CN117247345A - Selective preparation method of 5, 6-dihydroxyindoline and 5, 6-dihydroxyindole - Google Patents
Selective preparation method of 5, 6-dihydroxyindoline and 5, 6-dihydroxyindole Download PDFInfo
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- CN117247345A CN117247345A CN202311147413.8A CN202311147413A CN117247345A CN 117247345 A CN117247345 A CN 117247345A CN 202311147413 A CN202311147413 A CN 202311147413A CN 117247345 A CN117247345 A CN 117247345A
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- SGNZYJXNUURYCH-UHFFFAOYSA-N 5,6-dihydroxyindole Chemical compound C1=C(O)C(O)=CC2=C1NC=C2 SGNZYJXNUURYCH-UHFFFAOYSA-N 0.000 title claims abstract description 40
- VGSVNUGKHOVSPK-UHFFFAOYSA-N leukoaminochrome Chemical compound C1=C(O)C(O)=CC2=C1NCC2 VGSVNUGKHOVSPK-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000003960 organic solvent Substances 0.000 claims abstract description 65
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 27
- -1 5, 6-dibenzyloxyindoline Chemical compound 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 15
- IBGBGRVKPALMCQ-UHFFFAOYSA-N 3,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1O IBGBGRVKPALMCQ-UHFFFAOYSA-N 0.000 claims abstract description 14
- PCYGLFXKCBFGPC-UHFFFAOYSA-N 3,4-Dihydroxy hydroxymethyl benzene Natural products OCC1=CC=C(O)C(O)=C1 PCYGLFXKCBFGPC-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 72
- 239000000243 solution Substances 0.000 claims description 53
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 47
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 25
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 21
- 238000001035 drying Methods 0.000 claims description 19
- 238000001704 evaporation Methods 0.000 claims description 18
- 238000005406 washing Methods 0.000 claims description 18
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 17
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 13
- 239000012065 filter cake Substances 0.000 claims description 13
- 239000008367 deionised water Substances 0.000 claims description 12
- 229910021641 deionized water Inorganic materials 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 12
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 12
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims description 9
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 9
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 9
- 239000011230 binding agent Substances 0.000 claims description 9
- 238000007865 diluting Methods 0.000 claims description 9
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 9
- 238000001291 vacuum drying Methods 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000012670 alkaline solution Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 238000004537 pulping Methods 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 7
- 239000005695 Ammonium acetate Substances 0.000 claims description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 235000019257 ammonium acetate Nutrition 0.000 claims description 7
- 229940043376 ammonium acetate Drugs 0.000 claims description 7
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- 239000007868 Raney catalyst Substances 0.000 claims description 6
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000012047 saturated solution Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims 3
- 239000002994 raw material Substances 0.000 abstract description 9
- 238000006722 reduction reaction Methods 0.000 abstract description 7
- 229910052736 halogen Inorganic materials 0.000 abstract description 5
- 238000006396 nitration reaction Methods 0.000 abstract description 5
- 230000009467 reduction Effects 0.000 abstract description 5
- 239000000376 reactant Substances 0.000 abstract description 3
- 238000007363 ring formation reaction Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000009435 amidation Effects 0.000 abstract description 2
- 238000007112 amidation reaction Methods 0.000 abstract description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical compound NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 description 8
- 239000000118 hair dye Substances 0.000 description 7
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 6
- 238000004043 dyeing Methods 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- JXPQMHIXNPWEEK-UHFFFAOYSA-N 2-[3,4-bis(phenylmethoxy)phenyl]ethanamine Chemical compound C=1C=CC=CC=1COC1=CC(CCN)=CC=C1OCC1=CC=CC=C1 JXPQMHIXNPWEEK-UHFFFAOYSA-N 0.000 description 3
- XDDLXZHBWVFPRG-UHFFFAOYSA-N 3,4-bis(phenylmethoxy)benzaldehyde Chemical compound C=1C=CC=CC=1COC1=CC(C=O)=CC=C1OCC1=CC=CC=C1 XDDLXZHBWVFPRG-UHFFFAOYSA-N 0.000 description 3
- CHTJRVASYXOBSO-UHFFFAOYSA-N 4-(2-nitroethenyl)-1,2-bis(phenylmethoxy)benzene Chemical compound C=1C=CC=CC=1COC1=CC(C=C[N+](=O)[O-])=CC=C1OCC1=CC=CC=C1 CHTJRVASYXOBSO-UHFFFAOYSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 210000004209 hair Anatomy 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- CBCKQZAAMUWICA-UHFFFAOYSA-N 1,4-phenylenediamine Chemical compound NC1=CC=C(N)C=C1 CBCKQZAAMUWICA-UHFFFAOYSA-N 0.000 description 1
- TXMQOPNBBITFNX-UHFFFAOYSA-N 2,3-dihydro-1h-indole-5,6-diol;hydrobromide Chemical compound Br.C1=C(O)C(O)=CC2=C1NCC2 TXMQOPNBBITFNX-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- ASLSUMISAQDOOB-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)acetonitrile Chemical compound COC1=CC=C(CC#N)C=C1OC ASLSUMISAQDOOB-UHFFFAOYSA-N 0.000 description 1
- OSEQIDSFSBWXRE-UHFFFAOYSA-N 3,4-dimethoxybenzonitrile Chemical compound COC1=CC=C(C#N)C=C1OC OSEQIDSFSBWXRE-UHFFFAOYSA-N 0.000 description 1
- JEUGWNYIRZKHDS-UHFFFAOYSA-N 5,6-bis(phenylmethoxy)-1h-indole Chemical compound C=1C=CC=CC=1COC1=CC=2C=CNC=2C=C1OCC1=CC=CC=C1 JEUGWNYIRZKHDS-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010043275 Teratogenicity Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000001448 anilines Chemical group 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical class NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000007674 genetic toxicity Effects 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000008099 melanin synthesis Effects 0.000 description 1
- 210000002752 melanocyte Anatomy 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000211 teratogenicity Toxicity 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention relates to a selective preparation method of 5, 6-dihydroxyindoline and 5, 6-dihydroxyindole, belonging to the technical field of pharmaceutical organic synthesis. The method is characterized in that cheap 3, 4-dihydroxybenzaldehyde is used as a starting material, common catalysts are adopted, benzyl protection, nitration, reduction, amidation, halogen substitution, ring closure, hydrolysis and reduction reactions are sequentially carried out to obtain 5, 6-dibenzyloxyindoline, then the 5, 6-dibenzyloxyindoline is used as a reactant, and different organic solvents and reducing agents are added to selectively prepare the 5, 6-dihydroxyindoline and the 5, 6-dihydroxyindole. The invention effectively solves the problem that only 5, 6-dihydroxyindole can be prepared by a route in the prior art, the reactant is more environment-friendly and safe, and the raw materials are cheap and easy to obtain.
Description
Technical Field
The invention relates to a selective preparation method of 5, 6-dihydroxyindoline and 5, 6-dihydroxyindole, belonging to the technical field of pharmaceutical organic synthesis.
Background
The existing hair dyeing products in the market are various in variety, the main effective dyeing components are p-phenylenediamine and derivatives thereof, and the substances have adverse reactions such as carcinogenicity, teratogenicity, allergy, genetic toxicity and the like on human bodies, so that the physical health of people is seriously influenced. Therefore, there is an urgent need for a novel hair dye which is safe and effective and convenient to use.
5, 6-dihydroxyindoline is an important intermediate for melanin synthesis by melanocytes in hair follicles of organisms. Under physiological conditions, it can be further oxidized and polymerized in organisms to generate complex macromolecular substance melanin with color; the same changes can occur in an in vitro weakly alkaline environment or in an aerobic environment. The prior art reports that 5, 6-dihydroxyindoline hydrobromide is used as a hair dyeing component in human hair dyeing agents, and has good dyeing effect on keratin fibers. In addition, chinese patent document CN105380892a discloses a composite single-part hair dye, and 5, 6-dihydroxyindoline is one of several active ingredients in melanin precursors in the composite single-part hair dye. Therefore, the 5, 6-dihydroxyindoline is used as an active ingredient of a new generation of safe and green hair dye, and has high commercial value and industrial application value.
In recent years, with the development of synthesis of fine chemicals, 5, 6-dihydroxyindoline can be used as an intermediate in the preparation process of alkaloids, amino acids and the like, and other applications of the 5, 6-dihydroxyindoline are also new, for example, the 5, 6-dihydroxyindoline can be used as a synthetic raw material or an important intermediate of active ingredients in many medicaments; can also be used as the effective component in some additives such as degerming agent, antioxidant and antiseptic.
However, 5, 6-dihydroxyindoline is unstable in nature, is very sensitive to pH, temperature and oxygen, and has a problem in the synthetic process. Chinese patent document CN107540596A discloses a preparation method of a compound 5, 6-dihydroxyindoline and halogen acid salt thereof, in particular a method for synthesizing 5, 6-dihydroxyindoline and halogen acid salt thereof by taking 3, 4-dialkoxyphenethylamine as a raw material, but the final product is prepared into the halogen acid salt form due to the extremely unstable nature of the 5, 6-dihydroxyindoline. In addition, in the document Journal of MedicinalChemistry,1995, vol.38 (6), 917-922, a synthetic method using 3, 4-dimethoxybenzyl cyanide as a raw material is reported, and a final product 5, 6-dihydroxyindoline is obtained through chemical reactions such as nitration, hydrogenation reduction, high-temperature deprotection of acid solution and the like. However, the method has the problems of high raw material cost, complicated post-treatment of the nitration reaction, more byproducts after hydrogenation reduction, high price of reducing reagent and the like, and is difficult in actual operation and production.
The 5, 6-dihydroxyindole is also an important intermediate of natural melanin, has small irritation to human skin, high safety and definite action mechanism, and is gradually substituted with aniline compounds as the best choice of novel hair dye. Therefore, the 5, 6-dihydroxyindole is also used as an effective component of a new generation of safe green hair dye, and has high commercial value and industrial application value.
Based on the good effect of 5, 6-dihydroxyindole in hair dye and antioxidant application, large-scale cosmetic companies in the world such as Europea, baojie, king and the like in the early 90 th year of the last century have started to develop 5, 6-dihydroxyindole. In the middle 90 th century, some cosmetic companies in China start to entrust research work on 5, 6-dihydroxyindole successively, but the 5, 6-dihydroxyindole is sensitive to oxygen, transition metal, acid-base reagent and the like, the property is unstable and easy to deteriorate, and the existing production method is difficult to prepare high-purity 5, 6-dihydroxyindole due to low yield, harsh operating conditions and the like.
The literature Inorg.chem.2006,45,3657-3664 reports a one-step synthesis method of 5, 6-dihydroxyindole from levodopa, which uses a large amount of water, generates a large amount of wastewater, and has high treatment cost. The literature (fine petrochemical industry) 2007,24 (2) 53-55 reports that 3, 4-dimethoxy benzonitrile is used as a raw material to obtain 5, 6-dihydroxyindole through multi-step reactions such as demethylation, hydroxyl protection, nitration, reduction, cyclization and the like, and the yield of the method is higher and can reach more than 80 percent, but the preparation environment condition is harsh, and the industrial scale-up is difficult. The literature Hair Dye composition.2006,02,10 uses dopamine compounds as starting materials, and 5, 6-dihydroxyindole is obtained by cyclizing side chains with ortho substituents on benzene rings. The method has the advantages of less reaction steps, higher price of raw materials, unstable property after the exposed hydroxyl, yield of only 10 percent, poor economy and low purity of the obtained product, and is not suitable for being applied to the large-scale production of the process. There is therefore an urgent need to develop a low-cost, industrialized process for the preparation of 5, 6-dihydroxyindoline and 5, 6-dihydroxyindole.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a selective preparation method of 5, 6-dihydroxyindoline and 5, 6-dihydroxyindole.
The technical scheme of the invention is as follows:
a selective preparation method of 5, 6-dihydroxyindoline and 5, 6-dihydroxyindole comprises the following steps:
(1) Dissolving 3, 4-dihydroxybenzaldehyde and benzyl bromide in an organic solvent, reacting for 8-10 hours at the pH value of 8-11 and the temperature of 30-80 ℃, cooling the reaction system to 20-30 ℃, diluting, extracting, drying, decompressing and evaporating the solvent to obtain a compound II;
(2) Mixing acetic acid, nitromethane and ammonium acetate uniformly, adding a compound II under the stirring condition at 20-30 ℃ for uniform mixing, heating to 80-130 ℃ for reaction for 8-11 h, cooling the reaction system to 20-30 ℃, pouring into deionized water for separating out solids, filtering, washing, pulping and vacuum drying to obtain a compound III;
(3) Under the condition of nitrogen protection and ice bath stirring, dissolving a reducing agent in an organic solvent to prepare a solution A;
(4) Under the protection of nitrogen and stirring, dissolving a compound III in an organic solvent to prepare a solution B;
(5) Under the condition of nitrogen protection and ice bath stirring, slowly dripping the solution B into the solution A, reacting for 3-4 hours at 10-60 ℃, then cooling the reaction system to 20-30 ℃, continuously dripping alkaline solution under the ice bath stirring condition, adjusting the pH to 8-11, filtering, drying the filtrate, and evaporating the solvent under reduced pressure to obtain a compound IV;
(6) Dissolving a compound IV in an organic solvent, dropwise adding an acylating agent and an acid binding agent under ice bath stirring, reacting for 3-4 hours at 20-30 ℃, diluting the reaction solution, extracting, drying and evaporating the solvent under reduced pressure to obtain a compound V;
(7) Dissolving iodine in an organic solvent to prepare a solution C; dissolving a compound V in an organic solvent, dropwise adding a solution C into the organic solution of the compound V under the conditions of stirring at 20-30 ℃, then reacting at 40-50 ℃ for 8-10 hours, cooling the reaction system to 20-30 ℃, adjusting the pH to 8-9 by using an alkaline solution, washing, extracting, drying and evaporating the solvent under reduced pressure to obtain a compound VI;
(8) Dissolving a compound VI in an organic solvent, adding a catalyst, reacting for 3-4 hours at 110-160 ℃ under the protection of nitrogen, cooling a reaction system to 20-30 ℃ and diluting, extracting, drying and evaporating the solvent under reduced pressure to obtain a compound VII;
(9) Dissolving a compound VII in an alcohol solution, reacting for 4-5 hours under the protection of nitrogen and at the pH of 8-11 and the temperature of 50-100 ℃, cooling a reaction system to 20-30 ℃ to precipitate a solid, and obtaining the compound VIII after filtering, washing, crystallizing and vacuum drying;
(10) Dissolving compound VIII in organic solvent, adding reducing agent, adding the mixture into H 2 Protecting, reacting for 2-3 h at 20-30 ℃, filtering the reaction liquid in an anaerobic environment, and decompressing and evaporating the filtrate to remove the solvent to obtain 5, 6-dihydroxyindoline;
(11) Dissolving compound VIII in organic solvent, adding reducing agent, adding the mixture into H 2 Protecting, reacting for 2-3 h at 20-30 ℃, filtering the reaction liquid in an anaerobic environment, and decompressing and evaporating the filtrate to remove the solvent to obtain the 5, 6-dihydroxyindole.
According to the invention, in the step (1), the mass volume ratio of the 3, 4-dihydroxybenzaldehyde to the benzyl bromide is 8: (20-21), unit: g/mL; the organic solvent is one or more of dichloromethane, chloroform, diethyl ether, ethyl acetate, methanol, ethanol and N, N-dimethylformamide; the volume ratio of the organic solvent to the benzyl bromide is 30: (20-21).
Further preferably, the organic solvent is N, N-dimethylformamide.
According to the invention, in the step (1), the pH is adjusted to 8-11 by potassium hydroxide, sodium carbonate, potassium carbonate or lutidine; the reaction temperature is 40-60 ℃.
Further preferably, the pH is adjusted to 8 to 11 with potassium carbonate and the reaction temperature is 50 ℃. Because the potassium carbonate is cheap and easy to obtain, the cost can be further reduced, and the yield of the compound II is highest when the reaction temperature is 50 ℃.
According to the present invention, in the step (1), the dilution, extraction, drying and reduced pressure distillation of the solvent are specifically:
diluting the reaction system with dichloromethane, extracting with deionized water and saturated saline solution, drying with anhydrous sodium sulfate, and evaporating solvent under reduced pressure to obtain a compound II; the volume ratio of the dichloromethane to the benzyl bromide is 50: (20-21).
Further preferably, after the solvent is distilled off under reduced pressure, ethanol is added into the compound II to be pulped for 15-30 min, the mixture is filtered, a filter cake is washed by cold ethanol, and the mixture is dried in vacuum at 60 ℃ to obtain the purified compound II. Compound ii can be further purified by beating with ethanol.
According to the invention, in the step (2), the volume mass ratio of the acetic acid, the nitromethane and the ammonium acetate is (60-62): (10-13): (5-6), unit: mL/mL/g; the mass ratio of the sum compound II to the ammonium acetate is (14-15): (5-6); the volume ratio of the acetic acid to the deionized water is (30-31): (25-40).
According to a preferred embodiment of the present invention, in the step (2), the filtering, washing and vacuum drying are specifically:
filtering the precipitated solid, washing a filter cake with ethanol, adding ethyl acetate into the filter cake, pulping for 15-30 min, filtering again, washing the filter cake with filtrate, and drying in vacuum at 60 ℃ to obtain the compound III.
According to the invention, in the step (3), the reducing agent is one or more of sodium borohydride, lithium aluminum hydride, palladium acetate, palladium hydroxide and Raney nickel; the organic solvent is an ether solvent; the concentration of the solution A is 30-40 g/L.
Further preferably, the reducing agent is lithium aluminum hydride and the organic solvent is diethyl ether. The lithium aluminum hydride is used as a reducing agent, the yield is highest, and the lithium aluminum hydride is more stable in diethyl ether.
According to a preferred embodiment of the present invention, in the step (4), the organic solvent is tetrahydrofuran; the concentration of the solution A is 120-130 g/L.
According to the present invention, in the step (5), the volume ratio of the solution B to the solution a is (22 to 23): (34-35); the reaction temperature is 40 ℃; the alkaline solution is 10% NaOH solution, and the pH value is adjusted to 10.
According to the invention, in the step (6), the organic solvent is one or more of dichloromethane, chloroform, diethyl ether, ethyl acetate, methanol, ethanol and N, N-dimethylformamide; the acylating reagent is one or more of acetyl chloride, acetic acid and acetic anhydride; the acid binding agent is one or more of pyridine, diethylamine and triethylamine;
the mass volume ratio of the compound IV to the organic solvent is 1:6, and the unit is: g/mL; the volume ratio of the organic solvent to the acylating agent to the acid binding agent is 72: (6-7): (7-8).
Further preferably, the organic solvent is N, N-dimethylformamide; the acylating agent is acetic anhydride; the acid binding agent is triethylamine.
According to the invention, in the step (7), the organic solvent is one or more of dichloromethane, chloroform, diethyl ether, ethyl acetate, methanol, ethanol and N, N-dimethylformamide; the concentration of the solution C is 1-1.2 g/mL; the mass volume ratio of the compound V to the organic solvent is (13-14): (117 to 118), unit: g/mL; the mass volume ratio of the compound V to the solution C is (13-14): (26 to 27), unit: g/mL; the alkaline solution was a 0.4M NaOH solution.
Further preferably, the organic solvent is N, N-dimethylformamide.
According to the invention, in the step (8), the organic solvent is one or more of methanol, ethanol, isopropanol, diethyl ether, dichloromethane, chloroform and dimethyl sulfoxide; the catalyst is a mixture of cuprous iodide and potassium carbonate; the mass volume ratio of the compound VI to the organic solvent is (16-17): 220, units: g/mL; the mass ratio of the compound VI to the cuprous iodide to the potassium carbonate is (16-17): (1-1.5): (13-14).
Further preferably, the organic solvent is dimethyl sulfoxide.
According to the invention, in the step (9), the alcohol solution is one or more of absolute methanol, absolute ethanol, isopropanol, n-propanol and ethylene glycol; the mass volume ratio of the compound VII to the alcohol solution is (1.2-1.3): (21-22), unit: g/mL; the pH value is 8-11, and is regulated by saturated solution of sodium hydroxide or potassium hydroxide; the reaction temperature was 90 ℃.
Further preferably, the alcohol solution is absolute ethanol.
According to the invention, in the step (10), the organic solvent is one or more of tetrahydrofuran, absolute methanol, absolute ethanol, isopropanol, ethyl acetate and 1, 4-dioxane; the reducing agent is one or more of sodium borohydride, lithium aluminum hydride, palladium acetate, palladium hydroxide carbon, raney nickel and palladium carbon; the mass volume ratio of the compound VIII to the organic solvent to the reducing agent is (3-6): 200: (0.2 to 0.8), unit: g/mL/g.
Further preferably, the organic solvent is anhydrous methanol, and the reducing agent is palladium hydroxide carbon.
According to the invention, in the step (11), the organic solvent is one or more of tetrahydrofuran, absolute methanol, absolute ethanol, isopropanol, ethyl acetate and 1, 4-dioxane; the reducing agent is one or more of sodium borohydride, lithium aluminum hydride, palladium acetate, palladium hydroxide carbon, raney nickel and palladium carbon; the mass volume ratio of the compound VIII to the organic solvent to the reducing agent is (80-120): 1-2: (8-12), unit: mg/mL/mg.
Further preferably, the organic solvent is ethyl acetate, and the reducing agent is palladium hydroxide carbon.
The present invention is not limited to the details of the prior art.
The invention has the beneficial effects that:
1. the invention takes cheap 3, 4-dihydroxybenzaldehyde as an initial raw material, adopts common catalysts, and sequentially obtains 5, 6-dibenzyloxy indoline through benzyl protection, nitration, reduction, amidation, halogen substitution, ring closure, hydrolysis and reduction reaction, then takes the 5, 6-dibenzyloxy indoline as a reactant, and can selectively prepare the 5, 6-dihydroxyindoline and the 5, 6-dihydroxyindole by adding different organic solvents and reducing agents, thereby effectively overcoming the problem that the prior art can only prepare the 5, 6-dihydroxyindole in a single path. And the comprehensive yield of the 5, 6-dihydroxyindoline and the 5, 6-dihydroxyindole respectively reaches 23% and 28%, and compared with the prior art, the method reduces the cost and improves the yield.
2. The invention provides a novel reaction route and a novel preparation method for preparing 5, 6-dihydroxyindoline and 5, 6-dihydroxyindole, the reaction reagent is more environment-friendly and safer, the raw materials are cheap and easy to obtain, the reaction yield is high, the side reaction is less, and the method is suitable for industrial production.
Drawings
FIG. 1 is a synthetic scheme of 5, 6-dihydroxyindoline and 5, 6-dihydroxyindole of the present invention.
FIG. 2 is a diagram of 5, 6-dihydroxyindoline 1 H NMR spectrum.
FIG. 3 is a diagram of 5, 6-dihydroxyindole 1 H NMR spectrum.
Detailed Description
The invention will now be described in further detail with reference to the drawings and specific examples, which should not be construed as limiting the invention. The experimental procedures and reagents not shown in the formulation of the examples were all in accordance with the conventional conditions in the art.
Example 1
As shown in FIG. 1, a selective preparation method of 5, 6-dihydroxyindoline and 5, 6-dihydroxyindole comprises the following steps:
(1) Adding 80g of 3, 4-dihydroxybenzaldehyde and 206mL of benzyl bromide into 300mL of N, N-dimethylformamide, stirring uniformly, continuously adding 320g of potassium carbonate to adjust the pH to 10, heating to 50 ℃, reacting for 10 hours, cooling the reaction system to 25 ℃, diluting with 500mL of dichloromethane, extracting an organic phase with deionized water and saturated saline, drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure to obtain a solid compound, transferring the solid compound into a 1L beaker, adding 200mL of ethanol, pulping for 20 minutes, filtering, washing a filter cake with cold ethanol, and vacuum-drying at 60 ℃ to obtain 147g of 3, 4-dibenzyloxybenzaldehyde (compound II) with the yield of 80%;
(2) Mixing 614mL of acetic acid, 124mL of nitromethane and 54g of ammonium acetate uniformly, adding 146g of 3, 4-dibenzyloxybenzaldehyde (compound II) under the stirring condition at 25 ℃, heating to 100 ℃, reacting for 10 hours, cooling a reaction system to 25 ℃ after the reaction is finished, directly pouring reaction liquid into 600mL of deionized water, separating out solid, filtering the solid, washing a filter cake with ethanol, transferring the filter cake into a 1L beaker, adding 200mL of ethyl acetate, pulping for 20min, filtering, washing the filter cake with a filter liquid, and vacuum drying at 60 ℃ to obtain 146g of 3, 4-dibenzyloxy-beta-nitrostyrene (compound III) with the yield of 88%;
(3) 61g of lithium aluminum hydride is added into a 5L three-necked flask, nitrogen protection is carried out, 1737mL of anhydrous diethyl ether is added under ice bath stirring, and solution A is prepared;
(4) 145g of 3, 4-dibenzyloxy-beta-nitrostyrene (compound III) is added into a 1L three-necked flask, 1150mL of anhydrous tetrahydrofuran is added under the protection of nitrogen, and solution B is prepared;
(5) Under the protection of nitrogen and under the stirring condition of ice bath, slowly dripping the solution B into the solution A, heating to 40 ℃ after the dripping is finished, reacting for 4 hours, after the reaction is finished, dripping 10% sodium hydroxide solution under the stirring of ice bath until the reaction system is cooled to 25 ℃, regulating the pH to 9-10 (the color of the solution gradually turns to beige), precipitating a large amount of solid, filtering, washing a filter cake with 800mL of dichloromethane, transferring the filtrate into a separating funnel, extracting with deionized water and saturated saline water, drying with anhydrous sodium sulfate, and evaporating the solvent under reduced pressure to obtain 123g of oily 3, 4-dibenzyloxy phenethylamine (compound IV) with the yield of 92%;
(6) 720mL of methylene chloride is added into a 2L three-mouth bottle, 120g of 3, 4-dibenzyloxy phenethylamine (compound IV) is added under ice bath stirring, 62mL of acetic anhydride is then added dropwise, 75mL of triethylamine is then added dropwise, the ice bath is removed after the dropwise addition, the reaction is carried out for 3 hours at 25 ℃, after the reaction is finished, the reaction solution is diluted with 200mL of methylene chloride, deionized water and saturated saline solution are used for extraction, anhydrous sodium sulfate is used for drying, the solvent is distilled off under reduced pressure, 132g of oily 3, 4-dibenzyloxy phenylacetamide (compound V) is obtained, and the yield is 98%;
(7) 267g of iodine is weighed and dissolved in 267mL of N, N-dimethylformamide to prepare a solution C; adding 1172mL of N, N-dimethylformamide into a 3L three-mouth bottle, adding 132g of 3, 4-dibenzyloxy phenylacetamide (compound V) under stirring, slowly dripping the solution C into the 3, 4-dibenzyloxy phenylacetamide (compound V) solution, heating to 50 ℃, reacting for 10 hours, cooling the reaction system to 25 ℃, washing 3 times with saturated sodium sulfite solution under stirring, extracting an organic phase with deionized water and saturated saline solution, drying with anhydrous sodium sulfate, steaming under reduced pressure to remove a solvent to obtain a brown solid, pulping the solid with 400mL of diethyl ether for 20 minutes to obtain 166g of 4, 5-dibenzyloxy-1-iodo-2-phenylacetamide (compound VI) with the yield of 94%;
(8) 166g of 4, 5-dibenzyloxy-1-iodo-2-phenylacetamide (compound VI), 13g of cuprous iodide and 137g of potassium carbonate are added into a 5L three-port bottle, 2200mL of dimethyl sulfoxide is continuously added, reflux reaction is carried out for 4 hours at 140 ℃ under the protection of nitrogen, after the reaction is finished, the reaction system is cooled to 25 ℃, the reaction solution is diluted by 1000mL of methylene chloride, deionized water and saturated saline solution are used for extraction, anhydrous sodium sulfate is dried, the solvent is distilled off under reduced pressure, and 121g of 1-acetyl-5, 6-dibenzyloxy indoline (compound VII) is obtained, and the yield is 98%;
(9) In a 5L three-mouth bottle, 121g of 1-acetyl-5, 6-dibenzyloxy indoline (compound VII) is dissolved in 2160mL of absolute ethyl alcohol, saturated 1080mL of potassium hydroxide solution is continuously added to adjust the pH to 10, the mixture is reacted for 4 hours under the protection of nitrogen and at 90 ℃, then the reaction system is cooled to 25 ℃ to precipitate solid, the solid is filtered, the solid is precipitated after the filtrate is added with water, and the repeated crystallization is carried out, so that 99g of 5, 6-dibenzyloxy indoline (compound VIII) is obtained, and the yield is 92%;
(10) 5g of 5, 6-dibenzyloxy indoline (compound VIII), 500mg of palladium hydroxide carbon is added into 500mL of a three-necked flask, 200mL of absolute methanol is added, the mixture is reacted for 3 hours under the protection of hydrogen and the temperature of 30 ℃, after the reaction is finished, the mixture is filtered under the anaerobic environment, the filtrate is decompressed and the solvent is distilled off, and 1.2g of 5, 6-dihydroxyindoline (compound X) is obtained, and the yield is 52%;
(11) 100mg of 5, 6-dibenzyloxy indole (compound VIII), 10mg of palladium hydroxide carbon are added into 4mL of a single-mouth bottle, 1.6mL of ethyl acetate is added, the mixture is reacted for 3 hours under the protection of hydrogen gas and the temperature of 30 ℃, after the reaction is finished, the mixture is filtered under the anaerobic environment, the filtrate is distilled off under reduced pressure to remove the solvent, and 25mg of 5, 6-dihydroxyindole (compound IX) is obtained, and the yield is 55%.
Example 2
The physicochemical and spectroscopic data of each of the compounds prepared in example 1, 5, 6-dihydroxyindoline and 5, 6-dihydroxyindole are as follows:
1H-NMR (400 MHz, CDCl 3) delta (ppm) of 3, 4-dibenzyloxy benzaldehyde (compound II) =9.80 (s, 1H), 7.48 (d, J=1.9 Hz, 1H), 7.48-7.40 (m, 5H), 7.39 (d, J=2.4 Hz, 1H), 7.38-7.29 (m, 5H), 7.01 (d, J=8.2 Hz, 1H), 5.25 (s, 2H), 5.20 (s, 2H).
1H-NMR (400 MHz, CDCl 3) of 3, 4-dibenzyloxy- β -nitrostyrene (compound III) 7.88 (d, J=13.6 Hz, 1H), 7.45 (d, J=1.9 Hz, 1H), 7.43 (d, J=1.5 Hz, 2H), 7.41 (dd, J=10.1, 1.8Hz, 3H), 7.39-7.37 (m, 2H), 7.36 (s, 1H), 7.34 (t, J=1.6 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.11 (dd, J=8.4, 2.1Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 5.22 (s, 2H), 5.18 (s, 2H).
1H NMR (400 MHz, CDCl 3) delta 7.41-7.37 (m, 4H), 7.30 (d, J=3.6 Hz, 1H), 7.28 (d, J=2.0 Hz, 2H), 7.26 (d, J=2.0 Hz, 1H), 7.23 (dd, J=7.2, 1.8Hz, 2H), 6.82 (d, J=8.1 Hz, 1H), 6.75 (d, J=2.1 Hz, 1H), 6.64 (dd, J=8.1, 2.0Hz, 1H), 5.07 (s, 2H), 5.04 (s, 2H), 2.78 (t, J=6.8 Hz, 2H), 2.54 (t, J=6.8 Hz, 2H), 1.60 (s, 2H) of 3, 4-dibenzyloxy phenethylamine (compound IV).
1H NMR (400 MHz, CDCl 3) delta 7.45-7.42 (m, 4H), 7.37 (d, J=1.5 Hz, 1H), 7.35 (d, J=1.8 Hz, 2H), 7.33 (d, J=1.6 Hz, 1H), 7.31 (t, J=1.5 Hz, 1H), 7.30-7.27 (m, 1H), 6.87 (d, J=8.2 Hz, 1H), 6.77 (d, J=2.1 Hz, 1H), 6.68 (dd, J=8.1, 2.1Hz, 1H), 5.14 (s, 2H), 5.13 (s, 2H), 3.47-3.36 (m, 2H), 2.68 (t, J=6.9 Hz, 2H), 1.87 (s, 3H) of 3, 4-dibenzyloxy phenylacetamide (compound V).
1H NMR (400 MHz, (CD 3) 2SO-d 6) delta 7.91 (t, J=5.6 Hz), 7.45-7.42 (m, 4H), 7.41 (s, 1H), 7.40 (s, 1H), 7.38 (s, 2H), 7.36 (s, 1H), 7.34 (t, J=1.6 Hz, 1H), 7.33-7.30 (m, 1H), 7.02 (s, 1H), 5.11 (d, J=5.1 Hz, 4H), 3.22-3.16 (m, 2H), 2.72-2.67 (m, 2H), 1.78 (s, 3H) of 4, 5-dibenzyloxy-1-iodo-2-phenylacetamide (compound VI).
1H NMR (400 MHz, CDCl 3) delta 8.08 (s, 1H), 7.48 (d, J=7.0 Hz, 2H), 7.43-7.39 (m, 2H), 7.38-7.32 (m, 4H), 7.32-7.28 (m, 2H), 6.75 (s, 1H), 5.16 (s, 2H), 5.08 (s, 2), 3.96 (d, J=10.4 Hz, 2H), 3.08-3.01 (m, 2H), 2.16 (s, 3H) of 1H-acetyl-5, 6-dibenzyloxylindoline (compound VII).
1H NMR (400 MHz, CDCl 3) delta 7.42 (d, J=6.7 Hz, 4H), 7.37-7.28 (m, 6H), 6.81 (s, 1H), 6.41 (s, 1H), 5.08 (s, 2H), 5.03 (s, 2H), 3.52 (t, J=8.3 Hz, 2H), 2.93 (t, J=8.3 Hz, 2H) of 5, 6-dibenzyloxyindoline (compound VIII).
1H NMR (400 MHz, CD3 OD) delta 6.58 (s, 1H), 6.28 (s, 1H), 3.35 (d, J=8.1 Hz, 2H), 2.83 (t, J=8.1 Hz, 2H) of 5, 6-dihydroxyindoline (compound X).
1H NMR (400 MHz, CD3 OD) delta 6.95 (d, J=3.1 Hz, 1H), 6.88 (s, 1H), 6.79 (s, 1H), 6.17 (d, J=3.2 Hz, 1H) of 5, 6-dihydroxyindole (compound IX).
5, 6-dihydroxyindoline and 5, 6-dihydroxyindole prepared in example 1 1 H NMR charts are shown in fig. 2 and 3, respectively. From FIGS. 2 to 3 and the above data, it can be seen that 5, 6-dihydroxyindoline and 5, 6-dihydroxyindole were successfully prepared by the present invention. And the overall yield of 5, 6-dihydroxyindoline synthesized in this example was 28% and the overall yield of 5, 6-dihydroxyindole was 30%.
Example 3
A selective preparation method of 5, 6-dihydroxyindoline and 5, 6-dihydroxyindole is the same as in example 1, except that in step (1), the reaction temperature is 70 ℃;
in the step (3), the reducing agent is sodium borohydride;
in the step (6), the acylating agent is acetyl chloride and the acid binding agent is diethylamine.
The overall yield of 5, 6-dihydroxyindoline synthesized in this example was 18% and the overall yield of 5, 6-dihydroxyindole was 22%.
Example 4
A selective preparation method of 5, 6-dihydroxyindoline and 5, 6-dihydroxyindole, which is different from example 1 in that in the step (8), the addition amount of cuprous iodide is 10g;
in the step (10), the organic solvent is tetrahydrofuran, and the reducing agent is sodium borohydride;
in the step (11), the organic solvent is absolute ethyl alcohol, and the reducing agent is lithium aluminum hydride.
The overall yield of 5, 6-dihydroxyindoline synthesized in this example was 16% and the overall yield of 5, 6-dihydroxyindole was 23%.
Claims (10)
1. A selective preparation method of 5, 6-dihydroxyindoline and 5, 6-dihydroxyindole is characterized by comprising the following steps:
(1) Dissolving 3, 4-dihydroxybenzaldehyde and benzyl bromide in an organic solvent, reacting for 8-10 hours at the pH value of 8-11 and the temperature of 30-80 ℃, cooling the reaction system to 20-30 ℃, diluting, extracting, drying, decompressing and evaporating the solvent to obtain a compound II;
(2) Mixing acetic acid, nitromethane and ammonium acetate uniformly, adding a compound II under the stirring condition at 20-30 ℃ for uniform mixing, heating to 80-130 ℃ for reaction for 8-11 h, cooling the reaction system to 20-30 ℃, pouring into deionized water for separating out solids, filtering, washing, pulping and vacuum drying to obtain a compound III;
(3) Under the condition of nitrogen protection and ice bath stirring, dissolving a reducing agent in an organic solvent to prepare a solution A;
(4) Under the protection of nitrogen and stirring, dissolving a compound III in an organic solvent to prepare a solution B;
(5) Under the condition of nitrogen protection and ice bath stirring, slowly dripping the solution B into the solution A, reacting for 3-4 hours at 10-60 ℃, then cooling the reaction system to 20-30 ℃, continuously dripping alkaline solution under the ice bath stirring condition, adjusting the pH to 8-11, filtering, drying the filtrate, and evaporating the solvent under reduced pressure to obtain a compound IV;
(6) Dissolving a compound IV in an organic solvent, dropwise adding an acylating agent and an acid binding agent under ice bath stirring, reacting for 3-4 hours at 20-30 ℃, diluting the reaction solution, extracting, drying and evaporating the solvent under reduced pressure to obtain a compound V;
(7) Dissolving iodine in an organic solvent to prepare a solution C; dissolving a compound V in an organic solvent, dropwise adding a solution C into the organic solution of the compound V under the conditions of stirring at 20-30 ℃, then reacting at 40-50 ℃ for 8-10 hours, cooling the reaction system to 20-30 ℃, adjusting the pH to 8-9 by using an alkaline solution, washing, extracting, drying and evaporating the solvent under reduced pressure to obtain a compound VI;
(8) Dissolving a compound VI in an organic solvent, adding a catalyst, reacting for 3-4 hours at 110-160 ℃ under the protection of nitrogen, cooling a reaction system to 20-30 ℃ and diluting, extracting, drying and evaporating the solvent under reduced pressure to obtain a compound VII;
(9) Dissolving a compound VII in an alcohol solution, reacting for 4-5 hours under the protection of nitrogen and at the pH of 8-11 and the temperature of 50-100 ℃, cooling a reaction system to 20-30 ℃ to precipitate a solid, and obtaining a compound VIII after filtering, washing, crystallizing and vacuum drying;
(10) Dissolving compound VIII in organic solvent, adding reducing agent, adding the mixture into H 2 Protecting, reacting for 2-3 h at 20-30 ℃, filtering the reaction liquid in an anaerobic environment, and decompressing and evaporating the filtrate to remove the solvent to obtain 5, 6-dihydroxyindoline;
(11) Dissolving compound VIII in organic solvent, adding reducing agent, adding the mixture into H 2 Protecting, reacting for 2-3 h at 20-30 ℃, filtering the reaction liquid in an anaerobic environment, and decompressing and evaporating the filtrate to remove the solvent to obtain the 5, 6-dihydroxyindole.
2. The method according to claim 1, wherein in the step (1), the mass-to-volume ratio of the 3, 4-dihydroxybenzaldehyde to the benzyl bromide is 8: (20-21), unit: g/mL; the organic solvent is one or more of dichloromethane, chloroform, diethyl ether, ethyl acetate, methanol, ethanol and N, N-dimethylformamide; the volume ratio of the organic solvent to the benzyl bromide is 30: (20-21); adjusting the pH to 8-11 by potassium hydroxide, sodium carbonate, potassium carbonate or lutidine; the reaction temperature is 40-60 ℃;
the solvent is specifically diluted, extracted, dried and distilled under reduced pressure:
diluting the reaction system with dichloromethane, extracting with deionized water and saturated saline solution, drying with anhydrous sodium sulfate, and evaporating solvent under reduced pressure to obtain a compound II; the volume ratio of the dichloromethane to the benzyl bromide is 50: (20-21);
further preferably, the organic solvent is N, N-dimethylformamide; the pH value is regulated to 8-11 by potassium carbonate, and the reaction temperature is 50 ℃;
and (3) after the solvent is distilled off under reduced pressure, adding ethanol into the compound II, pulping for 15-30 min, filtering, washing a filter cake with cold ethanol, and vacuum drying at 60 ℃ to obtain the purified compound II.
3. The process according to claim 1, wherein in step (2), the volume/mass ratio of acetic acid, nitromethane and ammonium acetate is (60 to 62): (10-13): (5-6), unit: mL/mL/g; the mass ratio of the sum compound II to the ammonium acetate is (14-15): (5-6); the volume ratio of the acetic acid to the deionized water is (30-31): (25-40);
the steps of filtering, washing and vacuum drying are as follows:
filtering the precipitated solid, washing a filter cake with ethanol, adding ethyl acetate into the filter cake, pulping for 15-30 min, filtering again, washing the filter cake with filtrate, and drying in vacuum at 60 ℃ to obtain the compound III.
4. The preparation method of claim 1, wherein in the step (3), the reducing agent is one or more of sodium borohydride, lithium aluminum hydride, palladium acetate, palladium hydroxide and Raney nickel; the organic solvent is an ether solvent; the concentration of the solution A is 30-40 g/L;
in the step (4), the organic solvent is tetrahydrofuran; the concentration of the solution A is 120-130 g/L;
in the step (5), the volume ratio of the solution B to the solution A is (22-23): (34-35); the reaction temperature is 40 ℃; the alkaline solution is 10% NaOH solution, and the pH value is adjusted to 10.
5. The method according to claim 1, wherein in the step (6), the organic solvent is one or more of dichloromethane, chloroform, diethyl ether, ethyl acetate, methanol, ethanol, and N, N-dimethylformamide; the acylating reagent is one or more of acetyl chloride, acetic acid and acetic anhydride; the acid binding agent is one or more of pyridine, diethylamine and triethylamine;
the mass volume ratio of the compound IV to the organic solvent is 1:6, and the unit is: g/mL; the volume ratio of the organic solvent to the acylating agent to the acid binding agent is 72: (6-7): (7-8);
further preferably, the organic solvent is N, N-dimethylformamide; the acylating agent is acetic anhydride; the acid binding agent is triethylamine.
6. The preparation method according to claim 1, wherein in the step (7), the organic solvent is one or more of dichloromethane, chloroform, diethyl ether, ethyl acetate, methanol, ethanol, and N, N-dimethylformamide; the concentration of the solution C is 1-1.2 g/mL; the mass volume ratio of the compound V to the organic solvent is (13-14): (117 to 118), unit: g/mL; the mass volume ratio of the compound V to the solution C is (13-14): (26 to 27), unit: g/mL; the alkaline solution is 0.4M NaOH solution;
further preferably, the organic solvent is N, N-dimethylformamide.
7. The preparation method of claim 1, wherein in the step (8), the organic solvent is one or more of methanol, ethanol, isopropanol, diethyl ether, dichloromethane, chloroform and dimethyl sulfoxide; the catalyst is a mixture of cuprous iodide and potassium carbonate; the mass volume ratio of the compound VI to the organic solvent is (16-17): 220, units: g/mL; the mass ratio of the compound VI to the cuprous iodide to the potassium carbonate is (16-17): (1-1.5): (13-14);
further preferably, the organic solvent is dimethyl sulfoxide.
8. The method according to claim 1, wherein in the step (9), the alcohol solution is one or more of absolute methanol, absolute ethanol, isopropanol, n-propanol, and ethylene glycol; the mass volume ratio of the compound VII to the alcohol solution is (1.2-1.3): (21-22), unit: g/mL; the pH value is 8-11, and is regulated by saturated solution of sodium hydroxide or potassium hydroxide; the reaction temperature is 90 ℃;
further preferably, the alcohol solution is absolute ethanol.
9. The method according to claim 1, wherein in the step (10), the organic solvent is one or more of tetrahydrofuran, absolute methanol, absolute ethanol, isopropanol, ethyl acetate, and 1, 4-dioxane; the reducing agent is one or more of sodium borohydride, lithium aluminum hydride, palladium acetate, palladium hydroxide carbon, raney nickel and palladium carbon; the mass volume ratio of the compound VIII to the organic solvent to the reducing agent is (3-6): 200: (0.2 to 0.8), unit: g/mL/g;
further preferably, the organic solvent is anhydrous methanol, and the reducing agent is palladium hydroxide carbon.
10. The preparation method according to claim 1, wherein in the step (11), the organic solvent is one or more of tetrahydrofuran, absolute methanol, absolute ethanol, isopropanol, ethyl acetate, and 1, 4-dioxane; the reducing agent is one or more of sodium borohydride, lithium aluminum hydride, palladium acetate, palladium hydroxide carbon, raney nickel and palladium carbon; the mass volume ratio of the compound VIII to the organic solvent to the reducing agent is (80-120): 1-2: (8-12), unit: mg/mL/mg;
further preferably, the organic solvent is ethyl acetate, and the reducing agent is palladium hydroxide carbon.
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5536843A (en) * | 1992-02-12 | 1996-07-16 | Henkel Kommanditgesellschaft Auf Aktien | Synthesis of indoles by dehydrogenation of indolines |
WO2016134450A1 (en) * | 2015-02-26 | 2016-09-01 | Université de Montréal | Imidazopyridazine and imidazothiadiazole compounds |
CN107540596A (en) * | 2017-07-27 | 2018-01-05 | 烟台六谛医药科技有限公司 | A kind of preparation method of the dihydroxy indole quinoline of compound 5,6 and its halogen acid salt |
WO2018013609A2 (en) * | 2016-07-11 | 2018-01-18 | The Regents The University Of California | Synthetic melanin nanoparticles uses thereof |
WO2019225625A1 (en) * | 2018-05-23 | 2019-11-28 | 京都薬品工業株式会社 | Readthrough inducer and pharmaceutical use thereof |
-
2023
- 2023-09-07 CN CN202311147413.8A patent/CN117247345A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5536843A (en) * | 1992-02-12 | 1996-07-16 | Henkel Kommanditgesellschaft Auf Aktien | Synthesis of indoles by dehydrogenation of indolines |
WO2016134450A1 (en) * | 2015-02-26 | 2016-09-01 | Université de Montréal | Imidazopyridazine and imidazothiadiazole compounds |
WO2018013609A2 (en) * | 2016-07-11 | 2018-01-18 | The Regents The University Of California | Synthetic melanin nanoparticles uses thereof |
CN107540596A (en) * | 2017-07-27 | 2018-01-05 | 烟台六谛医药科技有限公司 | A kind of preparation method of the dihydroxy indole quinoline of compound 5,6 and its halogen acid salt |
WO2019225625A1 (en) * | 2018-05-23 | 2019-11-28 | 京都薬品工業株式会社 | Readthrough inducer and pharmaceutical use thereof |
Non-Patent Citations (2)
Title |
---|
LIAO, YIXIAN等: "Synthesis and SARs of dopamine derivatives as potential inhibitors of influenza virus PAN endonuclease", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 189, 31 December 2020 (2020-12-31), pages 112048 * |
ZENGSHENG WENG等: "A high-sensitivity thin-film MWNT@PDA-AgNP nanocomposite sensor for acquiring microscopic deformations", COMPOSITES SCIENCE AND TECHNOLOGY, vol. 229, 19 August 2022 (2022-08-19), pages 109689 * |
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