Brand-new intermediate of 5-cyanoindole and preparation method of brand-new intermediate
By using reactants such as 3-methyl-4-nitrobenzonitrile in the preparation process of 5-cyanoindole, the problems of complex steps, environmental hazards and low cyclic yields in the prior art are solved, and efficient and environmentally friendly 5-cyanoindole intermediate preparation is achieved.
Patent Information
- Application Number
- CN202510448661.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-10
- Publication Date
- 2025-06-13
- Estimated Expiration
- Not applicable · inactive patent
AI Technical Summary
The existing preparation method for 5-cyanoindole has problems such as complex steps, great harm to the environment and personnel, and insufficient activity of enamine intermediates leads to low yield of indole rings.
A completely new intermediate is produced by reacting 3-methyl-4-nitrobenzonitrile, a condensate, a catalyst and an aminoguanidine salt in an organic solvent, which plays a key role in the synthesis of 5-cyanoindole.
The reaction efficiency and product purity are significantly improved, and the preparation method has mild reaction conditions, easy operation, high yield and suitable for industrial production.
Smart Images
Figure CN120136744A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of organic synthesis, and particularly to a novel intermediate for synthesizing 5-cyanoindole and a preparation method thereof. Background Art
[0002] 5-Cyanoindole is an important organic compound, which is widely used in the fields of medicine, pesticides, and functional materials. However, in the existing technology, the preparation method of 5-cyanoindole has problems such as complex steps, great harm of cyanide reagents to the environment and personnel, and low indole cyclization yield due to insufficient activity of enamine intermediates. In particular, the lack of an efficient and environmentally friendly intermediate preparation method limits its industrial production and application. Therefore, it is of great significance to develop a novel intermediate and its preparation method. Summary of the Invention
[0003] The present invention provides a novel intermediate for 5-cyanoindole and a preparation method thereof. This intermediate plays a key role in the synthesis of 5-cyanoindole, can significantly improve the reaction efficiency and product purity, and the preparation method of this intermediate has the characteristics of mild reaction conditions, simple operation, high yield, and suitability for industrial production.
[0004] A novel intermediate for 5-cyanoindole, the chemical structural formula of the novel intermediate is shown as formula A:
[0005]
[0006] A preparation method of a novel intermediate for 5-cyanoindole, the novel intermediate is prepared by reacting 3-methyl-4-nitrobenzonitrile, a condensing agent, a catalyst, and an aminoguanidine salt in an organic solvent;
[0007] Preferably, the preparation method includes the following steps:
[0008] S1, Add 3-methyl-4-nitrobenzonitrile, a condensing agent, and a catalyst to organic solvent 1. Under nitrogen protection, heat up to reflux and stir for reaction for 2 - 4 h. After the reaction ends, remove the reaction solvent by vacuum distillation to obtain a dried product;
[0009] S2, Add organic solvent 2 and an aminoguanidine salt to the dried product, and react at room temperature for 1 - 3 h;
[0010] S3, After the reaction ends, remove part of the solvent by vacuum distillation, cool and crystallize, and filter; Recrystallize the filter cake, filter, and dry to obtain the novel intermediate for 5-cyanoindole.
[0011] Preferably, the condensing agent is one or more of N,N - diethylformamide dimethyl acetal, N,N - diethylformamide dimethyl acetal, N,N - dimethylformamide diethyl acetal, N,N - dimethylformamide dipropyl acetal, N,N - dimethylformamide diisopropyl acetal, N,N - dimethylformamide dibenzyl acetal.
[0012] Preferably, the catalyst is one or more of piperidine, pyrrolidine, piperazine, morpholine, imidazoline, 1,3 - oxazolidane, azetidine.
[0013] Preferably, the aminoguanidine salt is one or more of aminoguanidine carbonate, aminoguanidine sulfate.
[0014] Preferably, the organic solvent 1 is one or more of dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, preferably dioxane.
[0015] Preferably, the organic solvent 2 is methanol, ethanol, isopropanol, n - butanol, preferably methanol.
[0016] Preferably, the molar ratio of the condensing agent to 3 - methyl - 4 - nitrile is from 1:1 to 1.5:1, preferably 1.2:1.
[0017] Preferably, the molar ratio of the catalyst to 3 - methyl - 4 - nitrile is from 1:1 to 1.8:1, preferably 1.5:1.
[0018] Preferably, the molar ratio of the aminoguanidine salt to 3 - methyl - 4 - nitrile is from 1:1 to 1.8:1, preferably 1.5:1.
[0019] Preferably, the yield of the novel intermediate of 5 - cyanoindole reaches over 72.9%, and the product purity reaches over 98.2%; the yield is preferably 72.9% - 87.7%.
[0020] The present invention has the following technical effects:
[0021] 1. The novel intermediate provided by the present invention improves the stability and activity of the enamine intermediate, and solves the problem of low reduction cyclization yield in the existing Leimgruber - Batcho indole method.
[0022] 2. The preparation method provided by the present invention, the reaction steps and operating conditions adopted are relatively easy to control, without the need for complex and special instrument equipment, and the entire synthesis process can be completed in an ordinary organic synthesis laboratory, reducing the synthesis difficulty and cost.
[0023] 3. The raw materials used in the present invention are all commercially available common chemicals with low prices; the entire reaction process is easy to scale up and is suitable for large - scale production. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Figure 1 It is a synthetic route diagram of a brand-new intermediate of 5-cyanoindole provided by an embodiment of the present invention. SPECIFIC EMBODIMENTS
[0025] The preparation method of the present invention will be further described below through specific embodiments, but the present invention is not limited to these embodiments.
[0026] Example 1
[0027] 60.0 g of 3-methyl-4-nitrobenzonitrile (1.0 eq.) was added to a reaction flask, 65.4 g of N,N-diethylformamide dimethyl acetal (1.2 eq.), 47.3 g of piperidine (1.5 eq.), 150 ml of tetrahydrofuran. Under nitrogen protection, the temperature was raised to reflux and the reaction was kept for 3 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a dried product. 120 ml of methanol was added to the dried product, and an aminoguanidine carbonate solution (75.6 g of aminoguanidine carbonate (1.5 eq.), 60 ml of water) prepared in advance was added under stirring at room temperature, and the reaction was kept for 2 h. After the reaction was completed, half of the solvent was removed by distillation under reduced pressure. It was cooled to 5 °C, filtered, the filter cake was recrystallized with methanol, filtered, and dried to obtain 66.5 g of a brand-new intermediate of 5-cyanoindole, with a yield of 72.9% and a purity of 98.9%.
[0028] Example 2
[0029] 60.0 g of 3-methyl-4-nitrobenzonitrile (1.0 eq.) was added to a reaction flask, 65.4 g of N,N-dimethylformamide diethyl acetal (1.2 eq.), 47.8 g of piperazine (1.5 eq.), 150 ml of dioxane. Under nitrogen protection, the temperature was raised to reflux and the reaction was kept for 3 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a dried product. 120 ml of ethanol was added to the dried product, and a sulfamic acid aminoguanidine solution (95.6 g of sulfamic acid aminoguanidine (1.5 eq.), 60 ml of water) prepared in advance was added under stirring at room temperature, and the reaction was kept for 2 h. After the reaction was completed, half of the solvent was removed by distillation under reduced pressure. It was cooled to 5 °C, filtered, the filter cake was recrystallized with methanol, filtered, and dried to obtain 73.2 g of a brand-new intermediate of 5-cyanoindole, with a yield of 80.2% and a purity of 98.2%.
[0030] Example 3
[0031] Charge 60.0 g of 3-methyl-4-nitrobenzonitrile (1.0 eq.), 77.9 g of N,N-dimethylformamide dipropyl acetal (1.2 eq.), 48.4 g of morpholine (1.5 eq.) and 150 ml of ethylene glycol diethyl ether into a reaction flask. Under nitrogen protection, heat up to reflux and keep the reaction for 3 h. After the reaction is completed, remove the solvent by distillation under reduced pressure to obtain a dried residue. Add 120 ml of methanol to the dried residue, and add the pre-prepared guanidine sulfate solution (63.7 g of guanidine sulfate (1.0 eq.), 60 ml of water) under stirring at room temperature, and keep the reaction for 2 h. After the reaction is completed, remove half of the solvent by distillation under reduced pressure. Cool to 5 °C, filter, recrystallize the filter cake with methanol, filter and dry to obtain 75.4 g of a new intermediate of 5-cyanoindole, with a yield of 82.7% and a purity of 98.7%.
[0032] Example 4
[0033] Charge 60.0 g of 3-methyl-4-nitrobenzonitrile (1.0 eq.), 52.9 g of N,N-dimethylformamide dimethyl acetal (1.2 eq.), 39.5 g of pyrrolidine (1.5 eq.) and 150 ml of dioxane into a reaction flask. Under nitrogen protection, heat up to reflux and keep the reaction for 3 h. After the reaction is completed, remove the solvent by distillation under reduced pressure to obtain a dried residue. Add 120 ml of methanol to the dried residue, and add the pre-prepared guanidine sulfate solution (95.6 g of guanidine sulfate (1.5 eq.), 60 ml of water) under stirring at room temperature, and keep the reaction for 2 h. After the reaction is completed, remove half of the solvent by distillation under reduced pressure. Cool to 5 °C, filter, recrystallize the filter cake with methanol, filter and dry to obtain 79.9 g of a new intermediate of 5-cyanoindole, with a yield of 87.7% and a purity of 99.1%.
[0034] Example 5
[0035] Charge 60.0 g of 3-methyl-4-nitrobenzonitrile (1.0 eq.), 66.2 g of N,N-dimethylformamide dimethyl acetal (1.5 eq.), 40.1 g of imidazoline (1.5 eq.) and 150 ml of dioxane into a reaction flask. Under nitrogen protection, heat up to reflux and keep the reaction for 3 h. After the reaction is completed, remove the solvent by distillation under reduced pressure to obtain a dried residue. Add 120 ml of isopropanol to the dried residue, and add the pre-prepared guanidine sulfate solution (114.7 g of guanidine sulfate (1.8 eq.), 60 ml of water) under stirring at room temperature, and keep the reaction for 2 h. After the reaction is completed, remove half of the solvent by distillation under reduced pressure. Cool to 5 °C, filter, recrystallize the filter cake with methanol, filter and dry to obtain 78.7 g of a new intermediate of 5-cyanoindole, with a yield of 86.4% and a purity of 99.0%.
[0036] Example 6
[0037] Into the reaction flask, add 60.0 g of 3-methyl-4-nitrobenzonitrile (1.0 eq.), 77.9 g of N,N-dimethylformamide diisopropyl acetal (1.2 eq.), 31.7 g of azetidine (1.5 eq.), and 150 ml of diethylene glycol dimethyl ether. Under nitrogen protection, heat to reflux and keep the reaction for 3 h. After the reaction is completed, remove the solvent by distillation under reduced pressure to obtain a dried residue. Add 120 ml of isopropanol to the dried residue, and add the pre-prepared solution of aminoguanidine carbonate (75.6 g of aminoguanidine carbonate (1.5 eq.), 60 ml of water) while stirring at room temperature, and keep the reaction for 2 h. After the reaction is completed, distill off half of the solvent under reduced pressure. Cool to 5 °C, filter, and recrystallize the filter cake with methanol, filter, and dry to obtain 72.3 g of a new intermediate of 5-cyanoindole, with a yield of 79.3% and a purity of 98.5%.
[0038] Example 7
[0039] Into the reaction flask, add 60.0 g of 3-methyl-4-nitrobenzonitrile (1.0 eq.), 120.6 g of N,N-dimethylformamide dibenzyl acetal (1.2 eq.), 40.6 g of 1,3-oxazolidine (1.5 eq.), and 150 ml of ethylene glycol dimethyl ether. Under nitrogen protection, heat to reflux and keep the reaction for 3 h. After the reaction is completed, remove the solvent by distillation under reduced pressure to obtain a dried residue. Add 120 ml of n-butanol to the dried residue, and add the pre-prepared solution of aminoguanidine sulfate (114.7 g of aminoguanidine sulfate (1.8 eq.), 60 ml of water) while stirring at room temperature, and keep the reaction for 2 h. After the reaction is completed, distill off half of the solvent under reduced pressure. Cool to 5 °C, filter, and recrystallize the filter cake with methanol, filter, and dry to obtain 70.2 g of a new intermediate of 5-cyanoindole, with a yield of 76.9% and a purity of 98.7%.
Claims
1. A novel intermediate of 5-cyanoindole, characterized in that: The chemical structure of the new intermediate is shown in Formula A:
2. A method for preparing a novel intermediate of 5-cyanoindole, characterized in that: The novel intermediate is prepared by reacting 3-methyl-4-nitrobenzonitrile, a condensation agent, a catalyst and an aminoguanidine salt in an organic solvent.
3. A method for preparing a novel intermediate of 5-cyanoindole, characterized in that: The following steps are involved: S1, add 3-methyl-4-nitrobenzonitrile, condensation agent and catalyst into organic solvent 1, raise the temperature to reflux under nitrogen protection, and stir to react for 2-4h. After the reaction is completed, remove the reaction solvent by vacuum distillation to obtain an evaporated product; S2, adding organic solvent 2 and aminoguanidine salt to the evaporated product, and reacting at room temperature for 1-3h; S3, after the reaction is completed, part of the solvent is removed by distillation under reduced pressure, the mixture is cooled and crystallized, and filtered; the filter cake is recrystallized, filtered, and dried to obtain a new intermediate of 5-cyanoindole.
4. The preparation method according to claim 2 or 3, characterized in that: The condensing agent is one or more of N,N-diethylformamide dimethyl acetal, N,N-diethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide dipropyl acetal, N,N-dimethylformamide diisopropyl acetal and N,N-dimethylformamide dibenzyl acetal.
5. The preparation method according to claim 2 or 3, characterized in that: The catalyst is one or more of piperidine, tetrahydropyrrole, piperazine, morpholine, imidazoline, 1,3-oxazolidine, and azetidine.
6. The preparation method according to claim 2 or 3, characterized in that: The aminoguanidine salt is one or more of aminoguanidine carbonate and aminoguanidine sulfate.
7. The preparation method according to claim 2 or 3, characterized in that: The organic solvent 1 is one or more of dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, and diethylene glycol dimethyl ether, preferably dioxane; the organic solvent 2 is methanol, ethanol, isopropanol, and n-butanol, preferably methanol.
8. The preparation method according to claim 2 or 3, characterized in that: The molar ratio of the condensing agent to the 3-methyl-4-nitrobenzonitrile is 1:1 to 1.5:1, preferably 1.2:
1.
9. The preparation method according to claim 2 or 3, characterized in that: The molar ratio of the catalyst to the 3-methyl-4-nitrobenzonitrile is 1:1 to 1.8:1, preferably 1.5:
1.
10. The preparation method according to claim 2 or 3, characterized in that: The molar ratio of the aminoguanidine salt to the 3-methyl-4-nitrobenzonitrile is 1:1 to 1.8:1, preferably 1.5:1.