Preparation method of 10-methoxyiminostilbene

Abstract

The invention provides a preparation method of 10-methoxy iminostilbene, and belongs to the technical field of medicines. Alkali metal alkoxide and potassium hydroxide are used as alkali, methanol and aromatic solvent are used as reaction solvents, the reaction time can be shortened, the reaction is fully carried out, the purity and yield of the product are improved, the impurity content is reduced, the post-treatment steps of concentration, water adding for pulping and cooling for devitrification are adopted, the post-treatment process is simple, and the method is suitable for industrial production. The emulsification phenomenon is avoided, and the purity and the yield of the product are further improved. The result of the embodiment shows that when the 10-methoxy iminostilbene is prepared by adopting the preparation method disclosed by the invention, the yield of the 10-methoxy iminostilbene is more than 91% and the content of the impurity iminostilbene is less than 0.1% when the reaction time is 5h.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a method for preparing 10-methoxyiminostilbene. Background Technology

[0002] Oxcarbazepine is a keto derivative of carbamazepine. Compared to carbamazepine, oxcarbazepine exhibits better tolerability and less hepatic enzyme induction. Currently, oxcarbazepine is used in many countries as a novel first-line antiepileptic drug, replacing carbamazepine in clinical practice.

[0003] 10-Methoxyiminostilbene is an important intermediate in the synthesis of oxcarbazepine. Siminostilbene is also a key intermediate in the synthesis of carbamazepine, and a major impurity generated during the synthesis of 10-methoxyiminostilbene, making it difficult to remove. Siminostilbene is transferred to oxcarbazepine during the reaction and exists in the form of carbamazepine. Therefore, the content of iminostilbene directly affects the product quality of oxcarbazepine.

[0004]

[0005] Patent CN106467491B discloses a method for preparing 10-methoxyiminostilbene, the steps of which are as follows:

[0006]

[0007] Those skilled in the art who operate according to the embodiments (Examples 1-4) in this patent will find that, firstly, the material names are incorrect and the experimental materials are inconsistent with the described materials; secondly, based on the dosage, potassium hydroxide cannot be completely dissolved; and thirdly, based on the reaction time of 9 hours, the reaction cannot be completed.

[0008] Patent CN114957122A discloses a preparation method. Those skilled in the art, following the embodiments in this patent, found that potassium hydroxide could not be completely dissolved, and while a 9-hour reaction time was sufficient for complete reaction, the impurity iminostilbene was high (>5%). Emulsification occurred during post-processing, and the decolorization process using activated carbon was complex. Furthermore, the iminostilbene content in the product was also high (>0.6%), and repeated attempts failed to achieve the stated yield. In summary, the existing technology for preparing 10-methoxyiminostilbene involves long reaction times, complex post-processing, and the product yield and purity require further improvement. Summary of the Invention

[0009] The purpose of this invention is to provide a method for preparing 10-methoxyiminostilbene. The preparation method provided by this invention has a short reaction time, simple post-processing, and the product has excellent purity and yield.

[0010] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0011] This invention provides a method for preparing 10-methoxyiminostilbene, comprising the following steps:

[0012] (1) After mixing methanol with an alkali metal alkoxide, 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza- -5-carbonyl chloride, then potassium hydroxide and an aromatic solvent are added to react and a reaction solution is obtained; the reaction temperature is 80-110℃ and the reaction time is 4.5-5h.

[0013] (2) The reaction solution obtained in step (1) is concentrated, slurried with water and separated into solids in sequence to obtain solids. The solids are then dissolved in aromatic solvents, cooled and crystallized, separated into solids in the second solid-liquid separation and dried to obtain 10-methoxyiminostilbene.

[0014] Preferably, the aromatic solvent in step (1) includes toluene or xylene.

[0015] Preferably, the volume ratio of methanol to aromatic solvent in step (1) is 1:(1.5-2).

[0016] Preferably, the volume ratio of methanol to aromatic solvent in step (1) is 1:(1.5 to 1.8).

[0017] Preferably, in step (1), the 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza The mass ratio of 5-carbonyl chloride to the total volume of methanol and aromatic solvent is 1 g : (5-10) mL.

[0018] Preferably, in step (1), the 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza The mass ratio of 5-carbonyl chloride to the total volume of methanol and aromatic solvent is 1 g : (5-8) mL.

[0019] Preferably, the alkali metal alkoxide in step (1) includes sodium methoxide or potassium methoxide.

[0020] Preferably, in step (1), the 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza The molar ratio of 5-carbonyl chloride to alkali metal alkoxide and potassium hydroxide is 1:(3-7):(5-8).

[0021] Preferably, the reaction temperature in step (1) is 80-100°C and the reaction time is 5 hours.

[0022] Preferably, the reaction temperature in step (1) is 80°C and the reaction time is 5 hours.

[0023] This invention provides a method for preparing 10-methoxyiminostilbene, comprising the following steps: (1) mixing methanol with an alkali metal alkoxide and then adding 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza -5-Carboyl chloride, then add potassium hydroxide and aromatic solvent to react and obtain the reaction solution; the reaction temperature is 80-110℃ and the reaction time is 4.5-5h; (2) The reaction solution obtained in step (1) is concentrated, slurried with water and separated into solids in sequence to obtain solids. The solids are dissolved in aromatic solvents, cooled and crystallized, separated into solids in the second step and dried to obtain 10-methoxyiminostilbene. In this invention, alkali metal alkoxides and potassium hydroxide are used as bases, methanol and aromatic solvents are used as reaction solvents, and the bases are added in two steps. First, alkali metal alkoxides are added, and then potassium hydroxide is added. This can shorten the reaction time, and at the same time, make the reaction complete, improve the purity and yield of the product, and reduce the impurity content. The post-processing steps of concentration, slurrying with water and cooling and crystallization are simple and do not cause emulsification, further improving the purity and yield of the product. The results of the examples show that when 10-methoxyiminostilbene was prepared by the method of the present invention, the yield of 10-methoxyiminostilbene was above 91% when the reaction time was 5 h, and the content of impurity iminostilbene was <0.1%. Attached Figure Description

[0024] Figure 1 The liquid chromatogram of 10-methoxyiminostilbene prepared in Example 1 is shown. Detailed Implementation

[0025] This invention provides a method for preparing 10-methoxyiminostilbene, comprising the following steps:

[0026] (1) After mixing methanol with an alkali metal alkoxide, 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza- -5-carbonyl chloride, then potassium hydroxide and an aromatic solvent are added to react and a reaction solution is obtained; the reaction temperature is 80-110℃ and the reaction time is 4.5-5h.

[0027] (2) The reaction solution obtained in step (1) is concentrated, slurried with water and separated into solids in sequence to obtain solids. The solids are then dissolved in aromatic solvents, cooled and crystallized, separated into solids in the second solid-liquid separation and dried to obtain 10-methoxyiminostilbene.

[0028] Unless otherwise specified, the present invention does not impose any special restrictions on the source of the raw materials, and any commercially available products well known to those skilled in the art can be used.

[0029] This invention involves mixing methanol with an alkali metal alkoxide and then adding 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza- -5-carbonyl chloride is added to potassium hydroxide and an aromatic solvent to react and obtain the reaction solution.

[0030] In this invention, the alkali metal alkoxide preferably includes sodium methoxide or potassium methoxide.

[0031] In this invention, the aromatic solvent preferably includes toluene or xylene.

[0032] In this invention, the 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza The structural formula of -5-carbonyl chloride is:

[0033] In this invention, the volume ratio of methanol to aromatic solvent is preferably 1:(1.5-2). As one embodiment, the volume ratio of methanol to aromatic solvent may specifically be 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2.

[0034] In this invention, the 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza The preferred mass ratio of 5-carbonyl chloride to the total volume of methanol and aromatic solvent is 1 g:(5-10) mL. As one embodiment, the 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza The mass ratio of 5-carbonyl chloride to the total volume of methanol and aromatic solvent can be specifically 1g:5mL, 1g:6mL, 1g:7mL, 1g:8mL, 1g:9mL, or 1g:10mL.

[0035] In this invention, the 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza The preferred molar ratio of 5-carbonyl chloride to alkali metal alkoxide and potassium hydroxide is 1:(3-7):(5-8). As one embodiment, the 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza The molar ratio of 5-carbonyl chloride to alkali metal alkoxide and potassium hydroxide can be specifically 1:7:5, 1:7:6, 1:7:7 or 1:7:8.

[0036] In this invention, the reaction temperature is 80–110°C; the reaction time is 4.5–5 hours. As one embodiment, the reaction temperature can specifically be 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, or 110°C; the reaction time can specifically be 4.5 hours, 4.6 hours, 4.7 hours, 4.8 hours, 4.9 hours, or 5 hours.

[0037] The reaction process of this invention is divided into three stages: first, 10-bromoiminostilbene-5-carbonyl methyl ester is obtained; then, 10-bromoiminostilbene is obtained; and finally, 10-methoxyiminostilbene is obtained. The order of addition of each raw material is controlled. First, methanol and alkali metal alkoxide are mixed, and then 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza- -5-Carbohydryl chloride, an alkali metal alkoxide, can rapidly convert the product into a methyl ester form, avoiding the generation of impurities such as iminostilbene caused by direct addition of alkali. After conversion to methyl ester, potassium hydroxide and aromatic solvents are added to raise the solvent boiling point, allowing the reaction to continue and yield the target product, 10-methoxyiminostilbene. This invention involves the staged addition of two alkalis. In the first stage, a relatively weaker alkali is used to avoid side reactions that increase impurities. In the second stage, a sufficient amount of strong alkali is added to achieve the reaction objective, while an aromatic solvent is added to raise the solvent boiling point and reach the reaction temperature. By controlling the order of addition of each raw material and the amount of each component, the reaction time can be shortened, the impurity content reduced, and the product purity and yield improved.

[0038] After obtaining the reaction solution, the present invention sequentially concentrates the reaction solution, adds water to slurry and performs a first solid-liquid separation to obtain a solid. The solid is then sequentially dissolved in an aromatic solvent, cooled to crystallize, subjected to a second solid-liquid separation and dried to obtain 10-methoxyiminostilbene.

[0039] In this invention, the concentration is preferably carried out under reduced pressure. This invention does not impose any special limitations on the operation of the reduced pressure concentration; it employs techniques well-known to those skilled in the art, whereby the solvent is fully evaporated and the solution is concentrated to near dryness after the reaction.

[0040] In this invention, during the water addition and pulping process, 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza The preferred ratio of 5-carbonyl chloride to water is 1:(9-11), more preferably 1:10.

[0041] The present invention does not impose any special limitations on other operations of adding water and pulping, and any pulping technical solution known to those skilled in the art can be used.

[0042] The present invention does not have any special limitations on the operation of the first solid-liquid separation; solids can be obtained by using solid-liquid separation techniques well known to those skilled in the art.

[0043] In this invention, the aromatic solvent used for dissolution is preferably toluene or xylene; the 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza The preferred mass ratio of 5-carbonyl chloride to aromatic solvent is 1:(0.8-0.9).

[0044] In this invention, the preferred dissolution temperature of the aromatic solvent is 75–85°C, more preferably 80°C. This invention does not impose a specific time limit on the dissolution of the aromatic solvent; complete dissolution of the solid is sufficient.

[0045] In this invention, the endpoint temperature for cooling crystallization is preferably room temperature. This invention does not impose any special limitations on other operations related to cooling crystallization; any cooling crystallization techniques well-known to those skilled in the art can be used.

[0046] The present invention does not have any special limitations on the operation of the second solid-liquid separation; solids can be obtained by using solid-liquid separation techniques well known to those skilled in the art.

[0047] The present invention does not impose any special limitations on the drying operation; drying to constant weight can be achieved using drying techniques well known to those skilled in the art.

[0048] In the post-processing, existing technologies all use extraction, and an emulsion layer has been found to be generated in multiple operations. In actual testing, the target product was also found in the emulsion layer. Discarding the emulsion layer reduces the yield, and collecting the emulsion layer affects the product quality. This invention uses concentration to avoid extraction. After that, water is added to make a pulp, aromatic solvent is used to dissolve the pulp, and then it is cooled and crystallized to obtain the target product. The post-processing is simple and improves the purity and yield of the product, making it suitable for industrial production.

[0049] This invention controls the order of addition of each raw material, the amount of raw materials, the process parameters such as reaction temperature and time, and the post-processing, which can shorten the reaction time, reduce the impurity content, and improve the purity and yield of the product.

[0050] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0051] Example 1

[0052] A method for preparing 10-methoxyiminostilbene: (1) Add 15.80 kg of methanol and 4.55 kg of sodium methoxide to a reaction vessel. After complete dissolution, add 5.00 kg of 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza -5-Carboyl chloride (10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza) After adding 5.40 kg of potassium hydroxide (the mass ratio of 5-carbonyl chloride to the total volume of methanol and toluene is 1 g: 5 mL), 26.01 kg of toluene (the volume ratio of methanol to toluene is 1:1.5) was added, and the mixture was heated to 80 °C and reacted for 5 h to obtain the reaction solution.

[0053] (2) The reaction solution obtained in step (1) was concentrated to near dryness, 50.00 kg of water was added and the mixture was slurried and then the solid was separated to obtain a solid. Then 4.34 kg of toluene was added, the temperature was raised to 80 °C to completely dissolve the solid, and the solid was cooled to room temperature to precipitate. After solid-liquid separation and drying, 2.54 kg of 10-methoxyiminostilbene was obtained, with a yield of 95%.

[0054] Example 2

[0055] A method for preparing 10-methoxyiminostilbene: (1) Add 15.80 g of methanol and 4.55 g of sodium methoxide to a reaction vessel. After complete dissolution, add 5.00 g of 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza -5-Carboyl chloride (10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza) After adding 3.38 g of potassium hydroxide and 26.22 g of xylene (methanol to xylene volume ratio of 1:1.5), the mixture was heated to 80 °C and reacted for 5 h to obtain the reaction solution.

[0056] (2) The reaction solution obtained in step (1) was concentrated to near dryness, 50.00g of water was added and the mixture was slurried and then the solid was separated to obtain a solid. 4.34g of xylene was added, the temperature was raised to 80℃ to completely dissolve the solid, and the solid was cooled to room temperature to precipitate. After solid-liquid separation and drying, 2.44g of 10-methoxyiminostilbene was obtained, with a yield of 91%.

[0057] Example 3

[0058] A method for preparing 10-methoxyiminostilbene: (1) Add 15.80 g of methanol and 5.87 g of potassium methoxide to a reaction vessel. After complete dissolution, add 5.00 g of 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza -5-Carboyl chloride (10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza) After adding 4.11 g of potassium hydroxide (the mass ratio of 5-carbonyl chloride to the total volume of methanol and toluene was 1 g: 5 mL), and then adding 26.01 g of toluene (the volume ratio of methanol to toluene was 1: 1.5), the mixture was heated to 80 °C and reacted for 5 h to obtain the reaction solution.

[0059] (2) The reaction solution obtained in step (1) was concentrated to near dryness, 50.00g of water was added and the mixture was slurried and then the solid was separated to obtain a solid. 4.34g of toluene was added, the temperature was raised to 80℃ to completely dissolve the solid, and the solid was cooled to room temperature to precipitate. After solid-liquid separation and drying, 2.48g of 10-methoxyiminostilbene was obtained, with a yield of 93%.

[0060] The 10-methoxyiminostilbene prepared in Example 1 was analyzed by liquid chromatography, and the resulting liquid chromatogram is as follows: Figure 1 As shown in Table 1, the liquid chromatography data are as follows.

[0061] Table 1. Liquid chromatography data of 10-methoxyiminostilbene prepared in Example 1

[0062]

[0063] As can be seen from Table 1, the content of impurity iminostilbene in the 10-methoxyiminostilbene prepared in Example 1 is <0.1%.

[0064] Comparative Example 1

[0065] A method for preparing 10-methoxyiminostilbene, based on a scaled-down version of Example 1 in patent CN106467491B, specifically involves: adding 30.12 g of methanol to a 250 mL flask, cooling to 10 °C, and adding 20.57 g of potassium hydroxide in four portions, allowing the system temperature to drop to 10 °C after each addition before adding the next portion of potassium hydroxide. The system is then heated to reflux to ensure complete dissolution (it was found during the experiment that potassium hydroxide could not completely dissolve even under heating; this dissolution issue was ignored, and the addition continued). 30.00 g of toluene is then slowly added, and the system temperature is lowered to 35–40 °C. While maintaining the system temperature at 35–40 °C, 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza- 10.00 g of 5-carbonyl chloride was added, and the temperature was controlled at 82-92℃ for 9 h after the reaction to obtain the product.

[0066] The reaction product prepared in Comparative Example 1 was sent for testing, and it was found that the content of iminostilbene impurity was relatively large, and there were also many intermediate transition state impurities. The reaction was not complete after 9 hours. The specific data are shown in Table 2.

[0067] Table 2 shows the content of various impurities in the reaction product prepared in Comparative Example 1.

[0068]

[0069]

[0070] Comparative Example 2

[0071] A method for preparing 10-methoxyiminostilbene involves scaling down the sample according to the example in patent CN114957122A and performing post-treatment operations according to the water washing and crystallization steps to obtain 10-methoxyiminostilbene.

[0072] The liquid chromatography data of 10-methoxyiminostilbene prepared in Comparative Example 2 are shown in Table 3.

[0073] Table 3. Liquid chromatography data of 10-methoxyiminostilbene prepared in Comparative Example 2

[0074]

[0075] As can be seen from Table 3, the content of the impurity iminostilbene is 0.603%, and its post-processing is extremely complicated, requiring water washing, activated carbon washing, repeated filtration three times, and recrystallization. The post-processing time is very long, and the yield is only 52%, which is far from the 92.4% claimed in the patent.

[0076] Comparative Example 3

[0077] 52.02 g toluene, 30.12 g methanol, 10.08 g potassium hydroxide, 9.10 g sodium methoxide, and 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza 10.00 g of 5-carbonyl chloride was added to the reaction flask at once, and the temperature was raised to 80°C and reacted for 5 h. The reaction progress was detected by HPLC.

[0078] The contents of each impurity in the product prepared in Comparative Example 3 are shown in Table 4.

[0079] Table 4 shows the content of various impurities in the product prepared in Comparative Example 3.

[0080]

[0081]

[0082] As can be seen from Table 4, when materials are added simultaneously, the reaction cannot be completed within 5 hours, and the content of the impurity iminostilbene is also relatively high even when the reaction is incomplete.

[0083] Comparative Example 4

[0084] 100 mL of methanol and 20.00 g of 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza -5-carbonyl chloride, 18.20 g sodium methoxide and 20.16 g potassium hydroxide were mixed and heated to 80 °C for 20 h. The reaction progress was detected by HPLC.

[0085] The contents of each impurity in the product prepared in Comparative Example 4 are shown in Table 5.

[0086] Table 5 shows the content of various impurities in the products prepared in Comparative Example 4.

[0087]

[0088] As can be seen from Table 5, without the addition of toluene, the reaction still cannot be completely completed after 20 hours, and the content of the impurity iminostilbene is even higher.

[0089] In summary, the preparation method provided by this invention has a short reaction time, low impurity content, high purity and yield of 10-methoxyiminostilbene, and a simple post-processing procedure.

[0090] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing 10-methoxyiminostilbene, comprising the following steps: (1) After mixing methanol with an alkali metal alkoxide, 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza- -5-carbonyl chloride, then potassium hydroxide and an aromatic solvent are added to react and a reaction solution is obtained; the reaction temperature is 80-110℃ and the reaction time is 4.5-5h. (2) The reaction solution obtained in step (1) is concentrated, slurried with water and separated into solids in sequence to obtain solids. The solids are then dissolved in aromatic solvents, cooled and crystallized, separated into solids in the second solid-liquid separation and dried to obtain 10-methoxyiminostilbene.

2. The preparation method according to claim 1, characterized in that, The aromatic solvent in step (1) includes toluene or xylene.

3. The preparation method according to claim 1 or 2, characterized in that, In step (1), the volume ratio of methanol to aromatic solvent is 1:(1.5-2).

4. The preparation method according to claim 3, characterized in that, In step (1), the volume ratio of methanol to aromatic solvent is 1:(1.5 to 1.8).

5. The preparation method according to claim 1 or 2, characterized in that, In step (1), 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza The mass ratio of 5-carbonyl chloride to the total volume of methanol and aromatic solvent is 1 g : (5-10) mL.

6. The preparation method according to claim 5, characterized in that, In step (1), 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza The mass ratio of 5-carbonyl chloride to the total volume of methanol and aromatic solvent is 1 g : (5-8) mL.

7. The preparation method according to claim 1, characterized in that, The alkali metal alkoxide in step (1) includes sodium methoxide or potassium methoxide.

8. The preparation method according to claim 1 or 7, characterized in that, In step (1), 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]aza The molar ratio of 5-carbonyl chloride to alkali metal alkoxide and potassium hydroxide is 1:(3-7):(5-8).

9. The preparation method according to claim 1, characterized in that, The reaction temperature in step (1) is 80-100℃, and the reaction time is 5h.

10. The preparation method according to claim 9, characterized in that, The reaction temperature in step (1) is 80°C and the reaction time is 5 hours.

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