CN116574059A - Synthesis method of 10-methoxyiminostilbene - Google Patents
Synthesis method of 10-methoxyiminostilbene Download PDFInfo
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- CN116574059A CN116574059A CN202310607360.7A CN202310607360A CN116574059A CN 116574059 A CN116574059 A CN 116574059A CN 202310607360 A CN202310607360 A CN 202310607360A CN 116574059 A CN116574059 A CN 116574059A
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- Prior art keywords
- methoxyiminostilbene
- methanol
- synthesizing
- hexane
- solvent
- Prior art date
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- ZKHZWXLOSIGIGZ-UHFFFAOYSA-N 5-methoxy-11h-benzo[b][1]benzazepine Chemical compound COC1=CC2=CC=CC=C2NC2=CC=CC=C12 ZKHZWXLOSIGIGZ-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 238000001308 synthesis method Methods 0.000 title claims description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 111
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 52
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 16
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 14
- 239000011259 mixed solution Substances 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 230000009471 action Effects 0.000 claims abstract description 4
- 239000003513 alkali Substances 0.000 claims abstract description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 48
- 238000001035 drying Methods 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000003889 chemical engineering Methods 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 10
- 238000001816 cooling Methods 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 230000006872 improvement Effects 0.000 description 2
- CTRLABGOLIVAIY-UHFFFAOYSA-N oxcarbazepine Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 description 2
- 229960001816 oxcarbazepine Drugs 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- -1 takes 10 Chemical compound 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of pharmaceutical chemistry and chemical engineering, and provides a method for synthesizing 10-methoxyiminostilbene, which comprises 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. By the technical scheme, the problems of low yield and low purity in the synthesis process of the 10-methoxy iminostilbene in the prior art are solved.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry and chemical engineering, in particular to a method for synthesizing 10-methoxy iminostilbene.
Background
10-Methoxyiminostilbene, also known as 10-methoxy-5H-dibenzo [ b, f]Azepines of formula C 15 H 13 NO is light yellow to off-white crystal, and can be used for preparing the medicine oxcarbazepine. The structural formula is as follows:
at present, the existing synthesis process of 10-methoxyiminostilbene (Chinese invention patent CN106467491A, CN 114957122A) mainly takes 10, 11-dibromoiminodibenzyl as a reaction raw material, and prepares 10-methoxyiminostilbene under the action of potassium hydroxide or methanol solution of potassium methoxide, but as the 10-methoxyiminostilbene is an intermediate for preparing the medicine oxcarbazepine, the quality requirement on the key intermediate for preparing the medicine is higher and higher along with the improvement of the national requirement on raw materials. Based on this, researchers have been eager to develop a method for synthesizing 10-methoxyiminostilbene with high yield and purity.
Disclosure of Invention
The invention provides a method for synthesizing 10-methoxyiminostilbene, which solves the problems of low yield and low purity existing in the synthesis process of 10-methoxyiminostilbene in the related technology.
The technical scheme of the invention is as follows:
a method for synthesizing 10-methoxyiminostilbene comprises 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.
As a further technical scheme, the volume fraction of the n-hexane in the mixed solution of the methanol and the n-hexane is 15-25%.
As a further technical scheme, the volume fraction of the n-hexane in the mixed solution of the methanol and the n-hexane is 20%.
As a further technical scheme, the inorganic base is a strong base.
As a further technical scheme, the strong base is sodium hydroxide or potassium hydroxide.
As a further technical scheme, the mass ratio of the 10, 11-dibromoiminodibenzyl to the inorganic base is 1:1.5-2.5.
As a further technical scheme, the mass volume ratio of the 10, 11-dibromoiminodibenzyl to the solvent is 1 g:5-15 mL.
As a further technical scheme, the reaction temperature is 85-95 ℃ and the reaction time is 8-10 h.
As a further technical scheme, the method further comprises the steps of water washing, crystallization and drying after the reaction is finished, so as to obtain the 10-methoxyiminostilbene.
As a further technical scheme, the crystallization temperature is 3-10 ℃.
The working principle and the beneficial effects of the invention are as follows:
1. the invention takes the mixed solution of methanol and n-hexane as the solvent, improves the polarity strength of the solvent by adding n-hexane, further ensures the strength of inorganic base, and improves the yield and purity of 10-methoxyiminostilbene.
2. The invention limits the volume fraction of the n-hexane in the mixed solution of the methanol and the n-hexane to 15-25%, and further improves the yield and purity of the 10-methoxyiminostilbene.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by one of ordinary skill in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
10, 11-dibromoiminodibenzyl in the following examples and comparative examples was prepared by the method disclosed in CN100999497a, and had a purity of 98.5%.
Example 1
Mixing 800mL of methanol with 200g of potassium hydroxide, heating to 70 ℃ to reflux until the potassium hydroxide is completely dissolved, cooling to 50 ℃, adding 200mL of n-hexane, stirring uniformly, adding 100g of 10, 11-dibromoiminodibenzyl, heating to 90 ℃ to react for 9h, distilling methanol and n-hexane under reduced pressure, adding water, stirring, filtering, drying, adding methanol for dissolving, crystallizing at 5 ℃, filtering, and drying to obtain 10-methoxyiminostilbene.
Example 2
400mL of methanol and 150g of potassium hydroxide are mixed, the temperature is raised to 70 ℃ and the mixture is refluxed until the potassium hydroxide is completely dissolved, the temperature is reduced to 50 ℃, 100mL of normal hexane is added and stirred uniformly, 100g of 10, 11-dibromoiminodibenzyl is added, the temperature is raised to 85 ℃ and reacted for 10 hours, methanol and normal hexane are distilled out under reduced pressure, water is added and stirred, the mixture is filtered and dried, methanol is added and dissolved, the mixture is crystallized at 3 ℃, and the mixture is filtered and dried, so that 10-methoxyiminostilbene is obtained.
Example 3
Mixing 1200mL of methanol with 250g of sodium hydroxide, heating to 70 ℃ to reflux until potassium hydroxide is completely dissolved, cooling to 50 ℃, adding 300mL of n-hexane, stirring uniformly, adding 100g of 10, 11-dibromoiminodibenzyl, heating to 95 ℃ to react for 8 hours, distilling methanol and n-hexane under reduced pressure, adding water, stirring, filtering, drying, adding methanol for dissolving, crystallizing at 10 ℃, filtering, and drying to obtain 10-methoxyiminostilbene.
Example 4
Mixing 850mL of methanol with 200g of potassium hydroxide, heating to 70 ℃ to reflux until the potassium hydroxide is completely dissolved, cooling to 50 ℃, adding 150mL of n-hexane, stirring uniformly, adding 100g of 10, 11-dibromoiminodibenzyl, heating to 90 ℃ to react for 9h, distilling methanol and n-hexane under reduced pressure, adding water, stirring, filtering, drying, adding methanol for dissolving, crystallizing at 5 ℃, filtering, and drying to obtain 10-methoxyiminostilbene.
Example 5
Mixing 750mL of methanol with 200g of potassium hydroxide, heating to 70 ℃ to reflux until the potassium hydroxide is completely dissolved, cooling to 50 ℃, adding 250mL of n-hexane, stirring uniformly, adding 100g of 10, 11-dibromoiminodibenzyl, heating to 90 ℃ to react for 9h, distilling methanol and n-hexane under reduced pressure, adding water, stirring, filtering, drying, adding methanol for dissolving, crystallizing at 5 ℃, filtering, and drying to obtain 10-methoxyiminostilbene.
Comparative example 1
Mixing 1000mL of methanol with 200g of potassium hydroxide, heating to 70 ℃ to reflux until the potassium hydroxide is completely dissolved, cooling to 50 ℃, adding 100g of 10, 11-dibromoiminodibenzyl, heating to 90 ℃ to react for 9 hours, distilling off the methanol under reduced pressure, adding water, stirring, filtering, drying, adding the methanol for dissolving, crystallizing at 5 ℃, filtering, and drying to obtain 10-methoxyiminostilbene.
Comparative example 2
Mixing 800mL of methanol with 200g of potassium hydroxide, heating to 70 ℃ to reflux until the potassium hydroxide is completely dissolved, cooling to 50 ℃, adding 200mL of toluene, stirring uniformly, adding 100g of 10, 11-dibromoiminodibenzyl, heating to 90 ℃ to react for 9h, distilling off methanol and toluene under reduced pressure, adding water, stirring, filtering, drying, adding methanol for dissolving, crystallizing at 5 ℃, filtering, and drying to obtain 10-methoxyiminostilbene.
The purity of 10-methoxyiminostilbene obtained in examples 1 to 5 and comparative examples 1 to 2 was measured by HPLC, and the yield was calculated according to the following formula:
yield (%) = mass x purity of 10-methoxyiminostilbene actually obtained ≡theoretical yield x 100
The results are recorded in table 1.
TABLE 1 purity and yield of 10-Methoxyiminostilbene
As can be seen from Table 1, the method for synthesizing 10-methoxyiminostilbene provided by the invention has the advantages that the purity of the obtained 10-methoxyiminostilbene is up to more than 99.0%, the yield is up to more than 93.7%, and the method has high purity and high yield.
Example 1 compared with comparative example 1, the solvent used in example 1 was a mixed solution of methanol and n-hexane, the solvent used in comparative example 1 was methanol, and the purity and yield of 10-methoxyiminostilbene obtained in example 1 were both higher than those of comparative example 1, indicating that the purity and yield of 10-methoxyiminostilbene could be greatly improved by using a mixed solution of methanol and n-hexane as a reaction solvent.
Example 1 compared with comparative example 2, the solvent used in example 1 was a mixed solution of methanol and n-hexane, the solvent used in comparative example 2 was a mixed solution of methanol and toluene, and the purity and yield of 10-methoxyiminostilbene obtained in comparative example 2 were not as good as those of example 1, indicating that the use of a mixed solution of methanol and n-hexane as a solvent was better than that of methanol and toluene as a solvent, and the effect of improving the purity and yield of the synthesized 10-methoxyiminostilbene was good.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
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 ℃.
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| CN202310607360.7A CN116574059A (en) | 2023-05-26 | 2023-05-26 | Synthesis method of 10-methoxyiminostilbene |
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| CN202310607360.7A CN116574059A (en) | 2023-05-26 | 2023-05-26 | Synthesis method of 10-methoxyiminostilbene |
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