CN101245045A - Process for synthesizing indole-4-methanal - Google Patents
Process for synthesizing indole-4-methanal Download PDFInfo
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- CN101245045A CN101245045A CNA2008100244778A CN200810024477A CN101245045A CN 101245045 A CN101245045 A CN 101245045A CN A2008100244778 A CNA2008100244778 A CN A2008100244778A CN 200810024477 A CN200810024477 A CN 200810024477A CN 101245045 A CN101245045 A CN 101245045A
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- formaldehyde
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Abstract
The invention provides a synthesis method of indole-4-formaldehyde, which solves the problem of serious environmental pollution and avoids the explosion hazards of nitro compounds at high temperature. The technology is realized by the following processes: a. 2-formaldehyde-3-nitro benzyl alcohol is reduced by sodium borohydride by taking 2-methyl-3-nitro methyl benzoate as raw material; b. 2-methyl-3-nitro benzyl alcohol is used for preparing 2-methyl-3-nitrobenzaldehyde by oxidation catalysts; c. ethylene glycol is used for protecting the aldehyde groups of the 2-methyl-3-nitrobenzaldehyde; d. indole-4-formaldehyde products are synthesized by the condensation of DMFDMA of N, N-dimethylformamide dimethyl acetal, the reductive cyclization of Raney Ni-hydrazine hydrate and further hydrolysis for reaction. The method is a very promising method for synthesizing the indole-4-formaldehyde products and has higher industrial application values.
Description
Technical field
The invention belongs to the synthesis technique field of fine chemical product, particularly a kind of is the indole-4-methanal new synthetic process of starting raw material with 2-methyl-3-nitro methyl benzoate.
Background technology
The indole-4-methanal compound is the important medicine of a class, agricultural chemicals, spices and organic chemical industry's intermediate, progress along with its applied research, derive many important medicine, agricultural chemicals, dyestuff, spices by it and become at present the heterocyclic fine-chemical intermediate of focus both at home and abroad, the market requirement is very fast, and development prospect is wide.Do not wane lastingly about its applied research always, new Application Areas still constantly is being developed, since China this study on the one hand less relatively, research and preparation to the indole-4-methanal series compound lag behind some developed countries greatly, and therefore the research to the indole-4-methanal series compound has great significance.
At present, synthesis of indole-4-formaldehyde and derivative thereof mainly contain following several method both at home and abroad:
(1) is raw material with 2-methyl-3-nitro methyl benzoate,, gets the 4-skatoxyl with isobutoxy aluminum hydride or lithium aluminium hydride reduction again, obtain indole-4-methanal with active mno2 or potassium permanganate oxidation at last through L-B method elder generation synthesis of indole-4-methyl-formiate;
(2) be raw material with 2-methyl-3-nitro benzene nitrile, with the earlier synthetic 4-cyanoindole of L-B method, hydro-reduction gets indole-4-methanal more equally;
(3) with 4 oxos-4,5,6, the 7-tetrahydro indole is that raw material makes indole-4-methanal through hydrogenation, dehydrogenation, alkalization.
Method (1) uses isobutyl-aluminum hydride reduction requirement-70 ℃ of operations down, and need be anhydrous, needs the oxidation of manganese salt in addition, difficult realization industrialization; Method (2) reaction raw materials is difficult to obtain, and also is difficult to industrialization; Method (3) process complexity, cost is higher, the also difficult suitability for industrialized production scale that realizes.Also have the report of other synthesis of indole 4-formaldehyde in addition, all be difficult to realize the production of industrially scalable.
Summary of the invention
Technical problem: it is easy that the present invention aims to provide a kind of operating process, and synthesis condition is not had particular requirement, is fit to the synthesis technique of the indole-4-methanal of suitability for industrialized production.
Technical scheme: technical solution of the present invention can realize according to following mode:
A. be raw material with 2-methyl-3-nitro methyl benzoate, get 2-methyl-3-nitro phenylcarbinol through sodium borohydride reduction,
B.2-the methyl-3-nitro phenylcarbinol makes 2-methyl-3-nitro phenyl aldehyde through oxide catalyst,
C. spent glycol is protected the aldehyde radical of 2-methyl-3-nitro phenyl aldehyde,
D. through N, dinethylformamide dimethylacetal DMFDMA condensation, Raney Ni-hydrazine hydrate reduction cyclisation and one step of hydrolysis are reacted synthesis of indole-4-formaldehyde products.
Described catalyzer is 0.1～3% of a 2-methyl-3-nitro phenylcarbinol consumption.Described oxide catalyst is that alumino nickel adds hydrogen peroxide, and the mass ratio of alumino nickel and hydrogen peroxide is 1: 300～500.
Indole-4-methanal synthetic route of the present invention is:
Innovative point of the present invention:
(1) has novel oxidation of Benzaldehyde method for preparing catalyst;
(2) in condensation course, use the condensation stablizer, thereby avoided the danger of blast down of nitro-compound high temperature;
(3) reductive cyclization and one step of hydrolysis carry out, and make whole process be water solvent, do not relate to organic solvent.
1) discovery of oxide catalyst
Prepare phenylcarbinol from 2-methyl-3-nitro benzyl alcohol oxidation, traditional technology is to use active γ-Manganse Dioxide to carry out oxidation, and manganese salt has been one of pollutent of less use in the world.We use the alumino nickel of catalytic amount to add hydrogen peroxide low temperature mild oxidation promptly can higher yields obtain 2-methyl-3-nitro phenyl aldehyde raw material.
2) use of condensation stablizer
Ethylene glycol protection aldehyde radical after and N, the N of dinethylformamide dimethylacetal (DMFDMA), the condenses intermediate that condensation obtains in the dinethylformamide solution in purification process, involving the process that decompression removes solvent.Owing to contain the nitrotoluene class formation in this condenses intermediate structure, the similar structural unit of TNT just, in case misoperation, the danger of very easily blasting.And we have added a kind of condensation stablizer in purification process, make industrial operation become simple and easy to operate, can obtain the condenses intermediate in high quality.
3) organic solvent-free one step cyclisation and hydrolytic process
The catalysis of Buddhist nun's nickel and hydrazine hydrate organic solvent-free one step cyclisation and hydrolytic process drawn in use, makes whole commercial run environmental friendliness more, and the use of not only having saved organic solvent also can obtain the indole-4-methanal product in high yield ground.
Beneficial effect: the present invention has following having a few compared with the prior art:
1) indole-4-methanal synthesis technique provided by the invention, environmental friendliness is fit to suitability for industrialized production.
2) indole-4-methanal that obtains of the present invention is light yellow to light brown powder, purity 〉=98.0%.
3) indole-4-methanal ignition residue≤0.5% that obtains of the present invention.
Embodiment
The invention will be further described below in conjunction with drawings and Examples.
1,2-methyl-3-nitro phenylcarbinol 1 is synthetic
Adding 2-methyl-3-nitro methyl benzoate 39.0 (0.2mol) on the 1000mL there-necked flask of mechanical stirrer, reflux condensing tube and constant pressure funnel, trimethyl carbinol 600mL and NaBH are being housed
419.0 (0.5mol), be heated to backflow, drip methyl alcohol 150mL, drip and finish, continue back flow reaction 1h.Mixture adds suitable quantity of water after being cooled to room temperature, removes solvent under reduced pressure, adds entry and chloroform in resistates, tells organic layer, steam behind the anhydrous sodium sulfate drying to desolventize, cooling, solidify yellow solid 1 30.7g, productive rate 91.9%, m.p.69 ℃～71 ℃.
2,2-methyl-3-nitro phenyl aldehyde 2 is synthetic
In being housed, the 500mL there-necked flask of mechanical stirrer, reflux condensing tube and constant pressure funnel adds nickel alloy powder 0.2g and the H that is doped with cobalt
2O
280mL stirs the ethanolic soln 130mL that adding down contains 120g (120mmol), behind the 0.05MPa air room temperature blistering reaction 7-8h, adds toluene 100mL * 2 extractions.Combining extraction liquid also adds activated carbon 2g backflow 0.5h, the elimination activated carbon, and filtrate decompression is steamed and is desolventized, and cooling curing gets off-white color solid 2 14g through the ethanol/water recrystallization, productive rate 71.1%, m.p.54 ℃～56 ℃.
3, the protection 3 of aldehyde radical
In being housed, the 250mL flask of water trap adds 2 14g (85mmol), toluene 100mL and tosic acid 0.5g, heating reflux reaction 6h, stopped reaction when treating to tell in the water trap about 2mL water.The cooling reaction solution is also used saturated Na respectively
2CO
3Toluene layer is told in solution and water washing, spends the night pressure reducing and steaming part toluene postcooling crystalline light yellow solid 3 15g, yield 85.7%, m.p.62 ℃～64 ℃ with anhydrous sodium sulfate drying.
4, indole-4-methanal 4 is synthetic
In being installed, the 250mL there-necked flask of condensation reaction device adds 3 14g (67mmol), DMFDMA16g (130mmol), DMF80mL, hexahydropyridine 8.5g (100mmol), logical N
2Protection is heated to 130 ℃～140 ℃ reaction 5h.Reaction finishes postcooling to room temperature, adds 40% aqueous solution that contains the condensation stablizer, stir 0.5h after, filter white flour.Directly this solid is joined in the 80ml water, 2.5g RaneyNi, drip 80% hydrazine hydrate 40g (control reaction temperature is at 50 ℃～55 ℃) when being heated to 45 ℃～50 ℃, drip and finish, continue behind this thermotonus 2h～3h, to add 5g activated carbon backflow 0.5h, elimination Raney Ni and activated carbon, the direct pressure reducing and steaming water of filtrate (temperature is not higher than 50 ℃) gets yellow solid 42.5g, and content is more than 98%, yield 25.8%, m.p.140 ℃～142 ℃.
1H-NMR(DMSO-d6)：δ＝7.10-7.79(m，5H)，10.19(d，1H)，11.62(s，1H)
The test condition of liquid chromatography is as follows:
It is an amount of to get this product, adds moving phase and makes the solution that contains 2mg among every 1ml, according to the high performance liquid chromatography test, with octadecylsilane chemically bonded silica is weighting agent, [acetonitrile: water=55: 45] is moving phase, and the detection wavelength is 210nm, and sample size is 20 μ l detection level.
Protection scope of the present invention will not only be confined to above-mentioned embodiment, any with 2-methyl-3-nitro phenylcarbinol through atmospheric oxidation Synthetic 2-methyl-3-nitro phenyl aldehyde; Adding the condensation stablizer directly separates out condenses; And the synthesis technique that low temperature dewatering obtains indole-4-methanal all should be assert and falls within protection scope of the present invention.
The indole-4-methanal sample liquid analysis of hplc result that the present invention makes is as follows:
Claims (3)
1. the synthetic method of an indole-4-methanal is characterized in that this synthetic method is:
A. be raw material with 2-methyl-3-nitro methyl benzoate, get 2-methyl-3-nitro phenylcarbinol through sodium borohydride reduction,
B.2-the methyl-3-nitro phenylcarbinol makes 2-methyl-3-nitro phenyl aldehyde through oxide catalyst,
C. spent glycol is protected the aldehyde radical of 2-methyl-3-nitro phenyl aldehyde,
D. through N, dinethylformamide dimethylacetal DMFDMA condensation, Raney Ni-hydrazine hydrate reduction cyclisation and one step of hydrolysis are reacted synthesis of indole-4-formaldehyde products.
2, the synthetic method of indole-4-methanal according to claim 1 is characterized in that: described catalyzer is 0.1～3% of a 2-methyl-3-nitro phenylcarbinol consumption.
3, the synthetic method of indole-4-methanal according to claim 2 is characterized in that: described oxide catalyst is that alumino nickel adds hydrogen peroxide, and the mass ratio of alumino nickel and hydrogen peroxide is 1: 300～500.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100244778A CN101245045A (en) | 2008-03-25 | 2008-03-25 | Process for synthesizing indole-4-methanal |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746211A (en) * | 2012-06-27 | 2012-10-24 | 上海泰坦化学有限公司 | Method for preparing substituted indole-3-methanal compound |
| CN112321479A (en) * | 2020-11-04 | 2021-02-05 | 吉林大学 | Indole-4-formaldehyde compound with antibacterial activity in parasitic loranthus, preparation method and application thereof |
-
2008
- 2008-03-25 CN CNA2008100244778A patent/CN101245045A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746211A (en) * | 2012-06-27 | 2012-10-24 | 上海泰坦化学有限公司 | Method for preparing substituted indole-3-methanal compound |
| CN102746211B (en) * | 2012-06-27 | 2015-05-27 | 上海泰坦化学有限公司 | Method for preparing substituted indole-3-methanal compound |
| CN112321479A (en) * | 2020-11-04 | 2021-02-05 | 吉林大学 | Indole-4-formaldehyde compound with antibacterial activity in parasitic loranthus, preparation method and application thereof |
| CN112321479B (en) * | 2020-11-04 | 2022-02-08 | 吉林大学 | Indole-4-formaldehyde compound with antibacterial activity in parasitic loranthus, preparation method and application thereof |
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