CN103254112A - Bisindole alkaloid derivative, and synthesis method and application thereof - Google Patents
Bisindole alkaloid derivative, and synthesis method and application thereof Download PDFInfo
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Abstract
The invention discloses a synthesis method of a bisindole alkaloid derivative. A diazo compound, an indole derivative and isatin derivative are used as raw materials, rhodium acetate is used as a catalyst, an organic solvent is used as a solvent, and the raw materials, the catalyst and the solvent are reacted in one step at the temperature of minus 10 DEG C to 50 DEG C to obtain the indole alkaloid derivative. The synthesis method has the advantages of high-efficiency atom economy, high selectivity, high yield, low consumption of the catalyst, simplicity and safety in operation and the like. The bisindole alkaloid derivative can be used as an active molecule precursor to be widely applied in the medical chemical field.
Description
Technical field
The invention belongs to synthetic medicine, chemical field, relate generally to a kind of indole alkaloid derivative and synthetic method and application.
Background technology
The indole alkaloid derivative that has extensively exists at nature, is the important skeleton structure of natural product and medicine.2010 have reported to have extraordinary effect at anti-malarial by a kind of indole alkaloid derivative (Science 2010,329,1175-1180) at Science.The same year, Singapore Novartis research institute reported simultaneously composition optimizes indole alkaloid derivative antimalarial compound (J.Med.Chem.2010,53,5155-5164).Recently tropical agriculture institute of the Chinese Academy of Sciences from tropical plants, also separate obtain the indole alkaloid derivative (Org.Lett.2013, DOI:10.1021/o14002619).But traditional indole alkaloid derivatives chemical synthetic method that has is to be that raw material is through four-step reaction synthetic indole alkaloid derivative (J.Med.Chem.2010,53 with the indoles, 5155-5164), exist the cost height, productive rate is low, the shortcoming of complex operation.
Summary of the invention
The present invention has overcome existing above shortcoming in the prior art synthetic method, has proposed one-step synthesis and has had the synthetic method of two chiral centre indole alkaloid derivatives, have raw material be simple and easy to, working method is simple and convenient etc. that advantage arranged.Utilize synthetic method of the present invention to obtain high cis-selectivity indole alkaloid derivative by high yield.The synthetic indole alkaloid derivative that obtains of the present invention has efficient Atom economy, highly selective, advantages such as high yield.
The present invention proposes a kind of synthetic method of indole alkaloid derivative, being raw material with diazonium compound, indole derivatives, Isatine derivatives, is catalyzer with the acetic acid rhodium, is solvent with the organic solvent, through single step reaction, obtain the described indole alkaloid derivative of purpose product.
Building-up reactions of the present invention is shown in following reaction formula (I):
Wherein, R
1Comprise hydrogen, alkyl, alkoxyl group, halogen; R
2Comprise alkyl, aryl, silica-based; R
3, R
4Comprise hydrogen, alkyl, alkoxyl group, halogen; R
5Comprise hydrogen, methyl, benzyl.
In the building-up reactions of the present invention, the scope of the mol ratio of raw material and catalyzer is diazonium compound: indole derivatives: Isatine derivatives: acetic acid rhodium=2: 1: 1: 0.01～1: 2: 2: 0.001.
Wherein, said method comprising the steps of: elder generation is dissolved in described indole derivatives, acetic acid rhodium, Isatine derivatives in the described organic solvent and forms material solution, then, and under-10～50 ℃, add diazo solution in material solution, reaction obtains described indole alkaloid derivative.Wherein, described diazo solution is that described diazonium compound is dissolved in formed solution in the described organic solvent.
In this building-up reactions, further, the described indole alkaloid derivative that reaction is obtained carries out separation and purification.
Wherein, described purification procedures adopts column chromatography.Preferably, be to be ethyl acetate with volume ratio: the solution of sherwood oil=1: 20～1: 5 carries out column chromatography.
Wherein, described organic solvent comprises chloroparaffin, ethers, toluene, dimethylbenzene.
The invention allows for a kind of indole alkaloid derivative shown in structural formula (2) that utilizes synthetic method of the present invention to prepare.One of purpose of the present invention be innovation ground propose a kind of by be simple and easy to raw material, prepare new compound as a series of indole alkaloid derivatives of structural formula (2) expression by high yield:
Wherein, R
1Comprise hydrogen, alkyl, alkoxyl group, halogen; R
2Comprise alkyl, aryl, silica-based; R
3, R
4Comprise hydrogen, alkyl, alkoxyl group, halogen; R
5Comprise hydrogen, methyl, benzyl.
For reaching above-mentioned purpose, the present invention adopts acetic acid rhodium catalyzing indole derivative, Isatine derivatives and diazonium compound reaction to obtain product.The present invention is catalyzer by being raw material with diazonium compound, indole derivatives, Isatine derivatives with the metal lewis acid catalyst, utilizes three component reaction of acetic acid rhodium catalysis, and single stage method is prepared the novel cpd of a series of indole alkaloid derivatives.The present invention designs and has synthesized the indole alkaloid derivative, the present invention is raw material with diazonium compound, indole derivatives, Isatine derivatives, with three component reaction of acetic acid rhodium catalysis, this reaction is solvent with the organic solvent, prepares a series of indole alkaloid derivative.
Be different from prior art, the reaction mechanism of synthetic method of the present invention is that diazonium is decomposed to form metal carbene (I) under the metal catalytic, and the ion pair that metal carbene and indole derivatives form is caught by Isatine derivatives, form the indole alkaloid derivative, as shown below:
The present invention has realized utilizing three component reaction of indole derivatives, Isatine derivatives, diazonium compound first, by be simple and easy to raw material, efficiently made up the indole alkaloid derivative.Its beneficial effect comprises: can make up the indole alkaloid derivative, relatively have advantages such as highly selective, high yield with 2010 in the synthetic indole alkaloid derivative method of four steps that Science reports, and safety simple to operate.
The synthetic indole alkaloid derivative that obtains of the present invention can be used as the widespread use that the bioactive molecule precursor is applicable to field of medicine and chemical technology.In antimalarial medicine, the indole alkaloid derivative be a kind of can be oral compounds effective (J.Med.Chem.2010,53,5155-5164).The indole alkaloid derivative extensively exist at euphorbia plant (Org.Lett.2013, DOI:10.1021/o14002619).
Description of drawings
Figure 1 shows that the nucleus magnetic resonance of embodiment 1 indole alkaloid derivative of the present invention
1H NMR,
13C NMR collection of illustrative plates.
Figure 2 shows that the nucleus magnetic resonance of embodiment 2 indole alkaloid derivatives of the present invention
1H NMR,
13C NMR collection of illustrative plates.
Figure 3 shows that the nucleus magnetic resonance of embodiment 3 indole alkaloid derivatives of the present invention
1H NMR,
13C NMR collection of illustrative plates.
Figure 4 shows that the nucleus magnetic resonance of embodiment 4 indole alkaloid derivatives of the present invention
1H NMR,
13C NMR collection of illustrative plates.
Embodiment
In conjunction with following specific embodiments and the drawings, the present invention is described in further detail, and protection content of the present invention is not limited to following examples.Under the spirit and scope that do not deviate from inventive concept, variation and advantage that those skilled in the art can expect all are included in the present invention, and are protection domain with the appending claims.Implement process of the present invention, condition, reagent, experimental technique etc., except the following content of mentioning specially, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.
Shown in building-up reactions of the present invention is specific as follows:
Wherein, R
1Comprise hydrogen, alkyl, alkoxyl group, or halogen; R
2Comprise alkyl, aryl, or silica-based; R
3, R
4Comprise hydrogen, alkyl, alkoxyl group, or halogen; R
5Comprise hydrogen, methyl, or benzyl.
Embodiment 1:
With N-skatole (0.3mmol), Rh
2(OAc)
4(0.0025mmol), the red toluene (1ml) that is dissolved in of N-methyl indigo (0.3mmol), then, the phenyl diazoacetic acid methyl esters (0.25mmol) that will be dissolved in the toluene (1.0ml) was added drop-wise in the reaction system in 1 hour, reaction system is under 0 ℃, after dropwising, stirred the vacuum rotary steam desolventizing 1 hour, obtain crude product, its structure is suc as formula shown in (2-1).Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 20～1: 3) obtain straight product.Productive rate is 81%, d.r＞20: 1.Nucleus magnetic resonance
1H NMR,
13C NMR collection of illustrative plates as shown in Figure 1, product 2-1
1H NMR (400MHz, CDCl3) δ (ppm) 8.53 (s, 1H), 7.72 (d, J=6.7Hz, 1H), and 7.30-7.32 (m, 1H), 7.04-7.15 (m, 3H), 6.98 (m, 2H), 6.77-6.84 (m, 4H), and 6.68-6.70 (m, 1H), 6.69 (d, J=7.6Hz, 1H), 3.93 (s, 3H), 3.74 (s, 3H), 2.81 (s, 3H);
13C NMR (100Hz, CDCl3) δ (ppm) 175.96,174.40,143.65,131.40,129.76,126.95,126.88,126.44,125.81,122.59,122.09,121.53,118.95,110.17,109.12,107.65,82.94,60.86,52.65,33.22,25.56; HRMS (EI) C
27H
24N
2NaO
4(M)+and theoretical value 463.1634, measured value 463.1639.
Embodiment 2:
With N-skatole (0.3mmol), N-methyl-isatin (0.3mmol), Rh
2(OAc)
4(0.0025mmol), be dissolved in methylene dichloride (1ml), then, the p-methoxyphenyl diazoacetic acid methyl esters (0.25mmol) that will be dissolved in the methylene dichloride (1.0ml) was added drop-wise in the reaction system in 1 hour, reaction system is under 50 ℃, after dropwising, stirred the vacuum rotary steam desolventizing 1 hour, obtain crude product, its structure is suc as formula shown in (2-2).Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 20～1: 10) obtain straight product.Productive rate is 73%, d.r＞20: 1.Nucleus magnetic resonance
1H NMR,
13C NMR collection of illustrative plates as shown in Figure 2, product 2-2
1H NMR (400MHz, CDCl3) δ (ppm) 8.42 (s, 1H), 7.63 (d, J=5.9Hz, 1H), 7.22-7.24 (m, 1H), 6.99-7.05 (m, 3H), 6.66-6.74 (m, 5H), 6.24-6.60 (m, 3H), 3.84 (s, 3H), 3.66 (s, 3H), 3.56 (s, 3H), 2.75 (s, 3H);
13C NMR (100Hz, CDCl3) δ (ppm) 176.11,174.59,143.70,131.27,129.72,126.99,126.39,122.62,122.07,121.51,118.94,111.20,110.46,109.09,107.79,82.91,60.08,55.05,52.62,33.19,25.63; HRMS (EI) C
28H
16N
2NaO
5(M)+and theoretical value 483.4628, measured value 483.4627.
Embodiment 3:
With N-skatole (0.3mmol), N-methyl-isatin (0.3mmol), Rh
2(OAc)
4(0.0025mmol) be dissolved in dimethylbenzene (1ml), then, to be dissolved in the 4-bromophenyl diazoacetic acid methyl esters (0.25mmol in the dimethylbenzene (1.0ml),) in 1 hour, be added drop-wise in the reaction system, reaction system is under-10 ℃, after dropwising, stirred 1 hour, the vacuum rotary steam desolventizing obtains crude product, and its structure is suc as formula shown in (2-3).Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 20～1: 5) obtain straight product.Productive rate is 82%, d.r＞20: 1.Nucleus magnetic resonance
1H NMR,
13C NMR collection of illustrative plates as shown in Figure 3, product 2-3
1H NMR (400MHz, CDCl
3) δ (ppm) 8.51 (s, 1H), 7.71 (m, 1H), 7.31-7.33 (m, 1H), 7.11-7.13 (m, 3H), 6.98 (m, 2H), 6.82-6.83 (m, 2H), 6.65-6.67 (m, 2H), 6.37 (d, J=6.8Hz, 1H), 3.93 (s, 3H), 3.74 (s, 3H), 2.86 (s, 3H);
13C NMR (100Hz, CDCl
3) δ (ppm) 175.75,173.76,143.57,131.42,130.09,128.96,126.66,126.36,122.27,121.70,121.26,119.19,109.58,109.25,107.97,82.65,60.46,52.79,33.25,25.64; HRMS (EI) C
27H
23BrN
2NaO
4(M)+and theoretical value 541.0739, measured value 541.0740.
Embodiment 4:
With 1,7-dimethyl indole (0.3mmol), N-methyl-isatin (0.3mmol), Rh
2(OAc)
4(0.0025mmol) be dissolved in tetrahydrofuran (THF) (1ml), then, to be dissolved in the phenyl diazoacetic acid methyl esters (0.25mmol in the tetrahydrofuran (THF) (1.0ml),) in 1 hour, be added drop-wise in the reaction system, reaction system is under 25 ℃, after dropwising, stirred 10 hours, the vacuum rotary steam desolventizing obtains crude product, and its structure is suc as formula shown in (2-4).Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 20～1: 5) obtain straight product.Productive rate is 87%, d.r＞20: 1.Product 2-4
1H NMR (400MHz, CDCl
3) δ 8.44 (s, 1H), 7.72 (d, J=7.5Hz, 1H), 7.21-6.68 (m, 8H), 6.59 (dd, J=26.9,8.3Hz, 2H), 6.28 (d, J=7.8Hz, 1H), 3.89 (s, 3H), 3.74 (s, 3H), 2.79 (s, 3H), 2.41 (s, 3H);
13C NMR (101MHz, CDCl
3) δ 175.99,174.43,143.66,137.12,134.30,131.39,130.86,129.73,127.83,126.85,126.49,125.79,124.83,122.24,122.07,120.75,110.03,109.15,107.61,82.94,60.88,52.63,33.13,25.54,21.69; HRMS (EI) C
28H
26N
2NaO
4(M)+and theoretical value 477.1790, measured value 477.1790.
Embodiment 5:
The present embodiment experimental technique is basic identical with embodiment 2-1, and the diazonium compound that adopts in the present embodiment is 3-aminomethyl phenyl diazoacetic acid methyl esters, and resulting product is shown in structural formula (2-5).Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 20～1: 5) obtain straight product.Productive rate is 85%, d.r＞20: 1.Product 2-5
1H NMR (400MHz, CDCl
3) δ (ppm) 8.50 (s, 1H), 7.71 (d, J=6.0Hz, 1H), 7.29-7.31 (m, 1H), 7.06-7.11 (m, 2H), 6.70-6.81 (m, 7H), 6.29-6.31 (m, 1H), 3.91 (s, 3H), 3.72 (s, 3H), 2.81 (s, 3H), 2.14 (s, 3H);
13C NMR (100Hz, CDCl
3) δ (ppm) 176.09,174.65,143.75,136.42,131.35,129.69,126.55,126.43,122.68,122.03,121.49,118.89,110.38,109.08,107.66,82.92,60.50,52.60,33.20,25.58,20.91.HRMS (EI) C
28H
26N
2NaO
4(M)+and theoretical value 477.1790, measured value 477.1792.
Embodiment 6:
The present embodiment experimental technique is basic identical with embodiment 2-1, and the indole derivatives that adopts in the present embodiment is 6-bromo-1-skatole, and resulting product is shown in structural formula (2-6).Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 20～1: 5) obtain straight product.Productive rate is 78%, d.r＞20: 1.Product 2-6
1H NMR (400MHz, CDCl
3) δ 8.53 (s, 1H), 7.65 (d, J=7.3Hz, 1H), 7.23-7.13 (m, 2H), 7.06 (m, 3H), 6.82 (m, 5H), 6.30 (d, J=7.8Hz, 1H), 3.91 (s, 3H), 3.76 (s, 3H), 2.80 (s, 3H);
13C NMR (101MHz, CDCl
3) δ 175.77,174.33,143.68,135.44,133.61,132.48,131.28,129.84,128.56,127.60,127.17,126.28,125.98,124.82,124.60,122.09,112.61,110.64,110.10,107.73,82.87,60.71,52.76,33.40,25.56; HRMS (EI) C
27H
23BrN
2NaO
4(M)+and theoretical value 541.0739, measured value 541.0739.
Embodiment 7:
The present embodiment experimental technique is basic identical with embodiment 2-1, and the isatin that adopts in the present embodiment is unprotected isatin, and resulting product is shown in structural formula (2-7).Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 20～1: 2) obtain straight product.Productive rate is 88%, d.r＞20: 1.Product 2-7
1H NMR (400MHz, CDCl
3) δ (ppm) 8.51 (s, 1H), 7.70 (d, J=7.6Hz, 1H), 7.33 (d, J=8.2Hz, 1H), 7.24 (s, 1H), 7.11-7.16 (m, 1H), 7.00-7.05 (m, 2H), 6.92 (s, 1H), and 6.78-6.82 (m, 2H), 6.67 (d, J=8.2Hz, 1H), 6.40 (d, J=7.4Hz, 1H), 3.94 (s, 3H), 3.74 (s, 3H);
13C NMR (100Hz, CDCl
3) δ (ppm) 177.57,174.65,140.74,136.74,131.46,129.80,127.04,126.95,126.23,122.62,122.09,121.54,118.97,110.24,109.41,109.12,83.02,60.56,52.66,33.21.
Embodiment 8:
The present embodiment experimental technique is basic identical with embodiment 2-1, and the isatin that adopts in the present embodiment is 5-methyl isophthalic acid-benzyl isatin, and resulting product is shown in structural formula (2-8).Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 20～1: 8) obtain straight product.Productive rate is 95%, d.r＞20: 1.Product 2-8
1H NMR (400MHz, CDCl
3) δ 8.54 (s, 1H), 7.56 (s, 1H), 7.33 (d, J=8.2Hz, 1H), and 7.26-7.09 (m, 5H), 7.08-6.85 (m, 6H), 6.78 (dd, J=15.7,8.1Hz, 3H), 6.65 (d, J=8.1Hz, 1H), 6.13 (d, J=8.0Hz, 1H), 4.55 (dd, J=101.0,15.8Hz, 2H), 3.92 (s, 3H), 3.73 (s, 3H), 2.13 (s, 3H);
13C NMR (101MHz, CDCl
3) δ 176.16,174.59,140.79,136.80,135.24,134.56,131.92,131.59,131.53,130.02,128.58,128.01,127.43,127.38,127.20,127.06,126.86,126.33,122.69,121.58,119.01,110.54,109.19,108.85,83.04,60.52,52.68,43.69,33.23,2131.
Claims (8)
1. the synthetic method of an indole alkaloid derivative, it is characterized in that, described method is raw material with diazonium compound, indole derivatives, Isatine derivatives, be catalyzer with the acetic acid rhodium, be solvent with the organic solvent, through single step reaction, obtain described indole alkaloid derivative as the formula (2);
Described building-up reactions is shown in reaction formula (I):
Wherein, R
1Comprise hydrogen, alkyl, alkoxyl group, halogen; R
2Comprise alkyl, aryl, silica-based; R
3, R
4Comprise hydrogen, alkyl, alkoxyl group, halogen; R
5Comprise hydrogen, methyl, benzyl.
2. the synthetic method of indole alkaloid derivative according to claim 1, it is characterized in that the mol ratio of described raw material and catalyzer is diazonium compound: indole derivatives: Isatine derivatives: acetic acid rhodium=2: 1: 1: 0.01～1: 2: 2: 0.001.
3. the synthetic method of indole alkaloid derivative according to claim 1 is characterized in that, described synthetic method is under-10～50 ℃, adds diazo solution and react in raw material indole derivatives, Isatine derivatives, acetic acid rhodium; Wherein, described diazo solution is the solution that described diazonium compound forms in described organic solvent.
4. the synthetic method of indole alkaloid derivative according to claim 1 is characterized in that, further, described synthetic method comprises purification procedures.
5. the synthetic method of indole alkaloid derivative according to claim 4 is characterized in that, described separation and purification is to be ethyl acetate with volume ratio: the solution of sherwood oil=1: 20～1: 5 carries out column chromatography.
6. the synthetic method of indole alkaloid derivative according to claim 1 is characterized in that, described organic solvent comprises chloroparaffin, ethers, toluene, dimethylbenzene.
7. one kind according to the resulting indole alkaloid derivative of claim 1 synthetic method.
8. as the application of indole alkaloid derivative as described in the claim 7 in the antimalarial medicine of preparation.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104557665A (en) * | 2015-01-09 | 2015-04-29 | 华东师范大学 | Optically active 3-substituted indole derivatives as well as synthesis method and application thereof |
| CN108822116A (en) * | 2018-06-04 | 2018-11-16 | 南京中医药大学 | Indole alkaloid with anti-tumor activity and its preparation method and application |
-
2013
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104557665A (en) * | 2015-01-09 | 2015-04-29 | 华东师范大学 | Optically active 3-substituted indole derivatives as well as synthesis method and application thereof |
| CN108822116A (en) * | 2018-06-04 | 2018-11-16 | 南京中医药大学 | Indole alkaloid with anti-tumor activity and its preparation method and application |
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Application publication date: 20130821 |