A method for synthesizing 10-methoxy imino stilbene

Abstract

The application relates to the technical field of medical chemistry and chemical industry, and discloses a synthesis method of 10-methoxy imino stilbene, which comprises the following steps: taking 10,11-dibromo imino dibenzyl as a reaction raw material, and performing reaction under the action of inorganic alkali and a solvent to generate 10-methoxy imino stilbene; the solvent is a mixed solution of methanol and n-hexane. Through the technical scheme, the problems of low yield and low purity in the synthesis process of 10-methoxy imino stilbene in the prior art are solved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry and chemical engineering technology, specifically to a method for synthesizing 10-methoxyiminostilbene. Background Technology

[0002] 10-Methoxyiminostilbene, also known as 10-methoxy-5H-dibenzo[b,f]azapyrrolidone, has the molecular formula C1. 15 H 13 NO is a pale yellow to off-white crystalline powder used in the preparation of the drug oxcarbazepine. Its structural formula is as follows:

[0003]

[0004] Currently, existing synthetic processes for 10-methoxyiminostilbene (Chinese invention patents CN106467491A and CN114957122A) mainly use 10,11-dibromoiminodibenzyl as the reactant in a methanol solution of potassium hydroxide or potassium methoxide to prepare 10-methoxyiminostilbene. However, since 10-methoxyiminostilbene is an intermediate in the preparation of the drug oxcarbazepine, and with the increasing national requirements for active pharmaceutical ingredients, the quality requirements for key intermediates in drug preparation are also becoming increasingly stringent. Therefore, researchers are keen to develop a synthetic method for 10-methoxyiminostilbene with high yield and high purity. Summary of the Invention

[0005] This invention proposes a method for synthesizing 10-methoxyiminostilbene, which solves the problems of low yield and low purity in the synthesis process of 10-methoxyiminostilbene in related technologies.

[0006] The technical solution of the present invention is as follows:

[0007] A method for synthesizing 10-methoxyiminostilbene includes the following steps: using 10,11-dibromoiminodibenzyl as a reactant, a reaction is carried out under the action of an inorganic base and a solvent to generate 10-methoxyiminostilbene.

[0008] The solvent is a mixed solution of methanol and n-hexane.

[0009] As a further technical solution, the volume fraction of n-hexane in the methanol and n-hexane mixed solution is 15% to 25%.

[0010] As a further technical solution, the volume fraction of n-hexane in the methanol and n-hexane mixed solution is 20%.

[0011] As a further technical solution, the inorganic base is a strong base.

[0012] As a further technical solution, the strong alkali is sodium hydroxide or potassium hydroxide.

[0013] As a further technical solution, the mass ratio of 10,11-dibromoiminodibenzyl to inorganic base is 1:1.5 to 2.5.

[0014] As a further technical solution, the mass-to-volume ratio of the 10,11-dibromoiminodibenzyl to the solvent is 1g:5-15mL.

[0015] As a further technical solution, the reaction temperature is 85-95℃ and the time is 8-10h.

[0016] As a further technical solution, after the reaction is complete, the process includes washing with water, crystallization, and drying to obtain 10-methoxyiminostilbene.

[0017] As a further technical solution, the crystallization temperature is 3-10℃.

[0018] The working principle and beneficial effects of this invention are as follows:

[0019] 1. This invention uses a mixed solution of methanol and n-hexane as a solvent. By adding n-hexane, the polarity of the solvent is improved, thereby ensuring the strength of the inorganic base and thus improving the yield and purity of 10-methoxyiminostilbene.

[0020] 2. In this invention, the volume fraction of n-hexane in the mixed solution of methanol and n-hexane is limited to 15% to 25%, which further improves the yield and purity of 10-methoxyiminostilbene. Detailed Implementation

[0021] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0022] In the following examples and comparative examples, 10,11-dibromoiminodibenzyl was prepared by the method disclosed in CN100999497A, with a purity of 98.5%.

[0023] Example 1

[0024] Mix 800 mL of methanol with 200 g of potassium hydroxide, heat to 70 °C and reflux until the potassium hydroxide is completely dissolved. Cool to 50 °C, add 200 mL of n-hexane and stir well. Then add 100 g of 10,11-dibromoiminodibenzyl and heat to 90 °C and react for 9 h. Distill off methanol and n-hexane under reduced pressure, add water and stir, filter and dry. Add methanol to dissolve and crystallize at 5 °C. Filter and dry to obtain 10-methoxyiminostilbene.

[0025] Example 2

[0026] Mix 400 mL of methanol with 150 g of potassium hydroxide, heat to 70 °C and reflux until the potassium hydroxide is completely dissolved. Cool to 50 °C, add 100 mL of n-hexane and stir well. Then add 100 g of 10,11-dibromoiminodibenzyl and heat to 85 °C and react for 10 h. Distill off methanol and n-hexane under reduced pressure, add water and stir, filter and dry. Add methanol to dissolve and crystallize at 3 °C. Filter and dry to obtain 10-methoxyiminostilbene.

[0027] Example 3

[0028] Mix 1200 mL of methanol with 250 g of sodium hydroxide, heat to 70 °C and reflux until the potassium hydroxide is completely dissolved. Cool to 50 °C, add 300 mL of n-hexane and stir well. Then add 100 g of 10,11-dibromoiminodibenzyl and heat to 95 °C for 8 h. Distill off methanol and n-hexane under reduced pressure, add water and stir, filter and dry. Add methanol to dissolve and crystallize at 10 °C. Filter and dry to obtain 10-methoxyiminostilbene.

[0029] Example 4

[0030] Mix 850 mL of methanol with 200 g of potassium hydroxide, heat to 70 °C and reflux until the potassium hydroxide is completely dissolved. Cool to 50 °C, add 150 mL of n-hexane and stir well. Then add 100 g of 10,11-dibromoiminodibenzyl and heat to 90 °C and react for 9 h. Distill off methanol and n-hexane under reduced pressure, add water and stir, filter and dry. Add methanol to dissolve and crystallize at 5 °C. Filter and dry to obtain 10-methoxyiminostilbene.

[0031] Example 5

[0032] Mix 750 mL of methanol with 200 g of potassium hydroxide, heat to 70 °C and reflux until the potassium hydroxide is completely dissolved. Cool to 50 °C, add 250 mL of n-hexane and stir well. Then add 100 g of 10,11-dibromoiminodibenzyl, heat to 90 °C and react for 9 h. Distill off methanol and n-hexane under reduced pressure, add water and stir, filter and dry. Add methanol to dissolve, crystallize at 5 °C, filter and dry to obtain 10-methoxyiminostilbene.

[0033] Comparative Example 1

[0034] Mix 1000 mL of methanol with 200 g of potassium hydroxide, heat to 70 °C and reflux until the potassium hydroxide is completely dissolved. Cool to 50 °C, add 100 g of 10,11-dibromoiminodibenzyl, heat to 90 °C and react for 9 h. Distill off methanol under reduced pressure, add water and stir, filter and dry, add methanol again to dissolve, crystallize at 5 °C, filter and dry to obtain 10-methoxyiminostilbene.

[0035] Comparative Example 2

[0036] Mix 800 mL of methanol with 200 g of potassium hydroxide, heat to 70 °C and reflux until the potassium hydroxide is completely dissolved. Cool to 50 °C, add 200 mL of toluene and stir well. Then add 100 g of 10,11-dibromoiminodibenzyl, heat to 90 °C and react for 9 h. Distill off methanol and toluene under reduced pressure, add water and stir, filter and dry. Add methanol to dissolve, crystallize at 5 °C, filter and dry to obtain 10-methoxyiminostilbene.

[0037] The purity of the 10-methoxyiminostilbene obtained in Examples 1-5 and Comparative Examples 1-2 was determined by HPLC, and the yield was calculated according to the following formula:

[0038] Yield (%) = Actual mass of 10-methoxyiminostilbene obtained × Purity ÷ Theoretical yield × 100

[0039] The results are recorded in Table 1.

[0040] Table 1. Purity and yield of 10-methoxyiminostilbene

[0041]

[0042]

[0043] As can be seen from Table 1, the synthesis method of 10-methoxyiminostilbene provided by the present invention yields 10-methoxyiminostilbene with a purity of over 99.0% and a yield of over 93.7%, exhibiting high purity and high yield.

[0044] Compared with Comparative Example 1, Example 1 used a mixed solution of methanol and n-hexane as the solvent, while Comparative Example 1 used methanol as the solvent. The purity and yield of 10-methoxyiminostilbene obtained in Example 1 were both higher than those in Comparative Example 1, indicating that using a mixed solution of methanol and n-hexane as the reaction solvent can significantly improve the purity and yield of 10-methoxyiminostilbene.

[0045] Compared with Comparative Example 2, Example 1 used a mixed solution of methanol and n-hexane as the solvent, while Comparative Example 2 used a mixed solution of methanol and toluene as the solvent. The purity and yield of 10-methoxyiminostilbene obtained in Comparative Example 2 were not as good as those in Example 1. This shows that using a mixed solution of methanol and n-hexane as the solvent is more effective in improving the purity and yield of the synthesized 10-methoxyiminostilbene than using a mixed solution of methanol and toluene as the solvent.

[0046] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A type of 10 A method for synthesizing methoxyiminostilbene, characterized in that, Includes the following steps: With 10,11 Dibromoiminodibenzyl is used as a reactant in the presence of an inorganic base and solvent to produce 10 Methoxyiminostilbene; The solvent is a mixed solution of methanol and n-hexane; The volume fraction of n-hexane in the methanol and n-hexane mixture is 15% to 25%.

2. A 10 according to claim 1 A method for synthesizing methoxyiminostilbene, characterized in that, The inorganic base is a strong base.

3. A 10 according to claim 2 A method for synthesizing methoxyiminostilbene, characterized in that, The strong base is sodium hydroxide or potassium hydroxide.

4. A 10 according to claim 1 A method for synthesizing methoxyiminostilbene, characterized in that, The 10,11 The mass ratio of dibromoiminodibenzyl to inorganic base is 1:1.5~2.

5.

5. A 10 according to claim 1 A method for synthesizing methoxyiminostilbene, characterized in that, The 10,11 The mass-to-volume ratio of dibromoiminodibenzyl to solvent is 1 g: 5~15 mL.

6. A 10 according to any one of claims 1 to 5 A method for synthesizing methoxyiminostilbene, characterized in that, The reaction temperature is 85~95℃ and the time is 8~10h.

7. A 10 according to any one of claims 1 to 5 A method for synthesizing methoxyiminostilbene, characterized in that, After the reaction is complete, the process includes washing with water, crystallization, and drying to obtain 10 Methoxyiminostilbene.

8. A 10 according to claim 7 A method for synthesizing methoxyiminostilbene, characterized in that, The crystallization temperature is 3~10℃.

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