6.
Wherein, wherein organic base is selected from triethylamine or diisopropyl ethyl amine；It is NiCl2 (dppp), two boron of tetrahydroxy, organic
Alkali equivalent ratio is 0.01-0.03:2-3:2.5-4.
Third is walked to the 5th step：
Subsequent step and operating condition are the same as route one.
Invention advantageous effect：
Synthetic route advantages of simple of the present invention, raw material are easy to get, and reaction condition is mild, and especially the first step is reacted at ether, lead to
It crosses using methyl Grignard or Mitsunobu into ether, solves the problems, such as that routine operation yield is low, final step uses protobromide
Ketone ring closure reaction can generate cyclization product in the outer cyclization of ring and ring simultaneously, and there are significantly different with hexa-atomic cyclics for this.
Specific implementation mode
Below by specific example, invention is further explained.
These embodiments are interpreted as being merely to illustrate the present invention rather than limit the scope of the invention.It is reading
After the content of the invention recorded, those skilled in the art can make various modifications or changes to the present invention, these equivalent changes
Change and modification equally falls into the scope of the claims in the present invention.
Test method without specific conditions in following embodiment of the present invention carries out usually according to normal condition, and
It is carried out under nitrogen protection.
Raw material or reagent used in following embodiment of the present invention are commercially available in addition to special instruction.
20-25 DEG C of room temperature mean value described in following embodiment of the present invention.Unless otherwise indicated, the reagent is not special
Explanation is to be used without further purification.All solvents are purchased from commercialization supplier, and just can be used without processing.Reaction
Process is mainly detected by TLC, and HNMR identifies structure, and the termination of reaction is judged by the consumption of starting material.
Embodiment 1
The first step：The synthesis of 1- nitros -2- (propinyl oxygroup methyl)-benzene 4.
O-nitro benzyl alcohol 3 (15.3g, 0.1mol) and propargyl bromide (14.3g, 0.12mol) are added to by method one
After the anhydrous THF of 110mL, after stirring evenly, system temperature is down to 0 DEG C, and 60%NaH (4.8g, 0.12mol) is added portionwise and keeps
Temperature is finished at -20 DEG C to -10 DEG C, is slowly increased to be stirred at room temperature and be reacted 4-5 hours, after TLC detects raw material disappearance, pours into
In 200g water, MTBE100mL is extracted three times, merges organic phase, and saturated sodium bicarbonate water is washed, saturated common salt washing, and organic phase is dense
Contracting, using normal heptane/ethyl acetate 10:1 to 6:1 carries out column chromatography for separation, obtains 6.3g pale yellowish oils liquid 4, yield
33%.1H NMR(400MHz,CDCl3):7.78(dd,1H),7.54-7.58(m,2H),7.50(d,1H),7.06-7.09(m,
1H),4.86(s,2H),4.79(d,2H),2.58(t,1H)；M/z=192.11 (M+H).
Method two mixes o-nitro benzyl alcohol 3 (15.3g, 0.1mol) and the anhydrous THF of 85mL, and subsequent system temperature is down to 0
DEG C, 60%NaH (4.8g, 0.12mol) is added portionwise, finishes insulated and stirred 30 minutes, start be added dropwise propargyl bromide (14.3g,
0.12mol) keeps temperature to be no more than 0 DEG C with the anhydrous THF mixed solutions of 30mL, dropwise addition in the process, be then slowly increased to room temperature and stir
Reaction 3-5 hours to be mixed to pour into 200g water after TLC detects raw material disappearance, 100mL MTBE extractions three times, merge organic phase,
Saturated sodium bicarbonate water is washed, saturated common salt washing, organic phase concentration, using normal heptane/ethyl acetate 10:1 to 6:1 carries out column layer
Analysis separation, obtains 4.8g yellow oily liquids 4, yield 25%.
O-nitro benzyl alcohol 3 (15.3g, 0.1mol) and propargyl bromide (14.3g, 0.12mol) are added to by method three
After the anhydrous THF of 110mL, after stirring evenly, system temperature is down to -10 DEG C, and 3M methyl-magnesium-chloride tetrahydrofuran solutions are added dropwise
(0.12mol) is no more than 0 DEG C during being added dropwise, insulation reaction 1 hour is then slowly increased to that reaction 4-5 hours is stirred at room temperature,
It after TLC detects raw material disappearance, pours into 200g water, MTBE100mL is extracted three times, merges organic phase, saturated sodium bicarbonate water
It washes, saturated common salt washing, organic phase concentration, using normal heptane/ethyl acetate 10:1 to 6:1 carries out column chromatography for separation, obtains
13.0g yellow oily liquids 4, yield 68%.
Using 1M methyl-magnesium-bromide tetrahydrofuran solutions, similarly operated according to method three, separation yield 70%.
Method four, by o-nitro benzyl alcohol (15.3g, 0.1mol), propargyl alcohol (6.1g, 0.11mol) and triphenyl phosphorus
After (31.4g, 0.12mol) is added to 180mL dichloromethane, after stirring complete dissolved clarification, starts to be added dropwise at room temperature and contain azo two
Formic acid diethylester (20.9g, 1.2eq) and 50mL dichloromethane mixed solutions, drop Bi Jixu are stirred overnight at room temperature, and TLC detections are former
Material disappears, and system is cooled to -40 DEG C of standings, filters out complex solid by-product, filtrate concentration, and column chromatography affords to obtain
17.6g yellow oily liquids 4, yield 92%.
Embodiment 2
Second step：The synthesis of 2- (propinyl oxygroup methyl)-aniline 5
Under method one, mechanical agitation, by 1- nitros -2- (propinyl oxygroup methyl)-benzene 4 (19.1g, 0.1mol) and reduction
After iron powder (4.5eq) is added to 220mL ethyl alcohol, acetum (2.5eq) is added dropwise in 55-65 DEG C of control temperature, and heating is added dropwise
To back flow reaction 3 hours, TLC detection raw materials disappeared substantially, were cooled to 50 DEG C, and diatomite filtering, filter cake is eluted with ethyl alcohol,
Filtrate decompression is concentrated to dryness, and dichloromethane 120mL is added, and water layer adjusts pH=9-10 with saturated aqueous sodium carbonate, is saturated chlorine
Change sodium to wash, anhydrous sodium sulfate drying, filtering is concentrated under reduced pressure, using normal heptane/ethyl acetate 10:1 to 6:1 carries out column chromatography point
From obtaining yellow oily liquid 16.9g, yield 88%.1H NMR(400MHz,CDCl3):7.44(s,2H),7.10-7.13
(m,1H),6.91-6.93(m,1H),6.77-6.79(m,1H),6.69-6.71(m,1H),5.06(s,2H),4.53(d,2H),
2.52(t,1H)；M/z=162.20 (M+H).
Under method two, mechanical agitation, by 1- nitros -2- (propinyl oxygroup methyl)-benzene 4 (19.1g, 0.1mol), three second
After amine (3eq) and NiCl2 (dppp) (0.02eq) are added to 220mL ethyl alcohol, 40-45 DEG C of temperature is controlled, divides 5-8 batches four hydroxyls are added
Two boron solid (2.5eq) of base after every batch of is added, stirs 20 minutes, followed by being added lower batch, is added dropwise and is warming up to reflux instead
It answers 3 hours, TLC detects raw material point and disappears, and is down to room temperature, diatomite filtering, and filter cake is eluted with ethyl alcohol, filtrate decompression concentration
To dry, addition dichloromethane 120mL, water layer 5% sodium bicarbonate aqueous solution adjusting pH=9-10, saturated sodium-chloride is washed, anhydrous
Sodium sulphate is dried, and filtering is concentrated under reduced pressure, using normal heptane/ethyl acetate 10:1 to 6:1 carries out column chromatography for separation, obtains yellow oil
Shape liquid 14.6g, yield 91%.1H NMR(400MHz,CDCl3):7.44(s,2H),7.10-7.13(m,1H),6.91-
6.93(m,1H),6.77-6.79(m,1H),6.69-6.71(m,1H),5.06(s,2H),4.53(d,2H),2.52(t,1H)；
M/z=162.20 (M+H).
Embodiment 3
Third walks：The synthesis of 2- [(3- phenyl -2- alkynyloxy groups) methyl]-aniline 6
By iodobenzene (10.7g, 1.05eq), cuprous iodide (0.5g, 5mol%) and bis- (triphenyl) palladium chlorides (0.86g,
2.5mol%) be added to 100mL triethylamines, room temperature be added dropwise containing 2- (propinyl oxygroup methyl)-aniline 5 (8g, 0.05mol) and
18mL triethylamine mixed solutions, during dropwise addition, solution gradually becomes clarification, and then overnight, system salts out for room temperature reaction, by
Fade to aaerosol solution.HPLC detects product and is more than 80 with material rate:1, it is concentrated under reduced pressure and removes triethylamine, 80mL dichloros are added
Methane extracts, and is saturated ammonia scrubbing, saturated common salt washing, anhydrous magnesium sulfate drying, after filtering revolving, using normal heptane/acetic acid
Ethyl ester 15:1 to 6:1 carries out column chromatography for separation, obtains yellow oily liquid 11.7g, yield 98%.1H NMR(400MHz,
CDCl3):7.42(s,2H),7.38-7.42(m,4H),7.22-7.25(m,2H),7.05-7.08(m,3H),5.05(s,2H),
4.94(s,2H)；M/z=238.16 (M+H).
By o-nitro benzyl alcohol 3 (15.3g, 0.1mol), benzyne propyl alcohol 11 (13.5g, 0.102mol) and triphenyl phosphorus
After (31.4g, 0.12mol) is added to 200mL dichloromethane, after stirring complete dissolved clarification, starts to be added dropwise at room temperature and contain azo two
Formic acid diethylester (20.9g, 1.2eq) and 50mL dichloromethane mixed solutions, drop Bi Jixu are stirred overnight at room temperature, and TLC detections are former
Material disappears, and system is cooled to -40 DEG C of standings, filters out complex solid by-product and is directly added into and is added to after filtrate concentration
After 250mL ethyl alcohol and 3.5eq reduced iron powders, acetum (2.5eq) is added dropwise in 55-65 DEG C of control temperature, is added dropwise and is warming up to
Back flow reaction 3 hours, TLC detection raw materials disappear substantially, are cooled to 50 DEG C, diatomite filtering, filter cake is eluted with ethyl alcohol, is filtered
Liquid is concentrated to dryness, and dichloromethane 150mL is added, and water layer adjusts pH=9-10 with saturated aqueous sodium carbonate, is saturated chlorination
Sodium is washed, and anhydrous sodium sulfate drying, filtering is concentrated under reduced pressure, using normal heptane/ethyl acetate 10:1 to 6:1 carries out column chromatography for separation,
Obtain yellow oily liquid 19.2g, two step yields 81%.1H NMR(400MHz,CDCl3):7.42(s,2H),7.38-7.42
(m,4H),7.22-7.25(m,2H),7.05-7.08(m,3H),5.05(s,2H),4.94(s,2H)；M/z=238.16 (M+
H)。
Using 1.0 equivalent sodium hydrides or 1.0 equivalent butyl lithiums first with phenylpropyl alcohol alkynol in -10 DEG C to 0 DEG C deprotonations, then again
It reacts at room temperature, then 3.5eq iron powders/2.5eq acetic acid/ethyl alcohol again, is restored under counterflow condition, two with 0.95 equivalent adjacent nitro bromobenzyl
It is respectively 63% and 67% to walk separation yield.
Embodiment 4
4th step：The synthesis of 2- [(3- phenyl -2- alkynyloxy groups) methyl]-PG aniline 7
7a:PG=Ac：2- [(3- phenyl -2- alkynyloxy groups) methyl]-aniline 6 (8.8g, 37mmol), 13mL pyridines,
After the mixing of 0.3gDMAP and 65mL dichloromethane, it is completely dissolved under stirring.Temperature is reduced to 0 DEG C, control temperature is at 0-5 DEG C
Acetic anhydride (4.2g, 1.1eq) and 20mL dichloromethane mixed solutions is added dropwise, rear insulated and stirred 1h is added dropwise.Then rise naturally
To room temperature reaction 4 hours, TLC detection reactions terminated.5% salt acid elution, saturated sodium bicarbonate solution washing, saturation are used successively
Salt is washed, anhydrous sodium sulfate drying, after filtering revolving, using normal heptane/ethyl acetate 10:1 to 5:1 column chromatography for separation, obtains
To light yellow solid 9.8g, yield 96%.1H NMR(400MHz,CDCl3):8.38(d,1H),7.82(s,1H),7.40-
7.44(m,3H),7.30-7.35(m,2H),7.06-7.08(m,3H),5.08(s,2H),4.97(s,2H),2.19(s,3H)；
M/z=280.11 (M+H).
7b:PG=Bz：Using above-mentioned same method, chlorobenzoyl chloride replacement acetic anhydride is reacted, it is pale yellow after processing
Color solid, yield 91%.1H NMR(400MHz,CDCl3):8.53-8.66(m,2H),7.88-7.90(m,3H),7.33-
7.52(m,7H),7.06-7.12(m,3H),5.04(s,2H),4.98(s,2H)；M/z=342.16 (M+H).
7c:PG=Ts：2- [(3- phenyl -2- alkynyloxy groups) methyl]-aniline 6 (8.8g, 37mmol), triethylamine (2eq),
After the mixing of 0.3gDMAP and 65mL dichloromethane, it is completely dissolved under stirring.Temperature is reduced to 0 DEG C, control temperature is at 0-5 DEG C
TsCl (7.8g, 1.1eq) and 20mL dichloromethane mixed solutions is added dropwise, rear insulated and stirred 1h is added dropwise.Then rise to naturally
Room temperature reaction 4 hours, TLC detection reactions terminate.5% salt acid elution, saturated sodium bicarbonate solution washing, saturation food are used successively
Salt is washed, anhydrous sodium sulfate drying, after filtering revolving, is recrystallized using ethyl alcohol and heptane, is obtained light yellow solid 13.5g, received
Rate 93%.1H NMR(400MHz,CDCl3):8.43-8.55(m,2H),7.78-7.88(m,3H),7.21-7.46(m,6H),
7.01-7.06(m,3H),5.03(s,2H),4.92(s,2H),2.43(s,3H)；M/z=392.20 (M+H).
Embodiment 5
5th step：(E) -2- benzals -1,2,3,5- tetrahydro benzos [e] [1,4] oxygen azatropylidene 1 and 2- benzyls -1,5- two
The synthesis of hydrogen benzo [e] [1,4] oxygen azatropylidene 2
By 7a (9.8g, 35mmol), CuBr-Me2S (0.3eq), tetrabutylammonium bromide (1eq), cesium carbonate (11.4g,
1eq) it is uniformly mixed with 1,4- dioxane 250mL.It is then to slowly warm up to back flow reaction again to stay overnight, TLC shows that raw material is basic
It disappears, generates two new points, ratio is about 2:1, stop reaction, after being spin-dried for organic solvent, 150mL bis- is added in diatomite filtering
Chloromethanes and moisture liquid, organic phase use concentrated ammonia liquor, saturated common salt to wash, organic solvent are spin-dried for, using normal heptane/acetic acid successively again
Ethyl ester 15:1 to 5:1 column chromatography for separation obtains 5.2g cyclization isomers 8a and 2.1g cyclization isomers 9b.Then, by respective product
30% sodium hydroxide 5eq is added and 6 times of volumes methanols are warming up to reflux deprotection reaction 6 hours, TLC detects raw material and disappears, eventually
It only reacts, is concentrated under reduced pressure and removes methanol, 5% hydrochloric acid solution is added and adjusts pH=2-3, dichloromethane is extracted twice, and organic layer is again
PH=8-9, saturated common salt washing, anhydrous sodium sulfate drying, using normal heptane/acetic acid second are adjusted with 5% sodium bicarbonate aqueous solution
Ester 10:1 to 3:1 column chromatography for separation respectively obtains 3.7g light yellow liquids, is compound 1,45% He of yield through structure determination
1.6g light yellow solids are compound 2, yield 19% through structure determination.
Using same method, using 7b as raw material, it is 41% and 32% to respectively obtain compound 1 and 2 separation yields.
(E) -2- benzals -1,2,3,5- tetrahydro benzos [e] [Isosorbide-5-Nitrae] oxygen azatropylidene 1,1H NMR(400MHz,CDCl3):
8.52(s,1H),7.60(d,2H),7.33-7.39(m,3H),7.02-7.10(m,2H),6.79(m,1H),6.47(d,1H),
6.08(s,1H),4.66(s,2H),4.08(s,2H)；13C NMR(100MHz,CDCl3):142.9,141.5,136.8,
135.1,128.6,128.5,126.2,124.3,109.4,104.5,76.2,75.0；M/z=237.11 (M+H).
2- benzyls -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene 2,1H NMR (400MHz, CDCl3):8.48(s,1H),
7.37(m,2H),7.22-7.26(m,3H),7.02-7.08(m,2H),6.78(m,1H),6.47(d,1H),5.15(s,1H),
5.22(s,2H),4.23(s,2H)；13C NMR(100MHz,CDCl3):141.3,140.6,135.5,129.0,128.6,
128.5,128.4,125.9,125.7,124.4,115.3,110.2,70.6,39.7；M/z=237.11 (M+H).
By 7c (13.5g, 35mmol), CuI (0.3eq), tetrabutylammonium bromide (1eq), cesium carbonate (11.4g, 1eq) and 1,
4- dioxane 250mL is uniformly mixed.It is then to slowly warm up to back flow reaction again to stay overnight, TLC shows that raw material disappears substantially, generates
Two new points, ratio is about 1:1, stop reaction, after being spin-dried for organic solvent, 150mL dichloromethane and water is added in diatomite filtering
Liquid separation, organic phase use concentrated ammonia liquor, saturated common salt to wash, organic solvent are spin-dried for, using normal heptane/ethyl acetate 15 successively again:1 to
5:1 column chromatography for separation obtains 5.6g cyclization isomers 8c and 5.1g cyclization isomers 9c.Then, naphthalene solution is added in respective product
In, using 4eq metallic sodium deprotection reactions, 50-90 DEG C of controlling reaction temperature is reacted 4 hours, and TLC detects raw material and disappears, cooling
It is slowly added dropwise to 0 DEG C and is quenched into methanol, be concentrated under reduced pressure and remove methanol, 5% hydrochloric acid solution is added and adjusts pH=2-3, dichloromethane
It being extracted twice, organic layer adjusts pH=8-9, saturated common salt washing with 5% sodium bicarbonate aqueous solution again, and anhydrous sodium sulfate is dried,
Using normal heptane/ethyl acetate 10:1 to 3:1 column chromatography for separation respectively obtains 3.6g light yellow liquids, is chemical combination through structure determination
Object 1, yield 44% and 3.1g light yellow solids are compound 2, yield 38% through structure determination.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
Any one skilled in the art in the technical scope of present disclosure, according to the technique and scheme of the present invention and its
Inventive concept is subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (10)
1. a kind of method of multistep synthesis 2- benzyls -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, which is characterized in that reaction side
Formula is：
Include the following steps：1) nitro alcohol 3, propargyl bromide obtain chemical combination using methyl Grignard exchange reaction at ether
Object 2；2) compound 2 restores to obtain compound 5 using iron powder/acetic acid or NiCl2 (dppp)/two boron of tetrahydroxy/organic base；3) change
Object 5 is closed to be coupled to obtain compound 6 with iodobenzene under bis- (triphenyl phosphorus) palladium bichlorides and cuprous iodide catalysis；4) compound 6 is drawn
Enter acetyl group to protect to obtain compound 7；5) cyclization under the conditions of cuprous salt, tetrabutyl ammonium halide and cesium carbonate of compound 7 obtains
9, alkaline condition is deprotected to obtain 2- benzyls -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene 2.
2. according to the method that multistep in claim 1 synthesizes 2- benzyls -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, feature
It is：In first step reaction, nitro alcohol 3 is 1 with propargyl bromide molar ratio:1.5-1.6.
3. according to the method that multistep in claim 1 synthesizes 2- benzyls -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, feature
It is：In second step, iron powder uses after overactivation, and addition is the 2-5 equivalents of raw material 4；Organic base is selected from triethylamine or two
Diisopropylethylamine, NiCl2 (dppp), two boron of tetrahydroxy and organic alkali equivalent ratio are 0.01-0.03:2-3:2.5-4.
4. according to the method that multistep in claim 1 synthesizes 2- benzyls -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, feature
It is：In three-step reaction, 2- (propinyl oxygroup methyl)-aniline 5 and Pd (PPh3) 2Cl2, iodobenzene, triethylamine, iodate Asia ketone
Molar ratio be 1:0.025-0.03:1.05-1.2:1.5-1.7:0.05-0.08.
5. according to the method that multistep in claim 1 synthesizes 2- benzyls -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, feature
It is：In four-step reaction, introduces acetyl group and reacted under the conditions of organic base using chloroacetic chloride or acetic anhydride；Organic base is selected from pyrrole
Pyridine or triethylamine.
6. according to the method that multistep in claim 5 synthesizes 2- benzyls -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, feature
It is：In four-step reaction, compound 6, acetylation reagent and organic alkali equivalent ratio are 1:1-1.5:1.1-1.6.
7. according to the method that multistep in claim 1 synthesizes 2- benzyls -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, feature
It is：In the reaction of 5th step, tetrabutyl ammonium halide is selected from tetrabutylammonium iodide or tetrabutylammonium bromide, and cuprous salt is selected from protobromide
Copper or cuprous bromide-dimethyl sulphide.
8. according to the method that multistep in claim 1 synthesizes 2- benzyls -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, feature
It is：In the reaction of 5th step, compound 7 and the molar ratio of tetrabutyl ammonium halide, cuprous salt, cesium carbonate are 1:1.1-1.3:
0.35-0.4:1.1-1.5。
9. according to the method that multistep in claim 1 synthesizes 2- benzyls -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, feature
It is：In the reaction of 5th step, alkaline condition deprotection is selected from sodium hydroxide or methanolic potassium hydroxide aqueous solution.
10. according to the method that claim 1 multistep synthesizes 2- benzyls -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, feature
It is：Wherein, it is as follows to replace synthetic method for compound 6：
Compound 12 is obtained by the reaction by Mitsunbo with phenyl alkynol 11 in o-nitro benzyl alcohol 3, or with phenyl alkynol 11 in butyl
Compound 12 is obtained after lithium or sodium hydride deprotonation with 10 nucleophilic displacement of fluorine of adjacent nitro benzyl bromine, subsequent compound 12 passes through iron powder/second
Acid or NiCl2 (dppp)/two boron of tetrahydroxy/organic base restore to obtain compound 6.
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| CN110479377A (en) * | 2019-08-06 | 2019-11-22 | 南方医科大学 | A kind of catalyst reacted for 4- iodonitrobenzene and phenylacetylene |
| CN115594602A (en) * | 2021-07-09 | 2023-01-13 | 南京大学（Cn） | A kind of method for the synthesis of aromatic amine induced by visible light |
| CN115872967A (en) * | 2022-12-01 | 2023-03-31 | 浙江众立合成材料科技股份有限公司 | Preparation method of dicyclic carbonate containing benzene ring structure |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110479377A (en) * | 2019-08-06 | 2019-11-22 | 南方医科大学 | A kind of catalyst reacted for 4- iodonitrobenzene and phenylacetylene |
| CN110479377B (en) * | 2019-08-06 | 2021-11-16 | 南方医科大学 | Catalyst for reaction of 4-iodonitrobenzene and phenylacetylene |
| CN115594602A (en) * | 2021-07-09 | 2023-01-13 | 南京大学（Cn） | A kind of method for the synthesis of aromatic amine induced by visible light |
| CN115594602B (en) * | 2021-07-09 | 2024-01-30 | 南京大学 | A visible light-induced method for synthesizing aromatic amines |
| CN115872967A (en) * | 2022-12-01 | 2023-03-31 | 浙江众立合成材料科技股份有限公司 | Preparation method of dicyclic carbonate containing benzene ring structure |
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