CN116574059A - Synthesis method of 10-methoxyiminostilbene - Google Patents

Abstract

The present invention relates to the technical field of medicinal chemistry and chemical engineering, and proposes a synthesis method of 10-methoxyiminostilbene, comprising the following steps: using 10,11-dibromoiminodibenzyl as a reaction raw material under the action of an inorganic base and a solvent Under, carry out reaction, generate 10-methoxyiminostilbene; Described solvent is the mixed solution of methanol and n-hexane. Through the above technical scheme, the problems of low yield and low purity in the synthesis process of 10-methoxyiminostilbene in the prior art are solved.

Description

A kind of synthetic method of 10-methoxyiminostilbene

technical field

The present invention relates to the technical field of medicinal chemistry and chemical engineering, in particular to a method for synthesizing 10-methoxyiminostilbene.

Background technique

10-methoxyiminostilbene, also known as 10-methoxy-5H-dibenzo[b,f]azepine, has a molecular formula of C ₁₅ H ₁₃ NO, and is a light yellow to off-white crystal, which can be used to prepare The drug oxcarbazepine. Its structural formula is as follows:

At present, the existing synthesis technique of 10-methoxyiminostilbene (Chinese invention patent CN106467491A, CN114957122A) mainly uses 10,11-dibromoiminodibenzyl as the reaction raw material, in the methanol of potassium hydroxide or potassium methylate Under the action of the solution, 10-methoxyiminostilbene is prepared, but because 10-methoxyiminostilbene is an intermediate for preparing the drug oxcarbazepine, and as the country’s requirements for raw materials are increased, the key to the preparation of the drug is The quality requirements of intermediates are also getting higher and higher. Based on this, researchers are keen to develop a synthetic method of 10-methoxyiminostilbene with high yield and high purity.

Contents of the invention

The invention proposes a synthesis method of 10-methoxyiminostilbene, which solves the problems of low yield and low purity in the synthesis process of 10-methoxyiminostilbene in the related art.

Technical scheme of the present invention is as follows:

A method for synthesizing 10-methoxyiminostilbene, comprising the steps of: using 10,11-dibromoiminodibenzyl as a reaction raw material under the action of an inorganic base and a solvent to react to generate 10-methoxy iminostilbene;

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

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

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

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

As a further technical solution, the strong base is sodium hydroxide or potassium hydroxide.

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

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

As a further technical solution, the reaction temperature is 85-95° C., and the time is 8-10 hours.

As a further technical solution, after the reaction is finished, washing with water, crystallization and drying are also included to obtain 10-methoxyiminostilbene.

As a further technical solution, the crystallization temperature is 3-10°C.

Working principle of the present invention and beneficial effect are:

1. The present invention uses a mixed solution of methanol and n-hexane as a solvent, and improves the polarity of the solvent by adding n-hexane, thereby ensuring the strength of the inorganic base, thereby increasing the yield of 10-methoxyiminostilbene and purity.

2. The present invention limits the volume fraction of n-hexane in the mixed solution of methanol and n-hexane to 15% to 25%, further improving the yield and purity of 10-methoxyiminostilbene.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts all involve the protection scope of the present invention.

The 10,11-dibromoiminodibenzyl in the following examples and comparative examples are all prepared by the method disclosed in CN100999497A, with a purity of 98.5%.

Example 1

Mix 800mL of methanol and 200g of potassium hydroxide, heat up to 70°C and reflux until the potassium hydroxide is completely dissolved, cool down to 50°C, add 200mL of n-hexane and stir evenly, then add 100g of 10,11-dibromoiminodibenzyl, and heat up to React at 90°C for 9 hours, evaporate methanol and n-hexane under reduced pressure, add water to stir, filter and dry, then add methanol to dissolve, crystallize at 5°C, filter and dry to obtain 10-methoxyiminostilbene.

Example 2

Mix 400mL of methanol with 150g of potassium hydroxide, heat up to 70°C and reflux until the potassium hydroxide is completely dissolved, cool down to 50°C, add 100mL of n-hexane and stir evenly, then add 100g of 10,11-dibromoiminodibenzyl, and heat up to React at 85°C for 10 hours, evaporate methanol and n-hexane under reduced pressure, add water to stir, filter and dry, then add methanol to dissolve, crystallize at 3°C, filter and dry to obtain 10-methoxyiminostilbene.

Example 3

Mix 1200mL of methanol with 250g of sodium hydroxide, heat up to 70°C and reflux until the potassium hydroxide is completely dissolved, cool down to 50°C, add 300mL of n-hexane and stir well, then add 100g of 10,11-dibromoiminodibenzyl, and heat up to React at 95°C for 8 hours, evaporate methanol and n-hexane under reduced pressure, add water to stir, filter and dry, then add methanol to dissolve, crystallize at 10°C, filter and dry to obtain 10-methoxyiminostilbene.

Example 4

Mix 850mL of methanol with 200g of potassium hydroxide, heat up to 70°C and reflux until the potassium hydroxide is completely dissolved, cool down to 50°C, add 150mL of n-hexane and stir evenly, then add 100g of 10,11-dibromoiminodibenzyl, and heat up to React at 90°C for 9 hours, evaporate methanol and n-hexane under reduced pressure, add water to stir, filter and dry, then add methanol to dissolve, crystallize at 5°C, filter and dry to obtain 10-methoxyiminostilbene.

Example 5

Mix 750mL of methanol and 200g of potassium hydroxide, heat up to 70°C and reflux until the potassium hydroxide is completely dissolved, cool down to 50°C, add 250mL of n-hexane and stir evenly, then add 100g of 10,11-dibromoiminodibenzyl, and heat up to React at 90°C for 9 hours, evaporate methanol and n-hexane under reduced pressure, add water to stir, filter and dry, then add methanol to dissolve, crystallize at 5°C, filter and dry to obtain 10-methoxyiminostilbene.

Comparative example 1

Mix 1000mL of methanol with 200g of potassium hydroxide, heat up to 70°C and reflux until the potassium hydroxide is completely dissolved, cool down to 50°C, add 100g of 10,11-dibromoiminodibenzyl, heat up to 90°C for 9 hours, evaporate under reduced pressure Remove methanol, add water and stir, filter and dry, then add methanol to dissolve, crystallize at 5°C, filter and dry to obtain 10-methoxyiminostilbene.

Comparative example 2

Mix 800mL of methanol with 200g of potassium hydroxide, heat up to 70°C and reflux until the potassium hydroxide is completely dissolved, cool down to 50°C, add 200mL of toluene and stir evenly, then add 100g of 10,11-dibromoiminodibenzyl, heat up to 90°C React at ℃ for 9 hours, evaporate methanol and toluene under reduced pressure, add water to stir, filter and dry, then add methanol to dissolve, crystallize at 5℃, filter and dry to obtain 10-methoxyiminostilbene.

The 10-methoxyiminostilbene obtained in Examples 1-5 and Comparative Examples 1-2 was tested for purity by HPLC, and the yield was calculated according to the following formula:

Yield (%)=actually obtained 10-methoxyiminostilbene quality × purity ÷ theoretical yield × 100

The results are recorded in Table 1.

Table 1 Purity and yield of 10-methoxyiminostilbene

As can be seen from Table 1, the synthetic method of 10-methoxyiminostilbene provided by the present invention can obtain 10-methoxyiminostilbene with a purity of more than 99.0%, a yield of more than 93.7%, and high purity high yield.

Embodiment 1 is compared with comparative example 1, and the solvent that embodiment 1 uses is the mixed solution of methanol and n-hexane, and the solvent used in comparative example 1 is methyl alcohol, and the purity of the 10-methoxyiminostilbene that embodiment 1 obtains Both the yield and yield are higher than in Comparative Example 1, indicating that the use of a mixed solution of methanol and n-hexane as a reaction solvent can greatly improve the purity and yield of 10-methoxyiminostilbene.

Compared with comparative example 2 in embodiment 1, the solvent used in embodiment 1 is a mixed solution of methanol and normal hexane, and the solvent used in comparative example 2 is a mixed solution of methanol and toluene. The purity and the yield of aminostilbene are all inferior to embodiment 1, illustrate to use the mixed solution of methyl alcohol and normal hexane as solvent ratio and use the mixed solution of methyl alcohol and toluene as solvent, to the purity and the 10-methoxyiminostilbene that improves synthesis The yield effect is good.

The above are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention within.

Claims (9)

1. The synthesis method of the 10-methoxyiminostilbene is characterized by comprising the following steps: taking 10, 11-dibromoiminodibenzyl as a reaction raw material to react under the action of inorganic alkali and a solvent to generate 10-methoxyiminostilbene;

the solvent is a mixed solution of methanol and n-hexane.

2. The method for synthesizing 10-methoxyiminostilbene according to claim 1, wherein the volume fraction of n-hexane in the mixed solution of methanol and n-hexane is 15% -25%.

3. The method for synthesizing 10-methoxyiminostilbene according to claim 1, wherein the inorganic base is a strong base.

4. A method of synthesizing 10-methoxyiminostilbene according to claim 3, wherein said strong base is sodium hydroxide or potassium hydroxide.

5. The method for synthesizing 10-methoxyiminostilbene according to claim 1, wherein the mass ratio of 10, 11-dibromoiminodibenzyl to inorganic base is 1:1.5-2.5.

6. The method for synthesizing 10-methoxyiminostilbene according to claim 1, wherein the mass-volume ratio of 10, 11-dibromoiminodibenzyl to solvent is 1 g:5-15 mL.

7. The method for synthesizing 10-methoxyiminostilbene according to any of claims 1 to 6, wherein the reaction temperature is 85 to 95 ℃ and the time is 8 to 10 hours.

8. The method for synthesizing 10-methoxyiminostilbene according to any of claims 1 to 6, further comprising washing with water, crystallizing, and drying after the reaction is completed, thereby obtaining 10-methoxyiminostilbene.

9. The method for synthesizing 10-methoxyiminostilbene according to claim 8, wherein the crystallization temperature is 3-10 ℃.