A method for preparing a catalyst for synthesizing lisinopril intermediate

Abstract

The invention discloses a preparation method of a catalyst for synthesizing lisinopril intermediates, specifically comprising: step 1, treating coconut shell activated carbon with nitrogen-containing compounds and phosphorus-containing compounds in sequence to obtain surface-modified activated carbon; step 2, adding a complexing agent after mixing chloropalladic acid solution, auxiliary metal soluble salt solution and deionized water, adjusting pH, and obtaining a precursor complex system containing active components and auxiliary active components; step 3, spraying the precursor complex system containing active components and auxiliary active components onto surface-modified activated carbon; step 4, stirring reduction, filtering, washing, drying, and obtaining a catalyst for synthesizing lisinopril intermediates. The catalyst has a raw material conversion rate of up to 99.8%, a product yield of up to 66.1%, and an impurity content as low as 0.24% during the hydrogenation reaction of N2-(1-ethoxycarbonyl-3-phenylpropanoyl)-N6-trifluoroacetyl-L-lysine.

Description

Technical Field

[0001] The invention belongs to the technical field of catalyst technology, and particularly relates to a method for preparing a catalyst for synthesizing a lisinopril intermediate. Background Art

[0002] Lisinopril is a lysine derivative of enalaprilat. It is a third-generation long-acting angiotensin-converting enzyme inhibitor that can effectively treat hypertension and other cardiovascular and cerebrovascular diseases. It directly produces pharmacological effects without liver conversion, thus effectively treating hypertension and congestive heart failure. Compared with other antihypertensive drugs, lisinopril has the following characteristics: first, it has strong hydrophilicity and strong affinity for cells; second, it has a long duration of efficacy and a high trough-to-peak ratio for reducing systolic and diastolic blood pressure. The antihypertensive effect is relatively stable; third, it is the only drug for treating hypertension that is active without liver metabolism and biotransformation, with few side effects, and is particularly suitable for hypertensive patients with liver dysfunction. At present, lisinopril has become one of the first choice drugs for treating hypertension. Therefore, developing a process route with low production cost, stable product quality and international competitiveness is an urgent task to be solved in my country's production of ACEI drugs. The step of preparing lisinopril intermediates by catalytic hydrogenation plays a pivotal role in improving product yield and saving production costs, and the role of highly selective and stable catalysts is particularly important in this process.

[0003] Due to the technical bottleneck, the cost of lisinopril synthesis in China remains high, and it lacks competitiveness compared with similar products abroad. At present, the synthesis route of lisinopril at home and abroad is mainly to use ethyl benzoylacrylate as the starting material, and to react with trifluoroacetyl lysine under the action of lithium hydroxide to undergo an asymmetric addition reaction, and then to prepare it through Pd / C hydrogenation reduction, cyclization, condensation, hydrolysis and other reaction processes. It is the main method used in industrial production at present.

[0004] The main problems in the synthesis of lisinopril are harsh process conditions, high production costs, high impurity content, low product yield, low economic benefits, etc. The field of low-content, high-activity new catalysts has been widely studied and used abroad, but many fields in China still use traditional production processes, or use basic precious metal compounds as catalysts, which have low catalytic efficiency and high pollution, and it is difficult to achieve multiple reuse and recycling of catalysts. For example, the catalyst with Pd as the active component disclosed in the patent application document CN103506112 has the defects of high metal content, high cost and high cyclohexyl impurities. Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide a method for preparing a catalyst for synthesizing an intermediate of lisinopril in view of the deficiencies of the above-mentioned prior art. The method uses surface-modified activated carbon treated with nitrogen-containing compounds and phosphorus-containing compounds as a carrier, a precursor complex system containing active components and co-active components after complex reaction and pH adjustment as an impregnation liquid, and obtains a catalyst for synthesizing an intermediate of lisinopril through drum impregnation stabilization and reduction reaction. In the hydrogenation reaction process of N2-(1-ethoxycarbonyl-3-phenylpropanoyl)-N6-trifluoroacetyl-L-lysine, the catalyst has a raw material conversion rate of up to 99.8%, a product yield of up to 66.1%, an impurity content of as low as 0.24%, and has significantly improved catalytic reaction performance.

[0006] In order to solve the above technical problems, the technical solution adopted by the present invention is: a preparation method of a catalyst for synthesizing a lisinopril intermediate, characterized in that, in the preparation method, the raw materials include surface-modified activated carbon and a precursor complex containing an active component and an auxiliary agent, the active component is Pd, the auxiliary agent is two or more auxiliary metals, the auxiliary metal is Ni, Ru, Se or De, the mass of the active component is 6.0% to 6.5% of the mass of the catalyst, and the mass of the auxiliary metal is 0.05% to 1% of the mass of the catalyst;

[0007] The preparation method specifically comprises:

[0008] Step 1: Mix coconut shell activated carbon, deionized water and nitrogen-containing compounds, reflux at 80-100° C. for 3-5 hours, filter and dry to obtain a dried carrier;

[0009] Step 2: Mix the carrier, deionized water and phosphorus-containing compound after drying in step 1, stir and immerse at 20-25° C. for 10-15 hours, filter and dry to obtain surface-modified activated carbon;

[0010] Step 3: mixing a chloropalladic acid solution, an auxiliary metal soluble salt solution and deionized water to obtain a metal-containing mixed system, adding an aqueous solution of a complexing agent to the metal-containing mixed system at a temperature of 55 to 70° C. to obtain a metal-containing reaction system, and subjecting the metal-containing reaction system to a complexing reaction at 50 to 70° C. under ultrasonic conditions for 15 to 30 minutes to obtain a metal precursor complex system;

[0011] Step 4: adjusting the pH of the metal precursor complex system to 5-7, and stabilizing by ultrasound for 15-30 minutes to obtain a precursor complex system containing an active component and a co-active component;

[0012] Step 5, placing the surface-modified activated carbon in step 2 in an impregnation drum, placing the precursor complex system containing active components and co-active components in step 4 in an impregnation liquid transfer unit, and using a drum sprayer to spray the precursor complex system containing active components and co-active components onto the surface-modified activated carbon, stabilizing for 1 to 2 hours, and taking out to obtain a mixed material;

[0013] Step six, add deionized water, a buffer and a reducing agent to the mixed material in step five to obtain a carrier mixed slurry, carry out a stirring reduction reaction of the carrier mixed slurry at 60 to 100° C. for 30 to 40 minutes, filter, wash and dry the material after the stirring reduction reaction to obtain a catalyst for synthesizing a lisinopril intermediate.

[0014] The above-mentioned method for preparing a catalyst for synthesizing lisinopril intermediates is characterized in that, in step 1, the mass of the nitrogen-containing compound is 0.01 to 0.05 times the mass of coconut shell activated carbon, the nitrogen-containing compound is ethylenediamine or ammonium triacetate, the coconut shell activated carbon has a pore size of 2 to 4 nm, and a specific surface area of ​​800 to 1600 m 2 / g, and the drying is carried out at 90-120°C until the water content is less than 1wt%.

[0015] The above-mentioned method for preparing a catalyst for synthesizing an intermediate of lisinopril is characterized in that, in step 2, the mass of the phosphorus-containing compound is 0.01 to 0.05 times the mass of the coconut shell activated carbon in step 1, the phosphorus-containing compound is sodium dihydrogen phosphate or potassium dihydrogen phosphate, and the drying is carried out at 90 to 120° C. to a water content of <1wt%.

[0016] The above-mentioned method for preparing a catalyst for synthesizing a lisinopril intermediate is characterized in that, in step three, the complexing agent is citric acid, tartaric acid, ethylenediamine or ammonium triacetate, and the mass of the complexing agent is 3 to 6 times the mass of Pd and the mass of the auxiliary metal.

[0017] The above-mentioned method for preparing a catalyst for synthesizing a lisinopril intermediate is characterized in that, in step 4, the reagent for adjusting the pH is a sodium hydroxide solution, a sodium carbonate solution or a sodium bicarbonate solution.

[0018] The above-mentioned method for preparing a catalyst for synthesizing a lisinopril intermediate is characterized in that, in step five, the drum speed is 10 to 30 min / r, and the spraying rate is 0.5 to 1 ml / min.

[0019] The above-mentioned method for preparing a catalyst for synthesizing a lisinopril intermediate is characterized in that, in step six, the volume of the buffer is 0.5 to 1.0 times the mass of the catalyst for synthesizing a lisinopril intermediate, the volume of the buffer is in mL, and the mass of the catalyst is in g.

[0020] The above-mentioned method for preparing a catalyst for synthesizing a lisinopril intermediate is characterized in that, in step six, the mass of the reducing agent is 5 to 15 times the mass of Pd and the mass of the auxiliary metal.

[0021] The above-mentioned method for preparing a catalyst for synthesizing a lisinopril intermediate is characterized in that, in step six, the drying temperature is 90 to 120°C.

[0022] The above-mentioned method for preparing a catalyst for synthesizing a lisinopril intermediate is characterized in that, in step six, the buffer is a sodium bicarbonate solution or a sodium acetate solution, and the reducing agent is formaldehyde, potassium borohydride, sodium borohydride or formic acid.

[0023] Compared with the prior art, the present invention has the following advantages:

[0024] 1. The preparation method of the catalyst for synthesizing lisinopril intermediate of the present invention uses surface-modified activated carbon treated with nitrogen-containing compounds and phosphorus-containing compounds as a carrier, a precursor complex system containing active components and co-active components after complex reaction and pH adjustment as an impregnation liquid, and obtains a catalyst for synthesizing lisinopril intermediate by drum impregnation stabilization and reduction reaction. In the process of hydrogenation reaction of N2-(1-ethoxycarbonyl-3-phenylpropanoyl)-N6-trifluoroacetyl-L-lysine, the catalyst has a raw material conversion rate of up to 99.8%, a product yield of up to 66.1%, an impurity content of as low as 0.24%, and has significantly improved catalytic reaction performance.

[0025] 2. The preparation method of the catalyst for synthesizing lisinopril intermediates of the present invention includes a secondary modification treatment of activated carbon with N and P, which can effectively increase the specific surface area of ​​the carrier, improve the internal microporous structure, and make the precursor complex of the loaded active component and auxiliary agent firmly adsorbed on the carrier, with higher stability in use and less prone to metal component shedding.

[0026] 3. The preparation method of the catalyst for synthesizing lisinopril intermediate of the present invention comprises using a precursor complex system containing active components and auxiliary active components after complex reaction and pH adjustment as an impregnation liquid, and the alkaline nitrogen-containing and phosphorus-containing centers on the surface of the carrier activated carbon chelate palladium metal ions and auxiliary metal ions, so that the metal particles are evenly distributed inside and outside the pores of the activated carbon, and the particle size and distribution can be effectively controlled to avoid agglomeration, and the metal particles are firmly adsorbed on the surface of the activated carbon.

[0027] 4. The preparation method of the catalyst for synthesizing lisinopril intermediates of the present invention comprises using a precursor complex system containing active components and auxiliary active components after complex reaction and pH adjustment as an impregnation liquid, and spraying and impregnating the activated carbon placed in a rotating drum body, so that the precursor complex of the active component and the auxiliary agent can be fully adsorbed on the pore surface of the activated carbon carrier, with higher uniformity, stronger catalytic activity and stability.

[0028] 5. The preparation method of the catalyst for synthesizing lisinopril intermediate of the present invention has common and easily available raw materials, simple operation, easy industrialization, and high promotion and application value.

[0029] The technical solution of the present invention is further described in detail below in conjunction with embodiments. DETAILED DESCRIPTION

[0030] Example 1

[0031] The present embodiment provides a method for preparing a catalyst for synthesizing an intermediate of lisinopril. In the preparation method, the raw materials include surface-modified activated carbon and a precursor complex containing an active component and an auxiliary agent. In the precursor complex containing the active component and the auxiliary agent, the active component is Pd, and the mass of the active component is 6.0% of the mass of the catalyst. The auxiliary agents are Ni and Ru, and the mass of Ni and the mass of Ru are both 0.05% of the mass of the catalyst.

[0032] The preparation method specifically comprises:

[0033] Step 1: 20g of pore size 2nm, specific surface area 1000m 2 / g coconut shell activated carbon was placed in 200ml deionized water, 0.2g ammonium triacetate was added, and the mixture was refluxed at 90°C for 3h, filtered, and dried at 120°C until the water content was <1wt%, to obtain a dried carrier;

[0034] Step 2: Place the carrier dried in step 1 in 200 ml of deionized water, add 0.2 g of sodium dihydrogen phosphate, stir and immerse at 20-25° C. for 10 h, filter, and dry at 120° C. until the water content is less than 1 wt %, to obtain surface-modified activated carbon;

[0035] Step 3: Mix 24 mL of a 0.05 g / mL palladium chloropalladic acid solution, 0.2 mL of a 0.05 g / mL Ru chloride solution, and 0.2 mL of a 0.05 g / mL Ni chloride solution, add deionized water and dilute to 50 mL to obtain a metal-containing mixed system, and at a temperature of 55° C., dropwise add 36.6 mL of a 0.1 g / mL citric acid aqueous solution to the metal-containing mixed system to obtain a metal-containing reaction system, and subject the metal-containing reaction system to a complexation reaction at 55° C. under ultrasonic conditions for 15 min to obtain a metal precursor complex system;

[0036] Step 4: adjusting the pH of the metal precursor complex system to 5 with a 5% by mass NaOH solution, and stabilizing the system with ultrasound for 15 minutes to obtain a precursor complex system containing an active component and a co-active component;

[0037] Step 5: placing 18.78 g of the surface-modified activated carbon obtained in step 2 in the impregnation drum body, placing the precursor complex system containing the active component and the auxiliary active component in step 4 in the impregnation liquid transfer unit, and spraying the precursor complex system containing the active component and the auxiliary active component onto the surface-modified activated carbon using a drum nozzle, stabilizing for 1 hour, and taking out to obtain a mixed material; the drum speed is 10 min / r, and the spraying rate is 0.5 ml / min; the impregnation drum is purchased from Xi'an Jinzhuo Machinery Manufacturing Co., Ltd.;

[0038] Step six, add 200 ml of deionized water, 10 ml of 10% NaHCO3 solution and 6.1 ml of formaldehyde to the mixed material in step five to obtain a carrier mixed slurry, and carry out a stirring reduction reaction of the carrier mixed slurry at 65° C. for 30 min. The material after the stirring reduction reaction is filtered, washed, and dried at 120° C. to a water content of <1wt%, to obtain a catalyst for synthesizing lisinopril intermediates.

[0039] Example 2

[0040] The present embodiment provides a method for preparing a catalyst for synthesizing an intermediate of lisinopril. In the preparation method, the raw materials include surface-modified activated carbon and a precursor complex containing an active component and an auxiliary agent. In the precursor complex containing the active component and the auxiliary agent, the active component is Pd, and the mass of the active component is 6.05% of the mass of the catalyst. The auxiliary agents are Ni and Se, and the mass of Ni and the mass of Se are 1% and 0.05% of the mass of the catalyst, respectively.

[0041] The preparation method specifically comprises:

[0042] Step 1: 20g of pore size 2nm, specific surface area 1100m 2 / g coconut shell activated carbon was placed in 200ml deionized water, 0.3g ethylenediamine was added, and the mixture was refluxed at 95°C for 3h, filtered, and dried at 110°C until the water content was <1wt%, to obtain a dried carrier;

[0043] Step 2: Place the carrier dried in step 1 in 200 ml of deionized water, add 0.3 g of sodium dihydrogen phosphate, stir and immerse at 20-25° C. for 11 h, filter, and dry at 120° C. until the water content is less than 1 wt %, to obtain surface-modified activated carbon;

[0044] Step 3: Mix 24.2 mL of a 0.05 g / mL palladium chloropalladic acid solution, 4 mL of a 0.05 g / mL nickel chloride solution, and 0.2 mL of a 0.05 g / mL Se selenium oxide solution, add deionized water and dilute to 50 mL to obtain a metal-containing mixed system, and at 60° C., dropwise add 36.9 mL of a 0.1 g / mL tartaric acid aqueous solution to the metal-containing mixed system to obtain a metal-containing reaction system, and subject the metal-containing reaction system to a complexation reaction at 60° C. under ultrasonic conditions for 15 min to obtain a metal precursor complex system;

[0045] Step 4: adjusting the pH of the metal precursor complex system to 6 with a 5% by mass NaOH solution, and stabilizing the system with ultrasound for 15 minutes to obtain a precursor complex system containing an active component and a co-active component;

[0046] Step 5: placing 18.58 g of the surface-modified activated carbon obtained in step 2 in the impregnation drum body, placing the precursor complex system containing the active component and the auxiliary active component in step 4 in the impregnation liquid transfer unit, and spraying the precursor complex system containing the active component and the auxiliary active component onto the surface-modified activated carbon using a drum nozzle, stabilizing for 1 hour, and taking out to obtain a mixed material; the drum speed is 10 min / r, and the spraying rate is 0.5 ml / min;

[0047] Step six, add 200 ml of deionized water, 15 ml of 10% NaHCO3 solution and 6.15 ml of formaldehyde to the mixed material in step five to obtain a carrier mixed slurry, and carry out a stirring reduction reaction of the carrier mixed slurry at 60° C. for 30 min. The material after the stirring reduction reaction is filtered, washed, and dried at 120° C. to a water content of <1wt%, to obtain a catalyst for synthesizing lisinopril intermediates.

[0048] Example 3

[0049] The present embodiment provides a method for preparing a catalyst for synthesizing an intermediate of lisinopril. In the preparation method, the raw materials include surface-modified activated carbon and a precursor complex containing an active component and an auxiliary agent. In the precursor complex containing the active component and the auxiliary agent, the active component is Pd, and the mass of the active component is 6.05% of the mass of the catalyst. The auxiliary agents are Ru and Se, and the mass of Ru and the mass of Se are 1.0% and 0.05% of the mass of the catalyst, respectively.

[0050] The preparation method specifically comprises:

[0051] Step 1: 20g of pore size 3nm, specific surface area 1300m 2 / g coconut shell activated carbon was placed in 200ml deionized water, 0.4g ammonium triacetate was added, the mixture was refluxed at 95°C for 4h, filtered, and dried at 120°C until the water content was <1wt%, to obtain a dried carrier;

[0052] Step 2: Place the carrier dried in step 1 in 200 ml of deionized water, add 0.4 g of potassium dihydrogen phosphate, stir and immerse at 20-25° C. for 12 h, filter, and dry at 100° C. until the water content is less than 1 wt %, to obtain surface-modified activated carbon;

[0053] Step 3: Mix 24.2 mL of a 0.05 g / mL palladium chloropalladic acid solution, 4 mL of a 0.05 g / mL Ru chloride solution, and 0.2 mL of a 0.05 g / mL Se selenium oxide solution, add deionized water and dilute to 50 mL to obtain a metal-containing mixed system, and at 60° C., dropwise add 49.7 mL of a 0.1 g / mL tartaric acid aqueous solution to the metal-containing mixed system to obtain a metal-containing reaction system, and subject the metal-containing reaction system to a complexation reaction at 60° C. for 20 min under ultrasonic conditions to obtain a metal precursor complex system;

[0054] Step 4: adjusting the pH of the metal precursor complex system to 6.0 with a 5% by mass Na2CO3 solution, and stabilizing it by ultrasound for 20 minutes to obtain a precursor complex system containing an active component and a co-active component;

[0055] Step 5: placing 18.58 g of the surface-modified activated carbon obtained in step 2 in the impregnation drum body, placing the precursor complex system containing the active component and the auxiliary active component in step 4 in the impregnation liquid transfer unit, and spraying the precursor complex system containing the active component and the auxiliary active component onto the surface-modified activated carbon using a drum nozzle, stabilizing for 1 hour, and taking out to obtain a mixed material; the drum speed is 15 min / r, and the spraying rate is 0.7 ml / min;

[0056] Step six, add 200 ml of deionized water, 15 ml of 10% NaHCO3 solution and 7.38 g of potassium borohydride to the mixed material in step five to obtain a carrier mixed slurry, and carry out a stirring reduction reaction of the carrier mixed slurry at 70° C. for 30 min. The material after the stirring reduction reaction is filtered, washed, and dried at 120° C. to a water content of <1wt% to obtain a catalyst for synthesizing lisinopril intermediates.

[0057] Example 4

[0058] The present embodiment provides a method for preparing a catalyst for synthesizing an intermediate of lisinopril. In the preparation method, the raw materials include surface-modified activated carbon and a precursor complex containing an active component and an auxiliary agent. In the precursor complex containing the active component and the auxiliary agent, the active component is Pd, and the mass of the active component is 6.2% of the mass of the catalyst. The auxiliary agents are Ni and De, and the mass of Ni and the mass of De are both 0.05% of the mass of the catalyst.

[0059] The preparation method specifically comprises:

[0060] Step 1: 20g of pore size 4nm, specific surface area 1300m 2 / g coconut shell activated carbon was placed in 200ml deionized water, 0.6g ammonium triacetate was added, and the mixture was refluxed at 100°C for 3h, filtered, and dried at 120°C until the water content was <1wt%, to obtain a dried carrier;

[0061] Step 2: Place the carrier dried in step 1 in 200 ml of deionized water, add 0.5 g of sodium dihydrogen phosphate, stir and immerse at 20-25° C. for 15 h, filter, and dry at 120° C. until the water content is less than 1 wt %, to obtain surface-modified activated carbon;

[0062] Step 3: Mix 24.8 mL of a 0.05 g / mL palladium chloropalladic acid solution, 0.2 mL of a 0.05 g / mL nickel chloride solution, and 0.2 mL of a 0.05 g / mL De tellurium oxide solution, add deionized water and dilute to 50 mL to obtain a metal-containing mixed system, and at 60 ° C, dropwise add 50.4 mL of a 0.1 g / mL tartaric acid aqueous solution to the metal-containing mixed system to obtain a metal-containing reaction system, and subject the metal-containing reaction system to a complex reaction at 60 ° C under ultrasonic conditions for 20 min to obtain a metal precursor complex system;

[0063] Step 4: adjusting the pH of the metal precursor complex system to 6.0 with a 5% by mass Na2CO3 solution, and stabilizing it by ultrasound for 20 minutes to obtain a precursor complex system containing an active component and a co-active component;

[0064] Step 5: placing 18.74 g of the surface-modified activated carbon obtained in step 2 in the impregnation drum body, placing the precursor complex system containing the active component and the auxiliary active component in step 4 in the impregnation liquid transfer unit, and spraying the precursor complex system containing the active component and the auxiliary active component onto the surface-modified activated carbon using a drum nozzle, stabilizing for 1 hour, and taking out to obtain a mixed material; the drum speed is 15 min / r, and the spraying rate is 0.7 ml / min;

[0065] Step six, add 200 ml of deionized water, 15 ml of 10% NaHCO3 solution and 7.38 g of potassium borohydride to the mixed material in step five to obtain a carrier mixed slurry, and carry out a stirring reduction reaction of the carrier mixed slurry at 70° C. for 30 min. The material after the stirring reduction reaction is filtered, washed, and dried at 120° C. to a water content of <1wt% to obtain a catalyst for synthesizing lisinopril intermediates.

[0066] Example 5

[0067] The present embodiment provides a method for preparing a catalyst for synthesizing an intermediate of lisinopril. In the preparation method, the raw materials include surface-modified activated carbon and a precursor complex containing an active component and an auxiliary agent. In the precursor complex containing the active component and the auxiliary agent, the active component is Pd, and the mass of the active component is 6.2% of the mass of the catalyst. The auxiliary agents are Ru and De, and the mass of De and the mass of Ru are both 0.5% of the mass of the catalyst.

[0068] The preparation method specifically comprises:

[0069] Step 1: 20g of pore size 3nm, specific surface area 1500m 2 / g coconut shell activated carbon was placed in 200ml deionized water, 0.4ml ethylenediamine was added, and the mixture was refluxed at 80°C for 4h, filtered, and dried at 120°C until the water content was <1wt%, to obtain a dried carrier;

[0070] Step 2: Place the carrier dried in step 1 in 200 ml of deionized water, add 0.8 g of sodium dihydrogen phosphate, stir and immerse at 20-25° C. for 12 h, filter, and dry at 100° C. until the water content is less than 1 wt %, to obtain surface-modified activated carbon;

[0071] Step 3: Mix 24.8 mL of a 0.05 g / mL palladium chloropalladic acid solution, 2 mL of a 0.05 g / mL De tellurium oxide solution, and 2 mL of a 0.05 g / mL Ru ruthenium trichloride solution, add deionized water and dilute to 50 mL to obtain a metal-containing mixed system, and at 70° C., dropwise add 72 mL of a 0.1 g / mL ethylenediamine aqueous solution to the metal-containing mixed system to obtain a metal-containing reaction system, and subject the metal-containing reaction system to a complexation reaction at 70° C. for 20 min under ultrasonic conditions to obtain a metal precursor complex system;

[0072] Step 4: adjusting the pH of the metal precursor complex system to 6.0 with a 5% by mass NaHCO3 solution, and stabilizing it by ultrasound for 30 minutes to obtain a precursor complex system containing an active component and a co-active component;

[0073] Step 5: placing 18.56 g of the surface-modified activated carbon obtained in step 2 into the impregnation drum body, placing the precursor complex system containing the active component and the auxiliary active component in step 4 into the impregnation liquid transfer unit, and spraying the precursor complex system containing the active component and the auxiliary active component onto the surface-modified activated carbon using a drum nozzle, stabilizing for 1.5 hours, and taking out to obtain a mixed material; the drum speed is 20 min / r, and the spraying rate is 0.8 ml / min;

[0074] Step 6: Add 200 ml of deionized water, 20 ml of a 10% NaAC solution and 8.75 g of sodium borohydride to the mixed material in step 5 to obtain a carrier mixed slurry, and perform a stirring reduction reaction on the carrier mixed slurry at 60° C. for 30 min. After the stirring reduction reaction, the material is filtered, washed, and dried at 120° C. to a water content of <1 wt% to obtain a catalyst for synthesizing a lisinopril intermediate.

[0075] Example 6

[0076] The present embodiment provides a method for preparing a catalyst for synthesizing an intermediate of lisinopril. In the preparation method, the raw materials include surface-modified activated carbon and a precursor complex containing an active component and an auxiliary agent. In the precursor complex containing the active component and the auxiliary agent, the active component is Pd, and the mass of the active component is 6.3% of the mass of the catalyst. The auxiliary agents are Ru and Ni, and the mass of Ru and the mass of Ni are both 0.5% of the mass of the catalyst.

[0077] The preparation method specifically comprises:

[0078] Step 1: 20g of pore size 3nm, specific surface area 1400m 2 / g coconut shell activated carbon was placed in 200ml deionized water, 0.7g ammonium triacetate was added, and the mixture was refluxed at 100°C for 4h, filtered, and dried at 120°C until the water content was <1wt%, to obtain a dried carrier;

[0079] Step 2: Place the carrier dried in step 1 in 200 ml of deionized water, add 0.6 g of potassium dihydrogen phosphate, stir and immerse at 20-25° C. for 14 h, filter, and dry at 120° C. until the water content is less than 1 wt %, to obtain surface-modified activated carbon;

[0080] Step 3: Mix 25.2 mL of a 0.05 g / mL palladium chloropalladic acid solution, 2 mL of a 0.05 g / mL Ru chloride solution, and 2 mL of a 0.05 g / mL Ni chloride solution, add deionized water and dilute to 51.1 mL to obtain a metal-containing mixed system, and at 65° C., dropwise add 51.1 mL of a 0.1 g / mL tartaric acid aqueous solution to the metal-containing mixed system to obtain a metal-containing reaction system, and subject the metal-containing reaction system to a complexation reaction at 65° C. for 20 min under ultrasonic conditions to obtain a metal precursor complex system;

[0081] Step 4: adjusting the pH of the metal precursor complex system to 6.5 with a 5% by mass Na2CO3 solution, and stabilizing it by ultrasound for 20 minutes to obtain a precursor complex system containing an active component and a co-active component;

[0082] Step 5: placing 18.54 g of the surface-modified activated carbon obtained in step 2 in the impregnation drum body, placing the precursor complex system containing the active component and the auxiliary active component in step 4 in the impregnation liquid transfer unit, and spraying the precursor complex system containing the active component and the auxiliary active component onto the surface-modified activated carbon using a drum nozzle, stabilizing for 2 hours, and taking out to obtain a mixed material; the drum speed is 15 min / r, and the spraying rate is 0.6 ml / min;

[0083] Step six, add 200 ml of deionized water, 15 ml of 10% NaAC solution and 8.75 g of potassium borohydride to the mixed material in step five to obtain a carrier mixed slurry, and carry out a stirring reduction reaction of the carrier mixed slurry at 70 ° C for 30 min, and filter, wash and dry the material after the stirring reduction reaction at 120 ° C to a water content of <1wt% to obtain a catalyst for synthesizing lisinopril intermediates.

[0084] Example 7

[0085] The present embodiment provides a method for preparing a catalyst for synthesizing an intermediate of lisinopril. In the preparation method, the raw materials include surface-modified activated carbon and a precursor complex containing an active component and an auxiliary agent. In the precursor complex containing the active component and the auxiliary agent, the active component is Pd, and the mass of the active component is 6.3% of the mass of the catalyst. The auxiliary agents are De and Se, and the mass of De and the mass of Se are both 0.5% of the mass of the catalyst.

[0086] The preparation method specifically comprises:

[0087] Step 1: 20g of pore size 4nm, specific surface area 1500m 2 / g coconut shell activated carbon was placed in 200ml deionized water, 0.8ml ethylenediamine was added, and the mixture was refluxed at 90°C for 4h, filtered, and dried at 120°C until the water content was <1wt%, to obtain a dried carrier;

[0088] Step 2: Place the carrier dried in step 1 in 200 ml of deionized water, add 1.0 g of potassium dihydrogen phosphate, stir and immerse at 20-25° C. for 15 h, filter, and dry at 120° C. until the water content is less than 1 wt %, to obtain surface-modified activated carbon;

[0089] Step 3: Mix 25.2 mL of a 0.05 g / mL palladium chloropalladic acid solution, 2 mL of a 0.05 g / mL De tellurium oxide solution, and 2 mL of a 0.05 g / mL Se selenium oxide solution, add deionized water and dilute to 50 mL to obtain a metal-containing mixed system, and dropwise add 58.4 mL of a 0.1 g / mL tartaric acid aqueous solution to the metal-containing mixed system at 70° C. to obtain a metal-containing reaction system, and subject the metal-containing reaction system to a complexation reaction at 70° C. for 20 min under ultrasonic conditions to obtain a metal precursor complex system;

[0090] Step 4: adjusting the pH of the metal precursor complex system to 6.5 with a 5% by mass NaHCO3 solution, and stabilizing it by ultrasound for 30 minutes to obtain a precursor complex system containing an active component and a co-active component;

[0091] Step 5: placing 18.54 g of the surface-modified activated carbon obtained in step 2 in an impregnation drum, placing the precursor complex system containing active components and auxiliary active components in step 4 in an impregnation liquid transfer unit, and spraying the precursor complex system containing active components and auxiliary active components onto the surface-modified activated carbon using a drum nozzle, stabilizing for 1.5 hours, and taking out to obtain a mixed material; the drum speed is 20 min / r, and the spraying rate is 0.8 ml / min;

[0092] Step 6: Add 200 ml of deionized water, 20 ml of a 10% NaAC solution and 8.0 g of sodium borohydride to the mixed material in step 5 to obtain a carrier mixed slurry, and subject the carrier mixed slurry to a stirring reduction reaction at 70 ° C for 30 min. The material after the stirring reduction reaction is filtered, washed, and dried at 120 ° C to a water content of <1 wt% to obtain a catalyst for synthesizing a lisinopril intermediate.

[0093] Example 8

[0094] The present embodiment provides a method for preparing a catalyst for synthesizing an intermediate of lisinopril. In the preparation method, the raw materials include surface-modified activated carbon and a precursor complex containing an active component and an auxiliary agent. In the precursor complex containing the active component and the auxiliary agent, the active component is Pd, and the mass of the active component is 6.5% of the mass of the catalyst. The auxiliary agents are De and Se, and the mass of De and the mass of Se are both 1% of the mass of the catalyst.

[0095] The preparation method specifically comprises:

[0096] Step 1: 20g of pore size 4nm, specific surface area 1300m 2 / g coconut shell activated carbon was placed in 200ml deionized water, 1.0ml ethylenediamine was added, and the mixture was refluxed at 100°C for 4h, filtered, and dried at 100°C until the water content was <1wt%, to obtain a dried carrier;

[0097] Step 2: Place the carrier dried in step 1 in 200 ml of deionized water, add 1.0 g of sodium dihydrogen phosphate, stir and immerse at 20-25° C. for 10 h, filter, and dry at 100° C. until the water content is less than 1 wt %, to obtain surface-modified activated carbon;

[0098] Step 3: Mix 26 mL of a 0.05 g / mL palladium chloropalladic acid solution, 4 mL of a 0.05 g / mL De tellurium oxide solution, and 4 mL of a 0.05 g / mL Se selenium oxide solution, add deionized water and dilute to 50 mL to obtain a metal-containing mixed system, and at 70° C., dropwise add 68 mL of a 0.1 g / mL tartaric acid aqueous solution to the metal-containing mixed system to obtain a metal-containing reaction system, and subject the metal-containing reaction system to a complex reaction at 70° C. under ultrasonic conditions for 20 min to obtain a metal precursor complex system;

[0099] Step 4: adjusting the pH of the metal precursor complex system to 6.5 with a 5% by mass NaHCO3 solution, and stabilizing it by ultrasound for 30 minutes to obtain a precursor complex system containing an active component and a co-active component;

[0100] Step 5: placing 18.3 g of the surface-modified activated carbon obtained in step 2 in the impregnation drum body, placing the precursor complex system containing the active component and the auxiliary active component in step 4 in the impregnation liquid transfer unit, and spraying the precursor complex system containing the active component and the auxiliary active component onto the surface-modified activated carbon using a drum nozzle, stabilizing for 1.5 hours, and taking out to obtain a mixed material; the drum speed is 20 min / r, and the spraying rate is 0.8 ml / min;

[0101] Step 6: Add 200 ml of deionized water, 20 ml of a 10% NaAC solution and 25 g of sodium borohydride to the mixed material in step 5 to obtain a carrier mixed slurry, and subject the carrier mixed slurry to a stirring reduction reaction at 70 ° C for 30 min. After the stirring reduction reaction, the material is filtered, washed, and dried at 120 ° C to a water content of <1 wt% to obtain a catalyst for synthesizing a lisinopril intermediate.

[0102] Example 9

[0103] The present embodiment provides a method for preparing a catalyst for synthesizing an intermediate of lisinopril. In the preparation method, the raw materials include surface-modified activated carbon and a precursor complex containing an active component and an auxiliary agent. In the precursor complex containing the active component and the auxiliary agent, the active component is Pd, and the mass of the active component is 6.5% of the mass of the catalyst. The auxiliary agents are Ru and Ni, and the mass of Ni and the mass of Ru are both 1% of the mass of the catalyst.

[0104] The preparation method specifically comprises:

[0105] Step 1: 20g of pore size 4nm, specific surface area 1100m 2 / g coconut shell activated carbon was placed in 200ml deionized water, 0.8g ammonium triacetate was added, and the mixture was refluxed at 100°C for 3.5h, filtered, and dried at 110°C until the water content was <1wt%, to obtain a dried carrier;

[0106] Step 2: Place the carrier dried in step 1 in 200 ml of deionized water, add 0.6 g of potassium dihydrogen phosphate, stir and immerse at 20-25° C. for 15 h, filter, and dry at 110° C. until the water content is less than 1 wt %, to obtain surface-modified activated carbon;

[0107] Step 3: Mix 26 mL of a 0.05 g / mL palladium chloropalladic acid solution, 4 mL of a 0.05 g / mL Ru chloride solution, and 4 mL of a 0.05 g / mL Ni chloride solution, add deionized water and dilute to 50 mL to obtain a metal-containing mixed system, and at 65 ° C, dropwise add 76.5 mL of a 0.1 g / mL ammonium triacetate aqueous solution to the metal-containing mixed system to obtain a metal-containing reaction system, and subject the metal-containing reaction system to a complex reaction at 65 ° C under ultrasonic conditions for 30 min to obtain a metal precursor complex system;

[0108] Step 4: adjusting the pH of the metal precursor complex system to 6.5 with a 5% by mass NaCO3 solution, and stabilizing by ultrasound for 30 minutes to obtain a precursor complex system containing an active component and a co-active component;

[0109] Step 5: Place 18.3 g of the surface-modified activated carbon obtained in step 2 in the impregnation drum body, place the precursor complex system containing the active component and the auxiliary active component in step 4 in the impregnation liquid transfer unit, and use the drum nozzle to spray the precursor complex system containing the active component and the auxiliary active component onto the surface-modified activated carbon, stabilize for 2 hours, and take out to obtain a mixed material; the drum speed is 25 min / r, and the spraying rate is 0.5 ml / min;

[0110] Step 6: Add 200 ml of deionized water, 15 ml of a 10% NaAC solution and 15 ml of formic acid to the mixed material in step 5 to obtain a carrier mixed slurry, and subject the carrier mixed slurry to a stirring reduction reaction at 80 ° C for 30 min. After the stirring reduction reaction, the material is filtered, washed, and dried at 120 ° C to a water content of <1wt% to obtain a catalyst for synthesizing lisinopril intermediates.

[0111] Example 10

[0112] The present embodiment provides a method for preparing a catalyst for synthesizing an intermediate of lisinopril. In the preparation method, the raw materials include surface-modified activated carbon and a precursor complex containing an active component and an auxiliary agent. In the precursor complex containing the active component and the auxiliary agent, the active component is Pd, and the mass of the active component is 6.5% of the mass of the catalyst. The auxiliary agents are Ru and Se, and the mass of Ru and the mass of Se are 0.1% and 1% of the mass of the catalyst, respectively.

[0113] The preparation method specifically comprises:

[0114] Step 1: 20g of pore size 3.5nm, specific surface area 1100m 2 / g coconut shell activated carbon was placed in 200ml deionized water, 0.8ml ethylenediamine was added, and the mixture was refluxed at 90°C for 3.5h, filtered, and dried at 120°C until the water content was <1wt%, to obtain a dried carrier;

[0115] Step 2: Place the carrier dried in step 1 in 200 ml of deionized water, add 1.0 g of sodium dihydrogen phosphate, stir and immerse at 20-25° C. for 15 h, filter, and dry at 100° C. until the water content is less than 1 wt %, to obtain surface-modified activated carbon;

[0116] Step 3: Mix 26 mL of a 0.05 g / mL palladium chloropalladic acid solution, 0.4 mL of a 0.05 g / mL Ru chloride solution, and 4 mL of a 0.05 g / mL Se selenium oxide solution, add deionized water and dilute to 50 mL to obtain a metal-containing mixed system, and at 50° C., dropwise add 76 mL of a 0.1 g / mL citric acid aqueous solution to the metal-containing mixed system to obtain a metal-containing reaction system, and subject the metal-containing reaction system to a complexation reaction at 50° C. for 30 min under ultrasonic conditions to obtain a metal precursor complex system;

[0117] Step 4: adjusting the pH of the metal precursor complex system to 7.0 with a 5% by mass NaCO3 solution, and stabilizing it by ultrasound for 30 minutes to obtain a precursor complex system containing an active component and a co-active component;

[0118] Step 5: placing 18.48 g of the surface-modified activated carbon obtained in step 2 in the impregnation drum body, placing the precursor complex system containing the active component and the auxiliary active component in step 4 in the impregnation liquid transfer unit, and spraying the precursor complex system containing the active component and the auxiliary active component onto the surface-modified activated carbon using a drum nozzle, stabilizing for 2 hours, and taking out to obtain a mixed material; the drum speed is 25 min / r, and the spraying rate is 0.5 ml / min;

[0119] Step six, add 200 ml of deionized water, 15 ml of 10% NaHCO3 solution and 13.2 ml of formaldehyde to the mixed material in step five to obtain a carrier mixed slurry, and carry out a stirring reduction reaction of the carrier mixed slurry at 90° C. for 30 min. The material after the stirring reduction reaction is filtered, washed, and dried at 120° C. to a water content of <1wt%, to obtain a catalyst for synthesizing lisinopril intermediates.

[0120] Embodiment 11

[0121] The present embodiment provides a method for preparing a catalyst for synthesizing an intermediate of lisinopril. In the preparation method, the raw materials include surface-modified activated carbon and a precursor complex containing an active component and an auxiliary agent. In the precursor complex containing the active component and the auxiliary agent, the active component is Pd, and the mass of the active component is 6.05% of the mass of the catalyst. The auxiliary agents are Ni, Se and Ru, and the mass of Ni is 0.5% of the mass of the catalyst, the mass of Se is 0.5% of the mass of the catalyst, and the mass of Ru is 0.05% of the mass of the catalyst.

[0122] The preparation method specifically comprises:

[0123] Step 1: 20g of pore size 2nm, specific surface area 800m 2 / g coconut shell activated carbon was placed in 200ml deionized water, 0.3g ethylenediamine was added, and the mixture was refluxed at 95°C for 5h, filtered, and dried at 90°C until the water content was <1wt%, to obtain a dried carrier;

[0124] Step 2: Place the carrier dried in step 1 in 200 ml of deionized water, add 0.3 g of sodium dihydrogen phosphate, stir and immerse at 20-25° C. for 11 h, filter, and dry at 90° C. until the water content is less than 1 wt %, to obtain surface-modified activated carbon;

[0125] Step 3: Mix 24.2 mL of a 0.05 g / mL palladium chloropalladic acid solution, 2 mL of a 0.05 g / mL Ni chloride solution, 2 mL of a 0.05 g / mL Se selenium oxide solution, and 0.2 mL of a 0.05 g / mL Ru chloride solution, add deionized water and dilute to 50 mL to obtain a metal-containing mixed system, and at 60° C., dropwise add 71 mL of a 0.1 g / mL tartaric acid aqueous solution to the metal-containing mixed system to obtain a metal-containing reaction system, and subject the metal-containing reaction system to a complexation reaction at 60° C. under ultrasonic conditions for 15 min to obtain a metal precursor complex system;

[0126] Step 4: adjusting the pH of the metal precursor complex system to 6 with a 5% by mass NaOH solution, and stabilizing the system with ultrasound for 15 minutes to obtain a precursor complex system containing an active component and a co-active component;

[0127] Step 5: placing 18.58 g of the surface-modified activated carbon obtained in step 2 into an impregnation drum, placing the precursor complex system containing active components and auxiliary active components in step 4 into an impregnation liquid transfer unit, and spraying the precursor complex system containing active components and auxiliary active components onto the surface-modified activated carbon using a drum nozzle, stabilizing for 1 hour, and taking out to obtain a mixed material; the drum speed is 30 min / r, and the spraying rate is 1 ml / min;

[0128] Step six, add 200 ml of deionized water, 15 ml of 10% NaHCO3 solution and 6.15 ml of formaldehyde to the mixed material in step five to obtain a carrier mixed slurry, and carry out a stirring reduction reaction of the carrier mixed slurry at 100° C. for 40 min. The material after the stirring reduction reaction is filtered, washed, and dried at 90° C. to a water content of <1wt%, to obtain a catalyst for synthesizing lisinopril intermediates.

[0129] Example 12

[0130] The present embodiment provides a method for preparing a catalyst for synthesizing an intermediate of lisinopril. In the preparation method, the raw materials include surface-modified activated carbon and a precursor complex containing an active component and an auxiliary agent. In the precursor complex containing the active component and the auxiliary agent, the active component is Pd, and the mass of the active component is 6.5% of the mass of the catalyst. The auxiliary agents are Ni, Se, Ru and De, and the mass of Ni is 0.5% of the mass of the catalyst, the mass of Se is 0.5% of the mass of the catalyst, the mass of Ru is 0.05% of the mass of the catalyst, and the mass of De is 0.05% of the mass of the catalyst.

[0131] The preparation method specifically comprises:

[0132] Step 1: 20g of pore size 2nm, specific surface area 1600m 2 / g coconut shell activated carbon was placed in 200ml deionized water, 0.3g ethylenediamine was added, and the mixture was refluxed at 95°C for 4h, filtered, and dried at 100°C until the water content was less than 1wt%, to obtain a dried carrier;

[0133] Step 2: Place the carrier dried in step 1 in 200 ml of deionized water, add 0.3 g of sodium dihydrogen phosphate, stir and immerse at 20-25° C. for 11 h, filter, and dry at 100° C. until the water content is less than 1 wt %, to obtain surface-modified activated carbon;

[0134] Step 3: 26 mL of 0.05 g / mL palladium chloropalladic acid solution, 2 mL of 0.05 g / mL nickel chloride solution, 2 mL of 0.05 g / mL Se selenium oxide solution, 0.2 mL of 0.05 g / mL Ru trichloride solution and 0.2 mL of 0.05 g / mL De tellurium oxide solution were mixed, deionized water was added and the volume was adjusted to 50 mL to obtain a metal-containing mixed system, and 90.8 mL of 0.1 g / mL tartaric acid aqueous solution was added dropwise to the metal-containing mixed system at 60 ° C to obtain a metal-containing reaction system, and the metal-containing reaction system was subjected to complexation reaction at 60 ° C under ultrasonic conditions for 15 min to obtain a metal precursor complex system;

[0135] Step 4: adjusting the pH of the metal precursor complex system to 6 with a 5% by mass NaOH solution, and stabilizing the system with ultrasound for 15 minutes to obtain a precursor complex system containing an active component and a co-active component;

[0136] Step 5: placing 18.48 g of the surface-modified activated carbon obtained in step 2 in the impregnation drum body, placing the precursor complex system containing the active component and the auxiliary active component in step 4 in the impregnation liquid transfer unit, and spraying the precursor complex system containing the active component and the auxiliary active component onto the surface-modified activated carbon using a drum nozzle, stabilizing for 1 hour, and taking out to obtain a mixed material; the drum speed is 30 min / r, and the spraying rate is 1 ml / min;

[0137] Step six, add 200 ml of deionized water, 15 ml of 10% NaHCO3 solution and 6.15 ml of formaldehyde to the mixed material in step five to obtain a carrier mixed slurry, and carry out a stirring reduction reaction of the carrier mixed slurry at 100° C. for 35 min. The material after the stirring reduction reaction is filtered, washed, and dried at 100° C. to a water content of <1wt%, to obtain a catalyst for synthesizing lisinopril intermediates.

[0138] Comparative Example 1

[0139] This comparative example provides a method for preparing a catalyst for synthesizing a lisinopril intermediate. In the preparation method, the raw materials include activated carbon and a precursor complex containing an active component. In the precursor complex containing the active component, the active component is Pd, and the mass of the active component is 6.2% of the mass of the catalyst.

[0140] The method specifically comprises:

[0141] Step 1, dilute 24.8 mL of chloropalladic acid solution with a palladium concentration of 0.05 g / mL to 50 mL with deionized water to obtain a mixed system containing an active component, and at a temperature of 60° C., dropwise add 50.4 mL of a 0.1 g / mL tartaric acid aqueous solution to the mixed system containing the active component to obtain a metal-containing reaction system, and subject the metal-containing reaction system to a complex reaction at 50° C. under ultrasonic conditions for 20 min to obtain a metal precursor complex system;

[0142] Step 2: adjusting the pH of the metal precursor complex system to 6.0 with a 5% by mass Na2CO3 solution, and stabilizing it with ultrasound for 20 minutes to obtain a precursor complex system containing active components;

[0143] Step 3: 18.76 g of pore size 4 nm and specific surface area 1300 m 2 / g coconut shell activated carbon is placed in the impregnation drum body, the precursor complex system containing the active component is placed in the impregnation liquid transfer unit, and the precursor complex system containing the active component is sprayed onto the coconut shell activated carbon by using a drum nozzle, stabilized for 1 hour, and taken out to obtain a mixed material; the drum speed is 15min / r, and the spraying rate is 0.7ml / min;

[0144] Step 4: Add 200 ml of deionized water, 15 ml of a 10% NaHCO3 solution and 7.38 g of potassium borohydride to the mixed material to obtain a carrier mixed slurry, and subject the carrier mixed slurry to a stirring reduction reaction at 70° C. for 30 min. After the stirring reduction reaction, the material is filtered, washed, and dried at 120° C. to a water content of <1 wt% to obtain a catalyst for synthesizing a lisinopril intermediate.

[0145] Comparative Example 2

[0146] This comparative example provides a method for preparing a catalyst for synthesizing an intermediate of lisinopril. In the preparation method, the raw materials include activated carbon and a precursor complex containing an active component and an auxiliary agent. In the precursor complex containing the active component and the auxiliary agent, the active component is Pd, and the mass of the active component is 6.2% of the mass of the catalyst. The auxiliary agents are Ni and De, and the mass of Ni and the mass of De are both 0.05% of the mass of the catalyst.

[0147] The preparation method specifically comprises:

[0148] Step 1: 24.8 mL of chloropalladic acid solution with a palladium concentration of 0.05 g / mL, 0.2 mL of nickel chloride solution with a Ni concentration of 0.05 g / mL, and 0.2 mL of tellurium oxide solution with a De concentration of 0.05 g / mL were mixed, deionized water was added and the volume was adjusted to 50 mL to obtain a metal-containing mixed system, and 50.4 mL of 0.1 g / mL tartaric acid aqueous solution was added dropwise to the metal-containing mixed system at a temperature of 60° C. to obtain a metal-containing reaction system, and the metal-containing reaction system was subjected to complexation reaction at 60° C. under ultrasonic conditions for 20 min to obtain a metal precursor complex system;

[0149] Step 2: adjusting the pH of the metal precursor complex system to 6.0 with a 5% by mass Na2CO3 solution, and stabilizing it by ultrasound for 20 minutes to obtain a precursor complex system containing an active component and a co-active component;

[0150] Step 3: 18.74 g of pore size 4 nm and specific surface area 1300 m 2 / g coconut shell activated carbon is placed in the impregnation drum body, the precursor complex system containing active components and auxiliary active components is placed in the impregnation liquid transfer unit, and the precursor complex system containing active components and auxiliary active components is sprayed onto the coconut shell activated carbon by using a drum nozzle, stabilized for 1 hour, and taken out to obtain a mixed material; the drum speed is 15min / r, and the spraying rate is 0.7ml / min;

[0151] Step 4: Add 200 ml of deionized water, 15 ml of a 10% NaHCO3 solution and 7.38 g of potassium borohydride to the mixed material to obtain a carrier mixed slurry, and subject the carrier mixed slurry to a stirring reduction reaction at 70° C. for 30 min. After the stirring reduction reaction, the material is filtered, washed, and dried at 120° C. to a water content of <1 wt% to obtain a catalyst for synthesizing a lisinopril intermediate.

[0152] Comparative Example 3

[0153] This comparative example provides a method for preparing a catalyst for synthesizing an intermediate of lisinopril. In the preparation method, the raw materials include surface-modified activated carbon and a precursor complex containing an active component and an auxiliary agent. In the precursor complex containing the active component and the auxiliary agent, the active component is Pd, and the mass of the active component is 6.2% of the mass of the catalyst; the auxiliary agent is Ni, and the mass of Ni is 0.05% of the mass of the catalyst.

[0154] The preparation method specifically comprises:

[0155] Step 1: 20g of pore size 4nm, specific surface area 1300m 2 / g coconut shell activated carbon is placed in 200ml deionized water, 0.5g sodium dihydrogen phosphate is added, stirred and immersed at 20-25°C for 15h, filtered, and dried at 120°C until the water content is less than 1wt%, to obtain surface-modified activated carbon;

[0156] Step 2: Mix 24.8 mL of a 0.05 g / mL palladium chloropalladic acid solution and 0.2 mL of a 0.05 g / mL nickel chloride solution, add deionized water and dilute to 50 mL to obtain a metal-containing mixed system, and dropwise add 50.4 mL of a 0.1 g / mL tartaric acid aqueous solution to the metal-containing mixed system at 60° C. to obtain a metal-containing reaction system, and subject the metal-containing reaction system to a complexation reaction at 60° C. for 20 min under ultrasonic conditions to obtain a metal precursor complex system;

[0157] Step 3: adjusting the pH of the metal precursor complex system to 6.0 with a 5% by mass Na2CO3 solution, and stabilizing it by ultrasound for 20 minutes to obtain a precursor complex system containing an active component and a co-active component;

[0158] Step 4: placing 18.75 g of the surface-modified activated carbon in an impregnation drum, placing the precursor complex system containing the active component and the auxiliary active component in an impregnation liquid transfer unit, and spraying the precursor complex system containing the active component and the auxiliary active component onto the surface-modified activated carbon using a drum nozzle, stabilizing for 1 hour, and taking out to obtain a mixed material; the drum speed is 15 min / r, and the spraying rate is 0.7 ml / min;

[0159] Step 5: Add 200 ml of deionized water, 15 ml of a 10% NaHCO3 solution and 7.38 g of potassium borohydride to the mixed material to obtain a carrier mixed slurry, and subject the carrier mixed slurry to a stirring reduction reaction at 70° C. for 30 min. After the stirring reduction reaction, the material is filtered, washed, and dried at 120° C. to a water content of <1 wt% to obtain a catalyst for synthesizing a lisinopril intermediate.

[0160] Comparative Example 4

[0161] This comparative example provides a method for preparing a catalyst for synthesizing an intermediate of lisinopril. In the preparation method, the raw materials include surface-modified activated carbon and a precursor complex containing an active component and an auxiliary agent. In the precursor complex containing the active component and the auxiliary agent, the active component is Pd, and the mass of the active component is 6.2% of the mass of the catalyst; the auxiliary agent is De, and the mass of De is 0.05% of the mass of the catalyst.

[0162] The preparation method specifically comprises:

[0163] Step 1: 20g of pore size 4nm, specific surface area 1300m 2 / g coconut shell activated carbon was placed in 200ml deionized water, 0.6g ammonium triacetate was added, and the mixture was refluxed at 100°C for 3h, filtered, and dried at 120°C until the water content was less than 1wt%, to obtain surface-modified activated carbon;

[0164] Step 2: Mix 24.8 mL of a 0.05 g / mL palladium chloropalladic acid solution and 0.2 mL of a 0.05 g / mL De concentration tellurium oxide solution, add deionized water and dilute to 50 mL to obtain a metal-containing mixed system, and dropwise add 50.4 mL of a 0.1 g / mL tartaric acid aqueous solution to the metal-containing mixed system at 60° C. to obtain a metal-containing reaction system, and subject the metal-containing reaction system to a complex reaction at 60° C. under ultrasonic conditions for 20 min to obtain a metal precursor complex system;

[0165] Step 3: adjusting the pH of the metal precursor complex system to 6.0 with a 5% by mass Na2CO3 solution, and stabilizing it by ultrasound for 20 minutes to obtain a precursor complex system containing an active component and a co-active component;

[0166] Step 4: placing 18.74 g of the surface-modified activated carbon in an impregnation drum, placing the precursor complex system containing the active component and the auxiliary active component in an impregnation liquid transfer unit, and spraying the precursor complex system containing the active component and the auxiliary active component onto the surface-modified activated carbon using a drum nozzle, stabilizing for 1 hour, and taking out to obtain a mixed material; the drum speed is 15 min / r, and the spraying rate is 0.7 ml / min;

[0167] Step 5: Add 200 ml of deionized water, 15 ml of a 10% NaHCO3 solution and 7.38 g of potassium borohydride to the mixed material to obtain a carrier mixed slurry, and subject the carrier mixed slurry to a stirring reduction reaction at 70° C. for 30 min. After the stirring reduction reaction, the material is filtered, washed, and dried at 120° C. to a water content of <1 wt% to obtain a catalyst for synthesizing a lisinopril intermediate.

[0168] Comparative Example 5

[0169] This comparative example provides a method for preparing a catalyst for synthesizing an intermediate of lisinopril. In the preparation method, the raw materials include surface-modified activated carbon, an active component and an auxiliary agent, the active component is Pd and the auxiliary agent, the mass of the active component is 6.2% of the mass of the catalyst, the auxiliary agents are Ni and De, and the mass of Ni and the mass of De are both 0.05% of the mass of the catalyst.

[0170] The preparation method specifically comprises:

[0171] Step 1: 20g of pore size 4nm, specific surface area 1300m 2 / g coconut shell activated carbon was placed in 200ml deionized water, 0.6g ammonium triacetate was added, and the mixture was refluxed at 100°C for 3h, filtered, and dried at 120°C until the water content was <1wt%, to obtain a dried carrier;

[0172] Step 2: Place the dried carrier in 200 ml of deionized water, add 0.5 g of sodium dihydrogen phosphate, stir and immerse at 20-25° C. for 15 h, filter, and dry at 120° C. until the water content is less than 1 wt %, to obtain surface-modified activated carbon;

[0173] Step 3: Mix 24.8 mL of a chloropalladic acid solution having a palladium concentration of 0.05 g / mL, 0.2 mL of a nickel chloride solution having a Ni concentration of 0.05 g / mL, and 0.2 mL of a tellurium oxide solution having a De concentration of 0.05 g / mL, add deionized water and dilute to 50 mL to obtain a metal-containing mixed system;

[0174] Step 4, stabilizing the metal-containing mixed system by ultrasonic treatment for 20 minutes to obtain a stabilized metal-containing mixed system;

[0175] Step 5: placing 18.74 g of the surface-modified activated carbon in an impregnation drum, placing the stabilized metal-containing mixed system in an impregnation liquid transfer unit, and spraying the stabilized metal-containing mixed system onto the surface-modified activated carbon using a drum nozzle, stabilizing for 1 hour, and taking out to obtain a mixed material; the drum speed is 15 min / r, and the spraying rate is 0.7 ml / min;

[0176] Step six, add 200 ml of deionized water, 15 ml of 10% NaHCO3 solution and 7.38 g of potassium borohydride to the mixed material to obtain a carrier mixed slurry, and carry out a stirring reduction reaction of the carrier mixed slurry at 70° C. for 30 min. The material after the stirring reduction reaction is filtered, washed, and dried at 120° C. to a water content of <1wt% to obtain a catalyst for synthesizing lisinopril intermediates.

[0177] Comparative Example 6

[0178] This comparative example provides a method for preparing a catalyst for synthesizing an intermediate of lisinopril. In the preparation method, the raw materials include surface-modified activated carbon, an active component and an auxiliary agent, the active component is Pd, and the mass of the active component is 6.2% of the mass of the catalyst; the auxiliary agents are Ni and De, and the mass of Ni and the mass of De are both 0.05% of the mass of the catalyst.

[0179] The preparation method specifically comprises:

[0180] Step 1: 20g of pore size 4nm, specific surface area 1300m 2 / g coconut shell activated carbon was placed in 200ml deionized water, 0.6g ammonium triacetate was added, and the mixture was refluxed at 100°C for 3h, filtered, and dried at 120°C until the water content was <1wt%, to obtain a dried carrier;

[0181] Step 2: Place the dried carrier in 200 ml of deionized water, add 0.5 g of sodium dihydrogen phosphate, stir and immerse at 20-25° C. for 15 h, filter, and dry at 120° C. until the water content is less than 1 wt %, to obtain surface-modified activated carbon;

[0182] Step 3: Mix 24.8 mL of a chloropalladic acid solution having a palladium concentration of 0.05 g / mL, 0.2 mL of a nickel chloride solution having a Ni concentration of 0.05 g / mL, and 0.2 mL of a tellurium oxide solution having a De concentration of 0.05 g / mL, add deionized water and dilute to 50 mL to obtain a metal-containing mixed system;

[0183] Step 4: adjusting the pH of the metal-containing mixed system to 7.0 with a 5% by mass Na2CO3 solution, and stabilizing the mixture by ultrasonic for 20 minutes to obtain a stabilized metal-containing mixed system;

[0184] Step 5: placing 18.74 g of the surface-modified activated carbon in an impregnation drum, placing the stabilized metal-containing mixed system in an impregnation liquid transfer unit, and spraying the stabilized metal-containing mixed system onto the surface-modified activated carbon using a drum nozzle, stabilizing for 1 hour, and taking out to obtain a mixed material; the drum speed is 15 min / r, and the spraying rate is 0.7 ml / min;

[0185] Step six, add 200 ml of deionized water, 15 ml of 10% NaHCO3 solution and 7.38 g of potassium borohydride to the mixed material to obtain a carrier mixed slurry, and carry out a stirring reduction reaction of the carrier mixed slurry at 70° C. for 30 min. The material after the stirring reduction reaction is filtered, washed, and dried at 120° C. to a water content of <1wt% to obtain a catalyst for synthesizing lisinopril intermediates.

[0186] Application Examples

[0187] This embodiment provides a method for synthesizing a lisinopril intermediate by catalytic hydrogenation using any one of the catalysts in Examples 1 to 12 and Comparative Examples 1 to 6, comprising the following steps:

[0188] Hydrogenation reaction process: 55.9g N2-(1-ethoxycarbonyl-3-phenylpropanoyl)-N6-trifluoroacetyl-L-lysine was mixed with the above-mentioned synthetic lisinopril intermediate catalyst having a palladium content of 1.08g, placed in a high-pressure hydrogenation reactor containing 400ml of ethanol, stirred for 12h at a temperature of 40°C and a reaction pressure of 0.2Mpa, and the reaction was terminated. The palladium carbon was filtered and recovered to obtain a filtrate and a retentate. The filtrate was added with 200mL of water and the pH was adjusted to 4.5 with a sodium hydroxide solution having a mass percentage concentration of 30%. The mixture was concentrated under vacuum to recover the ethanol. The retentate was concentrated with 100mL of The reaction mixture was washed with water and filtered to obtain a white solid and a filtrate after filtration. The white solid was vacuum dried at 50° C. to obtain the product N2-(1-ethoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl-L-lysine. The filtrate after filtration was analyzed by liquid chromatography, and the results are shown in Table 1. The N2-(1-ethoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl-L-lysine is N2-(1-ethoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl-L-lysine obtained by Michael addition reaction of ethyl 3-benzoylacrylate (BZ) and trifluoroacetyl-lysine (LA1) as raw materials.

[0189] Table 1 Hydrogenation reaction performance results

[0190] catalyst Raw material conversion rate / % Product yield / % Impurities / % Example 1 99.1 61.1 0.3 Example 2 99.1 61.4 0.29 Example 3 99.2 63.0 0.28 Example 4 99.2 62.9 0.26 Example 5 99.2 63.2 0.25 Example 6 99.3 64.2 0.27 Example 7 99.3 64.5 0.25 Example 8 99.8 65.7 0.26 Example 9 99.7 66.1 0.25 Example 10 99.4 62.1 0.24 Embodiment 11 99.3 62.2 0.24 Example 12 99.4 62.3 0.25 Comparative Example 1 79.1 45.2 6.51 Comparative Example 2 90.4 56.1 5.25 Comparative Example 3 91.3 56.7 4.94 Comparative Example 4 92.1 56.8 4.86 Comparative Example 5 93.1 60.1 4.02 Comparative Example 6 94.0 61.1 3.95

[0191] As can be seen from Table 1, compared with Comparative Example 1 in which untreated activated carbon is directly used as a carrier and no auxiliary active component is added to the active component, or Comparative Example 2 in which untreated activated carbon is directly used as a carrier, or Comparative Examples 3 and 4 in which the carrier is only modified with N or P and one of Ru, Ni, Se, and De is added to the active component, or Comparative Examples 5 and 6 in which the reaction conditions for obtaining the impregnation solution are controlled, the catalyst for synthesizing lisinopril intermediates prepared by the method of the present invention has significantly improved raw material conversion rate and product yield, and the impurity content is significantly reduced, indicating that the catalyst for synthesizing lisinopril intermediates prepared by the method of the present invention has high activity and selectivity.

[0192] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any way. Any simple modification, change and equivalent structural change made to the above embodiment according to the technical essence of the invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A method for preparing a catalyst for synthesizing a lisinopril intermediate, characterized in that: In the preparation method, the raw materials include surface-modified activated carbon and a precursor complex containing an active component and an auxiliary agent, the active component is Pd, the auxiliary agent is two or more auxiliary metals, the auxiliary metal is Ni, Ru, Se or Te, the mass of the active component is 6.0% to 6.5% of the mass of the catalyst, and the mass of the auxiliary metal is 0.05% to 1% of the mass of the catalyst; The preparation method specifically comprises: Step 1: Mix coconut shell activated carbon, deionized water and nitrogen-containing compounds, reflux at 80-100°C for 3-5h, filter and dry to obtain a dried carrier; the mass of the nitrogen-containing compound is 0.01-0.05 times the mass of the coconut shell activated carbon, the nitrogen-containing compound is ethylenediamine or ammonium triacetate, the pore size of the coconut shell activated carbon is 2-4nm, and the specific surface area is 800-1600m 2 / g, wherein the drying is carried out at 90-120°C until the water content is less than 1wt%; Step 2: Mix the carrier, deionized water and phosphorus-containing compound after drying in step 1, stir and immerse at 20-25° C. for 10-15 hours, filter and dry to obtain surface-modified activated carbon; the mass of the phosphorus-containing compound is 0.01-0.05 times the mass of the coconut shell activated carbon in step 1, the phosphorus-containing compound is sodium dihydrogen phosphate or potassium dihydrogen phosphate, and the drying is drying at 90-120° C. until the water content is <1wt%; Step 3: mixing a chloropalladic acid solution, an auxiliary metal soluble salt solution and deionized water to obtain a metal-containing mixed system, adding an aqueous solution of a complexing agent to the metal-containing mixed system at a temperature of 55 to 70° C. to obtain a metal-containing reaction system, and subjecting the metal-containing reaction system to a complexing reaction at 50 to 70° C. under ultrasonic conditions for 15 to 30 minutes to obtain a metal precursor complex system; Step 4: adjusting the pH of the metal precursor complex system to 5-7, and stabilizing by ultrasound for 15-30 minutes to obtain a precursor complex system containing an active component and a co-active component; Step 5, placing the surface-modified activated carbon in step 2 in an impregnation drum, placing the precursor complex system containing active components and co-active components in step 4 in an impregnation liquid transfer unit, and using a drum sprayer to spray the precursor complex system containing active components and co-active components onto the surface-modified activated carbon, stabilizing for 1 to 2 hours, and taking out to obtain a mixed material; Step six, add deionized water, a buffer and a reducing agent to the mixed material in step five to obtain a carrier mixed slurry, carry out a stirring reduction reaction of the carrier mixed slurry at 60 to 100° C. for 30 to 40 minutes, filter, wash and dry the material after the stirring reduction reaction to obtain a catalyst for synthesizing a lisinopril intermediate.

2. The method for preparing a catalyst for synthesizing a lisinopril intermediate according to claim 1, characterized in that: In step three, the complexing agent is citric acid, tartaric acid, ethylenediamine or ammonium triacetate, and the mass of the complexing agent is 3 to 6 times the mass of Pd and the mass of the auxiliary metal.

3. The method for preparing a catalyst for synthesizing a lisinopril intermediate according to claim 1, characterized in that: In step 4, the reagent for adjusting pH is sodium hydroxide solution, sodium carbonate solution or sodium bicarbonate solution.

4. The method for preparing a catalyst for synthesizing a lisinopril intermediate according to claim 1, characterized in that: In step 5, the drum speed is 10-30 min / r, and the spraying rate is 0.5-1 ml / min.

5. The method for preparing a catalyst for synthesizing a lisinopril intermediate according to claim 1, characterized in that: In step six, the volume of the buffer is 0.5 to 1.0 times the mass of the catalyst used to synthesize the lisinopril intermediate, the volume of the buffer is in mL, and the mass of the catalyst is in g.

6. The method for preparing a catalyst for synthesizing a lisinopril intermediate according to claim 1, characterized in that: In step six, the mass of the reducing agent is 5 to 15 times the mass of Pd and the mass of the auxiliary metal.

7. The method for preparing a catalyst for synthesizing a lisinopril intermediate according to claim 1, characterized in that: In step six, the drying temperature is 90-120°C.

8. The method for preparing a catalyst for synthesizing a lisinopril intermediate according to claim 1, characterized in that: In step six, the buffer is sodium bicarbonate solution or sodium acetate solution, and the reducing agent is formaldehyde, potassium borohydride, sodium borohydride or formic acid.