A method for synthesizing iminostilbene

Abstract

The present invention discloses a method for synthesizing iminostilbene. Using 1-phenylindole as the starting material, under the action of a super strong protonic acid, 1-phenylindole undergoes an intramolecular rearrangement reaction to generate iminostilbene. Among them, the super strong protonic acid is one of chlorosulfonic acid, fluorosulfonic acid, trifluoromethanesulfonic acid, magic acid, fluoroantimonic acid, and sulfuric acid / zirconia. The present invention also optimizes the corresponding reaction conditions, shortens the reaction time, and reduces the occurrence of side reactions. Therefore, it has the advantages of high product yield and short reaction time. The highest product yield reaches 93.8%, the time is 4-8 hours, and the purity is 99%, achieving good technical effects.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a method for synthesizing iminostilbene. Background Art

[0002] Iminostilbene is an important raw material for synthesizing key intermediates such as the anti-epileptic drug carbamazepine and the anti-convulsant drug oxcarbazepine. In recent years, the demand for carbamazepine and oxcarbazepine has increased. Therefore, it is of great significance to study new and efficient synthetic process routes for iminostilbene.

[0003] Currently, there are many reported methods for preparing iminostilbene in the literature. Among them, the representative ones include: Su Weike (CN101307021A) uses iminodibenzyl as the raw material and prepares iminostilbene by high-temperature catalytic hydrogenation. This synthetic method has a high raw material cost and poor reaction safety; Yu Feng et al. (CN1616433A) uses a multi-step synthesis method starting from o-nitrotoluene to obtain iminostilbene through coupling and cyclization, with a total yield of about 40%. This method has a low yield, a complex reaction process, and many impurities; Song Guoqiang et al. (CN103113302A) propose a one-step synthesis of iminostilbene, starting from 1-phenylindole and obtaining the target product iminostilbene through catalysis by polyphosphoric acid (PPA). This method is simple to operate, but has disadvantages such as a long reaction time and a low yield.

[0004] In summary, in the current synthetic processes of iminostilbene, there are deficiencies such as high raw material costs, low yields, or complex reaction processes. Therefore, researching and developing new synthetic processes for it has great application value. Summary of the Invention

[0005] Aiming at the above technical problems existing in the prior art, the purpose of this application is to provide a method for synthesizing iminostilbene. The method of the present invention uses a super strong protonic acid for the reaction, and has the advantages of high yield, short reaction time, less three wastes, and simple process.

[0006] The method for synthesizing iminostilbene described in the present invention has a mechanism that uses 1-phenylindole as the starting material. 1-phenylindole is protonated under the catalysis of a super strong acid to obtain 1-phenyl-3H-indole ion, and forms a 1-phenylindole derivative by adding the anion of the protonic acid. Then, the 1-phenylindole derivative is protonated on the nitrogen atom to break the C-N bond, obtaining a carbocation. The carbocation undergoes intramolecular electrophilic substitution at the ortho position of the aryl group to form dihydroiminostilbene, and finally, the anion of the protonic acid is removed to promote intramolecular electron migration to obtain iminostilbene.

[0007] During the research of this application, it was found that when an acid with relatively weak acidity was used as the catalyst, the reaction effect was poor or there was no reaction. The superprotic acid used in this application, which has stronger acidity than 100% sulfuric acid, was used to catalyze the synthesis of iminostilbene, and a good yield was obtained. The reason is that the superprotic acid used is more conducive to forming protonation, opening the C-N bond, forming a catalytic cycle, thereby increasing the yield. By optimizing and screening the reaction conditions, the selectivity and yield of the reaction were further improved. The highest product yield reached 93.8%, and the purity was 99%. At the same time, the reaction time and the temperature required for the reaction were reduced, achieving good technical effects.

[0008] A method for synthesizing iminostilbene according to the present invention uses 1-phenylindole as the starting material. Under the action of a superprotic acid, 1-phenylindole undergoes an intramolecular rearrangement reaction to generate iminostilbene; wherein, the superprotic acid includes chlorosulfonic acid, fluorosulfonic acid, trifluoromethylsulfonic acid, magic acid, fluoroantimonic acid, sulfuric acid / zirconium dioxide, etc.

[0009] Specifically, the method for synthesizing iminostilbene includes the following steps: adding 1-phenylindole into a reactor, adding a certain amount of solvent, then adding a superprotic acid, stirring, heating to a reaction temperature of 50 - 120°C and carrying out a closed reaction for 4 - 8 hours, and monitoring the reaction process by TLC; after the reaction is completed, the reaction solution is post-treated to obtain the iminostilbene product; wherein, the molar ratio of 1-phenylindole to the superprotic acid is 1 : 1 - 5.

[0010] In the method for synthesizing iminostilbene, the solvent is one of bromobenzene, chlorobenzene, toluene, ethanol, hexane, and carbon tetrachloride.

[0011] In the method for synthesizing iminostilbene, the molar ratio of 1-phenylindole to the superprotic acid is 1 : 1 - 5.

[0012] In the method for synthesizing iminostilbene, the reaction temperature is 50 - 100°C, and the reaction time is 4 - 7 hours.

[0013] In the method for synthesizing iminostilbene, the process of post-treating the reaction solution is as follows: after cooling the reaction solution, adjusting the pH to 8 - 9 with an alkali solution, then extracting with an organic solvent and separating the layers. After the obtained organic phase is concentrated by rotary evaporation under reduced pressure, the concentrated residue is recrystallized with petroleum ether to obtain the target iminostilbene.

[0014] In the method for synthesizing iminostilbene, the alkali solution is a saturated aqueous solution of sodium bicarbonate, and the organic solvent is ethyl acetate.

[0015] Compared with the prior art, the beneficial effects of the present invention are:

[0016] The present invention uses a super strong protonic acid as a catalyst for the synthesis of iminostilbene. Meanwhile, the corresponding reaction conditions are optimized, the reaction time is shortened, and the occurrence of side reactions is reduced. Therefore, it has the advantages of high product yield and short reaction time. The highest product yield reaches 93.8%, and the purity is 99%, achieving good technical effects. Detailed implementation manners

[0017] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0018] Example 1:

[0019] A method for iminostilbene, using 1-phenylindole as the raw material, the operation steps are as follows:

[0020] In a 250 mL three-necked flask, add 19.3 g (0.1 mol) of the raw material 1-phenylindole, add 120 mL of chlorobenzene, and then add 45.0 g (0.3 mol) of trifluoromethanesulfonic acid. Heat up to 100 °C, stir, and react hermetically at 100 °C for 8 hours. Monitor the reaction process by TLC.

[0021] After the reaction is completed, cool the reaction solution to 30 - 40 °C and pour it into a saturated aqueous solution of sodium bicarbonate at 0 °C to adjust the pH to 8 - 9. Then extract with ethyl acetate to obtain an organic phase. Extract three times repeatedly, then dry with anhydrous sodium sulfate, concentrate by rotary evaporation under reduced pressure, and pour it into 200 mL of petroleum ether for recrystallization to obtain the target product iminostilbene. Product melting point: 197.3 - 199.2 °C. The product yield is 93.8%, and the purity is 99%.

[0022] Example 2:

[0023] Repeat the experimental process of Example 1, the only difference is that the feeding amount of trifluoromethanesulfonic acid is replaced with 30.0 g (0.2 mol), and other conditions and operation processes are the same as those in Example 1. Finally, the target product iminostilbene is obtained. The product yield is 83.0%, and the purity is 99%.

[0024] Example 3:

[0025] Repeat the experimental process of Example 1, the only difference is that "the feeding amount of trifluoromethanesulfonic acid is replaced with 60.0 g (0.4 mol)", and other conditions and operation processes are the same as those in Example 1. Finally, the target product iminostilbene is obtained. The product yield is 87.4%, and the purity is 99%.

[0026] Example 4:

[0027] The experimental process was repeated in Example 1, except that trifluoromethanesulfonic acid was replaced with magic acid. Other conditions and procedures were the same as in Example 1, and the target product, iminostilbene, was obtained in a yield of 89.7% and a purity of 99%.

[0028] Example 4:

[0029] The experimental process was repeated in Example 1, except that trifluoromethanesulfonic acid was replaced with fluorosulfonic acid. Other conditions and procedures were the same as in Example 1, and the target product, iminostilbene, was obtained in a yield of 85.9% and a purity of 99%.

[0030] Example 5:

[0031] The experimental process was repeated in Example 1, except that trifluoromethanesulfonic acid was replaced with chlorosulfonic acid. The reaction time was 7 hours and the reaction temperature was 80°C. Other conditions and procedures were the same as in Example 1, and the target product, iminostilbene, was obtained. The yield was 85.5% and the purity was 99%.

[0032] Example 6:

[0033] The experimental process was repeated as in Example 1, except that trifluoromethanesulfonic acid was replaced with fluoroantimonic acid and carbon tetrachloride was added as the solvent. Other conditions and procedures were the same as in Example 1, and the target product, iminostilbene, was obtained with a yield of 87.8% and a purity of 98%.

[0034] Example 7:

[0035] The experimental process was repeated in Example 1, except that trifluoromethanesulfonic acid was replaced with sulfuric acid / zirconium dioxide. The reaction time was 5 hours and the reaction temperature was 70°C. Other conditions and procedures were the same as in Example 1. The target product, iminostilbene, was obtained with a yield of 87.4% and a purity of 99%.

[0036] Example 8:

[0037] The experimental process was repeated as in Example 1, except that chlorobenzene was replaced with bromobenzene. The reaction time was 6 hours and the reaction temperature was 90°C. Other conditions and procedures were the same as in Example 1, and the target product, iminostilbene, was obtained with a yield of 82.7% and a purity of 99%.

[0038] Example 9:

[0039] The experimental process was repeated in Example 1, except that chlorobenzene was replaced with toluene. Other conditions and procedures were the same as in Example 1, and the target product, iminostilbene, was obtained with a yield of 85.3% and a purity of 99%.

[0040] Example 10:

[0041] The experimental procedure was repeated as in Example 1, except that "chlorobenzene was replaced with ethanol", and other conditions and operation procedures were the same as in Example 1. Finally, the target product, iminosstilbene, was obtained. The product yield was 85.7% and the purity was 99%.

[0042] Example 11:

[0043] The experimental procedure was repeated as in Example 1, except that "chlorobenzene was replaced with hexane", and other conditions and operation procedures were the same as in Example 1. Finally, the target product, iminosstilbene, was obtained. The product yield was 85.9% and the purity was 99%.

[0044] Example 12:

[0045] The experimental procedure was repeated as in Example 1, except that "chlorobenzene was replaced with carbon tetrachloride", and other conditions and operation procedures were the same as in Example 1. Finally, the target product, iminosstilbene, was obtained. The product yield was 87.0% and the purity was 99%.

[0046] Example 13:

[0047] The experimental procedure was repeated as in Example 1, except that "the reaction temperature was replaced with 90 °C", and other conditions and operation procedures were the same as in Example 1. Finally, the target product, iminosstilbene, was obtained. The product yield was 87.1% and the purity was 99%.

[0048] Example 14:

[0049] The experimental procedure was repeated as in Example 1, except that "the reaction temperature was replaced with 110 °C", and other conditions and operation procedures were the same as in Example 1. Finally, the target product, iminosstilbene, was obtained. The product yield was 87.5% and the purity was 99%.

[0050] Example 15:

[0051] The experimental procedure was repeated as in Example 1, except that "the reaction time was replaced with 7 hours", and other conditions and operation procedures were the same as in Example 1. Finally, the target product, iminosstilbene, was obtained. The product yield was 86.3% and the purity was 99%.

[0052] Example 16:

[0053] The experimental procedure was repeated as in Example 1, except that "the reaction time was replaced with 6 hours", and other conditions and operation procedures were the same as in Example 1. Finally, the target product, iminosstilbene, was obtained. The product yield was 87.9% and the purity was 99%.

[0054] The content described in this specification is only a list of the implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as limited to the specific forms stated in the examples.

Claims

1. A method for synthesizing iminostilbene, characterized in that, The method uses 1-phenylindole as a starting material, and under the action of a super strong proton acid, 1-phenylindole undergoes an intramolecular rearrangement reaction to produce iminostilbene. The method comprises the following steps: adding 1-phenylindole to a reactor, adding a certain amount of solvent, then adding a certain proportion of super strong proton acid, stirring, heating to a certain temperature for reaction, and monitoring the reaction progress by TLC; after the reaction is completed, the reaction solution is post-treated to obtain the iminostilbene product. The super proton acid is one of trifluoromethanesulfonic acid, chlorosulfonic acid, fluorosulfonic acid, magic acid, fluoroantimonic acid, and sulfuric acid / zirconium dioxide; the molar ratio of 1-phenylindole to the super proton acid is 1:1-5; and the reaction solution is post-treated as follows: cooling the reaction solution, adjusting the pH to 8-9 with alkaline solution, extracting with an organic solvent, separating the liquids, concentrating the obtained organic phase by rotary evaporation under reduced pressure, and recrystallizing the concentrated residue with petroleum ether to obtain the target iminostilbene.

2. a method for synthesizing iminostilbene as claimed in claim 1, is characterized in that, The method comprises the following steps: adding 1-phenylindole into a reactor, adding a certain amount of solvent, and then adding a super strong protonic acid, stirring, heating to a reaction temperature of 50-120°C, reacting in a sealed manner for 4-8 hours, and monitoring the reaction progress by TLC; after the reaction is completed, the reaction liquid is post-treated to obtain an iminostilbene product.

3. A method for synthesizing iminostilbene as claimed in claim 1, characterized in that, The solvent is one of bromobenzene, chlorobenzene, toluene, ethanol, hexane and carbon tetrachloride.

4. a method for synthesizing iminostilbene as claimed in claim 1, is characterized in that, The reaction temperature is 50-100°C and the reaction time is 4-7 hours.

5. A method for synthesizing iminostilbene as claimed in claim 1, characterized in that, The alkali solution is a saturated aqueous solution of sodium bicarbonate, and the organic solvent is ethyl acetate.