Benzoxycarbonyl deprotection reaction method and application
By using Raney nickel catalyst and ethanol dissolution reflux treatment combined with hydrogen atmosphere reaction, the problem of uneven dispersion of palladium on carbon catalyst was solved, realizing low-cost and high-efficiency production of benzyloxycarbonyl deprotection reaction, reducing production costs and improving catalyst utilization.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- ZHEJIANG GUOBANG PHARMA
- Filing Date
- 2026-02-11
- Publication Date
- 2026-05-12
AI Technical Summary
In existing technologies, the benzyloxycarbonyl deprotection reaction using palladium on carbon catalyst suffers from uneven catalyst dispersion, large particle size, and low palladium atom utilization, resulting in high production costs and making it difficult to achieve industrial application.
Raney nickel is used as a catalyst. The raw material is dissolved in ethanol and then refluxed and stirred. The reaction is carried out under a hydrogen atmosphere. After the catalyst is filtered out, it is activated and recycled for reuse, so as to realize the reduction of catalyst usage and multiple recycling, and maintain high conversion rate and yield.
It effectively reduced production costs, improved production efficiency, enabled multiple recycling and reuse of catalysts, reduced the cost of waste catalyst disposal, and maintained high conversion and yield rates.
Abstract
Description
Technical Field
[0001] This application relates to a method and application of benzyloxycarbonyl deprotection reaction, belonging to the field of catalytic chemistry technology. Background Technology
[0002] The most widely used macrolide antibiotics currently are tylosin and tilmicosin. Although both drugs have achieved good results, with the extension of use, varying degrees of drug resistance have emerged in many areas. Moreover, these two drugs are usually administered by mixing with feed or drinking water, and generally require repeated administration to achieve their therapeutic effect.
[0003] Tylosin is mainly used for the prevention and treatment of respiratory infections in cattle and pigs caused by susceptible bacteria, as well as infectious keratoconjunctivitis in cattle caused by Moraxella bovis. Its efficacy is stronger than tylosin and tilmicosin, and it possesses numerous advantages over other macrolide antibiotics, including being animal-specific, requiring smaller doses, being administered only once, having high bioavailability, a long elimination half-life, and low residue.
[0004] The synthesis of tylosin has been reported in the literature, and its synthetic route includes a one-step benzyloxycarbonyl (Cbz) deprotection reaction. The benzyloxycarbonyl group is typically used to protect non-reacting positions and functional groups such as amino and hydroxyl groups to prevent the multiple functional groups present in the organic macromolecule from reacting with other functional groups and generating more byproducts. Catalytic hydrogenation of the starting material is a common method for the deprotection of benzyloxycarbonyl. The catalyst in this method is mainly a palladium-on-carbon catalyst. Due to the weak interaction between the carbon support and palladium, palladium cannot be well dispersed, resulting in a large overall particle size and low palladium atom utilization. Therefore, a high palladium loading is required, making the industrial production of palladium-on-carbon difficult and significantly increasing production costs.
[0005] Therefore, achieving low cost, multiple catalyst recycling, and high conversion and yield for the benzyloxycarbonyl deprotection reaction is key to reducing the cost of benzyloxycarbonyl deprotection and promoting its industrialization. Summary of the Invention
[0006] In view of this, this application provides a method for benzyloxycarbonyl deprotection reaction. This method uses a special method to process the raw materials and uses Raney nickel as a catalyst. This not only halves the amount of Raney nickel catalyst and allows for multiple recycling and reuse of the catalyst, but also achieves 100% conversion and a yield of over 90%, effectively reducing production costs and improving production efficiency.
[0007] Specifically, this application is implemented through the following scheme: A method for benzyloxycarbonyl deprotection reaction, comprising the following steps: Cbz epoxy (CAS No.: 217649-77-9) was dissolved in ethanol, refluxed, and stirred before being transferred to a reactor. Raney nickel (at a weight ratio of 1:0.1 to 1:0.15) was added to the reactor. Nitrogen was purged to remove air, followed by hydrogen purging, maintaining the final hydrogen pressure in the reactor below 2 MPa. After stirring at room temperature, the Raney nickel was filtered off to obtain the reaction solution. The solution was then subjected to dropwise precipitation to crystallize, filtered, and dried to obtain the product. HPLC analysis revealed a 100% conversion rate and a yield exceeding 90%. The filtered Raney nickel was recycled at high temperature for at least 10 reuses before being replaced with new Raney nickel.
[0008] Furthermore, as a preferred option: The temperature of the reflux stirring treatment is 60~70℃.
[0009] The duration of the reflux stirring treatment is 1 to 2 hours.
[0010] The final pressure of hydrogen gas inside the reactor is 1~2 MPa.
[0011] The Raney nickel can be recycled and reused 10 to 20 times.
[0012] The specific method for the activation treatment is as follows: the filtered Raney nickel is first washed with water by stirring, and then washed with anhydrous ethanol by stirring to obtain activated Raney nickel. The temperature of water stirring and washing is 70~80℃ and the time is 1~2 hours; the temperature of anhydrous ethanol stirring and washing is 20~30℃ and the time is 1~2 hours.
[0013] The above-described benzyloxycarbonyl deprotection reaction method can be applied to the synthesis of deprotected epoxides of tylosin and other compounds.
[0014] The specific application steps are as follows: Step 1: Add the Cbz epoxy solid obtained from the epoxidation reaction to ethanol and stir to dissolve it. After reflux and stirring, the resulting product is transferred to the reaction vessel. Step 2: Add Raney nickel in a raw material weight ratio of 1:0.1 to 1:0.15 to the reactor. After purging the reactor with nitrogen to remove air, purge with hydrogen again to keep the final hydrogen pressure in the reactor below 2 MPa and react at room temperature. Step 3: After the reaction at room temperature is complete, filter out Raney nickel to obtain the reaction solution. Crystallize the reaction solution by dripping water, filter and dry to obtain the product. Step four: The filtered Raney nickel is activated and then recycled as a catalyst in step two. After the activated catalyst has been recycled and reused at least 10 times, replace it with new Raney nickel and repeat the above steps.
[0015] The reactor is a high-pressure reactor.
[0016] The beneficial effects of this invention are as follows: (1) In this invention, after pretreatment of the raw material Cbz epoxy by dissolving and refluxing with ethanol, Raney nickel with half the amount is added. This gives the benzyloxycarbonyl deprotection reaction a significant reduction in the amount of Raney nickel without affecting the reaction effect, thus effectively reducing the production cost.
[0017] (2) The method of the present invention can realize the effective recycling and reuse of Raney nickel after use, which reduces the production cost of the product and the smelting cost of waste Raney nickel post-processing, and has high economic benefits.
[0018] (3) The method of this application can be directly applied to the synthesis process of deprotected epoxides of tylosin, etc., to improve the reaction cost and efficiency of the process including benzyloxycarbonyl deprotection. Detailed Implementation
[0019] To make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, the technical solutions in the embodiments of this application will be further described in detail below. It should be understood that the specific embodiments described herein are only used to explain this application and are not intended to limit the technical solutions of this application. Based on the embodiments in this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.
[0020] The following examples use Cbz epoxy in the synthesis of tylosin as a starting material. The benzyloxycarbonyl deprotection reaction process in the synthesis of tylosin is as follows: .
[0021] Example 1
[0022] The benzyloxycarbonyl deprotection reaction method in this embodiment is as follows: S1, take 24.06g of Cbz epoxy solid, add 300g of ethanol and stir until dissolved. Reflux and stir at 60℃ for 1h, then transfer to an autoclave. Add 3.61g of Raney nickel to the autoclave, purge the air from the autoclave with nitrogen three times, then purge with hydrogen three times to maintain the final hydrogen pressure in the autoclave at 2MPa. Under these conditions, stir the reaction at room temperature for 10h.
[0023] S2. After the reaction is complete, Raney nickel is filtered out. 500g of water is added dropwise to the reaction solution to crystallize the crystals. After filtration and drying, 15.40g of product is obtained. The purity of related substances is 99.74%, and the yield is 98.61%.
[0024] S3. Wash the Raney nickel filtered out in S2 with water at 70°C for 1 hour with stirring. After washing, continue to wash with anhydrous ethanol for 1 hour with stirring. Filter to retain the Raney nickel to complete the activation process.
[0025] For S4, take 23.98g of Cbz epoxy solid, add 300g of ethanol and stir until dissolved. Reflux and stir at 60℃ for 1h, then transfer to an autoclave. Add 3.59g of Raney nickel (activated in S3) to the autoclave. After purging the autoclave with nitrogen three times to remove air, purge with hydrogen three times to maintain a final hydrogen pressure of 2MPa. Under these conditions, stir the reaction at room temperature for 10h.
[0026] S5. After the reaction is complete, Raney nickel is filtered out. 500g of water is added dropwise to the reaction solution to crystallize the crystals. After filtration and drying, 15.21g of product is obtained. The purity of related substances is 99.60%, and the yield is 98.17%.
[0027] S6. Wash the Raney nickel filtered out in S5 with water at 70°C for 1 hour with stirring. After washing, continue to wash with anhydrous ethanol for 1 hour with stirring. Filter to retain the Raney nickel to complete the activation process.
[0028] As can be seen from the above process, the decrease in purity and yield of related substances after one reuse is 0.14% and 0.4%, respectively, which can be ignored.
[0029] Example 2 The benzyloxycarbonyl deprotection reaction method in this embodiment is as follows: S1, take 24.06g of Cbz epoxy solid, add 300g of ethanol and stir until dissolved. Reflux and stir at 60℃ for 1h, then transfer to an autoclave. Add 3.61g of Raney nickel to the autoclave, purge the air from the autoclave with nitrogen three times, then purge with hydrogen three times to maintain the final hydrogen pressure in the autoclave at 2MPa. Under these conditions, stir the reaction at room temperature for 10h.
[0030] S2. After the reaction is complete, Raney nickel is filtered out. 500g of water is added dropwise to the reaction solution to crystallize the crystals. After filtration and drying, 15.40g of product is obtained. The purity of related substances is 99.74%, and the yield is 98.61%.
[0031] S3. Wash the Raney nickel filtered out in S2 with water at 70°C for 1 hour with stirring. After washing, continue to wash with anhydrous ethanol for 1 hour with stirring. Filter to retain the Raney nickel to complete the activation process.
[0032] For S4, take 23.98g of Cbz epoxy solid, add 300g of ethanol and stir until dissolved. Reflux and stir at 60℃ for 1h, then transfer to an autoclave. Add 3.58g of Raney nickel (activated in S3) to the autoclave. After purging the autoclave with nitrogen three times to remove air, purge with hydrogen three times to maintain a final hydrogen pressure of 2MPa. Under these conditions, stir the reaction at room temperature for 10h.
[0033] S5. After the reaction is complete, Raney nickel is filtered out. 500g of water is added dropwise to the reaction solution to crystallize the crystals. After filtration and drying, 15.21g of product is obtained. The purity of related substances is 99.60%, and the yield is 98.17%.
[0034] S6. Wash the Raney nickel filtered out in S5 with water at 70°C for 1 hour with stirring. After washing, continue to wash with anhydrous ethanol for 1 hour with stirring. Filter to retain the Raney nickel to complete the activation process.
[0035] For S7, take 23.88g of Cbz epoxy solid, add 300g of ethanol and stir until dissolved. Reflux and stir at 60℃ for 1h, then transfer to an autoclave. Add 3.56g of Raney nickel (activated in S6) to the autoclave. Purge the autoclave with nitrogen three times to remove air, then purge with hydrogen three times to maintain a final hydrogen pressure of 2MPa. Under these conditions, stir the reaction at room temperature for 10h.
[0036] S8. After the reaction is complete, Raney nickel is filtered out. 500g of water is added dropwise to the reaction solution to crystallize the crystals. After filtration and drying, 15.21g of product is obtained. The purity of related substances is 99.53%, and the yield is 97.76%.
[0037] S9. Wash the Raney nickel filtered out in S8 with water at 70°C for 1 hour by stirring. After washing, continue to wash with anhydrous ethanol for 1 hour by stirring. Filter to retain the Raney nickel to complete the activation process.
[0038] As can be seen from the above process, compared with new Raney nickel, the purity and yield of related substances reduced by 0.21% and 0.86% respectively after two reuses, which are negligible.
[0039] Example 3 The benzyloxycarbonyl deprotection reaction method in this embodiment is as follows: S1, take 24.06g of Cbz epoxy solid, add 300g of ethanol and stir until dissolved. Reflux and stir at 60℃ for 1h, then transfer to an autoclave. Add 3.61g of Raney nickel to the autoclave, purge the air from the autoclave with nitrogen three times, then purge with hydrogen three times to maintain the final hydrogen pressure in the autoclave at 2MPa. Under these conditions, stir the reaction at room temperature for 10h.
[0040] S2. After the reaction is complete, Raney nickel is filtered out. 500g of water is added dropwise to the reaction solution to crystallize the crystals. After filtration and drying, 15.40g of product is obtained. The purity of related substances is 99.74%, and the yield is 98.61%.
[0041] S3. Wash the Raney nickel filtered out in S2 with water at 70°C for 1 hour with stirring. After washing, continue to wash with anhydrous ethanol for 1 hour with stirring. Filter to retain the Raney nickel to complete the activation process.
[0042] For S4, take 23.98g of Cbz epoxy solid, add 300g of ethanol and stir until dissolved. Reflux and stir at 60℃ for 1h, then transfer to an autoclave. Add 3.59g of Raney nickel (activated in S3) to the autoclave. After purging the autoclave with nitrogen three times to remove air, purge with hydrogen three times to maintain a final hydrogen pressure of 2MPa. Under these conditions, stir the reaction at room temperature for 10h.
[0043] S5. After the reaction is complete, Raney nickel is filtered out. 500g of water is added dropwise to the reaction solution to crystallize the crystals. After filtration and drying, 15.21g of product is obtained. The purity of related substances is 99.60%, and the yield is 98.17%.
[0044] S6. Wash the Raney nickel filtered out in S5 with water at 70°C for 1 hour with stirring. After washing, continue to wash with anhydrous ethanol for 1 hour with stirring. Filter to retain the Raney nickel to complete the activation process.
[0045] For S7, take 24.24g of Cbz epoxy solid, add 300g of ethanol and stir until dissolved. Reflux and stir at 60℃ for 1h, then transfer to an autoclave. Add 3.57g of Raney nickel (activated in S6) to the autoclave. After purging the autoclave with nitrogen three times to remove air, purge with hydrogen three times to maintain a final hydrogen pressure of 2MPa. Under these conditions, stir the reaction at room temperature for 10h.
[0046] S8. After the reaction is complete, Raney nickel is filtered out. 500g of water is added dropwise to the reaction solution to crystallize the crystals. After filtration and drying, 15.21g of product is obtained. The purity of related substances is 99.53%, and the yield is 97.76%.
[0047] S9. Wash the Raney nickel filtered out in S8 with water at 70°C for 1 hour by stirring. After washing, continue to wash with anhydrous ethanol for 1 hour by stirring. Filter to retain the Raney nickel to complete the activation process.
[0048] For S10, take 23.89g of Cbz epoxy solid, add 300g of ethanol and stir until dissolved. Reflux and stir at 60℃ for 1h, then transfer to an autoclave. Add 3.54g of Raney nickel (activated in S9) to the autoclave. After purging the autoclave with nitrogen three times to remove air, purge with hydrogen three times to maintain a final hydrogen pressure of 2MPa. Under these conditions, stir the reaction at room temperature for 10h.
[0049] S11. After the reaction is complete, Raney nickel is filtered out. 500g of water is added dropwise to the reaction solution to crystallize the crystals. After filtration and drying, 15.01g of product is obtained. The purity of related substances is 99.39%, and the yield is 97.54%.
[0050] S12, wash the Raney nickel filtered out in S11 with water at 70°C for 1 hour by stirring, and then continue to wash with anhydrous ethanol for 1 hour by stirring. Filter to retain the Raney nickel to complete the activation process.
[0051] As can be seen from the above process, compared with new Raney nickel, the purity and yield of related substances decreased by 0.35% and 1.08% respectively after three reuses. The purity of related substances of the reaction products after reuse is still above 99% and the yield is above 97%.
[0052] Example 4 The benzyloxycarbonyl deprotection reaction method in this embodiment is as follows: S1, take 24.06g of Cbz epoxy solid, add 300g of ethanol and stir until dissolved. Reflux and stir at 60℃ for 1h, then transfer to an autoclave. Add 3.61g of Raney nickel to the autoclave, purge the air from the autoclave with nitrogen three times, then purge with hydrogen three times to maintain the final hydrogen pressure in the autoclave at 2MPa. Under these conditions, stir the reaction at room temperature for 10h.
[0053] S2. After the reaction is complete, Raney nickel is filtered out. 500g of water is added dropwise to the reaction solution to crystallize the crystals. After filtration and drying, 15.40g of product is obtained. The purity of related substances is 99.74%, and the yield is 98.61%.
[0054] S3. Wash the Raney nickel filtered out in S2 with water at 70°C for 1 hour with stirring. After washing, continue to wash with anhydrous ethanol for 1 hour with stirring. Filter to retain the Raney nickel to complete the activation process.
[0055] For S4, take 23.98g of Cbz epoxy solid, add 300g of ethanol and stir until dissolved. Reflux and stir at 60℃ for 1h, then transfer to an autoclave. Add 3.59g of Raney nickel (activated in S3) to the autoclave. After purging the autoclave with nitrogen three times to remove air, purge with hydrogen three times to maintain a final hydrogen pressure of 2MPa. Under these conditions, stir the reaction at room temperature for 10h.
[0056] S5. After the reaction is complete, Raney nickel is filtered out. 500g of water is added dropwise to the reaction solution to crystallize the crystals. After filtration and drying, 15.21g of product is obtained. The purity of related substances is 99.60%, and the yield is 98.17%.
[0057] S6. Wash the Raney nickel filtered out in S5 with water at 70°C for 1 hour with stirring. After washing, continue to wash with anhydrous ethanol for 1 hour with stirring. Filter to retain the Raney nickel to complete the activation process.
[0058] For S7, take 24.24g of Cbz epoxy solid, add 300g of ethanol and stir until dissolved. Reflux and stir at 60℃ for 1h, then transfer to an autoclave. Add 3.57g of Raney nickel (activated in S6) to the autoclave. After purging the autoclave with nitrogen three times to remove air, purge with hydrogen three times to maintain a final hydrogen pressure of 2MPa. Under these conditions, stir the reaction at room temperature for 10h.
[0059] S8. After the reaction is complete, Raney nickel is filtered out. 500g of water is added dropwise to the reaction solution to crystallize the crystals. After filtration and drying, 15.21g of product is obtained. The purity of related substances is 99.53%, and the yield is 97.76%.
[0060] S9. Wash the Raney nickel filtered out in S8 with water at 70°C for 1 hour by stirring. After washing, continue to wash with anhydrous ethanol for 1 hour by stirring. Filter to retain the Raney nickel to complete the activation process.
[0061] For S10, take 23.89g of Cbz epoxy solid, add 300g of ethanol and stir until dissolved. Reflux and stir at 60℃ for 1h, then transfer to an autoclave. Add 3.55g of Raney nickel (activated in S9) to the autoclave. After purging the autoclave with nitrogen three times to remove air, purge with hydrogen three times to maintain a final hydrogen pressure of 2MPa. Under these conditions, stir the reaction at room temperature for 10h.
[0062] S11. After the reaction is complete, Raney nickel is filtered out. 500g of water is added dropwise to the reaction solution to crystallize the crystals. After filtration and drying, 15.01g of product is obtained. The purity of related substances is 99.39%, and the yield is 97.54%.
[0063] S12, wash the Raney nickel filtered out in S11 with water at 70°C for 1 hour by stirring, and then continue to wash with anhydrous ethanol for 1 hour by stirring. Filter to retain the Raney nickel to complete the activation process.
[0064] For S13, take 23.88g of Cbz epoxy solid, add 300g of ethanol and stir until dissolved. Reflux and stir at 60℃ for 1h, then transfer to an autoclave. Add 3.52g of Raney nickel (activated in S12) to the autoclave. After purging the autoclave with nitrogen three times to remove air, purge with hydrogen three times to maintain a final hydrogen pressure of 2MPa. Under these conditions, stir the reaction at room temperature for 10h.
[0065] S14. After the reaction is complete, Raney nickel is filtered out. 500g of water is added dropwise to the reaction solution to crystallize the crystals. After filtration and drying, 15.06g of product is obtained. The purity of related substances is 99.27%, and the yield is 97.42%.
[0066] S15, wash the Raney nickel filtered out in S14 with water at 70°C for 1 hour by stirring, and then continue to wash with anhydrous ethanol for 1 hour by stirring. Filter to retain the Raney nickel to complete the activation process.
[0067] As can be seen from the above process, compared with new Raney nickel, the purity and yield of related substances decreased by 0.47% and 1.12% respectively after four reuses. The purity of related substances of the reaction products after reuse is still above 99% and the yield is above 97%.
[0068] Table 1: Effects of Reusing Activated Raney Nickel .
[0069] As can be seen from the above embodiments and Table 1, the method of this application can not only reduce the use of catalyst by half and reuse it at least 10 times, but also maintain the purity of related substances at more than 98% and the yield at more than 96%.
[0070] Comparative Example 1 Take 24.06g of Cbz epoxy solid, add 300g of acetone and stir until dissolved, then transfer to an autoclave. Add 6.02g of 10% Pd / C to the autoclave, purge the air from the autoclave three times with nitrogen, then purge with hydrogen three times, maintaining the final hydrogen pressure in the autoclave at 0.4MPa. Under these conditions, stir and react at 20-25℃ for 10h. After the reaction is complete, filter to remove Raney nickel, add 500g of water dropwise to crystallize, filter, and dry to obtain 15.39g of product with a purity of 98.40% and a yield of 97.63%.
[0071] Also used for the deprotection of Cbz epoxy hydrogenation, compared with Comparative Example 1, the method of this application can reduce the synthesis cost to 0.1%~0.3% of Comparative Example 1.
[0072] The above-described embodiments are merely illustrative of several feasible implementations of the present invention, and their descriptions are relatively specific and detailed. However, they should not be construed as limiting the scope of the present invention, nor are the embodiments intended to limit the scope of protection in the claims of the present invention. For those skilled in the art, various modifications and improvements can be made without departing from the concept of the present invention. All equivalent implementations or changes that do not depart from the present invention should be included in the technology of the present invention.
Claims
1. A method for benzyloxycarbonyl deprotection reaction, characterized in that: The raw material Cbz epoxy was dissolved in ethanol, refluxed and stirred, and the resulting product was transferred to a reactor. Raney nickel was then added, nitrogen was purged to remove air from the reactor, and hydrogen was purged again to maintain the final hydrogen pressure in the reactor below 2 MPa. After the reaction was completed at room temperature, Raney nickel was filtered off to obtain a reaction solution. The reaction solution was subjected to droplet water crystallization, filtered and dried to obtain the product. The filtered Raney nickel was activated and recycled for at least 10 times before being replaced with new Raney nickel. The weight ratio of the raw material to Raney nickel was 1:0.1~0.
15.
2. The method for benzyloxycarbonyl deprotection reaction according to claim 1, characterized in that: The temperature for reflux stirring is 60~70℃.
3. The method for benzyloxycarbonyl deprotection reaction according to claim 1, characterized in that: The duration of the reflux stirring treatment is 1 to 2 hours.
4. The method for benzyloxycarbonyl deprotection reaction according to claim 1, characterized in that: The final pressure of hydrogen gas inside the reactor is 1~2 MPa.
5. The method for benzyloxycarbonyl deprotection reaction according to claim 1, characterized in that: The Raney nickel can be recycled and reused 10 to 20 times.
6. The method for benzyloxycarbonyl deprotection reaction according to claim 1, characterized in that, The specific method of the activation treatment is as follows: the filtered Raney nickel is first washed with water and then washed with anhydrous ethanol to obtain activated Raney nickel. The temperature of the water washing is 70~80℃ and the time is 1~2 hours. The temperature for washing with anhydrous ethanol is 20~30℃, and the duration is 1~2 hours.
7. The application of the method according to any one of claims 1 to 6 in the synthesis reaction of tylosin deprotected epoxide.
8. The application according to claim 7, characterized in that, The steps are as follows: Step 1: Add the Cbz epoxy solid obtained from the epoxidation reaction to ethanol and stir to dissolve it. After reflux and stirring, the resulting product is transferred to the reaction vessel. Step 2: Add Raney nickel to the reactor, purge the air from the reactor with nitrogen, then purge with hydrogen again to keep the final hydrogen pressure in the reactor below 2 MPa, and react at room temperature. Step 3: After the reaction at room temperature is complete, filter out Raney nickel to obtain the reaction solution. Crystallize the reaction solution by dripping water, filter and dry to obtain the product. Step four: The filtered Raney nickel is activated and then recycled as a catalyst in step two. After the activated catalyst has been recycled and reused at least 10 times, replace it with new Raney nickel and repeat the above steps.