CN110981782A - Method for efficiently preparing 5, 6-dihydroxyindole - Google Patents
Method for efficiently preparing 5, 6-dihydroxyindole Download PDFInfo
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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 21
- 238000000034 method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- 239000007800 oxidant agent Substances 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000008367 deionised water Substances 0.000 claims abstract description 8
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 8
- 229960001149 dopamine hydrochloride Drugs 0.000 claims abstract description 8
- 230000001590 oxidative effect Effects 0.000 claims abstract description 8
- 239000000843 powder Substances 0.000 claims abstract description 8
- 239000007787 solid Substances 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 238000004809 thin layer chromatography Methods 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- 238000010992 reflux Methods 0.000 claims abstract description 5
- 229940125898 compound 5 Drugs 0.000 claims abstract description 3
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- AWDBHOZBRXWRKS-UHFFFAOYSA-N tetrapotassium;iron(6+);hexacyanide Chemical compound [K+].[K+].[K+].[K+].[Fe+6].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] AWDBHOZBRXWRKS-UHFFFAOYSA-N 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 4
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 2
- VTIIJXUACCWYHX-UHFFFAOYSA-L disodium;carboxylatooxy carbonate Chemical compound [Na+].[Na+].[O-]C(=O)OOC([O-])=O VTIIJXUACCWYHX-UHFFFAOYSA-L 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 2
- 229940045872 sodium percarbonate Drugs 0.000 claims description 2
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 10
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000007774 longterm Effects 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- 238000003860 storage Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000007795 chemical reaction product Substances 0.000 description 8
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 6
- 238000002390 rotary evaporation Methods 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 229960001701 chloroform Drugs 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000006174 pH buffer Substances 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 3
- 229940081310 piperonal Drugs 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- SGRSNYSOAPBTJP-UHFFFAOYSA-N 4-(2-aminoethyl)benzene-1,2-diol;hydron;bromide Chemical compound Br.NCCC1=CC=C(O)C(O)=C1 SGRSNYSOAPBTJP-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-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
- 239000004480 active ingredient Substances 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000001546 nitrifying effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- YOSOSDBZAUWJJT-UHFFFAOYSA-L sodium dithionite monohydrate Chemical compound O.[Na+].[Na+].[O-]S(=O)S([O-])=O YOSOSDBZAUWJJT-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical compound C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- IXWOUPGDGMCKGT-UHFFFAOYSA-N 2,3-dihydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1O IXWOUPGDGMCKGT-UHFFFAOYSA-N 0.000 description 1
- IXDSDBYUZFMVBW-UHFFFAOYSA-N 2-(3,4-dihydroxyphenyl)acetonitrile Chemical compound OC1=CC=C(CC#N)C=C1O IXDSDBYUZFMVBW-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
- FCGKFNYZQKSLSU-UHFFFAOYSA-N 2-[2-nitro-3,4-bis(phenylmethoxy)phenyl]acetonitrile Chemical compound C1=CC=C(C=C1)COC2=C(C(=C(C=C2)CC#N)[N+](=O)[O-])OCC3=CC=CC=C3 FCGKFNYZQKSLSU-UHFFFAOYSA-N 0.000 description 1
- JVNGVPICFBYTGS-UHFFFAOYSA-N 2-[3,4-bis(phenylmethoxy)phenyl]acetonitrile Chemical compound C=1C=CC=CC=1COC1=CC(CC#N)=CC=C1OCC1=CC=CC=C1 JVNGVPICFBYTGS-UHFFFAOYSA-N 0.000 description 1
- MYYAWHXKTHWBBN-UHFFFAOYSA-N 3,4-bis(phenylmethoxy)-1H-indole Chemical compound C1=CC=C(C=C1)COC2=CC=CC3=C2C(=CN3)OCC4=CC=CC=C4 MYYAWHXKTHWBBN-UHFFFAOYSA-N 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010043275 Teratogenicity Diseases 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
- 150000001448 anilines Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- -1 benzaldehyde compound Chemical class 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- QYCVHILLJSYYBD-UHFFFAOYSA-L copper;oxalate Chemical compound [Cu+2].[O-]C(=O)C([O-])=O QYCVHILLJSYYBD-UHFFFAOYSA-L 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000000118 hair dye Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000003061 melanogenesis Effects 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 238000006396 nitration reaction Methods 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
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000211 teratogenicity Toxicity 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
Images
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
Abstract
The invention provides a preparation method of a compound 5, 6-dihydroxyindole, which comprises the following steps: (1) dissolving 3, 4-dialkoxyphenylethylamine and a catalyst in an organic solvent, carrying out reflux reaction under a heating and stirring state, and tracking the reaction process by using thin-layer chromatography; (2) after the reaction in the step (1) is finished, concentrating to remove excessive acid, adding deionized water, extracting with an organic solvent, and further purifying to obtain white solid dopamine hydrochloride powder; (3) adding an oxidant into dopamine hydrochloride, preparing an intermediate compound I through oxidation reaction, and reducing the compound I with a reducing agent to finally obtain 5, 6-dihydroxyindole solid powder. The method has the advantages of cheap and easily obtained raw materials, catalysts and the like, high reaction yield, less side reactions, suitability for industrial production, less operation steps, short reaction flow, simple treatment after reaction, high purity of the obtained product, good stability and easy long-term storage and use.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a high-efficiency preparation method of a compound 5, 6-dihydroxyindole.
Background
5, 6-dihydroxyindole is an important intermediate of melanogenesis, which was first found in a plant in nature. The pure 5, 6-dihydroxyindole is colorless acicular crystal, has melting point of 140 ℃, is soluble in hot water and is insoluble in petroleum ether; it is stable in the crystalline state, but quickly oxidized to a melanin-like substance in a slightly alkaline solution. Because of its low irritation to human skin, it is used in some washing and chemical products as a black active ingredient instead of the aniline compounds (having the adverse effects of carcinogenicity, teratogenicity, and allergy), and for example, it is used as one of the main active ingredients in the hair dye of Japanese beauty. It is also a good antioxidant, and can be used as intermediate for synthesizing some amino acids, alkaloids and tryptamine.
In recent years, with the development of new fine chemical products, the use of 5, 6-dihydroxyindole has also been increasing. The synthesis research of the product is carried out by a plurality of units in China, but the report of batch supply is not available yet. According to the reports of the prior documents, the synthesis methods mainly comprise the following methods:
a process for preparing 5, 6-dihydroxyindole from the benzaldehyde compound containing two adjacent or protected hydroxy groups on the benzene ring of piperonal, vanillin, or dihydroxybenzaldehyde as initial raw material includes protecting hydroxy groups, condensing, nitrifying to obtain intermediate, and removing protecting group. As shown in the following reaction scheme, the steps can be reduced by adopting piperonal as a raw material, the reaction for introducing a hydroxyl protecting group is omitted, but the raw material has sharp toxicity and great operation difficulty. Meanwhile, piperonal is a material which is easy to produce toxicity and is controlled by the police department, and experiments are not feasible. In addition, the nitration reaction time in the route is long, the reaction time is often more than 30 hours, and the intermediate product after the condensation reaction needs column chromatography separation, so the actual operation is difficult.
The other method is that the 3, 4-dimethoxy benzyl cyanide is demethylated to obtain an intermediate product 3, 4-dihydroxy benzyl cyanide; then reacting with benzyl chloride to obtain 3, 4-dibenzyloxy benzyl cyanide to protect hydroxyl; nitrifying the protected intermediate to obtain 2-nitro-3, 4-dibenzyloxy benzyl cyanide; then obtaining 3, 4-dibenzyloxyindole through cyclization reaction, and finally removing benzyloxy protection to obtain the product 5, 6-dihydroxyindole. The method has high yield which can reach more than 80 percent, but the experimental time is long, the reaction steps are complicated, and the method is not suitable for being applied to large-scale production of the process.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a high-efficiency preparation method of 5, 6-dihydroxyindole.
The purpose of the invention is realized by the following technical scheme:
a preparation method of 5, 6-dihydroxyindole is characterized by comprising the following steps:
(1) dissolving 3, 4-dialkoxyphenylethylamine and a catalyst in an organic solvent, carrying out reflux reaction under a heating and stirring state, and tracking the reaction process by using thin-layer chromatography;
(2) after the reaction in the step (1) is finished, concentrating to remove excessive organic solvent, adding a certain amount of deionized water, extracting with the organic solvent, and further purifying to obtain white solid dopamine hydrochloride powder;
(3) adding a certain amount of oxidant into the dopamine hydrochloride obtained in the step (2), preparing an intermediate compound I through oxidation reaction, and reducing the compound I with a reducing agent to finally obtain 5, 6-dihydroxyindole solid powder.
The specific reaction route is as follows:
wherein R is1、R2Each independently represents any one of alkyl or R1+R2＝CH2。
Preferably, the molar ratio of the catalyst to the 3, 4-dialkoxyphenylethylamine in the step (1) is (5-15): 1. It is to be noted that when the ratio of the catalyst to the 3, 4-dialkoxyphenylethylamine is 5 to 10, the reaction time is generally more than 3 hours to complete the reaction, and it is advantageous that by-products can be easily removed in the post-treatment, and when the amount of the catalyst is out of the above range, the more the catalyst is used, the faster the reaction is, and the shorter the time required for complete conversion of the raw material is, for example, when the ratio of the catalyst to the 3, 4-dialkoxyphenylethylamine is 13, the reaction time is only 1 to 2 hours, but by-products are increased by this, the more copper oxalate is used, and the post-treatment of the reaction becomes complicated due to the need of removing by-products, and therefore, it is more preferable that the molar ratio of the catalyst to the 3, 4-dialkoxyphenylethylamine is (10 to.
Preferably, the catalyst in the step (1) is any one of trimethylchlorosilane, halogen acid, boron tribromide, aluminum trichloride and lithium chloride. Further, the hydrohalic acid may be specifically hydrochloric acid, hydrobromic acid, hydroiodic acid, and preferably hydrochloric acid.
Preferably, the heating temperature in step (1) is 120 ℃ to 180 ℃. Wherein when the temperature is 160-170 ℃, the raw material point disappears after 6 hours of reaction, the product yield can reach more than 90%, when the temperature is 120-140 ℃, the reaction time is increased to 8 hours, and the yield is only about 80%, therefore, the heating temperature is more preferably 140-170 ℃.
Preferably, the organic solvent in step (1) is any one of acetic acid, N-dimethylformamide, dimethyl sulfoxide and dichloromethane, and more preferably acetic acid.
Preferably, the organic solvent in step (2) is any one of chloroform, toluene and xylene, and more preferably chloroform.
Preferably, the mass ratio of the oxidant to the compound I in the step (3) is (2-5): 1. When the amount of the oxidizing agent and dopamine is 2-5, the oxidizing effect is good, the purity of the obtained target product is high, byproducts can be easily removed in post-treatment, and when the amount of the oxidizing agent exceeds the range, the purity of the obtained target product is reduced as the amount of the oxidizing agent is increased, for example, when the ratio of the oxidizing agent to the compound I is 10:1, the purity of the compound I is only less than 85%, and therefore, the mass ratio of the oxidizing agent to the compound I is preferably (2-5): 1.
Preferably, the oxidant in step (3) is any one of potassium hexacyanoferrate, sodium hypochlorite and sodium percarbonate, and more preferably potassium hexacyanoferrate.
Preferably, the mass ratio of the reducing agent to the compound I in the step (3) is (5-10): 1. When the ratio of the reducing agent to the compound X is 5-10, the reduction effect is good, the yield of the obtained target product is high and can reach more than 87%, and the post-treatment is easy. When the amount of the reducing agent is less than the above range, the yield of the target product is reduced with the use of less reducing agent, for example, when the ratio of the reducing agent to the compound i is 2:1, the yield of the target product is less than 70%, and thus the mass ratio of the oxidizing agent to the dopamine solution is preferably (5-10): 1.
Preferably, the reducing agent in step (3) is any one of potassium borohydride, sodium hydrosulfite and oxalic acid, and more preferably sodium hydrosulfite.
The invention has the beneficial effects that:
(1) the invention adopts cheap 3, 4-dimethoxy phenethylamine as a raw material and common catalysts such as hydrochloric acid to prepare the 5, 6-dihydroxyindole, and the raw material is cheap and easy to obtain, has high reaction yield and less side reaction and is suitable for industrial production.
(2) The whole process has the advantages of few operation steps, short reaction flow, simple treatment after reaction, high purity of the obtained product, good stability and easy long-term storage and use.
Drawings
FIG. 1 is an infrared spectrum of 5, 6-dihydroxyindole, a product of example 1 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.
Example 1
A high-efficiency preparation method of 5, 6-dihydroxyindole comprises the following steps:
(1) 3.6320g (about 0.02mol, molecular weight 181.23) of 3, 4-dimethoxy phenethylamine is weighed at room temperature, placed in a dry and clean three-neck round-bottom flask, dissolved in 50mL of glacial acetic acid and stirred uniformly to completely dissolve the 3, 4-dimethoxy phenethylamine;
(2) slowly adding 20mL of 37% hydrochloric acid solution (about 0.24mol) into the reaction system, gradually heating to 160 ℃, and carrying out reflux reaction for 6 hours at 800r/min under the protection of nitrogen;
(3) after the reaction is finished, concentrating under reduced pressure to remove redundant acid, adding deionized water into the reaction solution, cleaning the residual product on the wall, wherein the dosage is 10mL, repeating the steps for three times until no obvious residue is left on the wall, extracting for 3 times by using 30mL of trichloromethane, taking a water layer, removing the solvent by rotary evaporation, and drying for 1h in a vacuum drying oven to obtain 3.7256g of white solid powder dopamine hydrochloride, wherein the yield is about 98.6%.
(4) 9.8465g of potassium hexacyanoferrate and 5.5646g of sodium bicarbonate (used as pH buffer) are respectively dissolved in 50mL of deionized water, the deionized water is heated to be fully dissolved, then the temperature is reduced to room temperature, 1.9078g (about 0.01mol, the molecular weight is 189.13) of dopamine hydrochloride obtained in the step (3) is slowly added into the solution, the solution is reacted for 2 hours at 68 ℃ and under the nitrogen atmosphere and at the stirring speed of 1000r/min, and the reaction progress is tracked by using thin layer chromatography (the material point in the reaction product disappears, the color of the target product point becomes dark, and the reaction is determined to be finished).
(5) Water in the reaction solution was removed by rotary evaporation, 20mL of methanol was added to dissolve the reaction product, the insoluble matter was removed by suction filtration, and concentration under reduced pressure was carried out to obtain 1.7863g of compound I in about 93.6% yield.
(6) 6.5123g of sodium bicarbonate were dissolved in 50mL of water (as pH buffer) on a steam bath and cooled to room temperature. 9.6130g of sodium dithionite monohydrate was added to the cooled solution, followed by immediate addition of 1.7863g of compound I from step (5) to start the reaction. Reacting for 1 hour at 58 ℃ and a nitrogen atmosphere at a stirring speed of 800r/min, and tracking the reaction process by using thin-layer chromatography (the reaction product is judged to be finished as the point of the raw material disappears and the point of the target product turns dark in color).
(7) The water in the reaction solution was removed by rotary evaporation, 30mL of methanol was added to dissolve the reaction product, the insoluble matter was removed by suction filtration, and the reaction solution was concentrated under reduced pressure to obtain 1.6863g of 5, 6-dihydroxyindole in about 98.1% yield. Analyzing data:1H NMR(400MHz,d6-DMSO):δ(ppm)＝9.48(s,2H),8.75(s,1H),6.90(s,1H),6.86(s,1H),5.67(d,J＝12.4Hz,1H),5.33(d,J＝12.4Hz,1H)。
example 2
A high-efficiency preparation method of 5, 6-dihydroxyindole comprises the following steps:
(1) 7.2320g (about 0.04mol, molecular weight 181.23) of 3, 4-dimethoxy phenethylamine is weighed at room temperature, placed in a dry and clean three-neck round-bottom flask, dissolved in 100mL of glacial acetic acid and stirred uniformly to completely dissolve the 3, 4-dimethoxy phenethylamine;
(2) slowly adding 50mL of 48% hydrobromic acid solution (about 0.44mol) into the reaction system, gradually heating to 160 ℃, and carrying out reflux reaction at 800r/min for 8 hours under the protection of nitrogen;
(3) after the reaction is finished, concentrating under reduced pressure to remove redundant acid, adding deionized water into the reaction liquid, washing the residual product on the wall, wherein the dosage is 20mL each time, repeating for three times until no obvious residue is left on the wall, extracting for 3 times by using 30mL of trichloromethane, taking a water layer, removing the solvent through rotary evaporation, and drying in a vacuum drying oven for 1 hour to obtain 7.3256g of white solid dopamine hydrobromide powder, wherein the yield is about 96.4%.
(4) 17.4390g of potassium hexacyanoferrate and 11.0247g of sodium bicarbonate (as pH buffer) are respectively dissolved in 100mL of deionized water, the mixture is heated to be fully dissolved, then the temperature is reduced to room temperature, 3.8046g (about 0.04mol, molecular weight of 194.13) of dopamine hydrobromide obtained in the step (3) is slowly added into the solution, the mixture is reacted for 2 hours at 68 ℃ and under the nitrogen atmosphere and at the stirring speed of 1000r/min, and the reaction progress is tracked by using thin layer chromatography (the material point in the reaction product disappears, the color of the target product point becomes dark, and the reaction is determined to be finished).
(5) Water in the reaction solution was removed by rotary evaporation, 40mL of methanol was added to dissolve the reaction product, the insoluble matter was removed by suction filtration, and concentration under reduced pressure was carried out to obtain 3.5465g of compound I in a yield of about 94.5%.
(6) 12.1048g of sodium bicarbonate were dissolved in 100mL of water (as pH buffer) on a steam bath and cooled to room temperature. 18.5937g of sodium dithionite monohydrate was added to the cooled solution, followed by immediate addition of 3.5465g of compound I from step (5) to start the reaction. Reacting for 1 hour at 58 ℃ and a nitrogen atmosphere at a stirring speed of 800r/min, and tracking the reaction process by using thin-layer chromatography (the reaction product is judged to be finished as the point of the raw material disappears and the point of the target product turns dark in color).
(7) The water in the reaction solution was removed by rotary evaporation, 50mL of methanol was added to dissolve the reaction product, the insoluble matter was removed by suction filtration, and the reaction solution was concentrated under reduced pressure to obtain 3.3168g of 5, 6-dihydroxyindole in a yield of about 94.8%. Analyzing data:1H NMR(400MHz,d6-DMSO):δ(ppm)＝9.68(s,2H),8.55(s,1H),6.92(s,1H),6.83(s,1H),5.64(d,J＝12.4Hz,1H),5.39(d,J＝12.4Hz,1H)。
the above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (8)
1. A preparation method of a compound 5, 6-dihydroxyindole is characterized by comprising the following steps:
(1) dissolving 3, 4-dialkoxyphenylethylamine and a catalyst in an organic solvent, carrying out reflux reaction under a heating and stirring state, and tracking the reaction process by using thin-layer chromatography;
(2) after the reaction in the step (1) is finished, concentrating to remove excessive organic solvent, adding deionized water, extracting with the organic solvent, and further purifying to obtain white solid dopamine hydrochloride powder;
(3) adding an oxidant into the dopamine hydrochloride obtained in the step (2), preparing an intermediate compound I through oxidation reaction, reducing the compound I with a reducing agent to finally obtain 5, 6-dihydroxyindole solid powder,
the specific reaction route is as follows:
wherein R is1、R2Each independently represents any one of alkyl or R1+R2＝CH2。
2. The preparation method according to claim 1, wherein the molar ratio of the catalyst to the 3, 4-dialkoxyphenylethylamine in the step (1) is (5-15): 1, and the catalyst in the step (1) is any one of trimethylchlorosilane, halogen acid, boron tribromide, aluminum trichloride and lithium chloride.
3. The method according to claim 1, wherein the heating temperature in the step (1) is 120 to 180 ℃.
4. The method according to claim 3, wherein the heating temperature in the step (1) is 140 to 170 ℃.
5. The method according to claim 1, wherein the organic solvent in step (1) is any one of acetic acid, N-dimethylformamide, dimethyl sulfoxide and dichloromethane.
6. The method according to claim 5, wherein the organic solvent in step (2) is any one of chloroform, toluene and xylene.
7. The preparation method according to claim 1, wherein the mass ratio of the oxidant to the compound I in the step (3) is (2-5): 1, and the oxidant in the step (3) is any one of potassium hexacyanoferrate, sodium hypochlorite and sodium percarbonate.
8. The preparation method according to claim 7, wherein the mass ratio of the reducing agent to the compound I in the step (3) is (5-10): 1, and the reducing agent in the step (3) is any one of potassium borohydride, sodium hydrosulfite and oxalic acid.
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| CN113816891A (en) * | 2021-10-11 | 2021-12-21 | 河南省科学院化学研究所有限公司 | Synthesis method of 5, 6-dihydroxyindole and derivatives thereof |
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