CN103936648A - 2,2-di(1H-indole-3-yl)-2H-acenaphthene-1-ketone compound and preparation method thereof - Google Patents

Abstract

The invention discloses 2,2-bis(1H-indol-3-yl)-2H-acenaphth-1-one compounds and a preparation method thereof, belonging to the technical field of organic chemical synthesis. The preparation method is as follows: in an anhydrous alcohol solvent, acenaphthoquinone and indole compounds are used as raw materials, and reacted in the presence of sulfonic acid compounds. After the reaction is complete, the reaction solution is cooled to room temperature, and distilled water is added to precipitate a yellow color Solid powder, suction filtered, washed with absolute ethanol, and vacuum-dried to obtain 2,2-bis(1H-indol-3-yl)-2H-acenaphthyl-1-one compounds. The present invention uses anhydrous alcohol as a solvent and sulfonic acid compound as a catalyst. The raw materials are simple and easy to obtain, the requirements for equipment are low, the reaction conditions are mild, the catalytic effect is good, the operation procedure is simple, and the yield of the obtained product is as high as 97%. The purity is as high as 99%, and its structure has been certified by nuclear magnetic resonance, which is suitable for industrial production.

Description

2,2-bis(1H-indol-3-yl)-2H-acenaphthyl-1-one compound and its preparation method

technical field

The invention belongs to the technical field of organic chemical synthesis, and specifically relates to a 2,2-bis( 1H -indol-3-yl) -2H -acenaphthyl-1-one compound and a preparation method thereof.

Background technique

In the fields of pharmacology, medicine and biochemistry, indole derivatives are a series of important heterocyclic compounds. Among them, bis-indolylmethanes (BIAs) extracted from many terrestrial or marine natural products such as tunicates and sponges exhibit diverse pharmaceutical activities and have been widely used in the treatment of fibromyalgia, chronic fatigue, irritable bowel syndrome etc. Studies have shown that such substances can also effectively inhibit the proliferation and spread of estrogen-dependent and independent breast tumor cells. Therefore, the synthesis of bis-indolylmethanes (BIAs) has always been an important research direction in the field of organic chemistry.

After consulting the data, it was found that the preparation of bis-indolylmethanes (BIAs) by reacting indole with aldehydes or ketones has been reported, and many Lewis acids, heteropolyacids and ionic liquids can well catalyze such reactions. However, there are few reports on the preparation of bis-indolylmethanes by the reaction of indole and acenaphthoquinone. Recently, Feng Guo-liang et al reported the preparation of 2,2-bis(1 H -indol-3-yl)-2 H -acenaphthyl-1 by using solid superacid SO4 ^2- /TiO ₂ as a catalyst under grinding conditions. - Ketones, and purified by column chromatography (Feng Guo-liang, Chinese Chemical Letters. 2010, 21, 1057). Apparently, the method yield is low, and the operating procedure is loaded down with trivial details, is unfavorable for industrialized production.

Contents of the invention

In view of the above problems existing in the prior art, the object of the present invention is to provide a fast, efficient, high yield and suitable for industrial production of 2,2-bis( 1H -indol-3-yl) -2H -Acenaphthyl-1-one compound and its preparation method.

The structure of the 2,2-bis( 1H -indol-3-yl) -2H -acenaphthen-1-one compound is shown in the general formula (I):

(I)

Wherein: R ₁ , R ₂ , R ₃ are each independently selected from one of the following:

(1) Alkyl;

(2) Aromatic group;

(3) Aralkyl;

(4) Cycloalkyl;

(5) heterocyclic group;

(6) -COOH, -SO ₃ H, -NH ₂ , -CN, -NC, -OH, -F, -Cl, -Br, -I;

(7) Groups containing -COOH, -SO ₃ H, -NH ₂ , -CN, -NC, -OH, -F, -Cl, -Br, -I;

(8) Groups containing ester groups, sulfonate groups, and phosphate groups;

(9) Secondary amine, tertiary amine group.

The preparation method of the 2,2-bis( 1H -indol-3-yl) -2H -acenaphthyl-1-one compound is characterized in that the preparation method is: in an anhydrous alcohol solvent, Using acenaphthylquinone represented by formula (III) and indole compound represented by formula (II) as raw materials, react in the presence of sulfonic acid compounds, and obtain 2,2 -bis( 1H -indol-3-yl) -2H -acenaphthyl-1-ketone compounds, wherein, R ₁ in formula (II), R ₂ , R ₃ and R in formula (I) respectively ₁ , R ₂ and R ₃ are the same, and the anhydrous alcohol solvent includes anhydrous methanol, anhydrous ethanol, n-propanol, n-butanol, preferably anhydrous ethanol.

   

(Ⅱ) (Ⅲ)

The preparation method of the 2,2-bis( 1H -indol-3-yl) -2H -acenaphthyl-1-one compound is characterized in that the sulfonic acid compound is an alkyl group, an aryl group , alkaryl, alkoxyaryl, cycloalkyl or heterocyclyl substituted sulfonic acids.

The preparation method of the 2,2-bis(1 H -indol-3-yl)-2 H -acenaphthyl-1-one compound is characterized in that the sulfonic acid compound is C ₁ -C ₆ Alkylsulfonic acid, benzenesulfonic acid, benzenesulfonic acid whose hydrogen on the benzene ring is replaced by C ₂ -C ₆ alkyl, benzenesulfonic acid whose hydrogen on the benzene ring is replaced by C ₁ -C ₆ alkoxy, benzene ring Benzenesulfonic acid, furanylsulfonic acid, pyrrolylsulfonic acid, thienylsulfonic acid, pyridylsulfonic acid, quinolinylsulfonic acid, furanmethylsulfonic acid, pyrrolemethylsulfonic acid, thiophene Methanesulfonic acid, pyridinemethylsulfonic acid, quinolinemethylsulfonic acid or camphorsulfonic acid.

The preparation method of the 2,2-bis( 1H -indol-3-yl) -2H -acenaphthyl-1-one compound is characterized in that the sulfonic acid compound is benzenesulfonic acid or camphor sulfonic acid.

The preparation method of the 2,2-bis( 1H -indol-3-yl) -2H -acenaphthyl-1-one compound is characterized in that the acenaphthoquinone represented by the formula (III) and the formula (II The molar ratio of the indole compound shown in ) is 1.0: 2.0~2.4, preferably the molar ratio of 1.0: 2.0; : 1.0.

The preparation method of the 2,2-bis( 1H -indol-3-yl) -2H -acenaphthyl-1-one compound is characterized in that the acenaphthylquinone represented by the formula (III) and The feeding molar ratio of sulfonic acid compounds is 1.0:0.05~1.0, preferably the feeding molar ratio is 1.0:0.1.

The preparation method of the 2,2-bis( 1H -indol-3-yl) -2H -acenaphthyl-1-one compound is characterized in that the reaction temperature is 10~100°C, and the reaction time is 10-30 minutes.

The preparation method of the 2,2-bis( 1H -indol-3-yl) -2H -acenaphthyl-1-one compound is characterized in that the reaction temperature is 80°C and the reaction time is 15 minute.

The preparation method of the 2,2-bis( 1H -indol-3-yl) -2H -acenaphthyl-1-one compound is characterized in that the post-treatment method is as follows: after the reaction is complete, the reaction solution is cooled After reaching room temperature, add distilled water to precipitate a yellow solid powder, filter with suction, wash with absolute ethanol, and dry in vacuo to obtain the product.

Its reaction equation is as follows:

By adopting above-mentioned technology, compared with prior art, the beneficial effect of the present invention is as follows:

1) The present invention uses anhydrous alcohol as a solvent, especially anhydrous ethanol, which can be naturally degraded, does not pollute the environment, avoids the use of environmentally polluting solvents such as halogenated hydrocarbons, is cheap and easy to obtain, has mild reaction conditions, and is convenient for post-treatment, and The solvent can be recovered and reused, which reduces production costs and improves economic benefits;

2) The present invention uses conventional sulfonic acid compounds as catalysts, which has good catalytic efficiency and greatly improves the reaction rate;

3) The raw materials of the present invention are simple and easy to obtain, low requirements on equipment, mild reaction conditions, and simple operation procedures. The yield of the obtained product is as high as 97% and the purity is as high as 99%. Its structure has been certified by nuclear magnetic resonance and is suitable for industrial production.

Detailed ways

The present invention will be further described below in conjunction with embodiment:

Effect of catalyst on the reaction: select different catalysts (0.1 mol) in Table 1, use acenaphthoquinone (0.5 mmol) and indole (1.0 mmol) as raw materials, and reflux reaction in ethanol until the raw material acenaphthoquinone reacts completely. Its reaction equation is as follows:

The specific experimental results are shown in Table 1. It can be seen from Table 1 that when H ₃ BO ₃ and L-proline are used as catalysts, it takes 12 h to complete the reaction, and the yields are 49% and 59% respectively; when NiCl ₂ 6H ₂ O and ZnCl ₂ are used as catalysts, The reaction can be completed within 6 to 7 hours, and the yields reach 69% and 76% respectively; when CAN and _I2 are used as catalysts, the reaction can be completed within 2 hours, and the yields are 65% and 77% respectively; using p-TSA When used as a catalyst, the reaction can be completed in 0.5h, and the yield can reach 92%; when camphorsulfonic acid (CSA) is used as a catalyst, the reaction can be completed in 0.25h, and the yield can reach 99%; when the ninth experiment is used as p-TSA as a catalyst The comparative experiment gave 90% yield at room temperature for 1 h. The above results show that sulfonic acid compounds can efficiently catalyze the reaction, and the catalytic effect of camphorsulfonic acid is the best.

The influence of table 1 catalyst on reaction

serial number catalyst temperature/℃ time/h Yield/% 1 CAN 80 2 65 2 _ZnCl2 80 6 76 3 NiCl ₂ 6H ₂ O 80 7 69 4 I ₂ 80 2 77 5 L-proline 80 12 59 6 H ₃ BO ₃ 80 12 49 7 CSA 80 0.25 99 8 p -TSA 80 0.5 92 9 p -TSA 20 1 90

The following specific examples will help to understand the present invention, but do not limit the content of the present invention.

Example 1

In a 50 mL round bottom flask, add 91 mg acenaphthoquinone (MW=182, 0.5 mmol), 117 mg indole (MW=117, 1.0 mmol), 11.6 mg camphorsulfonic acid (CSA) (MW=232, 0.05 mmol), 5mL of absolute ethanol, the reaction solution was refluxed and stirred at 80°C for 15 minutes (the reaction progress was tracked and monitored by TLC, developer: 60-90 petroleum ether: ethyl acetate = 2:1, volume ratio). After the reaction was complete, the reaction solution was cooled to room temperature, 5 mL of distilled water was added, and a yellow solid powder was precipitated, filtered by suction, washed twice with 1 mL of cold absolute ethanol, and vacuum-dried to obtain 197.0 mg of the product, with a yield of 99%. The purity measured by HPLC was 99.5%. ¹ H NMR (500 MHz, DMSO -d ₆ ): δ 10.98 (s, 2H, NH), 8.37 (d, J = 8.0 Hz, 1H), 8.04–7.97 (m, 2H), 7.91–7.88 (m, 1H), 7.71–7.68 (m, 1H), 7.55 (d, J = 6.7 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.02–6.99 (m, 4H), 6.85 (s, 2H ), 6.74 (t, J = 7.4 Hz, 2H); ¹³ C NMR (125 MHz, DMSO -d ₆ ): δ 202.6, 143.9, 139.6, 137.0, 132.0, 131.5, 130.5, 129.0, 128.8, 125.8, 124.6, 124.1, 122.2, 121.7, 121.0, 120.6, 118.3, 114.9, 111.7, 57.7.

Example 2

Comparative example, other operations are with embodiment 1. The reaction solution was stirred at 20°C for 15 minutes, and treated according to Example 1 to obtain 185.0 mg of the product, with a yield of 93%.

Example 3

Comparative example, other operations are with embodiment 1. The reaction solution was stirred at 40°C for 15 minutes and treated according to Example 1 to obtain 189.1 mg of the product with a yield of 95%.

Example 4

Comparative example, other operations are with embodiment 1. The reaction solution was stirred at 60°C for 15 minutes and treated according to Example 1 to obtain 193.0 mg of the product with a yield of 97%.

Example 5

Comparative example, other operations are with embodiment 1. Only methanol was used instead of ethanol, and the reaction solution was stirred for 15 minutes at a reflux temperature of 65° C., and treated according to Example 1 to obtain 185.0 mg of the product, with a yield of 93%.

Example 6

Comparative example, other operations are with embodiment 1. Only n-propanol was used instead of ethanol, and the reaction solution was stirred for 15 minutes at a reflux temperature of 95° C., and treated according to Example 1 to obtain 153.1 mg of the product, with a yield of 76.9%.

Example 7

Comparative example, other operations are with embodiment 1. Only n-butanol was used instead of ethanol, and the reaction solution was stirred at a reflux temperature of 118° C. for 10 minutes. Referring to Example 1, the solution was black, and 1 ml of water was added for further treatment. The black-yellow product was obtained by suction filtration, with a yield of 31.6%.

Example 8

In a 50mL round bottom flask, add 91mg acenaphthoquinone (MW=182, 0.5mmol), 131mg 1-methylindole (MW=131, 1.0mmol), 8.6mg p-toluenesulfonic acid (MW=172, 0.05mmol), 5mL absolute ethanol, and the reaction solution was refluxed and stirred at 80°C for 15 minutes (the reaction progress was tracked and monitored by TLC, developer: 60-90 petroleum ether: ethyl acetate = 2:1, volume ratio). After the reaction was complete, the reaction solution was cooled to room temperature, 5 mL of distilled water was added, and a yellow solid powder was precipitated, filtered by suction, washed twice with 1 mL of cold absolute ethanol, and vacuum-dried to obtain 209.0 mg of the product, with a yield of 98%, and the purity was measured by HPLC. 99.4%. ¹ H NMR (500 MHz, DMSO -d ₆ ) : δ 8.37 (d, J = 8.1 Hz, 1H), 8.06–7.96 (m, 2H), 7.90 (t, J = 7.5 Hz, 1H), 7.70 (t , J = 7.6 Hz, 1H), 7.56 (d, J = 6.9 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H), 7.11–7.00 (m, 4H), 6.88 (s, 2H), 6.79 (t, J = 7.5 Hz, 2H), 3.68 (s, 6H, CH ₃ ); ¹³ C NMR (125 MHz, DMSO -d ₆ ): δ 202.4, 143.7, 137.4, 132.1, 131.4, 130.5, 129.0, 128.8 , 128.7, 126.1, 124.1, 122.3, 121.7, 121.1, 120.7, 118.5, 113.9, 109.8, 57.4, 32.3.

Example 9

In a 50 mL round bottom flask, add 91 mg acenaphthoquinone (MW=182, 0.5 mmol), 131 mg 2-methylindole (MW=131, 1.0 mmol), 4.8 mg methanesulfonic acid (MW=96, 0.05 mmol ), 5 mL of absolute ethanol, and the reaction solution was refluxed and stirred at 80°C for 15 minutes (the reaction progress was tracked and monitored by TLC, developer: 60-90 petroleum ether: ethyl acetate = 2:1, volume ratio). After the reaction was complete, the reaction solution was cooled to room temperature, 5 mL of distilled water was added, and a yellow solid powder was precipitated, filtered by suction, washed twice with 1 mL of cold absolute ethanol, and dried in vacuo to obtain 209.0 mg of the product, with a yield of 98%, and the purity was measured by HPLC. 99.4%. ¹ H NMR (500 MHz, DMSO -d ₆ ): δ 10.90 (s, 1H, NH), 10.88 (s, 1H, NH), 8.33 (d, J = 8.1 Hz, 1H), 8.07–7.99 (m, 2H), 7.87 (t, J = 7.6 Hz, 1H), 7.65 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 6.9 Hz, 1H), 7.21 (t, J = 7.0 Hz, 2H) , 6.87(dt, J = 11.1, 7.5 Hz, 2H), 6.59 (t, J = 7.5 Hz, 1H), 6.56– 6.50 (m, 2H), 6.33 (d, J = 8.1 Hz, 1H), 1.84 ( s, 3H, CH ₃ ), 1.79 (s, 3H, CH ₃ ); ¹³ C NMR (125 MHz, DMSO -d ₆ ): δ 202.0, 144.0, 140.0, 135.0, 134.9, 133.6, 133.3, 132.7, 131.6, 130.3, 128.9, 128.7, 127.6, 127.3, 124.0, 122.2, 121.8, 119.7, 119.6, 119.5, 119.4, 118.0, 117.9, 110.9, 110.3, 110.1, 53.4, 137.5,

Example 10

In a 50mL round bottom flask, add 91mg acenaphthoquinone (MW=182, 0.5 mmol), 147mg 5-methoxyindole (MW=147, 1.0 mmol), 7.9mg benzenesulfonic acid (MW=158, 0.05 mmol ), 5mL of absolute ethanol, and the reaction solution was refluxed and stirred at 80°C for 15 minutes (the reaction progress was tracked and monitored by TLC, developer: 60-90 petroleum ether: ethyl acetate = 2:1, volume ratio). After the reaction was complete, the reaction solution was cooled to room temperature, 5 mL of distilled water was added, and a yellow solid powder was precipitated, filtered by suction, washed twice with 1 mL of cold absolute ethanol, and vacuum-dried to obtain 230.9 mg of the product, with a yield of 97%. The purity measured by HPLC was 99.4%. ¹ H NMR (500 MHz, DMSO -d ₆ ): δ 10.82 (s, 2H, NH), 8.37 (d, J = 8.1 Hz, 1H), 8.01 (t, J = 7.0 Hz, 2H), 7.92–7.87 (m, 1H), 7.74–7.68 (m, 1H), 7.54 (d, J = 6.9 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.86 (s, 2H), 6.67 (dd, J = 8.7, 2.1 Hz, 2H), 6.41 (s, 2H), 3.40 (s, 6H, OCH ₃ ); ¹³ C NMR (125 MHz, DMSO -d ₆ ): δ 202.8, 152.5, 143.8, 139.7, 132.2 , 132.0, 131.7, 130.4, 129.0, 128.8, 126.2, 125.4, 124.0, 122.0, 121.7, 114.2, 112.1, 110.4, 103.2, 57.6, 54.9.

Claims (10)

1.2,2-two (1 h-indol-3-yl)-2 h-acenaphthene-1-ketone compounds, its structure is as shown in logical formula I:

（Ⅰ）

Wherein: R ₁, R ₂, R ₃independently be selected from separately one of following:

(1) alkyl;

(2) aromatic base;

(3) aralkyl;

(4) cycloalkyl;

(5) heterocyclic radical;

（6）-COOH，-SO ₃H，-NH ₂，-CN，-NC，-OH，-F，-Cl，-Br，-I；

(7) contain-COOH-SO ₃h ,-NH ₂,-CN ,-NC ,-OH ,-F ,-Cl ,-Br, the group of-I;

(8) containing ester group, sulfonate group, phosphate-based group;

(9) secondary amine, tertiary amines group.

One kind according to claim 12,2-two (1 h-indol-3-yl)-2 hthe preparation method of-acenaphthene-1-ketone compounds, it is characterized in that described preparation method is: in absolute alcohol solvent, taking the Benzazole compounds shown in the acenaphthenequinone shown in formula III and formula II as raw material, under the existence of sulfonic compound, react, obtain 2 shown in formula I through aftertreatment, 2-two (1 h-indol-3-yl)-2 h-acenaphthene-1-ketone compounds, wherein, the R in formula II ₁, R ₂, R ₃respectively with formula (I) in R ₁, R ₂, R ₃identical, described absolute alcohol solvent comprises anhydrous methanol, dehydrated alcohol, n-propyl alcohol, propyl carbinol, is preferably dehydrated alcohol.

3.

（Ⅱ） （Ⅲ）

According to claim 22,2-two (1 h-indol-3-yl)-2 hthe preparation method of-acenaphthene-1-ketone compounds, is characterized in that described sulfonic compound is the sulfonic acid that alkyl, aromatic base, alkylaryl, cycloalkyl or heterocyclic radical replace.

4. according to claim 22,2-two (1 h-indol-3-yl)-2 hthe preparation method of-acenaphthene-1-ketone compounds, is characterized in that described sulfonic compound is C ₁-C ₆alkylsulphonic acid, Phenylsulfonic acid, benzene ring hydrogen are by C ₂-C ₆phenylsulfonic acid, benzene ring hydrogen that alkyl replaces are by C ₁-C ₆the Phenylsulfonic acid that alkoxyl group replaces, Phenylsulfonic acid, furyl sulfonic acid, pyrryl sulfonic acid, thienyl sulfonic acid, pyridyl sulfonic acid, quinolyl sulfonic acid, furfuryl sulfonic acid, pyrroles's methylsulphonic acid, thenyl sulfonic acid, picolyl sulfonic acid, quinoline methylsulphonic acid or the camphorsulfonic acid that benzene ring hydrogen is replaced by halogen.

5. according to claim 42,2-two (1 h-indol-3-yl)-2 hthe preparation method of-acenaphthene-1-ketone compounds, is characterized in that described sulfonic compound is Phenylsulfonic acid or camphorsulfonic acid.

6. according to claim 22,2-two (1 h-indol-3-yl)-2 hthe preparation method of-acenaphthene-1-ketone compounds, the molar ratio that it is characterized in that the Benzazole compounds shown in the acenaphthenequinone shown in formula III and formula II is 1.0: 2.0 ~ 2.4, preferably molar ratio is 1.0: 2.0; The molar ratio of compound shown in described sulfonic compound and formula III is 0.05 ~ 1.0: 1.0.

7. according to claim 22,2-two (1 h-indol-3-yl)-2 hthe preparation method of-acenaphthene-1-ketone compounds, is characterized in that the acenaphthenequinone shown in described formula III and the molar ratio of sulfonic compound are 1.0: 0.05 ~ 1.0, and preferably molar ratio is 1.0: 0.1.

8. according to claim 22,2-two (1 h-indol-3-yl)-2 hthe preparation method of-acenaphthene-1-ketone compounds, is characterized in that described temperature of reaction is 10 ~ 100 DEG C, and the reaction times is 10 ~ 30 minutes.

9. according to claim 82,2-two (1 h-indol-3-yl)-2 hthe preparation method of-acenaphthene-1-ketone compounds, is characterized in that described temperature of reaction is 80 DEG C, and the reaction times is 15 minutes.

10. according to claim 22,2-two (1 h-indol-3-yl)-2 hthe preparation method of-acenaphthene-1-ketone compounds, is characterized in that post-treating method is as follows: after reacting completely, by reaction solution cool to room temperature, add distilled water to separate out yellow solid powder, and suction filtration, with absolute ethanol washing, vacuum-drying obtains product.