A process for the synthesis of iminodibenzyl

Abstract

The application relates to the technical field of drug intermediate synthesis, and proposes a synthesis method of iminodibenzyl, which comprises the following steps: S1, mixing petroleum ether, methanol and ethyl formate to obtain a mixed system, adding o-phenyltoluene and sodium methoxide, and reacting to obtain an intermediate 1; S2, adding the intermediate 1 into methanol, adding a palladium-carbon catalyst, passing in hydrogen, and reacting to obtain an intermediate 2; and S3, adding phosphoric acid into the intermediate 2, adding a catalyst, and reacting to obtain iminodibenzyl. Through the technical scheme, the problem of low iminodibenzyl yield in the prior art is solved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically to a method for synthesizing iminodibenzyl. Background Technology

[0002] Oxcarbazepine is a new generation of antiepileptic drug that blocks voltage-dependent sodium and potassium ion channels in the body of epilepsy patients. Iminobenzyl is a crucial intermediate in the synthesis of oxcarbazepine, and its quality directly affects the subsequent synthesis of the oxcarbazepine active pharmaceutical ingredient. Currently, the synthesis of iminodibenzyl mainly uses o-nitrotoluene as a raw material, proceeding through condensation, reduction, salt formation, and high-temperature cyclization reactions to obtain the final product. In this synthetic route, the condensation reaction is a one-pot cooking method, resulting in concentrated exothermic activity. This process poses safety risks and cannot be scaled up. The conversion rate of the reactants is low, at 55%–60%, producing a large amount of tar-like substances, leading to a yield of around 50%, which is low. Furthermore, the product requires two-step pulping and refining to allow for subsequent reactions, making the process quite cumbersome. The reduction reaction methods mainly include hydrazine hydrate reduction, catalytic hydrogenation reduction, and iron powder reduction. Hydrazine hydrate reduction and catalytic hydrogenation reduction both have high equipment requirements and high industrial production costs. Hydrazine hydrate is also relatively expensive, resulting in high industrial production costs. Iron powder reduction produces a large amount of high-salt wastewater and has a low product content, which increases industrial production costs. The existing process directly carries out the phosphate salt formation reaction after iron powder reduction. This process cannot accurately measure the raw material content, so the amount of phosphate used cannot be determined. In order for the subsequent reaction to proceed normally, the amount of phosphate used needs to be 50% excess, which increases material costs and wastewater generation. Therefore, it is extremely important to develop a high-yield synthesis method for iminodibenzyl. Summary of the Invention

[0003] This invention proposes a method for synthesizing iminodibenzyl, which solves the problem of low yield of iminodibenzyl in related technologies.

[0004] The technical solution of the present invention is as follows: This invention proposes a method for synthesizing iminodibenzyl, 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.

[0005] 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.

[0006] As a further technical solution, the loading of the active component in the supported catalyst is 5% to 10% of the mass of diatomite.

[0007] As a further technical solution, the amount of the supported catalyst added is 3% to 5% of the mass of intermediate 2.

[0008] As a further technical solution, the mass ratio of petroleum ether to methanol is 20:1 to 30:1.

[0009] 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.

[0010] As a further technical solution, the molar ratio of o-nitrotoluene to sodium methoxide is 1:0.5 to 1:1.

[0011] 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.

[0012] 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.

[0013] 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.

[0014] 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 reacted with ethyl formate as a catalyst to obtain intermediate 1. The reaction is more complete and side reactions are reduced. 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 catalyst to obtain intermediate 2. Intermediate 2 then undergoes a salt-forming cyclization reaction. The reaction is simple and the iminodibenzyl obtained has a high product yield.

[0015] 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.

[0016] 3. In this invention, by loading the active component of the supported catalyst onto diatomaceous earth, the specific surface area of ​​the supported catalyst is increased, which further improves the reaction efficiency of the salt formation cyclization reaction, thereby increasing the yield of the product iminodibenzyl.

[0017] 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

[0018] 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.

[0019] Example 1 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.

[0020] 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 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 245.8g of crude intermediate 1, with a yield of 58.9%. HPLC analysis shows a purity of 99.8%.

[0021] 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.

[0022] S3. Add 124.4g of free base intermediate 2 obtained in the previous step to a 2L three-necked flask. Under nitrogen protection, heat to 240℃, add 3.7g of supported catalyst, and slowly add 115.0g of 85% phosphoric acid dropwise over 45 minutes. After the addition is complete, heat to 280℃ and react for 3 hours. Then cool to 90℃, add 190g of toluene and 380g of water, stir for 0.5 hours, let stand for 1 hour, 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 -0.08Mpa~0.1Mpa at 60℃ until the system weight is 150g. Then cool to -5~-10℃, keep warm for 2 hours, filter, and dry to obtain 109.9g of iminodibenzyl, with a yield of 95.7%. The purity was 99.6% as determined by high performance liquid chromatography.

[0023] Example 2 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.

[0024] 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%.

[0025] S2. Add 245.0g 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 16.3g of palladium on carbon catalyst. After purging with nitrogen 6 times, purge with hydrogen 3 times. Heat to 80℃ and react at 1.5MPa 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 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 124.2g of distillation intermediate 2 product, with a yield of 64.8%. The purity is 99.6% as determined by high-performance liquid chromatography.

[0026] S3. Add 124.4g of free base intermediate 2 obtained in the previous step to a 2L three-necked flask. Under nitrogen protection, heat to 240℃, add 6.2g of supported catalyst, and slowly add 172.5g of 85% phosphoric acid dropwise over 45 minutes. After the addition is complete, heat to 300℃ and react for 1 hour. Then cool to 100℃, add 190g of toluene and 380g of water, stir for 0.5 hours, let stand for 1 hour, 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 -0.08Mpa~0.1Mpa at 60℃ until the system weight is 150g. Then cool to -5~-10℃, keep warm for 2 hours, filter, and dry to obtain 109.9g of iminodibenzyl, with a yield of 95.8%. The purity was 99.7% as determined by high performance liquid chromatography.

[0027] Example 3 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 are added to 100mL of water, then 200g of diatomaceous earth is added, the temperature is raised to 80℃, and the mixture is impregnated for 6 hours to obtain the supported catalyst. The final product obtained is 112.8g of iminodibenzyl, with a yield of 98.1%, and a purity of 99.5% as determined by high-performance liquid chromatography.

[0028] Example 4 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.

[0029] Example 5 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.

[0030] Example 6 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.

[0031] Example 7 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.

[0032] Example 8 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.

[0033] Example 9 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.

[0034] 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.

[0035] 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 method for synthesizing iminodibenzyl, characterized in that, Includes the following steps: S1. Petroleum ether, methanol and ethyl formate are mixed to obtain a mixed system. o-nitrotoluene and sodium methoxide are added and 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; 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.

2. The method for synthesizing iminodibenzyl according to claim 1, characterized in that, The loading of the active component in the supported catalyst is 5% to 10% of the mass of diatomite.

3. The method for synthesizing iminodibenzyl according to claim 1, characterized in that, The amount of the supported catalyst added is 3% to 5% of the mass of intermediate 2.

4. The method for synthesizing iminodibenzyl according to claim 1, characterized in that, The mass ratio of petroleum ether to methanol is 20:1 to 30:

1.

5. The method for synthesizing iminodibenzyl 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.

6. The method for synthesizing iminodibenzyl according to claim 1, characterized in that, The molar ratio of o-nitrotoluene to sodium methoxide is 1:0.5 to 1:

1.

7. The method for synthesizing iminodibenzyl 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.

8. The method for synthesizing iminodibenzyl 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.

9. The method for synthesizing iminodibenzyl according to claim 1, characterized in that, In step S1, o-nitrotoluene 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.