Preparation method of indolone alkynyl compound

Abstract

The invention relates to the technical field of organic synthesis, and particularly discloses a preparation method of an indolone alkynyl compound. The preparation method of the indolone alkynyl compound comprises the following steps: uniformly mixing indolone, an alkynyl compound, alkali, an oxidizing agent and a solvent in a nitrogen atmosphere to obtain a mixed solution; the mixed solution is subjected to a heating reaction, and the indalone alkynyl compound is obtained. The preparation method of the indolone alkynyl compound has the advantages of mild reaction conditions, simple steps and no generation of harmful by-products, meets the requirements of industrial production, and has a wide application prospect.

Description

Technical Field

[0001] The present application relates to the technical field of organic synthesis, and in particular to a method for preparing an indole ketone alkynyl compound. Background Art

[0002] Indolone is an important class of organic compounds, which has attracted wide attention due to its wide applications in medicine, pesticides and functional materials. Indolone derivatives, especially those containing alkynyl substituents, have important application value in drug design, catalytic reactions and functional material development, and have become one of the hot topics in organic chemistry research in recent years. Alkynylation reaction is an important means to construct organic compounds with diverse structures, especially in the functional modification of indolone.

[0003] At present, several studies have reported the acetylation reaction of indolone. For example, the prior art proposes a method for synthesizing 3-alkynyl indole by reacting indolone with 1-iodo-2-phenylacetylene through base catalysis. The method is carried out at 120°C and can effectively achieve the acetylation of indolone. However, the existing method has the following limitations: first, the reaction conditions are harsh and need to be carried out at a higher temperature, which may lead to side reactions and thus reduce the purity of the product; second, the synthons used are relatively complex, requiring the synthesis of 1-iodo-2-phenylacetylene and the generation of hydrogen iodide after the reaction, which has many steps and is not conducive to environmental protection.

[0004] Therefore, there is an urgent need to develop an efficient indole acetylenylation method under mild conditions that can simplify the reaction steps, reduce the reaction temperature, and increase the reaction yield while avoiding complex synthons and harmful byproducts, thereby meeting the needs of industrial production. Summary of the invention

[0005] In view of the above-mentioned deficiencies in the prior art, the purpose of the present application is to provide a method for preparing an indole ketone alkynyl compound, aiming to solve the problems of harsh reaction conditions and complex synthesis steps in the existing indole ketone alkynylation method.

[0006] The technical solution of this application is as follows:

[0007] In a first aspect of the present application, a method for preparing an indole ketone alkynyl compound is provided, comprising the steps of:

[0008] Indolinone, an alkynyl compound, a base, an oxidant and a solvent are mixed uniformly under a nitrogen atmosphere to obtain a mixed solution; the mixed solution is heated to react to obtain the indolinone alkynyl compound.

[0009] Preferably, the molar ratio of the indolone, the alkynyl compound, the alkaline catalyst and the oxidant is 2:1:2:2.

[0010] Preferably, the alkynyl compound includes one or both of phenylacetylene and methylphenylacetylene.

[0011] Preferably, the base comprises at least one of potassium carbonate, sodium hydroxide and potassium hydroxide.

[0012] Preferably, the oxidizing agent comprises the oxidizing agent being silver carbonate.

[0013] Preferably, the solvent includes chlorobenzene, and the solvent is chlorobenzene. 1 mL of the solvent is the best, and increasing or decreasing the amount of the solvent will reduce the yield.

[0014] Preferably, the temperature of the heating reaction is 90-110 degrees Celsius, and the time of the heating reaction is 6-12 hours.

[0015] Preferably, the product obtained by heating the mixed solution is purified to obtain the indole ketone alkynyl compound.

[0016] Preferably, the purification method is selected from column chromatography.

[0017] Beneficial effects of the present application: The preparation method of the indole ketone alkynyl compound in the present application utilizes indole ketone and alkynyl compounds to directly couple to synthesize indole ketone alkynyl under the catalytic action of a basic catalyst and an oxidant. Compared with the previous method, the reaction temperature is reduced by 30°C, and direct dehydrogenation coupling of indole ketone and alkynyl is achieved without the need for additional reaction steps. The byproduct of the process is hydrogen, which fully meets the requirements of green chemistry and does not cause environmental pollution. DETAILED DESCRIPTION

[0018] In order to make the purpose, technical solutions and advantages of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below in combination with the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments of the present application, all other embodiments obtained by ordinary technicians in this field without making creative work belong to the protection scope of the present application. In the absence of conflict, the following embodiments and features in the embodiments can be combined with each other.

[0019] It should be noted that if there are descriptions involving "first", "second", etc. in the implementation of this application, the descriptions of "first", "second", etc. are only used for descriptive purposes and cannot be understood as indicating or suggesting their relative importance and implicitly indicating the number of technical features indicated. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In addition, the technical solutions between the various embodiments can be combined with each other, but they must be based on the fact that ordinary technicians in the field can implement them. When the combination of technical solutions is contradictory or cannot be implemented, it should be deemed that such combination of technical solutions does not exist and is not within the scope of protection required by this application.

[0020] The preparation method of indole alkynyl compound (alkynylation method of indole) in the prior art has the following problems:

[0021] (1) Harsh reaction conditions: Most existing methods require reactions to be carried out at relatively high temperatures, such as 120°C, which can easily lead to side reactions and reduce the purity of the product. Therefore, how to carry out efficient reactions under mild conditions to avoid side reactions and improve the purity of the product has become an urgent problem to be solved in this field.

[0022] (2) Complex synthesis of synthons: Existing technologies usually require the synthesis of complex reactants (such as 1-iodo-2-phenylethyne) and involve multiple synthesis steps. This not only increases the operational difficulty of the reaction, but also brings higher costs and environmental burdens. Simplifying the synthesis process of synthons and reducing unnecessary intermediates are the key to improving the economic and environmental performance of the reaction.

[0023] (3) The reaction steps are complicated and the yield is low: Existing methods often require multiple steps to obtain the target product, and sometimes the yield is unstable. How to improve the reaction efficiency, shorten the reaction time and increase the yield is still a difficult problem in this technical field.

[0024] Based on this, the present invention provides a method for preparing an indole ketone alkynyl compound, comprising the steps of:

[0025] S1. Mixing indolinone, alkynyl compound, base, oxidant and solvent uniformly under nitrogen atmosphere to obtain a mixed solution;

[0026] S2, heating the mixed solution obtained in S1 to obtain the indone alkynyl compound.

[0027] The synthetic route of indole ketone alkynyl compounds is as follows:

[0028]

[0029] Indolone alkynyl is synthesized by direct coupling of indolone and alkynyl under the catalysis of potassium carbonate and silver carbonate, achieving direct dehydrogenation coupling of indolone and alkynyl without the need for additional reaction steps. The byproduct of this process is hydrogen, which fully meets the requirements of green chemistry and does not cause environmental pollution.

[0030] The alkaline catalyst is used to adjust the reaction environment, the oxidant is used to promote the dehydrogenation coupling reaction between indolone and the alkynyl compound, and the solvent is preferably an organic solvent.

[0031] In some embodiments, the molar ratio of indolone, alkynyl compound, base, and oxidant is 2:1:2:2.

[0032] In some embodiments, the amount of potassium carbonate and silver carbonate used in the reaction process can be appropriately adjusted according to the amount of the reactants. Preferably, the amount of potassium carbonate is 1 times that of the indole ketone, and the amount of silver carbonate is 1 times that of the alkynyl compound.

[0033] In some embodiments, the alkynyl compound includes, but is not limited to, one or both of phenylacetylene, methylphenylacetylene, or other substituted alkynyl compounds.

[0034] In some embodiments, the alkaline catalyst includes at least one of potassium carbonate, sodium hydroxide, and potassium hydroxide.

[0035] In some embodiments, the oxidizing agent is silver carbonate.

[0036] In some embodiments, the solvent includes chlorobenzene. 1 mL of the solvent is the best, and increasing or decreasing the amount of the solvent will reduce the yield.

[0037] In some embodiments, the temperature of the heating reaction is 90-110 degrees Celsius. For example, the temperature of the heating reaction is 90 degrees Celsius, 91 degrees Celsius, 92 degrees Celsius, 93 degrees Celsius, 94 degrees Celsius, 95 degrees Celsius, 96 degrees Celsius, 97 degrees Celsius, 98 degrees Celsius, 99 degrees Celsius, 100 degrees Celsius, 101 degrees Celsius, 102 degrees Celsius, 103 degrees Celsius, 104 degrees Celsius, 105 degrees Celsius, 106 degrees Celsius, 107 degrees Celsius, 108 degrees Celsius, 109 degrees Celsius or 110 degrees Celsius, etc. The time of the heating reaction is 6-12 hours. For example, the time of the heating reaction is 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours or 12 hours, etc.

[0038] If the temperature is too high, side reactions may occur, while if the temperature is too low, the reaction rate may decrease. Compared with the existing methods, the reaction temperature of the method for preparing the indole ketone alkynyl compound provided in the embodiment of the present application is reduced by about 30 degrees Celsius, the reaction conditions are mild, and the product yield is high.

[0039] In some embodiments, the method for preparing an indole ketone alkynyl compound further comprises the steps of:

[0040] S21. The mixed solution is heated and the reaction is monitored by thin layer chromatography (TLC).

[0041] The amount of each material in the reaction process is monitored by thin layer chromatography or gas chromatography to accurately determine the termination time of the reaction and ensure the yield of the indole ketone alkynyl compound.

[0042] S22, purifying the product obtained by heating the mixed solution.

[0043] The purification method is column chromatography. In some embodiments, the stationary phase of the chromatography column used in the column chromatography is selected from silica gel, and the mobile phase is selected from petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 10:1.

[0044] The following is further described by means of specific examples.

[0045] First, the reagents and equipment used in the examples are described.

[0046] Raw materials: indole ketone, phenylacetylene, acetylene, potassium carbonate, silver carbonate, chlorobenzene, purchased conventionally.

[0047] Experimental equipment: Reaction flask: used for mixing and heating the reaction solution. Constant temperature heating plate: used for precise control of the reaction temperature. Purification column: used for separation of the product after the reaction. Evaporator: used for solvent removal and product concentration.

[0048] Example 1

[0049] In a 5 mL round-bottom flask, 44.6 mg (0.2 mmol) of indolone, 10.2 mg (0.1 mmol) of phenylacetylene, 27.6 mg (0.2 mmol) of potassium carbonate and 54.8 mg (0.2 mmol) of silver carbonate were added under nitrogen atmosphere. 1 mL of chlorobenzene (PhCl) was added as solvent, the reaction temperature was set at 90°C, and the reaction was carried out for 12 hours. After the reaction was completed, the solvent was removed, and the product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain an indolone alkynyl compound with a yield of (75)%. After nuclear magnetic resonance and mass spectrometry analysis, the purity of the obtained indolone alkynyl compound was 98%.

[0050] Example 2

[0051] In a 5 mL round-bottom flask, under nitrogen atmosphere, 47.4 mg (0.2 mmol) of methyl indole ketone, 10.2 mg (0.1 mmol) of phenylacetylene, 27.6 mg (0.2 mmol) of potassium carbonate and 54.8 mg (0.2 mmol) of silver carbonate were added. 1 mL of chlorobenzene (PhCl) was added as solvent, the reaction temperature was set at 90°C, and the reaction was carried out for 12 hours. After the reaction was completed, the solvent was removed, and the product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain an indole ketone alkynyl compound with a yield of (62)%. After nuclear magnetic resonance and mass spectrometry analysis, the purity of the obtained indole ketone alkynyl compound was 98%.

[0052] Example 3

[0053] In a 5 mL round-bottom flask, under nitrogen atmosphere, 44.6 mg (0.2 mmol) indole ketone, 10.2 mg (0.1 mmol) phenylacetylene, 8.0 mg (0.2 mmol) sodium hydroxide and 54.8 mg (0.2 mmol) silver carbonate were added. 1 mL chlorobenzene (PhCl) was added as solvent, the reaction temperature was set at 90°C, and the reaction was carried out for 12 hours. After the reaction was completed, the solvent was removed, and the product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain an indole ketone alkynyl compound with a yield of (65)%. After nuclear magnetic resonance and mass spectrometry analysis, the purity of the obtained indole ketone alkynyl compound was 98%.

[0054] Example 4

[0055] In a 5 mL round-bottom flask, 44.6 mg (0.2 mmol) of indolone, 10.2 mg (0.1 mmol) of phenylacetylene, 11.2 mg (0.2 mmol) of potassium hydroxide and 54.8 mg (0.2 mmol) of silver carbonate were added under nitrogen atmosphere. 1 mL of chlorobenzene (PhCl) was added as solvent, the reaction temperature was set at 90°C, and the reaction was carried out for 12 hours. After the reaction was completed, the solvent was removed, and the product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain an indolone alkynyl compound with a yield of (59)%. After nuclear magnetic resonance and mass spectrometry analysis, the purity of the obtained indolone alkynyl compound was 98%.

[0056] Example 5

[0057] In a 5 mL round-bottom flask, 44.6 mg (0.2 mmol) of indolone, 10.2 mg (0.1 mmol) of phenylacetylene, 4.8 mg (0.2 mmol) of lithium hydroxide and 54.8 mg (0.2 mmol) of silver carbonate were added under nitrogen atmosphere. 1 mL of chlorobenzene (PhCl) was added as solvent, the reaction temperature was set at 90°C, and the reaction was carried out for 12 hours. After the reaction was completed, the solvent was removed, and the product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain an indolone alkynyl compound with a yield of (52)%. After nuclear magnetic resonance and mass spectrometry analysis, the purity of the obtained indolone alkynyl compound was 98%.

[0058] In summary, the preparation method of the indole ketone alkynyl compound in the present application has low reaction temperature, mild conditions, simple reaction steps, and the by-product only includes hydrogen, which avoids the formation of complex synthons and harmful by-products, improves the reaction efficiency, can meet the needs of industrial production, and has broad application prospects.

[0059] It should be understood that the application of the present application is not limited to the above examples. For ordinary technicians in this field, improvements or changes can be made based on the above description. All these improvements and changes should fall within the scope of protection of the claims attached to this application.

Claims

1. A method for preparing an indole ketone alkynyl compound, characterized in that: Includes steps: Indolinone, an alkynyl compound, a base, an oxidant and a solvent are mixed uniformly under a nitrogen atmosphere to obtain a mixed solution; The mixed solution is heated for reaction to obtain the indole ketone alkynyl compound.

2. The method for preparing an indole ketone alkynyl compound according to claim 1, characterized in that: The molar ratio of the indolone, the alkynyl compound, the base and the oxidant is 2:1:2:

2.

3. The method for preparing an indole ketone alkynyl compound according to claim 1, characterized in that: The alkynyl compound includes one or both of phenylacetylene and methylphenylacetylene.

4. The method for preparing an indole ketone alkynyl compound according to claim 1, characterized in that: The alkali includes at least one of potassium carbonate, sodium hydroxide and potassium hydroxide.

5. The method for preparing an indole ketone alkynyl compound according to claim 1, characterized in that: The oxidizing agent is silver carbonate.

6. The method for preparing an indole ketone alkynyl compound according to claim 1, characterized in that: The solvent is chlorobenzene. 1 mL of the solvent is the best, and increasing or decreasing the amount of the solvent will reduce the yield.

7. The method for preparing an indole ketone alkynyl compound according to claim 1, characterized in that: The temperature of the heating reaction is 90-110 degrees Celsius, and the time of the heating reaction is 6-12 hours.

8. The method for preparing an indole ketone alkynyl compound according to claim 1, characterized in that: The mixed solution is subjected to a heating reaction and the product obtained is purified to obtain the indole ketone alkynyl compound.

9. The method for preparing an indole ketone alkynyl compound according to claim 9, characterized in that: The purification method is selected from column chromatography.

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