CN100381422C - Synthesis method of indole - Google Patents
Synthesis method of indole Download PDFInfo
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- CN100381422C CN100381422C CNB2006100154984A CN200610015498A CN100381422C CN 100381422 C CN100381422 C CN 100381422C CN B2006100154984 A CNB2006100154984 A CN B2006100154984A CN 200610015498 A CN200610015498 A CN 200610015498A CN 100381422 C CN100381422 C CN 100381422C
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Abstract
The indole synthesizing process includes the following steps: 1. the hydroxymethylation reaction of alkali catalyst, o-nitrotuluene, paraformaldehyde and polar solvent through stirring at 0-150 deg.c for 10 min to 5 hr, regulating pH and decompression fractionizing to obtain o-nitro phenethyl alcohol; 2. the catalytic hydrogenation reaction of o-nitro phenethyl alcohol with added skeletal nickel catalyst at 50-200 deg.c and 1-100 atm hydrogen pressure for 1-20 hr to obtain o-amino phenethyl alcohol; and 3. cyclization reaction of o-amino phenethyl alcohol with added metal modified skeletal catalyst at 110-300 deg.c for 1-10 hr to obtain indole. The present invention has facile cheap material, low cost of catalyst, short reaction time and simple indole synthesizing process, and the product indole has wide use and high economic value.
Description
Technical field
The present invention relates to a kind of synthetic method of indoles.
Background technology
Indoles is a kind of important fine chemical material, is widely used in fields such as medicine, agricultural chemicals, spices, food and feed additive, dyestuff, does not wane lastingly about its applied research always, and new Application Areas still constantly is being developed.Industrialized at present indoles synthetic technology mainly contains three kinds of aniline process, adjacent aminoethylbenzene method and ortho-chlorotolu'ene methods.Aniline process need be used the higher aniline of price, and in its reaction process, aniline must be excessive in greatly to guarantee essential selectivity simultaneously, and lower with regard to the per pass conversion of aniline calculating, these have all influenced the economy of this method.Adjacent aminoethylbenzene method needs at high temperature (generally will arrive about 600 ℃) to carry out, and uses expensive platinum catalyst simultaneously, and yield and selectivity are not high yet.The ortho-chlorotolu'ene method adopts ortho-chlorotolu'ene to make dihydroindole through chlorination, cyaniding, ammonification, dehydration, then dehydrogenation and indoles.Used step is long, and yield is low; Will use chlorine and hypertoxic prussiate simultaneously, environmental issue is more serious.
Document J.Org.Chem., 1990,55, mention among the 580-584 by Ortho Nitro Toluene be raw material through methylolation, three steps of hydrogenation and cyclization prepare the method for indoles.But this method has the following disadvantages: (1) its hydroxymethylation uses organic quaternary ammonium hydroxide Triton B to be catalyzer, costs an arm and a leg; (2) its step of hydrogenation institute adopts the zinc powder reduction method to example, and three wastes problem is serious.Another kind method is used expensive noble metal catalyst, and as Pd/C and Rh/C, the reaction times reaches 7-17 hour; (3) its cyclization step adopts the homogeneous phase complex catalyst, and it is extremely unstable simultaneously to cost an arm and a leg, and separates with product and has any problem, and the reaction times is also longer.Document Applied Catalysis, 20 (1986), 305-312 has mentioned by adjacent amino-benzene ethanol and has adopted the gas phase fixed bed, under the effect of copper-loading catalyst, the method for cyclization synthesis of indole.But its activity of such catalysts is not high, and the life-span is shorter.The clear 61-134370 of Japanese Patent (1986) has mentioned the employing Raney's nickel, and thunder Buddhist nun cobalt and raney copper catalyst are by the method for adjacent amino-benzene ethanol synthesis of indole.But its reaction times is longer, and the yield of indoles is lower, and selectivity is relatively poor.Therefore, simple, the economic Indomethacin synthetic technology of exploitation is very necessary.
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, a kind of economical and practical method by the Ortho Nitro Toluene synthesis of indole is provided.
Technical scheme of the present invention is summarized as follows:
A kind of synthetic method of indoles, form by following step:
(1) hydroxymethylation: will be 1 by weight: the basic catalyst of 10-1000: 1-500: 0-5000: Ortho Nitro Toluene: Paraformaldehyde 96 or trioxymethylene or gaseous formaldehyde or weight percent be the formalin of 20%-41%: polar solvent mixes, stir down in 0～150 ℃, reacted 10 minutes～5 hours, regulate pH to 6～7.5, vacuum fractionation obtains ortho-nitrophenyl ethanol;
(2) catalytic hydrogenation: in ortho-nitrophenyl ethanol, add skeletal nickel catalyst or skeletal copper catalyst or skeletal Co catalysts, add and be equivalent to ortho-nitrophenyl ethanol 0～20 quality solvent doubly, the consumption of described skeletal nickel catalyst or skeletal copper catalyst or skeletal Co catalysts accounts for 0.5%～25% of reactant gross weight, in 50～200 ℃, under 1atm～100atm hydrogen pressure catalytic hydrogenation 1-20 hour, obtain adjacent amino-benzene ethanol;
(3) ring-closure reaction: in adjacent amino-benzene ethanol, add the skeleton catayst that metal is modified, with be equivalent to adjacent amino-benzene ethanol 0～0.5 quality triphenylphosphine doubly, add and be equivalent to adjacent amino-benzene ethanol 0～20 quality solvent doubly, the consumption of the skeleton catayst that described metal is modified accounts for 0.5%～45% of reactant gross weight, reacts cyclization in 1-10 hour down in 110～300 ℃ and becomes indoles.
Described basic catalyst can be at least a in alkalimetal oxide, alkaline earth metal oxide, zinc oxide, aluminum oxide, alkali metal hydroxide, alkaline earth metal hydroxides, zinc hydroxide, aluminium hydroxide, alkaline carbonate, alkaline earth metal carbonate, zinc carbonate, aluminium carbonate, basic metal subcarbonate, alkaline-earth metal subcarbonate, zinc subcarbonate, Aluminum Carbonate Basic, organic quaternary ammonium hydroxide, phenol sodium, the sodium alkoxide.
Described polar solvent is lower paraffin hydrocarbons alcohol, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, benzene,toluene,xylene, ethylbenzene, isopropyl benzene, methyl-sulphoxide, propylene glycol, acetone, water or the N of C1～C6, dinethylformamide.
Solvent described in described step (2) and the step (3) is mixture, hexanaphthene, methylcyclohexane, dioxane, tetrahydrofuran (THF), benzene,toluene,xylene, ethylbenzene, isopropyl benzene, ether, ethyl acetate, acetone, lower paraffin hydrocarbons alcohol, water, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, propylene glycol, Virahol or the trimethyl carbinol of C1～C6 of alkane of alkane, the C5～C20 of sherwood oil, C5～C20.
The synthetic method of another kind of indoles, form by following step:
(1) hydroxymethylation: will be 1 by weight: the basic catalyst of 10-1000: 1-500: 0-5000: Ortho Nitro Toluene: Paraformaldehyde 96 or trioxymethylene or gaseous formaldehyde or weight percent be the formalin of 20%-41%: polar solvent mixes, stir down in 0～150 ℃, reacted 10 minutes～5 hours, regulate pH to 6～7.5, vacuum fractionation obtains ortho-nitrophenyl ethanol;
(2) catalytic hydrogenation and ring-closure reaction: in ortho-nitrophenyl ethanol, add skeletal nickel catalyst or skeletal copper catalyst or skeletal Co catalysts, add and be equivalent to ortho-nitrophenyl ethanol 0～20 quality solvent doubly, the consumption of described skeletal nickel catalyst or skeletal copper catalyst or skeletal Co catalysts accounts for 0.5%～45% of reactant gross weight, in 50～200 ℃, under 1atm～100atm hydrogen pressure catalytic hydrogenation 1-20 hour, pressure is decompressed to 1atm, reacts cyclization in 1-10 hour down in 110～300 ℃ and become indoles.
Described basic catalyst can select in alkalimetal oxide, alkaline earth metal oxide, zinc oxide, aluminum oxide, alkali metal hydroxide, alkaline earth metal hydroxides, zinc hydroxide, aluminium hydroxide, alkaline carbonate, alkaline earth metal carbonate, zinc carbonate, aluminium carbonate, basic metal subcarbonate, alkaline-earth metal subcarbonate, zinc subcarbonate, Aluminum Carbonate Basic, organic quaternary ammonium hydroxide, phenol sodium, the sodium alkoxide at least a.
Described polar solvent is lower paraffin hydrocarbons alcohol, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, benzene,toluene,xylene, ethylbenzene, isopropyl benzene, methyl-sulphoxide, propylene glycol, acetone, water or the N of C1～C6, dinethylformamide.
Solvent described in the described step (2) is mixture, hexanaphthene, methylcyclohexane, dioxane, tetrahydrofuran (THF), benzene,toluene,xylene, ethylbenzene, isopropyl benzene, ether, ethyl acetate, acetone, lower paraffin hydrocarbons alcohol, water, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, propylene glycol, Virahol or the trimethyl carbinol of C1～C6 of alkane of alkane, the C5～C20 of sherwood oil, C5～C20.
The present invention had following advantage compared with former technology:
The first step hydroxymethylation has adopted the alkaline derivant of basic metal or alkaline-earth metal, and price is lower, and simple washing can separate with product after the neutralization.
The second step catalytic hydrogenation adopts skeletal nickel catalyst, and price is cheaply a lot of than noble metal catalysts such as Pd/C and especially Rh/C, and recovery and recycled are also comparatively convenient.Another advantage is exactly to shorten greatly in the reaction times, by original 7～17 hours, shortens to present 1.5 hours.If with another kind of method, i.e. zinc powder reduction method is compared, then in cost or three wastes processing, all have great advantage.
We find in the ring-closure reaction test of the 3rd step, to being impregnated with the skeletal nickel catalyst of precious metal such as ruthenium, rhodium, when adding a small amount of triphenylphosphine, can shorten the reaction times greatly with respect to the clear 61-134370 of Japanese Patent (1986), Fan Ying selectivity and product yield all have raising in various degree simultaneously.For example adopt skeletal nickel catalyst, polymer alkane is solvent, and when reacting down for 200 ℃, its reaction times needs 5 hours approximately.But after adopting the skeletal nickel catalyst that floods rhodium, adding a certain amount of triphenylphosphine, similarity condition reaction down only needs about 50 minutes.
Ortho Nitro Toluene is a kind of basic chemical raw materials, and output is big and cheap.The present invention is risen through two or three-step reaction by Ortho Nitro Toluene, can obtain of many uses easy, economically and the product indoles of higher economic worth is arranged.
Description of drawings
Fig. 1 is the infrared spectrogram of indoles;
Fig. 2 is an indoles
1H-NMR figure;
Fig. 3 is an indoles
13C-NMR figure.
Embodiment
Further specify technical characterstic of the present invention below by embodiment, but example should not be considered to restriction that scope of the present invention is made.
The chemical reaction that the present invention relates to is as follows:
In the hydroxymethylation of the present invention, the source of formaldehyde can be gaseous formaldehyde, formalin, trioxymethylene or Paraformaldehyde 96.
Above-mentioned suitable polar solvent comprises lower paraffin hydrocarbons alcohol, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, benzene,toluene,xylene, ethylbenzene, isopropyl benzene, methyl-sulphoxide, propylene glycol, acetone, water or the N of C1～C6, dinethylformamide.
Basic catalyst can be an alkalimetal oxide, alkaline earth metal oxide, zinc oxide, aluminum oxide, alkali metal hydroxide, alkaline earth metal hydroxides, zinc hydroxide, aluminium hydroxide, alkaline carbonate, alkaline earth metal carbonate, zinc carbonate, aluminium carbonate, the basic metal subcarbonate, the alkaline-earth metal subcarbonate, zinc subcarbonate, at least a and hydrate in the Aluminum Carbonate Basic, perhaps the mixture of one or more above-mentioned substances can also be organic quaternary ammonium hydroxide, phenol sodium, the aqueous solution of at least a and these materials or lower paraffin hydrocarbons alcoholic solution in the sodium alkoxide (C1～C6).
In the catalytic hydrogenation of the present invention, skeletal nickel catalyst can adopt usual method by the Al-Ni binary alloy, ternary alloys such as Al-Ni-Cu, Al-Ni-Cr, Al-Ni-Mn, Al-Ni-Ti, perhaps quad alloy preparation.For example according to the " method of catalyzer handbook (Chemical Industry Press), sodium hydroxide with 1.3～1.5 times of alloy amounts is mixed with the aqueous solution (20～25%), in 50～60 ℃, fully stir and in sodium hydroxide solution, repeatedly add alloy powder down on a small quantity, after interpolation finishes fully, continue reaction 30～120 minutes down in 50～100 ℃.Adding a certain amount of water washing to pH value with decantation is 8～9, can directly use.Or, be kept in the ethanol standby again with after the small amount of ethanol washing.
In the ring-closure reaction of the present invention, both skeletal nickel catalyst used in the catalytic hydrogenation be can adopt, corresponding skeleton copper or skeletal Co catalysts also can be adopted.Its preparation method is similar.Be added with one or more other metal component in the used skeleton catayst to change its selectivity and activity.These metals can join in the skeleton catayst by methods such as the pickling process or the precipitator method, also can mix with skeleton catayst with the certain activity form.These metal components comprise basic metal such as sodium and potassium; Alkaline-earth metal such as calcium and magnesium; I B-group metal such as copper and silver; IIB family metal such as zinc and cadmium; VIII family metallic iron, cobalt, nickel, ruthenium, rhodium, palladium, osmium, iridium and platinum; IVB family metal such as titanium and zirconium; VB family metal such as vanadium and niobium; Group vib metal such as chromium, molybdenum; VIIB family metal such as manganese and rhenium; And IIIB family metal.Its add-on of other metal components of being added accounts for 0.01～50% of skeletal nickel catalyst total mass.
The present invention's solvent for use in catalytic hydrogenation comprises the various alkane of sherwood oil, C5～C20 or its mixture, hexanaphthene, methylcyclohexane, dioxane, tetrahydrofuran (THF), benzene,toluene,xylene, ethylbenzene, isopropyl benzene, ether, ethyl acetate, acetone, lower paraffin hydrocarbons alcohol (C1～C6), water, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, propylene glycol, Virahol, the trimethyl carbinol.
The present invention's solvent for use in ring-closure reaction also can be selected from the catalytic hydrogenation solvent for use, mainly considers the adaptability of its boiling point and temperature of reaction, and in general to be higher than temperature of reaction relatively good for boiling point.From experiment, find in addition, in skeleton catayst, add some noble metal component such as ruthenium, rhodium, palladium, platinum, can shorten the reaction times greatly.It is little to the reaction influence to add separately triphenylphosphine, but when it joined the skeleton catayst that has added some other metal components such as ruthenium, rhodium, palladium, platinum, its synergy can further shorten the reaction times, improves throughput greatly.
Catalytic hydrogenation of the present invention and ring-closure reaction also can be together in series and carry out, the hydrogenation that promptly pressurizes earlier, and emptying hydrogen was not adjusted temperature again and is got final product to ring-closure reaction is required to normal pressure after reaction was not extremely inhaled hydrogen, did not influence its yield and selectivity.Last in emptying, the most handy a kind of rare gas element such as nitrogen replacement are to keep the normal pressure system.
Embodiment 1:
A kind of synthetic method of indoles, form by following step:
(1) with the 137g Ortho Nitro Toluene, the 220g methyl-sulphoxide, the 15g Paraformaldehyde 96, the 5g 20%NaOH aqueous solution is put into the 1000ml there-necked flask successively, solution is brownish black at this moment, under agitation, be warming up to 50 ℃ of reactions 70 minutes, stop heating, in reaction system, add concentrated hydrochloric acid and transfer pH to 7, the reaction solution of underpressure distillation gained, some watery distillates of reject front, obtain the mixed solution of DMSO and Ortho Nitro Toluene, last brownish black liquid is ortho-nitrophenyl ethanol crude product in the bottle, and gained crude product vacuum fractionation is removed the dihydroxymethyl thing of by product Ortho Nitro Toluene, obtains the pure product 50g of ortho-nitrophenyl ethanol, yield 36.5% collects rate 80% with the Ortho Nitro Toluene amount that consumes;
(2) with 446g ortho-nitrophenyl ethanol, the 2000g whiteruss is added to 5 risings and presses reactor, adds the 28g skeletal nickel catalyst, leak test is caught up with gas with 4 * 2Mpa hydrogen, is warming up to 90 ℃, logical hydrogen pressure begins to stir, after 1.5 hours to 20atm, basically no longer inhale hydrogen, reaction finishes, and draws off reaction solution, leave standstill layering, separatory, obtain the adjacent amino-benzene ethanol of reddish brown (Huang) colour response product 354g, yield 97%, HPLC purity＞99%.
(3) get the adjacent amino-benzene ethanol of 10g, 2g skeletal nickel catalyst, 10g whiteruss are put into is furnished with mechanical stirring, thermometer, inlet mouth is in the 50ml four-hole bottle of water trap (upper end adds prolong), use the nitrogen replacement system, begin to stir, be warming up to 200 ℃ of reactions, 5.5 after hour, HPLC analytical reaction system has not had raw material, about cooling reaction solution to 100 ℃, remove by filter skeleton nickel, continue the cooling reaction solution, separate out tawny solid (indoles crude product), heavy 7.5g, the yield 87.8% of Ji Suaning according to this.The purity about 98% of HPLC analysed preparation.The sign of indoles is seen Fig. 1, Fig. 2 and Fig. 3.
The preparation of skeletal nickel catalyst in step (2):
Take by weighing 150g sodium hydroxide, it is mixed with 20% the aqueous solution.Take by weighing 100gNi-Al alloy (50/50,80～120 orders, Jinzhou City Catalyst Platn).In 55 ℃, fully stir down and in sodium hydroxide solution, repeatedly add alloy powder on a small quantity, dose fully finish after, be warming up to 80 ℃ and continue reaction 50 minutes down.After reaction is finished, be 8～9, can directly use with certain water gaging decantation washing catalyst to pH value.Or, be kept in the ethanol standby again with after the washing of small amount of ethanol decantation.
Embodiment 2
Hydroxymethylation: will be 1: 1000: 500 by weight: 100 potassium hydroxide: Ortho Nitro Toluene: trioxymethylene: N, dinethylformamide mixes, and stirs down in 100 ℃, reacted 10 minutes, regulate pH to 7.5, vacuum fractionation obtains ortho-nitrophenyl ethanol.
Embodiment 3
Hydroxymethylation: will be 1: 10: 5 by weight: 50 sodium phenylate: Ortho Nitro Toluene: weight percent be the formalin of 37-41%: ethylene glycol monomethyl ether mixes, stir down in 150 ℃, reacted 4 hours, regulate pH to 7, vacuum fractionation obtains ortho-nitrophenyl ethanol.
Embodiment 4
Hydroxymethylation: the sodium methylate that will be 1: 10: 1 by weight: Ortho Nitro Toluene: Paraformaldehyde 96 mixes, and stirs down in 0 ℃, reacts 5 hours, regulates pH to 6, and vacuum fractionation obtains ortho-nitrophenyl ethanol.
Embodiment 5
Hydroxymethylation: the magnesium oxide that will be 1: 10: 10 by weight: Ortho Nitro Toluene: weight percent is that 20% formalin mixes, and stirs down in 60 ℃, reacts 2 hours, regulates pH to 7, and vacuum fractionation must be to ortho-nitrophenyl ethanol.
Embodiment 6
Catalytic hydrogenation: in ortho-nitrophenyl ethanol, add skeletal copper catalyst, add and be equivalent to ortho-nitrophenyl ethanol 4 quality ethanol doubly, described skeletal copper catalyst consumption accounts for 10% of reactant gross weight, in 200 ℃, catalytic hydrogenation is 5 hours under the 100atm hydrogen pressure, obtains adjacent amino-benzene ethanol.
Embodiment 7
Catalytic hydrogenation: in ortho-nitrophenyl ethanol, add skeletal Co catalysts, add and be equivalent to ortho-nitrophenyl ethanol 20 quality ethylene glycol doubly, the consumption of described skeletal Co catalysts accounts for 25% of reactant gross weight, in 100 ℃, catalytic hydrogenation is 20 hours under the 50atm hydrogen pressure, obtains adjacent amino-benzene ethanol.
Embodiment 8
Catalytic hydrogenation: add skeletal nickel catalyst in ortho-nitrophenyl ethanol, the consumption of described skeletal nickel catalyst accounts for 0.5% of reactant gross weight, and in 90 ℃, catalytic hydrogenation is 10 hours under the 20atm hydrogen pressure, obtains adjacent amino-benzene ethanol.
Embodiment 9
The Preparation of catalysts that metal is modified: take by weighing 0.1g three hydration rhodium chlorides, it is dissolved in the 50ml water.Take by weighing the 5g skeletal nickel catalyst and put into above-mentioned solution, left standstill 5～10 minutes, stirred then 30～40 minutes, abandoning supernatant, with 100ml washing twice, standby with alcohol washing back again.
Catalytic hydrogenation: in ortho-nitrophenyl ethanol, add the skeletal nickel catalyst that metal is modified, add and be equivalent to ortho-nitrophenyl ethanol 5 quality toluene doubly, the consumption of the skeletal nickel catalyst that described metal is modified accounts for 5% of reactant gross weight, in 50 ℃, catalytic hydrogenation is 4 hours under the 1atm hydrogen pressure, obtains adjacent amino-benzene ethanol.
Embodiment 10:
Get the adjacent amino-benzene ethanol of 80 grams, the 14g skeletal nickel catalyst is put into 150ml four-hole reaction flask, and other steps with embodiment 1 (3) were reacted 10 hours, leached the catalyzer postcooling, obtained 60.3g tawny crystalline solid (indoles crude product).The yield 88.3% of Ji Suaning according to this, HPLC analyzes its purity about 98%.
Embodiment 11:
Ring-closure reaction: in adjacent amino-benzene ethanol, add the skeleton catayst that palladium is modified, with be equivalent to adjacent amino-benzene ethanol 0.5 quality triphenylphosphine doubly, add and be equivalent to adjacent amino-benzene ethanol 20 quality dimethylbenzene doubly, the consumption of the skeleton catayst that described metal is modified accounts for 45% of reactant gross weight, reacts cyclization in 1 hour down in 110 ℃ and becomes indoles.
Embodiment 12:
Ring-closure reaction: in adjacent amino-benzene ethanol, add the skeleton catayst that platinum is modified, with be equivalent to adjacent amino-benzene ethanol 0.05 quality triphenylphosphine doubly, the consumption of the skeleton catayst that described metal is modified accounts for 0.5% of reactant gross weight, reacts cyclization in 10 hours down in 300 ℃ and becomes indoles.
Embodiment 13:
Ring-closure reaction: in adjacent amino-benzene ethanol, add the skeleton catayst that rhodium is modified, with be equivalent to adjacent amino-benzene ethanol 0.05 quality triphenylphosphine doubly, the consumption of the skeleton catayst that described metal is modified accounts for 15% of reactant gross weight, reacts cyclization in 50 minutes down in 200 ℃ and becomes indoles.
Embodiment 14:
Catalytic hydrogenation and ring-closure reaction: in ortho-nitrophenyl ethanol, add skeletal nickel catalyst, add and be equivalent to ortho-nitrophenyl ethanol 10 quality solvent doubly, the consumption of described skeletal nickel catalyst accounts for 0.5% of reactant gross weight, in 200 ℃, catalytic hydrogenation is 20 hours under the 1atm hydrogen pressure, pressure is decompressed to 1atm, reacts cyclization in 10 hours down in 300 ℃ and become indoles.
Embodiment 15:
Catalytic hydrogenation and ring-closure reaction: in ortho-nitrophenyl ethanol, add skeletal copper catalyst, add and be equivalent to ortho-nitrophenyl ethanol 20 quality solvent doubly, the consumption of described skeletal copper catalyst accounts for 45% of reactant gross weight, in 100 ℃, catalytic hydrogenation is 1 hour under the 50atm hydrogen pressure, pressure is decompressed to 1atm, reacts cyclization in 1 hour down in 200 ℃ and become indoles.
Embodiment 16:
Catalytic hydrogenation and ring-closure reaction: in ortho-nitrophenyl ethanol, add skeletal Co catalysts, the consumption of described skeletal Co catalysts accounts for 25% of reactant gross weight, and in 50 ℃, catalytic hydrogenation is 5 hours under the 100atm hydrogen pressure, pressure is decompressed to 1atm, reacts cyclization in 5 hours down in 110 ℃ and become indoles.
Claims (8)
1. the synthetic method of an indoles is characterized in that being made up of following step:
(1) hydroxymethylation: will be 1 by weight: the basic catalyst of 10-1000: 1-500: 0-5000: Ortho Nitro Toluene: Paraformaldehyde 96 or trioxymethylene or gaseous formaldehyde or weight percent be the formalin of 20%-41%: polar solvent mixes, stir down in 0～150 ℃, reacted 10 minutes～5 hours, regulate pH to 6～7.5, vacuum fractionation obtains ortho-nitrophenyl ethanol;
(2) catalytic hydrogenation: in ortho-nitrophenyl ethanol, add skeletal nickel catalyst or skeletal copper catalyst or skeletal Co catalysts, add and be equivalent to ortho-nitrophenyl ethanol 0～20 quality solvent doubly, the consumption of described skeletal nickel catalyst or skeletal copper catalyst or skeletal Co catalysts accounts for 0.5%～25% of reactant gross weight, in 50～200 ℃, under 1atm～100atm hydrogen pressure catalytic hydrogenation 1-20 hour, obtain adjacent amino-benzene ethanol;
(3) ring-closure reaction: in adjacent amino-benzene ethanol, add noble metal decorated skeleton catayst, with be equivalent to adjacent amino-benzene ethanol 0～0.5 quality triphenylphosphine doubly, add and be equivalent to adjacent amino-benzene ethanol 0～20 quality solvent doubly, the consumption of described noble metal decorated skeleton catayst accounts for 0.5%～45% of reactant gross weight, in 110～300 ℃ down reaction cyclization in 1-10 hour become indoles.
2. the synthetic method of a kind of indoles according to claim 1 is characterized in that described basic catalyst is at least a in alkalimetal oxide, alkaline earth metal oxide, zinc oxide, aluminum oxide, alkali metal hydroxide, alkaline earth metal hydroxides, zinc hydroxide, aluminium hydroxide, alkaline carbonate, alkaline earth metal carbonate, zinc carbonate, aluminium carbonate, basic metal subcarbonate, alkaline-earth metal subcarbonate, zinc subcarbonate, Aluminum Carbonate Basic, organic quaternary ammonium hydroxide, phenol sodium, the sodium alkoxide.
3. the synthetic method of a kind of indoles according to claim 1, it is characterized in that described polar solvent is lower paraffin hydrocarbons alcohol, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, benzene,toluene,xylene, ethylbenzene, isopropyl benzene, methyl-sulphoxide, propylene glycol, acetone, water or the N of C1～C6, dinethylformamide.
4. the synthetic method of a kind of indoles according to claim 1 is characterized in that solvent described in described step (2) and the step (3) is mixture, hexanaphthene, methylcyclohexane, dioxane, tetrahydrofuran (THF), benzene,toluene,xylene, ethylbenzene, isopropyl benzene, ether, ethyl acetate, acetone, lower paraffin hydrocarbons alcohol, water, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, propylene glycol, Virahol or the trimethyl carbinol of C1～C6 of alkane of alkane, the C5～C20 of sherwood oil, C5～C20.
5. the synthetic method of an indoles is characterized in that being made up of following step:
(1) hydroxymethylation: will be 1 by weight: the basic catalyst of 10-1000: 1-500: 0-5000: Ortho Nitro Toluene: Paraformaldehyde 96 or trioxymethylene or or the gaseous formaldehyde weight percent be the formalin of 20%-41%: polar solvent mixes, stir down in 0～150 ℃, reacted 10 minutes～5 hours, regulate pH to 6～7.5, vacuum fractionation obtains ortho-nitrophenyl ethanol;
(2) catalytic hydrogenation and ring-closure reaction: in ortho-nitrophenyl ethanol, add skeletal nickel catalyst or skeletal copper catalyst or skeletal Co catalysts, add and be equivalent to ortho-nitrophenyl ethanol 0～20 quality solvent doubly, the consumption of described skeletal nickel catalyst or skeletal copper catalyst or skeletal Co catalysts accounts for 0.5%～45% of reactant gross weight, in 50～200 ℃, under 1atm～100atm hydrogen pressure catalytic hydrogenation 1-20 hour, pressure is decompressed to 1atm, reacts cyclization in 1-10 hour down in 110～300 ℃ and become indoles.
6. the synthetic method of a kind of indoles according to claim 5 is characterized in that described basic catalyst is at least a in alkalimetal oxide, alkaline earth metal oxide, zinc oxide, aluminum oxide, alkali metal hydroxide, alkaline earth metal hydroxides, zinc hydroxide, aluminium hydroxide, alkaline carbonate, alkaline earth metal carbonate, zinc carbonate, aluminium carbonate, basic metal subcarbonate, alkaline-earth metal subcarbonate, zinc subcarbonate, Aluminum Carbonate Basic, organic quaternary ammonium hydroxide, phenol sodium, the sodium alkoxide.
7. the synthetic method of a kind of indoles according to claim 5, it is characterized in that described polar solvent is lower paraffin hydrocarbons alcohol, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, benzene,toluene,xylene, ethylbenzene, isopropyl benzene, methyl-sulphoxide, propylene glycol, acetone, water or the N of C1～C6, dinethylformamide.
8. the synthetic method of a kind of indoles according to claim 5 is characterized in that solvent described in the described step (2) is mixture, hexanaphthene, methylcyclohexane, dioxane, tetrahydrofuran (THF), benzene,toluene,xylene, ethylbenzene, isopropyl benzene, ether, ethyl acetate, acetone, lower paraffin hydrocarbons alcohol, water, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, propylene glycol, Virahol or the trimethyl carbinol of C1～C6 of alkane of alkane, the C5～C20 of sherwood oil, C5～C20.
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| CN102924962A (en) * | 2012-11-27 | 2013-02-13 | 华东理工大学 | Method for preparing novel rhodamine laser dye |
| CN108329248B (en) * | 2018-04-14 | 2020-10-30 | 北京成宇化工有限公司 | Preparation method of 2-methylindoline |
| CN112279799B (en) * | 2019-07-26 | 2022-02-22 | 中石化南京化工研究院有限公司 | Method for preparing spice-grade indole by extraction crystallization |
| CN110526852B (en) * | 2019-09-18 | 2020-10-09 | 湖北斯柏生物科技有限公司 | Preparation method of indole |
| CN112047871B (en) * | 2020-10-14 | 2022-06-21 | 南京大学 | Preparation method of indole compound |
| CN114409545A (en) * | 2022-01-26 | 2022-04-29 | 江苏飞宇医药科技股份有限公司 | Method for continuously preparing 2- (2-nitrophenyl) ethanol |
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| US4937353A (en) * | 1982-06-24 | 1990-06-26 | Mitsui Toatsu Chemicals, Incorporated | Preparation process for indoles |
| JPH06184106A (en) * | 1992-12-16 | 1994-07-05 | Mitsui Toatsu Chem Inc | Production of indole or indole derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4937353A (en) * | 1982-06-24 | 1990-06-26 | Mitsui Toatsu Chemicals, Incorporated | Preparation process for indoles |
| JPH06184106A (en) * | 1992-12-16 | 1994-07-05 | Mitsui Toatsu Chem Inc | Production of indole or indole derivative |
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| Ruthenium Catalyzed Reduction of Nitroarenes andAzaaromatic Compounds Using Formic Acid. Yoshihisa WATANABE et al..Bull.Chem.Soc.Jpn.,,Vol.57 No.9. 1984 * |
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