CN104592088B - The method that laurel acid catalysis prepares 3- amine alkyl-indol - Google Patents
The method that laurel acid catalysis prepares 3- amine alkyl-indol Download PDFInfo
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- CN104592088B CN104592088B CN201510011864.8A CN201510011864A CN104592088B CN 104592088 B CN104592088 B CN 104592088B CN 201510011864 A CN201510011864 A CN 201510011864A CN 104592088 B CN104592088 B CN 104592088B
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- Prior art keywords
- indol
- aromatic aldehyde
- indoles
- amine
- amine alkyl
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Classifications
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- 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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
Abstract
The present invention relates to a kind of preparation methods of organic synthesis intermediate 3- amine alkyl-indol.The present invention directlys adopt lauric acid as catalyst, prepares 3- amine alkyl-indol by aromatic aldehyde, indoles and secondary amine one-step method.The present invention has the features such as catalyst is inexpensive without preparation, safety, and reaction condition is mild, easy to operate, and reaction process is avoided using organic solvent, and yield is higher.
Description
Technical field
The present invention relates to a kind of preparation method of indole derivatives more particularly to a kind of use linear saturated fatty acids laurels
Acid is catalyst, the method for preparing 3- amine alkyl-indol by aromatic aldehyde, indoles and secondary amine.
Background technique
Indoles is important pharmaceutical intermediate, and structural unit is present in many important natural prodcuts.Known
In more than 3000 kinds of natural indole derivatives, more than 40 kinds are therapeutic type drugs.Many drugs all contain indoles knot currently on the market
Structure unit, wherein 3- substituted indole derivative occupies certain ratio, such as tryptophan is necessary amino acid and various colors
The biosynthesis precursor of amine, indoles；Psilocybin is that certain toadstools cause unreal ingredient；Bufotenine has anesthetic effect；Brazilian alkali
It is resistant to the phytoalexin of microbial challenge；5- hydroxyl color ammonia is important transmitter substance, and derivative can treat partially
Headache；Indocin is for treating rheumatic arthritis etc..The synthesis of current most of 3- amine alkyl-indol compounds is organic molten
It is carried out in agent, VOCs pollution is generated to environment, does not meet the Economic Development Mode of green low-carbon.
Summary of the invention
The object of the present invention is to provide a kind of without preparation, the inexpensive saturated fatty acid lauric acid of safety as catalyst,
Using aromatic aldehyde, indoles and secondary amine as raw material, one-step method mildly prepares 3- amine alkyl-indol in water method.
Technical solution of the present invention is as follows:
The present invention directlys adopt aromatic aldehyde, indoles and secondary amine and reacts in water, is used as and is urged by saturated fatty acid lauric acid
Agent is stirred to react preparation 3- amine alkyl-indol.The wherein aromatic aldehyde, R are hydrogen, halogen, alkoxy or nitro.This hair
Bright reaction equation is as follows:
The method that the present invention prepares 3- amine alkyl-indol, steps are as follows:
1) aromatic aldehyde, methylphenylamine, catalyst lauric acid and a certain amount of aqueous solvent are added into reaction flask, wherein virtue
Fragrant aldehyde and methylphenylamine molar ratio are 1: 1.0~1.5, and aromatic aldehyde and lauric molar ratio are stirred under the conditions of being 1: 0.2,80 DEG C
Reaction 5-10min is mixed, white opacity thing imine intermediate is obtained, the indoles equal with aromatic aldehyde molal quantity is added later and continues to stir
It mixes reaction certain time, TLC tracking reaction.
2) ethyl acetate extraction is added after reaction and dries organic phase with anhydrous sodium sulfate, obtained slightly after solvent is evaporated off
Product.Crude product petroleum ether and ethyl acetate do after eluant, eluent carries out column chromatography for separation and obtain aubergine solid 3- amine alkyl Yin
Diindyl.
The preferred aromatic aldehyde of the step 1), methylphenylamine and indoles molar ratio are 1: 1.2: 1；
Preferably, step 1) the catalyst lauric acid is 20% relative to the mole percent of aromatic aldehyde.
For the present invention with catalyst without preparation, safety is inexpensive, and the reaction time is short, mild condition, environmental-friendly, operation is simple
Singly, the advantages that yield is higher.
Specific embodiment
The present invention will be further explained with reference to the examples below, but not limited to this.
The synthesis of embodiment 1, N- (3- indyl-phenyl) methyl-N-methyl aniline, structural formula are as follows:
In 25ml round-bottomed flask be added 1.0mmol benzaldehyde, 1.2mmol methylphenylamine, 0.2mmol lauric acid and
2.0ml aqueous solvent, 80 DEG C of whens, are stirred to react 5 minutes, 1.0mmol indoles are added later, continues to be stirred to react 3.5 hours, TLC inspection
Stop reaction after surveying fully reacting.After being cooled to room temperature, ethyl acetate extraction is added and dries organic phase with anhydrous sodium sulfate, adopts
Solvent ethyl acetate, which is removed, with Rotary Evaporators obtains crude product.Crude product ethyl acetate and petroleum ether make eluant, eluent (acetic acid
Ethyl ester: petroleum ether=1: 4), using gradient elution, after carrying out column chromatography for separation (200-300 mesh silica gel), obtaining purity is 99%
Red brown solid N- (3- indyl-phenyl) methyl-N-methyl aniline 244.0mg, separation yield is 78.1%, and fusing point is
128-130℃。
The identification of N- (3- indyl-phenyl) methyl-N-methyl aniline:
Infrared spectrogram IR (KBr) v:735,1453,1509,1612,2927,3363,3409cm-1.
Nuclear magnetic resonance data:1H NMR (500MHz, CDCl3): δ 2.77 (s, 3H), 5.54 (s, 1H), 6.52 (d, J=
8.0Hz, 3H), 6.69-6.83 (m, 3H), 7.04 (d, J=10.0Hz, 2H), 7.13-7.35 (m, 6H), 7.57 (s, 1H),
7.88 (s, 1H) ppm.13C NMR (125MHz, CDCl3): δ 30.6,47.8,111.0,112.4,119.3,119.8,122.1,
124.0,126.8,128.1,128.9,129.5,130.2,133.1,136.6,144.9,147.9.
Product is identified consistent with document report.
The synthesis of embodiment 2, N- (3- indyl-(4- nitrobenzophenone)) methyl-N-methyl aniline, structural formula are as follows:
1.0mmol paranitrobenzaldehyde, 1.2mmol methylphenylamine, the 0.2mmol month are added in 25ml round-bottomed flask
Cinnamic acid and 2.0ml aqueous solvent, 80 DEG C of whens, are stirred to react 5 minutes, and 1.0mmol indoles is added later, continue to be stirred to react 2.5 small
When, TLC stops reaction after detecting fully reacting.After being cooled to room temperature, the extraction of addition ethyl acetate is simultaneously dry with anhydrous sodium sulfate
Organic phase removes solvent ethyl acetate using Rotary Evaporators and obtains crude product.Crude product is washed with ethyl acetate and petroleum ether
De- agent (ethyl acetate: petroleum ether=1: 4), is obtained after carrying out column chromatography for separation (200-300 mesh silica gel) using gradient elution
Red brown solid N- (3- indyl-(4- nitrobenzophenone)) methyl-N-methyl aniline 286.6mg that purity is 99%, separation produce
Rate is 80.2%, and fusing point is 60-62 DEG C.
The identification of N- (3- indyl-(4- nitrobenzophenone)) methyl-N-methyl aniline:
Infrared spectrogram IR (KBr) v:739,1347,1456,1521,1608,2935,3411cm-1.
Nuclear magnetic resonance data:1H NMR (500MHz, CDCl3): δ 2.85 (s, 3H), 5.57 (s, 1H), 6.49-6.54 (m,
3H), 6.89-7.00 (m, 3H), 7.12-7.19 (m, 2H), 7.28-7.53 (m, 4H), 8.01 (s, 1H), 8.13 (d, J=
10.0Hz, 2H)；13C NMR (125MHz, CDCl3): δ 31.1,47.6,111.0,112.3,119.6,120.2,122.3,
123.5,124.0,126.7,129.3,130.8,136.7,146.2,147.9,152.2.
Product is identified consistent with document report.
Embodiment 3, N- (synthesis of 3- indyl-(4- methoxyphenyl) methyl-N-methyl aniline, structural formula are as follows:
1.0mmol P-methoxybenzal-dehyde, 1.2mmol methylphenylamine, 0.2mmol are added in 25ml round-bottomed flask
Lauric acid and 2.0ml aqueous solvent, 80 DEG C of whens, are stirred to react 5 minutes, and 1.0mmol indoles is added later, continue to be stirred to react 4.5 small
When, TLC stops reaction after detecting fully reacting.After being cooled to room temperature, the extraction of addition ethyl acetate is simultaneously dry with anhydrous sodium sulfate
Organic phase removes solvent ethyl acetate using Rotary Evaporators and obtains crude product.Crude product is washed with ethyl acetate and petroleum ether
De- agent (ethyl acetate: petroleum ether=1: 4), is obtained after carrying out column chromatography for separation (200-300 mesh silica gel) using gradient elution
Red brown solid N- (3- indyl-(4- methoxyphenyl) methyl-N-methyl aniline 234.5mg, the separation that purity is 98.5%
Yield is 68.5%, and fusing point is 142-143 DEG C.
N- (identification of 3- indyl-(4- methoxyphenyl) methyl-N-methyl aniline:
Infrared spectrogram IR (KBr) v:IR (KBr): 745,1026,1181,1451,1510,1616,2925,3041,
3403cm-1.
Nuclear magnetic resonance data:1H NMR (500MHz, CDCl3): δ 2.79 (s, 3H), 3.77 (s, 3H), 5.53 (s, 1H),
6.50-6.57 (m, 2H), 6.82-6.89 (m, 3H), 6.98-7.07 (m, 3H), 7.13 (d, J=10.0,3H), 7.23-7.39
(m, 3H), 7.87 (s, 1H)；13C NMR (125MHz, CDCl3): δ 30.8,47.7,55.1,111.2,112.5,113.6,
119.7,119.8,121.8,123.5,123.7,127.0,129.6,129.7,133.1,136.8,147.5,157.6.
Product is identified consistent with document report.
According to the disclosure of the present invention, those skilled in the art can be to greatest extent using the present invention.Therefore,
Above-mentioned preferred embodiment is merely illustrative of, rather than is limited the scope of the invention in any way.
Claims (1)
1. a kind of method for preparing 3- amine alkyl-indol as raw material using aromatic aldehyde, indoles and secondary amine, it is characterised in that at 80 DEG C
Aromatic aldehyde and methylphenylamine are added in distilled water, while lauric acid is added and makees catalyst reaction 5 minutes, lauric acid dosage is
Indoles is added later and continues to be stirred to react 2.5-6 hours, wherein aromatic aldehyde, N- methylbenzene for the 20% of aromatic aldehyde mole percent
Amine and indoles molar ratio are 1: 1.2: 1, and the R of the aromatic aldehyde is hydrogen, halogen, alkoxy or nitro, crude by column chromatography point
3- amine alkyl-indol sterling is obtained from after
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020198252A1 (en) * | 2001-05-24 | 2002-12-26 | Joseph Payack | Process for the preparation of alkylamine substituted indoles |
| CN102015642A (en) * | 2008-02-19 | 2011-04-13 | 赛诺菲-安万特 | Novel 3-aminoalkyl-1,3-dihydro-2H-indol-2-one derivatives, preparation thereof and therapeutic use thereof |
| CN103342675A (en) * | 2013-05-17 | 2013-10-09 | 安徽工业大学 | Preparation method of diindolylmethane derivative through catalysis |
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2015
- 2015-01-05 CN CN201510011864.8A patent/CN104592088B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020198252A1 (en) * | 2001-05-24 | 2002-12-26 | Joseph Payack | Process for the preparation of alkylamine substituted indoles |
| CN102015642A (en) * | 2008-02-19 | 2011-04-13 | 赛诺菲-安万特 | Novel 3-aminoalkyl-1,3-dihydro-2H-indol-2-one derivatives, preparation thereof and therapeutic use thereof |
| CN103342675A (en) * | 2013-05-17 | 2013-10-09 | 安徽工业大学 | Preparation method of diindolylmethane derivative through catalysis |
Non-Patent Citations (5)
| Title |
|---|
| Carboxylic Acid Catalyzed Three-Component Aza-Friedel-Crafts Reactions in Water for the Synthesis of 3-Substituted Indoles;Seiji Shirakawa，等;《Org. Lett.》;20060923;第8卷(第21期);4939-4942 |
| Catalyst-free, ethylene glycol promoted one-pot three component synthesis of 3-amino alkylated indoles via Mannich-type reaction;U. Chinna Rajesh，等;《Tetrahedron Letters》;20140403(第55期);第2977–2981页 |
| L-Proline catalysed multicomponent synthesis of 3-amino alkylated indoles via a Mannich-type reaction under solvent-free conditions;Atul Kumar，等;《Green Chem.》;20121231;第14卷;290-295 |
| One-Pot Synthesis of 3-[(N-Alkylanilino)(aryl)methyl]indoles via a Transition Metal Assisted Three-Component Condensation at Room Temperature;Goutam Brahmachari，等;《Journal of Heterocyclic Chemistry》;20140418;E140-E145 |
| One-pot synthesis of 3-substituted indole derivatives using moisture stable, reusable, and task specific ionic liquid catalysts;Ravindran, Anaswara，等;《 Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry 》;20130131;第52B卷(第1期);129-135 |
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Granted publication date: 20190101 Termination date: 20200105 |