Process for the synthesis of an oxcarbazepine intermediate
By combining supported catalysts and palladium-on-carbon catalysts, the synthesis process of oxcarbazepine intermediates was optimized, solving the problems of high polymer impurities and excessive use of phosphoric acid, and achieving the preparation of oxcarbazepine intermediates with high yield and high purity.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- HUBEI HUAZHOU PHARM CO LTD
- Filing Date
- 2025-12-31
- Publication Date
- 2026-06-09
AI Technical Summary
In existing oxcarbazepine intermediate synthesis processes, the high content of polymeric impurities leads to low product purity, and excessive use of phosphoric acid increases material costs and wastewater generation, making it difficult to achieve high-yield, high-purity preparation.
A supported catalyst was used, with the active component being a complex of boron trifluoride and ferric chloride, and diatomaceous earth as the support, to catalyze the salt formation cyclization reaction. Combined with palladium on carbon catalytic hydrogenation and specific reaction conditions, the reaction process and side reaction control were optimized.
This method improves the yield and purity of iminodibenzyl, simplifies the production process, reduces costs, and enables the efficient preparation of high-purity oxcarbazepine intermediates.
Abstract
Description
Technical Field
[0001] This invention relates to pharmaceutical intermediate preparation technology, and in particular, to a method for synthesizing an oxcarbazepine intermediate. Background Technology
[0002] Oxcarbazepine (OCBZ) is a Class II Western medicine, a new generation of antiepileptic drugs, and its derivatives are important drug synthesis intermediates. It can also be used in the treatment of mental illnesses and has a broad market.
[0003] Currently, there are many synthetic routes for iminodibenzyl, among which the process of cyclizing iminodibenzyl with diaminobibenzyl has a relatively high theoretical yield and production rate. During production, it was found that using polyphosphoric acid for deamination, compared to phosphoric acid, reduces equipment corrosion and increases the yield. However, due to the larger reaction rate, the content of high-polymer impurities generated by side reactions in the product increases. The content of high-polymer impurities in the unrefined crude product after cyclization reaches 0.27 wt%, and these impurities cannot be separated by water washing, which is detrimental to obtaining high-purity products.
[0004] The existing process involves direct phosphate salt formation after iron powder reduction. However, this process cannot accurately measure the raw material content, making it impossible to determine the amount of phosphate used. To ensure the subsequent reaction proceeds normally, an excess of 50% phosphate is required, which increases material costs and wastewater generation. Therefore, it is extremely important to develop a high-yield synthesis method for iminobenzyl. Summary of the Invention
[0005] In view of this, the purpose of this invention is to provide a method for synthesizing oxcarbazepine intermediates.
[0006] To solve the above-mentioned technical problems, the technical solution of the present invention is as follows: This invention proposes a method for synthesizing oxcarbazepine intermediates, comprising the following steps: S1. Petroleum ether, methanol, and ethyl formate are mixed to obtain a mixed system. o-phenyltoluene and sodium methoxide are added, and the mixture is reacted to obtain intermediate 1. S2. Add intermediate 1 to methanol, add palladium on carbon catalyst, introduce hydrogen gas, and react to obtain intermediate 2. S3. Add phosphoric acid and a supported catalyst to intermediate 2, and react to obtain iminodibenzyl.
[0007] As a further technical solution, the catalyst is a supported catalyst, the active component of the supported catalyst is a composite of boron trifluoride and ferric chloride in a mass ratio of 5:5 to 7:3, and the support of the supported catalyst is diatomaceous earth.
[0008] As a further technical solution, the loading of the active component in the supported catalyst is 5% to 10% of the mass of diatomite.
[0009] As a further technical solution, the amount of the supported catalyst added is 3% to 5% of the mass of intermediate 2.
[0010] As a further technical solution, the mass ratio of petroleum ether to methanol is 20:1 to 30:1.
[0011] As a further technical solution, the mass ratio of o-nitrotoluene to the mixed solvent is 1:3 to 1:5 g / mL, and the mass ratio of o-nitrotoluene to ethyl formate is 2:1 to 5:1.
[0012] As a further technical solution, the molar ratio of o-nitrotoluene to sodium methoxide is 1:0.5 to 1:1.
[0013] As a further technical solution, the reaction temperature in step S1 is 3~11℃ and the reaction time is 7~9h; the reaction temperature in step S2 is 75~80℃ and the reaction time is 4~6h, and the reaction pressure is 1.0~1.5MPa; the reaction temperature in step S3 is 280~300℃ and the reaction time is 1~3h.
[0014] As a further technical solution, the mass ratio of intermediate 1 to palladium on carbon catalyst is 10:1 to 15:1; the molar ratio of intermediate 2 to phosphoric acid is 1:2 to 1:3.
[0015] As a further technical solution, in step S1, o-phenyltoluene is added dropwise, and sodium methoxide is added in batches, specifically by dividing sodium methoxide into 4 equal parts and adding them in 4 batches.
[0016] The working principle and beneficial effects of this invention are as follows: 1. In this invention, o-nitrotoluene and sodium methoxide are added to a mixture of methanol and petroleum ether, and a catalyst is used... The reaction under the action of ethyl formate yields intermediate 1, which is more complete and reduces side reactions. Intermediate 1 obtained by the reaction does not need to be pulped and purified before proceeding to the next reaction, which greatly simplifies the production process and operation. Intermediate 1 is catalytically hydrogenated under palladium on carbon to obtain intermediate 2. Intermediate 2 then undergoes a salt formation cyclization reaction, which is simple and yields iminodibenzyl with a high product yield.
[0017] 2. In this invention, the composite system of boron trifluoride and ferric chloride is used as the active component of the supported catalyst to catalyze the salt cyclization reaction, which further accelerates the reaction process and thus improves the yield of the product iminodibenzyl.
[0018] 3. In this invention, by loading the active component of the supported catalyst onto diatomaceous earth, the catalytic activity of the supported catalyst is increased. The specific surface area of the oxidizing agent further improves the reaction efficiency of the salt-forming cyclization reaction, thereby increasing the yield of the product iminodibenzyl.
[0019] 4. In this invention, in the condensation reaction of o-phenyltoluene and sodium methoxide, by changing the way o-phenyltoluene and methanol are added, o-phenyltoluene is added dropwise and sodium methoxide is added in batches, so that the exothermic reaction of the condensation reaction is more stable, thereby achieving safe and stable production of the entire process. Detailed Implementation
[0020] The specific embodiments of the present invention will be further described below to make the technical solution of the present invention easier to understand and master. Example
[0021] Preparation method of supported catalyst: Add 10g boron trifluoride to 100mL water, add 200g diatomaceous earth, heat to 80℃, and impregnate for 6h to obtain the supported catalyst.
[0022] S1. Add 600g petroleum ether, 30g methanol, and 70g ethyl formate to a 2L three-necked flask. Under nitrogen protection, lower the temperature of the system to 5-9℃. Divide 165.5g sodium methoxide into four equal portions of 41.4g each and add them in four batches. Add 210g of o-nitrotoluene dropwise over approximately 2 hours. After the addition is complete, maintain the temperature at 5-9℃ for 9 hours. HPLC analysis shows that the conversion rate of o-nitrotoluene in the raw material is above 85%. Add 350g water and 100g hydrochloric acid, maintaining the temperature at 20-25℃ during the addition process. After stirring and maintaining the temperature for 2 hours, filter the mixture. Wash the filter cake with methanol and dry it to obtain 245.8g of crude intermediate 1, with a yield of 58.9%. HPLC analysis shows a purity of 99.8%.
[0023] S2. Add 245g of the crude intermediate 1 obtained in the previous step to a 2L high-pressure hydrogenation reactor. Add water and ethanol to make a slurry, then add 750g of methanol and 24.5g of palladium on carbon catalyst. After purging with nitrogen 6 times, purging with hydrogen 3 times, heat to 75℃, and react at 1.0MPa for 6 hours. Take a sample for testing. If the remaining raw material is less than 0.1%, filter to remove the catalyst. Concentrate at atmospheric pressure and 95℃ to remove methanol from the system, obtaining 225g of crude intermediate 2. The crude product is distilled at 120℃ under vacuum controlled at -0.08MPa~0.1MPa. When the temperature reaches 200℃, collect the outflowing liquid. When no liquid flows out, the vacuum distillation is complete. Distill for about 3 hours to obtain 124.4g of distillation intermediate 2 product, with a yield of 64.9%. The purity is 99.6% as determined by high performance liquid chromatography.
[0024] S3. Add 124.4 g of free base intermediate 2 obtained in the previous step to a 2L three-necked flask. Under nitrogen protection, heat to 240℃, add 3.7 g of supported catalyst, and slowly add 115.0 g of 85% phosphoric acid dropwise over 45 min. After the addition is complete, heat to 280℃ and react for 3 h. Then cool to 90℃, add 190 g of toluene and 380 g of water, stir for 0.5 h, let stand for 1 h, and after hot filtration, let the filtrate stand to separate the lower aqueous phase. After the organic and aqueous phases are neutralized, concentrate under negative pressure at -0.08 MPa to 0.1 MPa at 60℃ to 150 g of the system. Then cool to -5 to -10℃, keep warm for 2 h, filter, and dry to obtain 109.9 g of iminodibenzyl, with a yield of 95.7%. The purity was 99.6% as determined by high performance liquid chromatography. Example
[0025] Preparation method of supported catalyst: Add 20g of ferric chloride to 100mL of water, add 200g of diatomaceous earth, heat to 80℃, and impregnate for 6h to obtain the supported catalyst.
[0026] S1. Add 1016g petroleum ether, 34g methanol, and 42g ethyl formate to a 2L three-necked flask. Under nitrogen protection, lower the temperature of the system to 5-7℃. Divide 82.7g sodium methoxide into four equal portions of 20.6g each and add them in four batches. Add 210g of o-nitrotoluene dropwise over approximately 2 hours. After the addition is complete, maintain the temperature at 5-7℃ for 8 hours. HPLC analysis of the sample shows that the conversion rate of o-nitrotoluene in the raw material is above 85%. Add 350g water and 100g hydrochloric acid, maintaining the temperature at 20-25℃ during the addition process. After stirring and maintaining the temperature for 2 hours, filter the mixture. Wash the filter cake with methanol and dry it to obtain 246.9g of crude intermediate 1, with a yield of 59.1%. HPLC analysis shows a purity of 99.7%.
[0027] S2. Add 245.0 g of the crude intermediate 1 obtained in the previous step to a 2L high-pressure hydrogenation reactor. Add water and ethanol to make a slurry, then add 750 g of methanol and 16.3 g of palladium on carbon catalyst. After purging with nitrogen 6 times, purging with hydrogen 3 times, heat to 80℃, and react at 1.5 MPa for 4 hours. Take a sample for testing. If the remaining raw material is less than 0.1%, filter to remove the catalyst. Concentrate at atmospheric pressure and 95℃ to remove methanol from the system, obtaining 225 g of crude intermediate 2. The crude product is distilled at 120℃ under vacuum controlled at -0.08 MPa to 0.1 MPa. When the temperature reaches 200℃, collect the outflowing liquid. When no liquid flows out, the vacuum distillation is complete. Distill for about 3 hours to obtain 124.2 g of distillation intermediate 2 product, with a yield of 64.8%. The purity is 99.6% as determined by high-performance liquid chromatography.
[0028] S3. Add 124.4 g of free base intermediate 2 obtained in the previous step to a 2L three-necked flask. Under nitrogen protection, heat to 240℃, add 6.2 g of supported catalyst, and slowly add 172.5 g of 85% phosphoric acid dropwise over 45 min. After the addition is complete, heat to 300℃ and react for 1 h. Then cool to 100℃, add 190 g of toluene and 380 g of water, stir for 0.5 h, let stand for 1 h, and after hot filtration, let the filtrate stand to separate the lower aqueous phase. After the organic and aqueous phases are neutralized, concentrate under negative pressure at -0.08 MPa to 0.1 MPa at 60℃ until the system weight is 150 g. Then cool to -5 to -10℃, keep warm for 2 h, filter, and dry to obtain 109.9 g of iminodibenzyl, with a yield of 95.8%. The purity was 99.7% as determined by high performance liquid chromatography. Example
[0029] The difference between this embodiment and Example 1 lies in the preparation method of the supported catalyst added in step S3: 5g of boron trifluoride and 5g of ferric chloride were added to 100mL of water, and then 200g of diatomaceous earth was added. The mixture was heated to 80℃ and impregnated for 6 hours to obtain a supported catalyst. The final product, iminodibenzyl, was 112.8g, with a yield of 98.1%. The purity was 99.5% as determined by high-performance liquid chromatography. Example
[0030] The difference between this embodiment and Example 1 lies in the preparation method of the supported catalyst: 6g of boron trifluoride and 4g of ferric chloride were added to 100mL of water, and then 200g of diatomaceous earth was added. The mixture was heated to 80℃ and impregnated for 6 hours to obtain the supported catalyst. The final product obtained was 112.7g of iminodibenzyl, with a yield of 98.3%, and a purity of 99.8% as determined by high-performance liquid chromatography. Example
[0031] The difference between this embodiment and Example 1 lies in the preparation method of the supported catalyst: 7g of boron trifluoride and 3g of ferric chloride were added to 100mL of water, and then 200g of diatomaceous earth was added. The mixture was heated to 80℃ and impregnated for 6 hours to obtain the supported catalyst. The final product obtained was 113.3g of iminodibenzyl, with a yield of 98.6%, and a purity of 99.6% as determined by high-performance liquid chromatography. Example
[0032] The difference between this embodiment and Example 1 lies in the preparation method of the supported catalyst: 5g of boron trifluoride and 5g of ferric chloride were added to 100mL of water, and then 200g of kaolinite was added. The mixture was heated to 80℃ and impregnated for 6 hours to obtain the supported catalyst. The final product obtained was 110.9g of iminodibenzyl, with a yield of 96.5%, and a purity of 99.6% as determined by high-performance liquid chromatography. Example
[0033] The difference between this embodiment and Example 3 lies in the preparation method of the supported catalyst: 4g of boron trifluoride and 6g of ferric chloride were added to 100mL of water, and then 200g of diatomaceous earth was added. The mixture was heated to 80℃ and impregnated for 6 hours to obtain the supported catalyst. The final product obtained was 110.9g of iminodibenzyl, with a yield of 96.5%, and a purity of 99.6% as determined by high-performance liquid chromatography. Example
[0034] The difference between this embodiment and Example 3 lies in the preparation method of the supported catalyst: 8g of boron trifluoride and 2g of ferric chloride were added to 100mL of water, and then 200g of diatomaceous earth was added. The mixture was heated to 80℃ and impregnated for 6 hours to obtain the supported catalyst. The final product obtained was 111.1g of iminodibenzyl, with a yield of 96.8%, and a purity of 99.7% as determined by high-performance liquid chromatography. Example
[0035] The difference between this embodiment and Example 3 lies in the preparation method of the supported catalyst: 15g of boron trifluoride and 15g of ferric chloride were added to 100mL of water, and then 200g of diatomaceous earth was added. The mixture was heated to 80℃ and impregnated for 6 hours to obtain the supported catalyst. The final product obtained was 111.4g of iminodibenzyl, with a yield of 96.6%, and a purity of 99.5% as determined by high-performance liquid chromatography.
[0036] Comparative Example 1 The only difference between this embodiment and Example 1 is the addition of 3.7g of boron trifluoride catalyst in step S3. The final product obtained was 107.9g of iminodibenzyl, with a yield of 93.6%, and a purity of 99.3% as determined by high-performance liquid chromatography.
[0037] Of course, the above are just typical examples of the present invention. In addition, the present invention may have many other specific embodiments. All technical solutions formed by equivalent substitution or equivalent transformation fall within the scope of protection claimed by the present invention.
Claims
1. A process for synthesizing oxcarbazepine intermediates, characterized in that, Includes the following steps: S1. Petroleum ether, methanol, and ethyl formate are mixed to obtain a mixed system. o-phenyltoluene and sodium methoxide are added, and the mixture is reacted to obtain intermediate 1. S2. Add intermediate 1 to methanol, add palladium on carbon catalyst, introduce hydrogen gas, and react to obtain intermediate 2. S3. Add phosphoric acid and a catalyst to intermediate 2, and react to obtain iminodibenzyl.
2. The synthesis process of oxcarbazepine intermediate according to claim 1, characterized in that, The catalyst is a supported catalyst, and the active component of the supported catalyst is a composite of boron trifluoride and ferric chloride in a mass ratio of 5:5 to 7:
3. The support of the supported catalyst is diatomaceous earth.
3. The synthesis process of an oxcarbazepine intermediate according to claim 2, characterized in that, The loading of the active component in the supported catalyst is 5% to 10% of the mass of diatomite.
4. The synthesis process of an oxcarbazepine intermediate according to claim 2, characterized in that, The amount of the supported catalyst added is 3% to 5% of the mass of intermediate 2.
5. The synthesis process of an oxcarbazepine intermediate according to claim 1, characterized in that, The mass ratio of petroleum ether to methanol is 20:1 to 30:
1.
6. The synthesis process of an oxcarbazepine intermediate according to claim 1, characterized in that, The mass-to-volume ratio of o-nitrotoluene to the mixed solvent is 1:3 to 1:5 g / mL, and the mass-to-volume ratio of o-nitrotoluene to ethyl formate is 2:1 to 5:1 g / mL.
7. The synthesis process of an oxcarbazepine intermediate according to claim 1, characterized in that, The molar ratio of o-nitrotoluene to sodium methoxide is 1:0.5 to 1:
1.
8. The synthesis process of an oxcarbazepine intermediate according to claim 1, characterized in that, In step S1, the reaction temperature is 3~11℃ and the reaction time is 7~9h; in step S2, the reaction temperature is 75~80℃ and the reaction time is 4~6h, and the reaction pressure is 1.0~1.5MPa; in step S3, the reaction temperature is 280~300℃ and the reaction time is 1~3h.
9. The synthesis process of an oxcarbazepine intermediate according to claim 1, characterized in that, The mass ratio of intermediate 1 to palladium on carbon catalyst is 10:1 to 15:1; the molar ratio of intermediate 2 to phosphoric acid is 1:2 to 1:
3.
10. The synthesis process of an oxcarbazepine intermediate according to claim 1, characterized in that, In step S1, o-phenyltoluene is added dropwise, and sodium methoxide is added in batches, specifically by dividing sodium methoxide into four equal parts and adding them in four batches.