CN100376555C - Process for preparing diindolylmethane derivatives - Google Patents
Process for preparing diindolylmethane derivatives Download PDFInfo
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- CN100376555C CN100376555C CNB2006100505209A CN200610050520A CN100376555C CN 100376555 C CN100376555 C CN 100376555C CN B2006100505209 A CNB2006100505209 A CN B2006100505209A CN 200610050520 A CN200610050520 A CN 200610050520A CN 100376555 C CN100376555 C CN 100376555C
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- indoles
- indole
- aldehyde
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Abstract
The present invention discloses a preparation method for a diindolylmethane derivative. Methanol or alcohol is taken as a reaction solvent, and electrophilic reaction is carried out on indole and aldehyde for 0.1 to 5 hours under the catalysis of TBABr3; then, a diindolylmethane derivate of high yield is obtained after the separation, wherein the mol equivalent weight proportion of the indole and the aldehyde is 1.8 to 2.2: 1; and the dosage of the catalyst TBABr3 is 1 to 10% of the mol equivalent weight of the indole. Compared with the existing synthetic method, the present invention has the advantages that the reaction condition is mild, the reaction can be carried out without isolating the air, and the reaction time is short; the cheap TBABr3 is used as the catalyst; batch charging and post processing are very simple, and industrialized mass production is easy to realize.
Description
Technical field
The present invention relates to the indoles synthetic method, relate in particular to a kind of preparation method of di-indole methyl hydride derivative.
Background technology
Benzazole compounds not only extensively exists at nature, and have many physiologically actives, being that raw material is synthetic with the indole nucleus has the natural product of physiologically active or a large amount of compound of deriving all is the research core of indoles chemistry for the usefulness of screening active ingredients all the time; Therefore to they research very extensively and profoundly, particularly how more efficiently and greenly the synthesis of indole derivative especially receive people's huge concern.In the middle of various indole derivativeses, di-indole methyl hydride is the important skeleton of a class in the design of the complete synthesis and molecular drug target of natural product.Therefore, research di-indole methyl hydride derivative just is extremely important, and many methods have been reported the preparation method of this compounds.Wherein, a kind of method that simply and directly prepares di-indole methyl hydride derivative electrophilic substitution reaction that is protonic acid or Louis acid catalysis indoles and aldehyde.For example, (1) document Tetrahedron 1991, (47) have reported that direct catalyzing indole of protonic acid and aldehyde reaction prepare the method for di-indole methyl hydride in 9225; (2) document J.Chem.Soc., Perkin Trans.1 1980,553. have reported the electrophilic substitution reaction of aluminum chloride catalyzing indole and aldehyde; (3) document Adv.Synth.Catal.2003, (345), 349. have reported the another kind of approach of the electrophilic substitution reaction of the indoles of ionic liquid catalyst and aldehyde.Yet it is acid that directly the conjugate addition reaction of protonic acid catalyzing indole often needs careful control, with the generation of side reactions such as the dimerization that prevents indoles itself or poly.In addition, in the preparation method who has reported, there are many experimentations to relate to the variety of problems such as reagent, low-yield, aftertreatment complexity and long reaction time of strong acid condition, costliness.Thereby in the indoles chemistry, under condition gentleness, eco-friendly, it is very important solving the synthetic of di-indole methyl hydride efficiently.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of di-indole methyl hydride indole derivatives.
It is to be reaction solvent with the alcohols, and under tetra-n-butylammonium tribromide catalysis, indoles and aldehyde generation electrophilic substitution reaction 0.1-5 hour obtain the di-indole methyl hydride derivative of high yield through separation, and the molar equivalent ratio of indoles and aldehyde is 1.8-2.2: 1; The consumption of catalyzer tetra-n-butylammonium tribromide is the 1-10% molar equivalent of indoles.Reaction formula is:
Wherein X=H, halogen, alkyl or alkoxyl group, wherein alkyl is C
nH
2n+1, n=1-4; The R=alkyl or aryl, wherein alkyl is C
nH
2n+1, n=1-4.
Said alcohols reaction solvent is methyl alcohol or ethanol.The said reaction times is 0.2-4 hour.
The molar equivalent ratio of said indoles and aldehyde is 1.9-2.1: 1; The consumption of catalyzer tetra-n-butylammonium tribromide is the 3-8% molar equivalent of indoles.
Said tetra-n-butylammonium tribromide can be according to document Tetrahedron Lett., reported method preparation in 1998,39,8163.
The present invention compares with existing synthetic method, has the following advantages:
1) the reaction conditions gentleness is reacted without secluding air, and the reaction times is short;
2) use cheap tetra-n-butylammonium tribromide to make catalyzer;
3) feed intake and aftertreatment all very simple, be easy to realize industrialized production.
Specific implementation method
The general molecular formula of di-indole methyl hydride derivative is:
Wherein X=H, halogen, alkyl or alkoxyl group, wherein alkyl is C
nH
2n+1, n=1-4; R
1, R
2=alkyl or aryl, wherein alkyl is C
nH
2n+1, n=1-4.
The preparation method's of di-indole methyl hydride derivative concrete reactions steps is as follows:
With methyl alcohol or ethanol is reaction solvent, and under tetra-n-butylammonium tribromide catalysis, indoles and aldehyde generation electrophilic substitution reaction 0.1-5 hour add entry, separate out product, after filtration, drying obtains the di-indole methyl hydride derivative.Wherein the molar equivalent ratio of indoles and aldehyde is 1.8-2.2: 1; The consumption of catalyzer tetra-n-butylammonium tribromide is the 1-10% molar equivalent of indoles.Temperature of reaction is 20-25 ℃; Reaction times is 0.5-2 hour; Recommending the molar equivalent ratio of indoles and aldehyde is 2: 1; Recommending the consumption of catalyzer tetra-n-butylammonium tribromide is 5% molar equivalent of indoles.
Following examples will help to understand the present invention, but be not limited to content of the present invention:
Embodiment 1
0.02 mole indoles and 0.01 mole of dissolution of benzaldehyde are in 10 ml methanol, add 0.5 mmole tetra-n-butylammonium tribromide then, 20 ℃ of stirring reactions of room temperature 1 hour, finish reaction, add 20 ml waters, separate out product, obtain two (3-indoles) phenylmethane, productive rate 90% through simple filtration, drying process.
mp?123～125℃；IR(KBr)3415，1631，1380，734cm
-1；
1H?NMR(500MHz，CDCl
3)δ7.89(brs，2H)，7.38(d，J＝8.0Hz，2H)，7.33-7.35(m，4H)，7.19-7.30(m，5H)，7.00(m，2H)，6.64(d，J＝1.0Hz，2H)，5.88(s，1H)ppm；
13C?NMR(125MHz，CDCl
3)δ144.2，136.8，128.9，128.4，127.2，126.3，123.8，122.1，120.1，119.8，119.4，111.2，40.3ppm；MSm/z322(M
+)；HRMS(EI)calcd?for?C
23H
18N
2：322.1470；Found?322.1473.
Embodiment 2
0.02 mole indoles and 0.01 mole of aubepine are dissolved in 10 milliliters of ethanol, add 0.4 mmole tetra-n-butylammonium tribromide then, 25 ℃ of stirring reactions of room temperature 0.5 hour, finish reaction, add 20 ml waters, separate out product, obtain two (3-indyls)-(4-anisole) methane, productive rate 94% through simple filtration, drying process.
mp?179-181℃.IR，：742，1417，1454，1508，1610，2924，3396cm
-1.
1H?NMR(400Hz，CDCl
3)：3.76(s，3H)，5.80(s，1H)，6.59(d，J＝2.4Hz，2H)，6.78(d，J＝8.1Hz，2H)，6.93(t，2H)，7.12(t，2H)，7.20-7.38(m，6H)，7.80(brs，2H，NH)ppm.
13C-NMR(100MHz，CDCl
3)：39.2，56.0，110.8，113.6，118.6，119.4，121.8，123.0，126.4，136.2ppm.EIMS：m/z(％)：352(20，M
+)，236(100).
Embodiment 3
0.021 mole 5-methoxyl group indoles and 0.01 mole to the phenyl dissolution of benzaldehyde in 12 ml methanol, add 0.6 mmole tetra-n-butylammonium tribromide then, 15 ℃ of stirring reactions of room temperature 1.5 hours, reaction finishes, add 25 ml waters, separate out product, obtain two (5-methoxyl groups-3-indyl)-(4-phenyl benzene) methane, productive rate 92% through simple filtration, drying process.
mp?194-196℃；IR(KBr)：3470，2965，1270，770cm
-1；
1H?NMR(500MHz，CDCl
3)：3.72(s，6H)，5.84(s，1H)，6.69(d，J＝1.7Hz，2H)，6.86(m，4H)，7.21-7.61(m，11H)，7.81(br?s，2H，NH)ppm.
13C?NMR(125MHz，CDCl
3)：40.17，56.10，102.24，111.97，112.13，119.36，124.73，127.15，127.19，127.24，127.73，128.96，129.36，132.11，139.07，141.30，143.35，153.94ppm.EIMS：m/z(％)：458(M
+).Anal.Calcd?for?C
31H
26N
2O
2：C，81.20；H，5.72；N，6.11；Found：C，81.20；H，5.76；N，6.14.
Embodiment 4
0.02 mole indoles and 0.01 mole of 2-Furan Aldehydes are dissolved in 10 ml methanol, add 0.5 mmole tetra-n-butylammonium tribromide then, 20 ℃ of stirring reactions of room temperature 2 hours, reaction finishes, add 25 ml waters, separate out product, obtain two (3-indyls)-(2-furyl) methane, productive rate 85% through simple filtration, drying process.
mp?113-115℃.IR(KBr)：745，782，1009，1040，1146，1169，1241，1340，1551，1614，1726，2926，3055，3414cm
-1.
1H-NMR(400MHz，CDCl
3)：5.82(s，1H)，5.95(d，J＝3.4Hz，1H)，6.28(d，J＝2.2Hz，1H)，6.72(d，J＝2.4Hz，1H)，6.98(t，2H)，7.12(t，2H)，7.21-7.42(m，5H)，7.71(brs，2H，NH)ppm.
13C-NMR(100MHz，CDCl
3)：34.6，106.2，109.8，111.0，117.4，119.2，119.4，122.0，124.0，126.6，136.2，141.2ppm.EIMS：m/z(％)：312(8，M
+)，43(100).
Embodiment 5
0.02 mole 5-bromo indole and 0.01 mole of p-bromobenzaldehyde are dissolved in 12 milliliters of ethanol, add 0.5 mmole tetra-n-butylammonium tribromide then, 25 ℃ of stirring reactions of room temperature 1.5 hours, reaction finishes, add 25 ml waters, separate out product, obtain two (5-bromo-3-indyl)-(4-bromobenzene) methane, productive rate 85% through simple filtration, drying process.
1H?NMR(500MHz，CDCl
3)：5.71(s，1H)，6.63(d，J＝1.5Hz，2H)，7.16(d，J＝8.5Hz，2H)，7.23-7.27(m，4H)，7.42(d，J＝8.5Hz，2H)，7.45(s，2H)，8.00(br?s，2H，NH).EIMS：m/z(％)：559(M
+)；
IR(KBr)：3468，3032，1270，770cm
-1.
Anal.Calcd?for?C
23H
15Br
3N
2：C，49.41；H，2.70；N，5.01?Found：C，49.44；H，2.65；N，5.03.
Claims (3)
1. the preparation method of a di-indole methyl hydride derivative, it is characterized in that it is is reaction solvent with methyl alcohol or ethanol, under tetra-n-butylammonium tribromide catalysis, indoles and aldehyde generation electrophilic substitution reaction 0.1-5 hour, obtain the di-indole methyl hydride derivative of high yield through separation, the molar equivalent ratio of indoles and aldehyde is 1.8-2.2: 1; The consumption of catalyzer tetra-n-butylammonium tribromide is the 1-10% molar equivalent of indoles; Reaction formula is:
Wherein X=H, halogen, alkyl or methoxyl group, wherein alkyl is C
nH
2n+1, n=1-4; R=phenyl, 4-p-methoxy-phenyl, 4-phenyl, furans-2-base, 4-bromophenyl.
2. the preparation method of a kind of di-indole methyl hydride derivative according to claim 1 is characterized in that the said reaction times is 0.2-4 hour.
3. the preparation method of a kind of di-indole methyl hydride derivative according to claim 1, the molar equivalent ratio that it is characterized in that said indoles and aldehyde is 1.9-2.1: 1; The consumption of catalyzer tetra-n-butylammonium tribromide is the 3-8% molar equivalent of indoles.
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| CN100376555C true CN100376555C (en) | 2008-03-26 |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102153500B (en) * | 2011-03-02 | 2012-09-05 | 河北大学 | Method for synthesizing diindolylmethane derivative |
| CN103342675B (en) * | 2013-05-17 | 2015-01-21 | 安徽工业大学 | Preparation method of diindolylmethane derivative through catalysis |
| CN103333097A (en) * | 2013-06-18 | 2013-10-02 | 重庆大学 | Synthesis method of diindolylmethane derivatives |
| CN104177283B (en) * | 2014-07-10 | 2016-08-17 | 陕西师范大学 | The method preparing bisindole methane derivative in the presence of amine salt |
| CN107827804A (en) * | 2017-11-27 | 2018-03-23 | 菏泽海诺知识产权服务有限公司 | A kind of preparation method of diindolylmethane derivative |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5391762A (en) * | 1991-10-30 | 1995-02-21 | Ciba-Geigy Corporation | Nir dyes, methods of preparing them and their use |
| US20040126308A1 (en) * | 2002-12-16 | 2004-07-01 | Council Of Scientific And Industrial Research | Process for preparing quaternary ammonium tribromides |
| US20040235929A1 (en) * | 2000-10-06 | 2004-11-25 | Safe Stephen H. | Compositions containing C-substituted diindolylmethane compounds |
-
2006
- 2006-04-26 CN CNB2006100505209A patent/CN100376555C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5391762A (en) * | 1991-10-30 | 1995-02-21 | Ciba-Geigy Corporation | Nir dyes, methods of preparing them and their use |
| US20040235929A1 (en) * | 2000-10-06 | 2004-11-25 | Safe Stephen H. | Compositions containing C-substituted diindolylmethane compounds |
| US20040126308A1 (en) * | 2002-12-16 | 2004-07-01 | Council Of Scientific And Industrial Research | Process for preparing quaternary ammonium tribromides |
Non-Patent Citations (3)
| Title |
|---|
| An Environmentally Benign Synthesis of Organic AmmoniumTribromides(OATB) and Bromination of Selected OrganicSubstrates by Tetrabutylammonium Tribromide(TBATB). Mihir K. Chaudhuri, et al.Tetrahedron Letters,Vol.39 . 1998 * |
| Efficient and Eco-Friendly Process for the Synthesis ofBis(1H-indol-3-yl)methanes using Ionic Liquids. J.S.Yadav, et al.Adv.Synth.Catal.,Vol.345 No.3. 2003 * |
| PHOTOCHEMICAL SYNTHESIS OFDIINDOLYLMETHANES. Maurizio D'Auria.Tetrahedron,Vol.47 No.44. 1991 * |
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