CN118005554A - Synthesis method of 5, 6-dihydroxyindole and intermediate thereof - Google Patents
Synthesis method of 5, 6-dihydroxyindole and intermediate thereof Download PDFInfo
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- CN118005554A CN118005554A CN202311808397.2A CN202311808397A CN118005554A CN 118005554 A CN118005554 A CN 118005554A CN 202311808397 A CN202311808397 A CN 202311808397A CN 118005554 A CN118005554 A CN 118005554A
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- reaction
- dihydroxyindole
- solvent
- carbobenzoxy
- synthesizing
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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 127
- 238000001308 synthesis method Methods 0.000 title abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 169
- -1 1-carbobenzoxy-5, 6-dibenzyloxyindoline Chemical compound 0.000 claims abstract description 71
- 238000000034 method Methods 0.000 claims abstract description 50
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 18
- 239000003112 inhibitor Substances 0.000 claims abstract description 17
- 238000006116 polymerization reaction Methods 0.000 claims abstract description 17
- 230000008569 process Effects 0.000 claims abstract description 17
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 13
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 12
- VGSVNUGKHOVSPK-UHFFFAOYSA-N leukoaminochrome Chemical compound C1=C(O)C(O)=CC2=C1NCC2 VGSVNUGKHOVSPK-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 125000006239 protecting group Chemical group 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims description 56
- 239000000543 intermediate Substances 0.000 claims description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- 239000000047 product Substances 0.000 claims description 32
- 230000002194 synthesizing effect Effects 0.000 claims description 28
- 239000003513 alkali Substances 0.000 claims description 26
- 239000003153 chemical reaction reagent Substances 0.000 claims description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- IOKWTWPEEJJYFC-UHFFFAOYSA-N benzyl 5,6-dihydroxy-2,3-dihydroindole-1-carboxylate Chemical compound C1=2C=C(O)C(O)=CC=2CCN1C(=O)OCC1=CC=CC=C1 IOKWTWPEEJJYFC-UHFFFAOYSA-N 0.000 claims description 19
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 17
- 235000006708 antioxidants Nutrition 0.000 claims description 16
- 230000003078 antioxidant effect Effects 0.000 claims description 15
- 238000012544 monitoring process Methods 0.000 claims description 15
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 13
- 239000007788 liquid Substances 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 150000008282 halocarbons Chemical class 0.000 claims description 12
- 239000007800 oxidant agent Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 235000011181 potassium carbonates Nutrition 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 9
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 9
- 229910052751 metal Inorganic materials 0.000 claims description 9
- 239000002184 metal Substances 0.000 claims description 9
- 230000001590 oxidative effect Effects 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 9
- 239000000376 reactant Substances 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- 150000002170 ethers Chemical class 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- DKCPKDPYUFEZCP-UHFFFAOYSA-N 2,6-di-tert-butylphenol Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=C1O DKCPKDPYUFEZCP-UHFFFAOYSA-N 0.000 claims description 7
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 229930003268 Vitamin C Natural products 0.000 claims description 7
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 7
- 229940073608 benzyl chloride Drugs 0.000 claims description 7
- 230000001105 regulatory effect Effects 0.000 claims description 7
- 235000019154 vitamin C Nutrition 0.000 claims description 7
- 239000011718 vitamin C Substances 0.000 claims description 7
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 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
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 6
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 6
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 6
- 239000001095 magnesium carbonate Substances 0.000 claims description 6
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 5
- 235000010216 calcium carbonate Nutrition 0.000 claims description 5
- 238000012512 characterization method Methods 0.000 claims description 5
- 235000014380 magnesium carbonate Nutrition 0.000 claims description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 5
- 239000011736 potassium bicarbonate Substances 0.000 claims description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 5
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 5
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012298 atmosphere Substances 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- 241001122767 Theaceae Species 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 3
- 150000008442 polyphenolic compounds Chemical class 0.000 claims description 3
- 235000013824 polyphenols Nutrition 0.000 claims description 3
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 3
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 3
- 229960005055 sodium ascorbate Drugs 0.000 claims description 3
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 3
- 235000013616 tea Nutrition 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 238000000622 liquid--liquid extraction Methods 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 1
- 230000005311 nuclear magnetism Effects 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 abstract description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 2
- 238000003860 storage Methods 0.000 abstract description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract 1
- 125000005842 heteroatom Chemical group 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 10
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 6
- 238000006356 dehydrogenation reaction Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 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 4
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 4
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000118 hair dye Substances 0.000 description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 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 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 229960003638 dopamine Drugs 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 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 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 239000001744 Sodium fumarate Substances 0.000 description 2
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000000306 component Substances 0.000 description 2
- MSJMDZAOKORVFC-SEPHDYHBSA-L disodium fumarate Chemical compound [Na+].[Na+].[O-]C(=O)\C=C\C([O-])=O MSJMDZAOKORVFC-SEPHDYHBSA-L 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 229940005573 sodium fumarate Drugs 0.000 description 2
- 235000019294 sodium fumarate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical compound C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 description 2
- AMCDZTCOQXPOAZ-UHFFFAOYSA-N 1-hydroxy-2,3-dihydroindol-2-ol Chemical compound C1=CC=C2N(O)C(O)CC2=C1 AMCDZTCOQXPOAZ-UHFFFAOYSA-N 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 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
- 206010043275 Teratogenicity Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000012670 alkaline solution Substances 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
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008358 core component Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- MHUWZNTUIIFHAS-CLFAGFIQSA-N dioleoyl phosphatidic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC MHUWZNTUIIFHAS-CLFAGFIQSA-N 0.000 description 1
- 230000009982 effect on human Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 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
- 238000009776 industrial production Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical class N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 231100000211 teratogenicity Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention provides a synthesis method of 5, 6-dihydroxyindole and an intermediate thereof, wherein 5, 6-dihydroxyindoline hydrohalate or other acid salts (IC 241-01) are used as raw materials, heteroatom nitrogen and phenolic hydroxyl are protected successively to obtain an intermediate compound 1-carbobenzoxy-5, 6-dibenzyloxyindoline (IC 241-03), the intermediate compound 1-carbobenzoxy-5, 6-dibenzyloxyindole (IC 241-04) is further obtained through oxidation reaction, and a protecting group is removed by catalytic hydrogenation in the presence of a trace amount of antioxidants and polymerization inhibitors to obtain 5, 6-Dihydroxyindole (DHI). The method disclosed by the invention has the advantages that the reaction conditions are mild, the large-scale production can be stably realized, the raw materials are easy to obtain, the cost is controllable, and the process reproducibility is good; based on the synthesis strategy of finally removing the protecting group, and due to the actions of a trace amount of antioxidants and polymerization inhibitors, the target product 5, 6-Dihydroxyindole (DHI) has the comprehensive advantages of light color, good purity, convenience in storage and subsequent use and the like.
Description
Technical Field
The invention belongs to the technical field of organic synthesis processes, relates to a synthesis process route and a purification preparation method of a functional chemical 5, 6-Dihydroxyindole (DHI) for a healthy hair dye, and particularly relates to a synthesis method and an intermediate of 5, 6-dihydroxyindole.
Background
Melanin is a natural pigment formed in a living body, and has functions of antioxidation, radical capturing, ultraviolet absorption, and the like. 5, 6-Dihydroxyindole (DHI) is one of the key intermediates of melanin, and is initially found in the living body in nature, and research shows that the DHI has no toxic or side effect on human bodies. Pure 5, 6-Dihydroxyindole (DHI) is relatively stable in the crystalline state, but oxidizes rapidly in slightly alkaline solutions to a melanin-like substance. The effective black dyeing component commonly used in the traditional hair dye is an aniline compound, and the compound has potential adverse effects on human body such as carcinogenicity, teratogenicity, allergy and the like. Because the 5, 6-Dihydroxyindole (DHI) has small irritation to human skin, the DHI is used for replacing the core component aniline compound of the traditional hair dye in some daily chemical hair dyeing products, and is an ideal effective component of a new generation of safe and healthy hair dye. It is also a good antioxidant and can be used as an important intermediate for synthesizing some amino acids, alkaloids and tryptamine.
Because 5, 6-Dihydroxyindole (DHI) has important uses in a plurality of fields, internationally known daily chemical enterprises such as Europea, france begin to research the production process and application of 5, 6-Dihydroxyindole (DHI) in the last 80 th century, and the layout of the patent application is carried out. In recent years, research on 5, 6-Dihydroxyindole (DHI) is increasing internationally. Because 5, 6-Dihydroxyindole (DHI) is extremely easy to oxidize or polymerize and deteriorate, the process difficulty of synthesizing the product with the purity of more than 95% in batches is great, most of the currently reported synthesis methods still stay in the laboratory research stage, and are difficult to apply to large-scale industrial production. According to the existing domestic and foreign literature reports, the synthesis method mainly comprises the following three main categories:
First category: classical indole heterocycle construction method
Based on the literature reports of U.S. Pat. No. 3,4,595,765 (nitroolefin synthesis indole, 1986), U.S. Pat. No. 3, 5,410,067 (ortho-nitroacetonitrile synthesis indole, 1995), U.S. Pat. No. 5,6,160,127 (nitroolefin synthesis indole, 2000) and the like, the target molecule 5, 6-Dihydroxyindole (DHI) is directly or indirectly obtained by starting from raw materials such as 3, 4-dialkoxy-substituted benzaldehyde, benzyl cyanide and the like, through multi-step reactions, particularly nitration, and subsequent ring closure reactions, and ring closure of ortho-position difunctional groups. The common problems are that dangerous nitration is used in the intermediate reaction, the steps are long, and the comprehensive yield is not high. Particularly, the problem is that the final synthesis of target molecule 5, 6-Dihydroxyindole (DHI) is operated in one step, the product is easy to deteriorate, and the qualified product is difficult to obtain for subsequent application and development.
The second category: DOPA or dopamine redox
Based on published papers (Tetrahedron,1996,vol.52,#11,p.3947-3952;Bioorganic and Medicinal Chemistry,2012,vol.20,#14,p.4364-4370), and European patent EP 1820491 A1 (dopa redox, 2007, engl ish), U.S. Pat. No. 2020/270208, A1 (dopa oxidation, 2020), chinese patent CN 110981782A (dopamine redox, 2020), and other literature reports, the target molecule 5, 6-Dihydroxyindole (DHI) is obtained from dopa or dopamine through oxidation reaction and reduction reaction as shown in the scheme. The common problem is that the actual yield of the target molecule 5, 6-Dihydroxyindole (DHI) is not high, the color of the product is deep and easy to deteriorate, and a qualified product is difficult to obtain for subsequent industrialization.
Third category: direct dehydrogenation oxidation method of indoline
Based on published papers (Molecules, vol.23; nb.8; 2018; art. No: 1943.), and the like, as well as in U.S. Pat. No. 5,536,843 (dehydrogenation of sodium fumarate or ammonium persulfate, 1996), U.S. Pat. No. 5,578,735 (dehydrogenation of cyclohexene, 1996), and the like, as shown in the above-mentioned roadmap, dehydrogenation oxidation reaction is realized by directly carrying out hydrogen transfer reagent sodium fumarate, ammonium persulfate or cyclohexene, etc. from 5, 6-double protected hydroxy or bare dihydroxyindoline, and the corresponding indoline is directly converted into target molecule 5, 6-Dihydroxyindole (DHI). Although the synthesis paths of the processes are shorter, the obvious problems are that high-temperature reaction conditions are needed, the dehydrogenation reaction is difficult to control, the side reaction is obvious, the actual yield of target molecule 5, 6-Dihydroxyindole (DHI) is low, the color of the product is deep and easy to deteriorate, and the qualified product is still difficult to obtain to meet the industrial application.
Therefore, the technicians in this field are still developing various research and development works, and a new process method is expected to be capable of producing a5, 6-Dihydroxyindole (DHI) product with high purity and stable quality, which meets the requirements of multiple fields, and especially a process route and a preparation method which are mild in reaction condition, suitable for large-scale production, controllable in cost and convenient for product preservation and use are expected.
Disclosure of Invention
Aiming at the defects and shortcomings of a 5, 6-Dihydroxyindole (DHI) synthesis route and a process technology in the prior art, the first aim of the invention is to provide a synthesis method of 5, 6-Dihydroxyindole (DHI), which has mild reaction conditions, can stably realize large-scale production, and has the advantages of easily available raw materials, controllable cost and good process reproducibility.
A second object of the present invention is to provide a method for preventing deterioration of a5, 6-Dihydroxyindole (DHI) product: the antioxidant and the polymerization inhibitor are added, so that the 5, 6-Dihydroxyindole (DHI) product has light color, good purity and convenient preservation and subsequent use.
A third object of the present invention is to provide an intermediate compound of formula (IC 241-03) for synthesizing 5, 6-Dihydroxyindole (DHI) and a method for preparing the same.
A fourth object of the present invention is to provide an intermediate compound of formula (IC 241-04) for synthesizing 5, 6-Dihydroxyindole (DHI) and a method for preparing the same.
In order to achieve the above object, the present invention adopts the following technical scheme:
A synthesis method of 5, 6-dihydroxyindole, which starts from a convenient and easily available 5, 6-dihydroxyindoline halogen acid salt or other acid salt, and finally realizes the synthesis of 5, 6-Dihydroxyindole (DHI) by preparing key intermediates of 1-carbobenzoxy-5, 6-dibenzyloxyindoline (IC 241-03) and 1-carbobenzoxy-5, 6-dibenzyloxyindole (IC 241-04), and comprises the following four steps:
(1) The starting reactant 5, 6-dihydroxyindoline hydrohalate or other acid salt (IC 241-01) reacts with a carbobenzoxy reagent under the conditions of proper solvent, proper alkali and proper temperature to prepare an intermediate 1-carbobenzoxy-5, 6-dihydroxyindoline (IC 241-02);
(2) Reacting the intermediate 1-benzyloxycarbonyl-5, 6-dihydroxyindoline (IC 241-02) obtained in the step (1) with a benzyl halide reagent under a suitable solvent, a suitable base and a suitable temperature condition to obtain an intermediate 1-benzyloxycarbonyl-5, 6-dibenzyloxyindoline (IC 241-03);
(3) The intermediate 1-carbobenzoxy-5, 6-dibenzyloxyindoline (IC 241-03) obtained in the step (2) reacts with a proper oxidant in a proper solvent under a proper temperature condition, and is oxidized to obtain an intermediate 1-carbobenzoxy-5, 6-dibenzyloxyindole (IC 241-04);
(4) Intermediate 1-carbobenzoxy-5, 6-dibenzyloxy indole (IC 241-04) obtained in the step (3) is dissolved in a proper solvent, a proper amount of additives such as an antioxidant, a polymerization inhibitor and the like are added, a proper metal catalyst is added, and a protecting group is removed under a proper hydrogen pressure and temperature condition to obtain target product molecules 5, 6-Dihydroxyindole (DHI).
Further, in step (1), the solvent used in the reaction is selected from the group consisting of ethers, esters, halogenated hydrocarbons, acetonitrile, DMSO, DMF, water, or a combination thereof; the alkali used in the reaction is selected from one of organic alkali such as triethylamine, DIEA and the like, and inorganic alkali such as calcium carbonate, magnesium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and the like; the reaction temperature is from 0 to 50 ℃; the carbobenzoxy reagent used in the reaction comprises benzyl chloroformate or benzyl succinimide carbonate.
Further, in the step (1), more preferably, ethyl acetate with a volume ratio of 5-10 times is selected as a solvent, benzyl chloroformate and 5, 6-dihydroxyindoline hydrohalogenate (IC 241-01) are selected to be fed according to the equimolar ratio, calcium carbonate is used as alkali (1.2 molar equivalent), the reaction is carried out at room temperature, TLC monitors the reaction progress, and the reaction is carried out for 5-24 hours generally completely, so as to obtain an intermediate 1-carbobenzoxy-5, 6-dihydroxyindoline (IC 241-02).
Further, in the step (1), the reaction of converting the formula (IC 241-01) into the formula (IC 241-02) is performed as follows: adding solvent into a reaction vessel, then adding main raw material compound (IC 241-01), adding proper amount of alkali, stirring under ice water bath, dropwise adding carbobenzoxy reagent, gradually heating to room temperature for reaction for 5-24 hours, and monitoring by TLC until the reaction is completed.
Further, in the step (1), the compound formula (IC 241-02) obtained by the following operation treatment is used after the completion of the reaction: filtering, regulating pH value of the filtrate to about 5 with dilute hydrochloric acid, extracting with ethyl acetate in a liquid-separated mode, and combining organic solvent phases to directly use for the next reaction.
Further, wherein in step (2), preferably, the solvent used for the reaction is selected from the group consisting of ethers, esters, halogenated hydrocarbons, acetonitrile, acetone, DMSO, DMF, water, or a combination thereof;
the alkali used in the reaction is selected from one of organic alkali such as triethylamine, DIEA and the like, and inorganic alkali such as calcium carbonate, magnesium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and the like;
The reaction temperature is from 0 to 100 ℃;
The benzyl halide reagent used in the reaction comprises benzyl chloride, benzyl bromide and the like;
the feeding mole ratio of the halogenated benzyl reagent to the reactant 1-carbobenzoxy-5, 6-dihydroxyindoline (IC 241-02) is (2-3): 1;
Further, in the step (2), ethyl acetate with a volume ratio of 5-8 times is selected as a solvent, and benzyl chloride and 1-benzyloxycarbonyl-5, 6-dihydroxyindoline (IC 241-02) 2.2:1 molar ratio, potassium carbonate as base (2.5 molar equivalent), at 50 ℃, TLC monitoring the progress of the reaction, usually 8-24 hours reaction is complete, obtaining intermediate 1-carbobenzoxy-5, 6-dibenzyloxyindoline (IC 241-03).
Further, in the step (2), the reaction of converting the formula (IC 241-02) into the formula (IC 241-03) is carried out as follows: adding the compound solution of the formula (IC 241-02) obtained in the step (1) into a reaction vessel, adding a proper amount of alkali, stirring at room temperature, dropwise adding a benzyl halide reagent, gradually raising the temperature to 50 ℃ for reaction for 8-24 hours, and monitoring by TLC until the reaction is completed.
Further, in the step (2), the compound represented by the following formula (IC 241-03) was used after the completion of the reaction: after the reaction, the pH value is regulated to about 5-6 by dilute hydrochloric acid, ethyl acetate is used for liquid extraction, organic solvent phases are combined and concentrated, and the obtained viscous liquid is mainly in a compound formula (IC 241-03), and besides a small amount of column chromatography purification is used for nuclear magnetic characterization, other liquid can directly enter the next step without purification.
Further wherein in step (3) the solvent used in the reaction is selected from the group consisting of ethers, esters, halogenated hydrocarbons, acetonitrile, water or a combination thereof;
The reaction temperature is from 0 to 50 ℃;
Oxidizing agents used in the reaction include DDQ, manganese dioxide, and the like;
The molar ratio of the oxidant used in the reaction to the reactant 1-carbobenzoxy-5, 6-dibenzyloxyindoline (IC 241-03) is (1-10): 1;
Further, in the step (3), dichloromethane with the volume ratio of 5-10 times is selected as a solvent, and manganese dioxide and 1-carbobenzoxy-5, 6-dibenzyloxyindoline (IC 241-03) 5 are selected as follows: 1 molar ratio, at room temperature, TLC monitors the progress of the reaction, usually for 12-36 hours, to obtain intermediate 1-carbobenzoxy-5, 6-dibenzyloxyindole (IC 241-04).
Further, in the step (3), the reaction of converting the formula (IC 241-03) into the formula (IC 241-04) is carried out as follows: dissolving the crude viscous liquid of the compound of formula (IC 241-03) obtained in the step (2) with a proper amount of solvent, transferring the solvent into a reaction vessel, adding a proper amount of oxidant, stirring at room temperature for reaction for 8-24 hours, and monitoring by TLC until the reaction is completed.
Further, in the step (3), the compound represented by the following formula (IC 241-04) was used after the completion of the reaction: after the reaction is finished, filtering, adding a proper amount of water into the solution for liquid extraction, combining organic solvent phases, drying and concentrating the organic solvent phases by using a drier, and purifying the organic solvent phases by using a short silica gel column to obtain a compound formula (IC 241-04) which is a white powder solid and is ready for the next reaction.
Further wherein in step (4) the solvent used in the reaction is selected from the group consisting of alcohols, ethers, esters, halogenated hydrocarbons, acetonitrile, water or a combination thereof;
The reaction temperature is from 0 to 50 ℃;
The antioxidant and polymerization inhibitor used in the reaction comprise sodium ascorbate, vitamin C, tea polyphenol, phenol, 2, 6-di-tert-butylphenol and the like or a combination thereof in a mass ratio of 0.01-1%;
The metal catalyst used in the reaction comprises palladium carbon, palladium hydroxide carbon and the like;
the hydrogen pressure used for the reaction is from 1 to 5 atmospheres;
ethanol with the volume ratio of 5-10 times is selected as a solvent, 0.1% of vitamin C and 0.05% of 2, 6-di-tert-butylphenol are added as an antioxidant and a polymerization inhibitor, a wet palladium-carbon catalyst with the water content of 50% of 10% is added, air in a reaction system is pumped out, 1 atmosphere hydrogen is introduced for reaction at room temperature, TLC monitors the reaction progress, and the reaction is completed in 12-36 hours generally, thus obtaining the target product 5, 6-Dihydroxyindole (DHI).
Further, in the step (4), the reaction for converting the formula (IC 241-04) into the target product 5, 6-Dihydroxyindole (DHI) is carried out as follows: adding a solvent into a reaction container, then adding the compound of the formula (IC 241-04) obtained in the step (3), adding a proper amount of antioxidant and polymerization inhibitor, adding a proper amount of metal catalyst, vacuumizing the system, introducing hydrogen, reacting at room temperature for 12-36 hours, and monitoring by TLC until the reaction is completed.
Further, in the step (4), the target product 5, 6-Dihydroxyindole (DHI) obtained by the following operation is used after the completion of the reaction: after the reaction is finished, filtering under the nitrogen atmosphere, concentrating the solution to about one third to one fourth of the volume, adding a proper amount of poor solvent such as methyl tertiary butyl ether and the like, and recrystallizing to obtain the target product 5, 6-Dihydroxyindole (DHI) which is a beige to off-white powder solid.
The invention also provides a key intermediate 1 in the method for synthesizing the 5, 6-dihydroxyindole, wherein the key intermediate is 1-carbobenzoxy-5, 6-dibenzyloxyindoline (IC 241-03), and the structural formula is as follows:
the invention also provides a key intermediate 2 in the method for synthesizing the 5, 6-dihydroxyindole, wherein the key intermediate is 1-carbobenzoxy-5, 6-dibenzyloxyindole (IC 241-04), and the structural formula is as follows:
The beneficial effects of the invention are as follows:
(1) By adopting the method for preparing the 5, 6-dihydroxyindole, disclosed by the invention, the reaction condition is mild, the large-scale production can be stably realized, the raw materials are easy to obtain, the cost is controllable, and the process reproducibility is good.
(2) The method is based on a synthesis strategy of finally removing the protecting group, and the antioxidant and the polymerization inhibitor are added, so that the target product 5, 6-Dihydroxyindole (DHI) has the comprehensive advantages of light color, good purity, convenience in storage and subsequent use and the like.
Drawings
FIG. 1 is a process scheme showing a method for synthesizing 5, 6-dihydroxyindole according to an embodiment of the present invention;
FIG. 2 is a H1-NMR nuclear magnetic spectrum of a key intermediate 1-benzyloxycarbonyl-5, 6-dibenzyloxyindoline (IC 241-03);
FIG. 3 is a H1-NMR nuclear magnetic spectrum of a key intermediate 1-benzyloxycarbonyl-5, 6-dibenzyloxyindole (IC 241-04);
FIG. 4 is a H1-NMR nuclear magnetic spectrum of the target product 5, 6-Dihydroxyindole (DHI);
FIG. 5 is a sample appearance of the final product 5, 6-Dihydroxyindole (DHI);
FIG. 6 is a sample appearance of the starting material 5, 6-dihydroxyindoline hydrobromide (IC 241-01).
Detailed Description
The invention is described in detail below with reference to the drawings and the specific embodiments.
The examples set forth below serve the purpose of illustrating the invention only and are not meant or construed in any way as limiting the invention. Those skilled in the art will appreciate that many routine modifications and improvements can be made to the following examples without departing from the spirit and scope of the invention.
As shown in FIG. 1, a method for synthesizing 5, 6-dihydroxyindole, which starts from a convenient and easily available 5, 6-dihydroxyindole hydrohalogenate (which can also comprise other acid salts), and finally realizes the synthesis of 5, 6-Dihydroxyindole (DHI) by preparing key intermediates 1-benzyloxycarbonyl-5, 6-dibenzyloxyiindoline (IC 241-03) and 1-benzyloxycarbonyl-5, 6-dibenzyloxyindole (IC 241-04), and comprises the following four steps:
(1) The intermediate 1-carbobenzoxy-5, 6-dihydroxyindoline (IC 241-02) is prepared by various methods based on published papers, patent and other literature reports or obtained from a starting reactant of 5, 6-dihydroxyindoline hydrohalogenate (IC 241-01) on the market and reacts with carbobenzoxy reagent under the conditions of proper solvent, proper alkali and proper temperature;
(2) Reacting the intermediate 1-benzyloxycarbonyl-5, 6-dihydroxyindoline (IC 241-02) obtained in the step (1) with a benzyl halide reagent under a suitable solvent, a suitable base and a suitable temperature condition to obtain an intermediate 1-benzyloxycarbonyl-5, 6-dibenzyloxyindoline (IC 241-03);
(3) The intermediate 1-carbobenzoxy-5, 6-dibenzyloxyindoline (IC 241-03) obtained in the step (2) reacts with a proper oxidant in a proper solvent under a proper temperature condition, and is oxidized to obtain an intermediate 1-carbobenzoxy-5, 6-dibenzyloxyindole (IC 241-04);
(4) Intermediate 1-carbobenzoxy-5, 6-dibenzyloxy indole (IC 241-04) obtained in the step (3) is dissolved in a proper solvent, a proper amount of additives such as an antioxidant, a polymerization inhibitor and the like are added, a proper metal catalyst is added, and a protecting group is removed under a proper hydrogen pressure and temperature condition to obtain target product molecules 5, 6-Dihydroxyindole (DHI).
In this embodiment, in step (1), it is preferable that: the solvent used in the reaction is selected from ether, ester, halogenated hydrocarbon, acetonitrile, DMSO, DMF, water or a combination solvent thereof; the alkali used in the reaction is selected from one of organic alkali such as triethylamine, DIEA and the like, and inorganic alkali such as calcium carbonate, magnesium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and the like; the reaction temperature is from 0 to 50 ℃; the carbobenzoxy reagent used in the reaction comprises benzyl chloroformate or benzyl succinimide carbonate and the like.
In the step (1), more preferably, ethyl acetate with the volume ratio of 5-10 times is selected as a solvent, benzyl chloroformate and 5, 6-dihydroxyindoline hydrohalogenate (IC 241-01) are selected to be fed according to the equimolar ratio, calcium carbonate is used as alkali (1.2 molar equivalent), the reaction is carried out at room temperature, TLC monitors the reaction progress, and the reaction is carried out for 5-24 hours normally, so that an intermediate 1-benzyloxycarbonyl-5, 6-dihydroxyindoline (IC 241-02) is obtained.
The process according to the invention, wherein in step (1), the reaction for converting the formula (IC 241-01) into the formula (IC 241-02) is carried out as follows: adding solvent into a reaction vessel, then adding main raw material compound (IC 241-01), adding proper amount of alkali, stirring under ice water bath, dropwise adding carbobenzoxy reagent, gradually heating to room temperature for reaction for 5-24 hours, and monitoring by TLC until the reaction is completed.
In the step (1), the compound formula (IC 241-02) obtained by the following operation treatment was used after the completion of the reaction: filtering, regulating pH value of the filtrate to about 5 with dilute hydrochloric acid, extracting with ethyl acetate in a liquid-separated mode, and combining organic solvent phases to directly use for the next reaction.
In this embodiment, wherein in step (2), preferably, the solvent used for the reaction is selected from the group consisting of ethers, esters, halogenated hydrocarbons, acetonitrile, acetone, DMSO, DMF, water, or a combination thereof;
In step (2), preferably, the base used in the reaction is selected from one of organic bases such as triethylamine, DIEA, etc., inorganic bases such as calcium carbonate, magnesium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, etc.;
in step (2), preferably, the reaction temperature is from 0 to 100 ℃;
In step (2), preferably, the benzyl halide reagent used in the reaction includes benzyl chloride or benzyl bromide, etc.;
In step (2), preferably, the molar ratio of the halogenated benzyl reagent used in the reaction to the feed of reactant 1-benzyloxycarbonyl-5, 6-dihydroxyindoline (IC 241-02) is (2-3): 1;
in the step (2), more preferably, ethyl acetate with a volume ratio of 5-8 times is selected as a solvent, and benzyl chloride and 1-benzyloxycarbonyl-5, 6-dihydroxyindoline (IC 241-02) 2.2:1 molar ratio, potassium carbonate as base (2.5 molar equivalent), at 50 ℃, TLC monitoring the progress of the reaction, usually 8-24 hours reaction is complete, obtaining intermediate 1-carbobenzoxy-5, 6-dibenzyloxyindoline (IC 241-03).
The process according to the invention, wherein in step (2), the reaction for converting the formula (IC 241-02) into the formula (IC 241-03) is carried out as follows: adding the compound solution of the formula (IC 241-02) obtained in the step (1) into a reaction vessel, adding a proper amount of alkali, stirring at room temperature, dropwise adding a benzyl halide reagent, gradually raising the temperature to 50 ℃ for reaction for 8-24 hours, and monitoring by TLC until the reaction is completed.
In the step (2), the compound of formula (IC 241-03) obtained by the following operation treatment was used after the completion of the reaction: after the reaction, the pH value is regulated to about 5-6 by dilute hydrochloric acid, ethyl acetate is used for liquid extraction, organic solvent phases are combined and concentrated, and the obtained viscous liquid is mainly in a compound formula (IC 241-03), and besides a small amount of column chromatography purification is used for nuclear magnetic characterization, other liquid can directly enter the next step without purification.
In this embodiment, wherein in step (3), preferably, the solvent used for the reaction is selected from the group consisting of ethers, esters, halogenated hydrocarbons, acetonitrile, water, or a combination thereof;
In step (3), preferably, the reaction temperature is from 0 to 50 ℃;
In step (3), preferably, the oxidizing agent used for the reaction includes DDQ, manganese dioxide, and the like;
In step (3), preferably, the molar ratio of the oxidant used in the reaction to the feed of reactant 1-benzyloxycarbonyl-5, 6-dibenzyloxyindoline (IC 241-03) is (1-10): 1;
In the step (3), more preferably, dichloromethane with the volume ratio of 5-10 times is selected as a solvent, and manganese dioxide and 1-carbobenzoxy-5, 6-dibenzyloxyindoline (IC 241-03) 5:1 molar ratio, at room temperature, TLC monitors the progress of the reaction, usually for 12-36 hours, to obtain intermediate 1-carbobenzoxy-5, 6-dibenzyloxyindole (IC 241-04).
The process according to the invention, wherein in step (3), the reaction for converting the formula (IC 241-03) into the formula (IC 241-04) is carried out as follows: dissolving the crude viscous liquid of the compound of the formula (IC 241-03) obtained in the step (2) by using a proper amount of solvent, transferring the solution into a reaction vessel, adding a proper amount of oxidant, stirring the reaction at room temperature for 8-24 hours, and monitoring by TLC until the reaction is completed.
In the step (3), the compound of formula (IC 241-04) obtained by the following operation treatment was used after the completion of the reaction: after the reaction is finished, filtering, adding a proper amount of water into the solution for liquid extraction, combining organic solvent phases, drying and concentrating the organic solvent phases by using a drier, and purifying the organic solvent phases by using a short silica gel column to obtain a compound formula (IC 241-04) which is a white powder solid and is ready for the next reaction.
In this embodiment, in step (4), preferably, the solvent used in the reaction is selected from alcohols, ethers, esters, halogenated hydrocarbons, acetonitrile, water or a combination thereof;
in step (4), preferably, the reaction temperature is from 0 to 50 ℃;
In step (4), preferably, the antioxidants and polymerization inhibitors used in the reaction include sodium ascorbate, vitamin C, tea polyphenols, phenol, 2, 6-di-t-butylphenol, etc. or a combination thereof in an amount of 0.01-1% by mass;
in step (4), preferably, the metal catalyst used for the reaction includes palladium on carbon, palladium hydroxide on carbon, and the like;
in step (4), preferably, the reaction uses a hydrogen pressure of from 1 to 5 atmospheres;
In the step (4), more preferably, ethanol with the volume ratio of 5-10 times is selected as a solvent, 0.1% of vitamin C and 0.05% of 2, 6-di-tert-butylphenol are added as an antioxidant and a polymerization inhibitor, 10% of wet palladium-carbon catalyst with the water content of 50% are added, air in a reaction system is pumped out, 1 atmosphere of hydrogen is introduced for reaction at room temperature, TLC monitors the reaction progress, and the reaction is completed in 12-36 hours generally, so that the target product 5, 6-Dihydroxyindole (DHI) is obtained.
The process according to the invention, wherein in step (4), the reaction of converting the formula (IC 241-04) into the target product 5, 6-Dihydroxyindole (DHI) is carried out as follows: adding a solvent into a reaction container, then adding the compound of the formula (IC 241-04) obtained in the step (3), adding a proper amount of antioxidant and polymerization inhibitor, adding a proper amount of metal catalyst, vacuumizing the system, introducing hydrogen, reacting at room temperature for 12-36 hours, and monitoring by TLC until the reaction is completed.
In the step (4), the target product 5, 6-Dihydroxyindole (DHI) obtained by the following operation is used after the reaction is finished: after the reaction is finished, filtering under the nitrogen atmosphere, concentrating the solution to about one third to one fourth of the volume, adding a proper amount of poor solvent such as methyl tertiary butyl ether and the like, and recrystallizing to obtain the target product 5, 6-Dihydroxyindole (DHI) which is a beige to off-white powder solid.
Example 1: preparation of the key intermediate 1-benzyloxycarbonyl-5, 6-dibenzyloxyindoline (IC 241-03)
To the reaction vessel was added 28.5 g (FW: 285,0.10 mol) of the compound of formula (IC 241-02) in 200ml of ethyl acetate, 34.6 g (2.5 molar equivalents, 0.25mol, FW: 138.2) of potassium carbonate was added, 27.8 g (2.2 molar equivalents, 0.22mol, FW: 126.5) of benzyl chloride was stirred and added dropwise at room temperature, the reaction was gradually raised to 50℃and after 15 hours TLC was monitored for completion. The pH value is regulated to about 6 by dilute hydrochloric acid, ethyl acetate is used for liquid-liquid extraction, organic solvent phases are combined, and the mixture is concentrated to obtain 50.2 g of crude product of light yellow viscous liquid. Column chromatography purification (EA: PE,1:50,1:20, 1:10) gave 45.1 g of 1-benzyloxycarbonyl-5, 6-dibenzyloxyindoline (IC 241-03) in 97% molar yield.
As shown in FIG. 2, the 1-benzyloxycarbonyl-5, 6-dibenzyloxyindoline (IC 241-03) nuclear magnetic resonance characterization H1NMR data was analyzed as follows ：1H-NMR(600MHz,d6-DMSO):δ(ppm)＝7.545-7.578(m,1H,Ar-H),7.116-7.478(m,15H,Ar-H),6.992(s,1H,Ar-H),4.862-5.446(m,6H,Bn-CH2),3.927-3.986(brs,2H,-CH2),2.507(brs,2H,-CH2).
Example 2: preparation of the key intermediate 1-benzyloxycarbonyl-5, 6-dibenzyloxylindole (IC 241-04)
1-Benzyloxycarbonyl-5, 6-dibenzyloxyindoline (IC 241-03) 37.2 g (FW: 465,0.08 mol) was dissolved in 250 ml of methylene chloride, 34.8 g (5.0 eq, FW:87,0.08 mol) of manganese dioxide was added to the solution, the reaction was carried out at room temperature, and the progress of the reaction was monitored by TLC, after 24 hours, the reaction was completed. Filtering, adding 100 ml of water into the solution, separating and extracting twice, combining organic solvent phases, drying by a drying agent, concentrating, and purifying by a short silica gel column to obtain 35.2 g of 1-carbobenzoxy-5, 6-dibenzyloxyindole (IC 241-04) as white powder solid with the yield of 95 percent.
As shown in FIG. 3, the 1-benzyloxycarbonyl-5, 6-dibenzyloxylindole (IC 241-04) nuclear magnetic resonance characterization H1NMR data was analyzed as follows ：1H-NMR(600MHz,CDCl 3):δ(ppm)＝7.888(brs,1H,Ar'-H),7.285-7.521(m,16H,Ar-H),7.107(s,1H,Ar-H),6.469-6.475(m,1H,Ar'-H),5.444(s,2H,Ar-H),5.166-5.198(m,4H,Ar-H).
Example 3: preparation of the target product 5, 6-Dihydroxyindole (DHI)
32.4 G (FW: 463,0.07 mol) of 1-benzyloxycarbonyl-5, 6-dibenzyloxyindole (IC 241-04) was dissolved in 200 ml of an ethanol solvent, 0.1% by mass of vitamin C (32 mg) and 0.05% by mass of 2, 6-di-t-butylphenol (16 mg) were added as an antioxidant and a polymerization inhibitor, 10% by mass of a wet palladium on charcoal catalyst (3.24 g) containing 50% by mass of water were added, the air in the reaction system was evacuated, 1 atmosphere of hydrogen was introduced for reaction at room temperature, and TLC was allowed to monitor the progress of the reaction for 24 hours to completion. Filtering under nitrogen atmosphere, concentrating the solution to about 60 ml, adding 100 ml of methyl tertiary butyl ether, dissolving the micro-heating system, cooling to 0 ℃, and crystallizing gradually to separate off white solid powder. Filtration under nitrogen afforded 9.6 g of off-white powder, which was characterized by nuclear magnetic H1NMR as the target product 5, 6-Dihydroxyindole (DHI) in 91% yield.
As shown in FIG. 4, the 5, 6-Dihydroxyindole (DHI) nuclear magnetic resonance (H1 NMR) data were analyzed for 98.2% purity as measured at ：1H-NMR(400MHz,d6-DMSO):δ(ppm)＝10.429(s,1H,NH),8.370(brs,2H,-OH),6.995-7.006(m,1H,Ar'-H),6.827(s,1H,Ar-H),6.757(s,1H,Ar-H),6.130-6.133(m,3H,Ar'-H);HPLC:214nm below.
As shown in FIG. 5, FIG. 5 is a sample appearance diagram of the final product, i.e., 5, 6-Dihydroxyindole (DHI) as a target product.
As shown in FIG. 6, FIG. 6 is a sample appearance of the starting material 5, 6-dihydroxyindoline hydrobromide (IC 241-01).
While the invention has been described in terms of the specific embodiments thereof, it will be appreciated by those skilled in the art that the invention is not limited to the foregoing examples, which are set forth in the above description and are intended to illustrate the principles of the invention, but rather to provide various changes and modifications within the spirit and scope of the invention as hereinafter claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (20)
1. A method for synthesizing 5, 6-dihydroxyindole, which is characterized in that the method is started from 5, 6-dihydroxyindoline halogen acid salt or other acid salt which is convenient and easy to obtain, and the synthesis of 5, 6-Dihydroxyindole (DHI) is finally realized through preparing key intermediates 1-carbobenzoxy-5, 6-dibenzyloxyindoline (IC 241-03) and 1-carbobenzoxy-5, 6-dibenzyloxyindole (IC 241-04), and the method comprises the following four steps:
(1) The starting reactant 5, 6-dihydroxyindoline hydrohalate or other acid salt (IC 241-01) reacts with a carbobenzoxy reagent under the conditions of proper solvent, proper alkali and proper temperature to prepare an intermediate 1-carbobenzoxy-5, 6-dihydroxyindoline (IC 241-02);
(2) Reacting the intermediate 1-benzyloxycarbonyl-5, 6-dihydroxyindoline (IC 241-02) obtained in the step (1) with a benzyl halide reagent under a suitable solvent, a suitable base and a suitable temperature condition to obtain an intermediate 1-benzyloxycarbonyl-5, 6-dibenzyloxyindoline (IC 241-03);
(3) The intermediate 1-carbobenzoxy-5, 6-dibenzyloxyindoline (IC 241-03) obtained in the step (2) reacts with a proper oxidant in a proper solvent under a proper temperature condition, and is oxidized to obtain an intermediate 1-carbobenzoxy-5, 6-dibenzyloxyindole (IC 241-04);
(4) Intermediate 1-carbobenzoxy-5, 6-dibenzyloxy indole (IC 241-04) obtained in the step (3) is dissolved in a proper solvent, proper antioxidant and polymerization inhibitor additives are added, proper metal catalyst is added, and protective groups are removed under proper hydrogen pressure and temperature conditions to obtain target product molecules 5, 6-Dihydroxyindole (DHI).
2. The method for synthesizing 5, 6-dihydroxyindole according to claim 1, wherein in the step (1), a solvent used in the reaction is selected from the group consisting of an ether, an ester, a halogenated hydrocarbon, acetonitrile, DMSO, DMF, water, and a combination solvent thereof; the alkali used in the reaction is selected from one of organic alkali such as triethylamine and DIEA, and inorganic alkali such as calcium carbonate, magnesium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide; the reaction temperature is from 0 to 50 ℃; the carbobenzoxy reagent used in the reaction comprises benzyl chloroformate or benzyl succinimide carbonate.
3. The method for synthesizing 5, 6-dihydroxyindole according to claim 2, wherein in the step (1), ethyl acetate with a volume ratio of 5-10 times is selected as a solvent, benzyl chloroformate and 5, 6-dihydroxyindoline hydrohalogenate (IC 241-01) are selected to be added according to equimolar amounts, calcium carbonate is selected as base (1.2 molar equivalent), the reaction is carried out at room temperature, TLC monitors the reaction progress, and the reaction is carried out for 5-24 hours normally, so that intermediate 1-benzyloxycarbonyl-5, 6-dihydroxyindoline (IC 241-02) is obtained.
4. The method for synthesizing 5, 6-dihydroxyindole according to claim 2, wherein in the step (1), the reaction for converting 5, 6-dihydroxyindoline hydrohalogenate (IC 241-01) into 1-benzyloxycarbonyl-5, 6-dihydroxyindoline (IC 241-02) is performed as follows: adding solvent into a reaction vessel, then adding main raw material 5, 6-dihydroxyindoline (IC 241-01) compound, adding proper amount of alkali, stirring under ice water bath, dropwise adding carbobenzoxy reagent, gradually raising the temperature to room temperature for reaction for 5-24 hours, and monitoring by TLC until the reaction is completed.
5. The method for synthesizing 5, 6-dihydroxyindole according to any one of claims 2 to 4, wherein in the step (1), the compound 1-benzyloxycarbonyl-5, 6-dihydroxyindoline (IC 241-02) obtained by the following treatment is used after the completion of the reaction: filtering, regulating pH value of the filtrate to about 5 with dilute hydrochloric acid, extracting with ethyl acetate in a liquid-separated mode, and combining organic solvent phases to directly use for the next reaction.
6. The method for synthesizing 5, 6-dihydroxyindole according to claim 1, wherein in the step (2), a solvent used in the reaction is selected from the group consisting of ether, ester, halogenated hydrocarbon, acetonitrile, acetone, DMSO, DMF, water, and a combination solvent thereof;
The alkali used in the reaction is selected from one of organic alkali such as triethylamine and DIEA, and inorganic alkali such as calcium carbonate, magnesium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide;
The reaction temperature is from 0 to 100 ℃;
the benzyl halide reagent used in the reaction comprises benzyl chloride or benzyl bromide.
7. The method for synthesizing 5, 6-dihydroxyindole according to claim 6, wherein in the step (2), a molar ratio of a benzyl halide reagent used in the reaction to a reactant 1-benzyloxycarbonyl-5, 6-dihydroxyindoline (IC 241-02) is (2-3): 1.
8. The method for synthesizing 5, 6-dihydroxyindole according to claim 6, wherein in the step (2), ethyl acetate with a volume ratio of 5-8 times is selected as a solvent, and benzyl chloride and 1-benzyloxycarbonyl-5, 6-dihydroxyindoline (IC 241-02) 2.2:1 molar ratio, potassium carbonate as base (2.5 molar equivalent), at 50 ℃, TLC monitoring the progress of the reaction, usually 8-24 hours reaction is complete, obtaining intermediate 1-carbobenzoxy-5, 6-dibenzyloxyindoline (IC 241-03).
9. The method for synthesizing 5, 6-dihydroxyindole according to any one of claims 6 to 8, wherein in the step (2), the reaction for converting 1-benzyloxycarbonyl-5, 6-dihydroxyindoline (IC 241-02) into 1-benzyloxycarbonyl-5, 6-dibenzyloxyline (IC 241-03) is carried out as follows: adding the 1-carbobenzoxy-5, 6-dihydroxyindoline (IC 241-02) compound solution obtained in the step (1) into a reaction vessel, adding a proper amount of alkali, stirring at room temperature, dropwise adding a benzyl halide reagent, gradually raising the temperature to 50 ℃ for reaction for 8-24 hours, and monitoring by TLC until the reaction is completed.
10. The method for synthesizing 5, 6-dihydroxyindole according to claim 6, wherein in the step (2), the compound 1-benzyloxycarbonyl-5, 6-dibenzyloxyindoline (IC 241-03) obtained by the following treatment is used after the completion of the reaction: after the reaction, the pH value is regulated to about 5-6 by dilute hydrochloric acid, ethyl acetate is used for liquid-liquid extraction, organic solvent phases are combined and concentrated to obtain a viscous liquid which is mainly the compound 1-carbobenzoxy-5, 6-dibenzyloxyindoline (IC 241-03), and other materials are directly used for the next step without purification except a small amount of column chromatography purification for nuclear magnetism characterization.
11. The method for synthesizing 5, 6-dihydroxyindole according to claim 1, wherein in the step (3), the solvent used in the reaction is selected from the group consisting of ether, ester, halogenated hydrocarbon, acetonitrile, water and a combination solvent thereof;
The reaction temperature is from 0 to 50 ℃;
oxidizing agents used in the reaction include DDQ and manganese dioxide;
the molar ratio of the oxidant used in the reaction to the reactant 1-benzyloxycarbonyl-5, 6-dibenzyloxyindoline (IC 241-03) is (1-10): 1.
12. The method for synthesizing 5, 6-dihydroxyindole according to claim 11, wherein in the step (3), dichloromethane with a volume ratio of 5-10 times is selected as a solvent, and manganese dioxide and 1-benzyloxycarbonyl-5, 6-dibenzyloxyindoline (IC 241-03) 5:1 molar ratio, at room temperature, TLC monitors the progress of the reaction, usually for 12-36 hours, to obtain intermediate 1-carbobenzoxy-5, 6-dibenzyloxyindole (IC 241-04).
13. The method for synthesizing 5, 6-dihydroxyindole according to claim 11, wherein in the step (3), the reaction for converting 1-benzyloxycarbonyl-5, 6-dibenzyloxyindoline (IC 241-03) into 1-benzyloxycarbonyl-5, 6-dibenzyloxyindole (IC 241-04) is carried out as follows: dissolving the crude 1-carbobenzoxy-5, 6-dibenzyloxyindoline (IC 241-03) compound viscous liquid obtained in the step (2) by using a proper amount of solvent, transferring the solvent into a reaction vessel, adding a proper amount of oxidant, stirring at room temperature for reaction for 8-24 hours, and monitoring by TLC until the reaction is completed.
14. The method for synthesizing 5, 6-dihydroxyindole according to any one of claims 11 to 13, wherein in the step (3), the compound of formula (IC 241-04) obtained by the following treatment is used after the completion of the reaction: after the reaction is finished, filtering, adding a proper amount of water into the solution, extracting, merging organic solvent phases, drying and concentrating the organic solvent phases by using a drier, and purifying the organic solvent phases by using a short silica gel column to obtain the compound 1-carbobenzoxy-5, 6-dibenzyloxyindole (IC 241-04) which is white powder solid and is ready to enter the next reaction.
15. The method for synthesizing 5, 6-dihydroxyindole according to claim 1, wherein in the step (4), the solvent used in the reaction is selected from the group consisting of alcohols, ethers, esters, halogenated hydrocarbons, acetonitrile, water and a combination solvent thereof;
The reaction temperature is from 0 to 50 ℃;
The antioxidant and polymerization inhibitor used in the reaction comprise 0.01-1% by mass of sodium ascorbate, vitamin C, tea polyphenol, phenol, 2, 6-di-tert-butylphenol or a combination thereof;
The metal catalyst used in the reaction comprises palladium carbon and palladium hydroxide carbon;
the reaction uses a hydrogen pressure of from 1 to 5 atmospheres.
16. The method for synthesizing 5, 6-dihydroxyindole according to claim 15, wherein in the step (4), ethanol with a volume ratio of 5-10 times is selected as a solvent, 0.1% of vitamin C and 0.05% of 2, 6-di-tert-butylphenol are added as an antioxidant and a polymerization inhibitor, a wet palladium-carbon catalyst with a water content of 50% of 10% are added, air in a reaction system is pumped out, 1 atmosphere of hydrogen is introduced for reaction at room temperature, TLC monitors the reaction progress, and the reaction is completed in 12-36 hours generally, so that the target product 5, 6-Dihydroxyindole (DHI) is obtained.
17. The method for synthesizing 5, 6-dihydroxyindole according to claim 15, wherein in the step (4), the reaction for converting 1-benzyloxycarbonyl-5, 6-dibenzyloxyindole (IC 241-04) into the target product 5, 6-Dihydroxyindole (DHI) is performed as follows: adding a solvent into a reaction container, then adding the 1-carbobenzoxy-5, 6-dibenzyloxyindole (IC 241-04) compound obtained in the step (3), adding a proper amount of antioxidant and polymerization inhibitor, adding a proper amount of metal catalyst, vacuumizing the system, introducing hydrogen, reacting for 12-36 hours at room temperature, and monitoring by TLC until the reaction is completed.
18. The method for synthesizing 5, 6-dihydroxyindole according to any one of claims 15 to 17, wherein in the step (4), the target product 5, 6-Dihydroxyindole (DHI) obtained by the following treatment is used after the reaction: after the reaction is finished, filtering under the nitrogen atmosphere, concentrating the solution to about one third to one fourth of the volume, adding a proper amount of methyl tertiary butyl ether poor solvent, and recrystallizing to obtain the target product 5, 6-Dihydroxyindole (DHI) which is a beige to white powder solid.
19. An intermediate in a process for synthesizing the 5, 6-dihydroxyindole according to any one of claims 1 to 18, wherein the intermediate is 1-benzyloxycarbonyl-5, 6-dibenzyloxyindoline (IC 241-03) having the structural formula:
20. An intermediate in a process for synthesizing the 5, 6-dihydroxyindole according to any one of claims 1 to 18, wherein the intermediate is 1-benzyloxycarbonyl-5, 6-dibenzyloxyindole (IC 241-04) having the structural formula:
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