A modified Raney nickel catalyst for the synthesis of pregabalin intermediate II and its preparation method

Abstract

This invention relates to the technical field of alloy catalysts, and discloses a modified Raney nickel catalyst for the synthesis of pregabalin intermediate II and its preparation method, comprising the following steps: Step 1: preparing a porous acrylamide gel support; the porous acrylamide gel support is a porous acrylamide gel support containing nano-titanium dioxide modified by iron ion surface modification; Step 2: preparing a Ni-Al alloy, and then grinding it into alloy powder; Step 3: adding the alloy powder to an alkaline solution, then adding the porous acrylamide gel support, and ultrasonically treating; then removing and freeze-drying to obtain the modified Raney nickel catalyst. This invention, by loading Ni-Al alloy powder onto a porous acrylamide gel support, not only reduces the amount of catalyst added and shortens the reaction time, but also improves catalytic selectivity, product yield and conversion rate, and allows for multiple recycling.

Description

Technical Field

[0001] This invention relates to the technical field of alloy catalysts, and in particular to a modified Raney nickel catalyst for the synthesis of pregabalin intermediate II and its preparation method. Background Technology

[0002] Pregabalin, chemically known as (S)-3-aminomethyl-5-methylhexanoic acid, is an antiepileptic drug primarily used clinically to treat two types of neuropathic pain: diabetic peripheral neuropathy and postherpetic neuralgia. Pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), but it does not directly bind to GABAA, GABAB, or benzodiazepine receptors. Neuropathic pain is associated with alterations in calcium ion channels in the nervous system, which are composed of four subunits: α1, β, γ, and α2-δ. Pregabalin binds to the α2-δ subunit of calcium ion channels in the nervous system, inhibiting the influx of Ca ions into the presynaptic membrane of neurons and reducing the release of excitatory neurotransmitters (glutamate, substance P, and calcitonin gene-related peptide), thereby controlling pain.

[0003] Pregabalin has broad application prospects, and the synthesis of its active pharmaceutical ingredient and intermediates has become a research hotspot in the chemical industry, with various synthetic methods available. One such synthetic route uses 3-cyano-5-methylhexanonitrile as a starting material. 3-cyano-5-methylhexanonitrile is selectively hydrolyzed by cyanohydrolase to generate (S)-3-cyano-5-methylhexanoic acid (pregabalin intermediate I) and R-3-cyano-5-methylhexanonitrile. After racemic recovery of 3-cyano-5-methylhexanonitrile from R-3-cyano-5-methylhexanonitrile, (S)-3-cyano-5-methylhexanoic acid is catalytically hydrogenated in the presence of Raney nickel catalyst to generate (S)-3-aminomethyl-5-methylhexanoic acid (pregabalin intermediate II). The resulting product is purified by crystallization to obtain the pregabalin active pharmaceutical ingredient. Raney nickel catalyst is a widely used reduction catalyst, mainly used in the catalytic hydrogenation reaction of organic compounds. However, in the catalytic hydrogenation reaction of (S)-3-cyano-5-methylhexanoic acid, the commercially available Raney nickel catalyst used in the prior art has low activity and selectivity, poor catalytic hydrogenation effect, and large catalyst dosage, resulting in low yield and conversion of pregabalin intermediate II. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides a modified Raney nickel catalyst for the synthesis of pregabalin intermediate II and its preparation method. By loading the parent alloy onto a porous acrylamide gel support, the enrichment effect of the alloy is improved, while the catalyst is easily recyclable. Furthermore, the porous acrylamide gel support also contains metal catalytic active centers, which can synergistically interact with the parent alloy, thereby achieving better catalytic effects, reducing the amount of catalyst used, and increasing the yield and conversion rate of the product.

[0005] The objective of this invention is achieved through the following technical solution: In a first aspect, the present invention provides a method for preparing a modified Raney nickel catalyst for the synthesis of pregabalin intermediate II, comprising the following steps: Step 1: Preparation of porous acrylamide gel carrier; the porous acrylamide gel carrier is a porous acrylamide gel carrier containing nano-titanium dioxide modified by iron ion surface modification; Step 2: Prepare Ni-Al alloy, then grind it into alloy powder; Step 3: Add the alloy powder to an alkaline solution, then add a porous acrylamide gel carrier, and sonicate; then remove and freeze-dry to obtain the modified Raney nickel catalyst.

[0006] This invention utilizes a porous acrylamide gel carrier to support Ni-Al alloy powder. The high mechanical strength of the gel carrier enables it to bind and adsorb more Ni-Al alloy powder, while the porous structure improves the diffusion efficiency of the reactants. Simultaneously, the iron-modified nano-titanium dioxide contained in the carrier forms more metal catalytic active centers. The Ni-Al alloy, in synergy with iron and titanium, can exert a better catalytic effect, while the porous structure increases the specific surface area, thereby further improving catalytic selectivity. This not only reduces the amount of catalyst added and shortens the reaction time, but also improves the yield and conversion rate of the product.

[0007] Furthermore, adding the alloy powder to a porous acrylamide gel support and then sonicating it before freeze-drying improves the loading stability of the alloy powder, which is beneficial for better synergistic catalysis with the metal catalytic active centers in the support and also facilitates better catalyst recovery. Alkaline solution treatment can extract Ni-Al alloy powder, dissolving some of the aluminum, thus forming a three-dimensional porous structure in the powder. This structure differs in pore size from the porous structure in the support, further enhancing synergistic effects, improving the diffusion of reactants and the selectivity of the catalyst, thereby increasing catalytic efficiency.

[0008] Preferably, the method for preparing the porous acrylamide gel carrier includes the following steps: (1) Dissolve maleimide, acrylamide, sodium acrylate, N,N'-methylenediacrylamide and porogen in water to obtain the first solution; (2) The nano-titanium dioxide was mixed with an aqueous solution of 3-mercaptopropyltriethoxysilane and ball-milled, then dried; then it was mixed with a ferrous nitrate solution and ball-milled, and dried again to obtain modified nano-titanium dioxide; (3) The modified nano-titanium dioxide, tetraborate, initiator, tetramethylethylenediamine and water are mixed to obtain a second solution; (4) The first solution and the second solution are mixed and reacted; then immersed in an acid solution for post-treatment to obtain a porous acrylamide gel carrier.

[0009] The porous acrylamide gel support in this invention uses a cross-linked structure of maleimide, acrylamide, sodium acrylate, and N,N'-methylenediacrylamide as the gel matrix. A pore-forming agent is added during acid solution post-treatment to form a porous structure. Nano-titanium dioxide modified with 3-mercaptopropyltriethoxysilane and ferrous nitrate is added to the gel matrix. The 3-mercaptopropyltriethoxysilane molecule contains abundant thiol groups, exhibiting excellent metal ion adsorption performance. Therefore, the nano-titanium dioxide surface-treated with 3-mercaptopropyltriethoxysilane can better adsorb ferrous nitrate. Iron and titanium can synergistically exert better catalytic activity, and also enable the gel support to better adsorb and fix the alloy powder. Simultaneously, the nano-titanium dioxide surface-treated with 3-mercaptopropyltriethoxysilane has better dispersibility in the gel matrix. The Fe2+ in the further modified ferrous nitrate undergoes a coordination reaction with -NH and C=O in the gel matrix, synergistically cross-linking to form a more stable network structure, thus resulting in higher catalyst recycling stability.

[0010] Preferably, in step (1), the mass ratio of maleimide, acrylamide, sodium acrylate, N,N'-methylenediacrylamide, pore-forming agent and water is 2-3:2-3:0.5-1:0.05-0.08:5-6:30.

[0011] Preferably, the pore-forming agent is a carbonate, more preferably sodium carbonate.

[0012] Preferably, in step (2), the mass-to-volume ratio of the nano-titanium dioxide, the aqueous solution of 3-mercaptopropyltriethoxysilane, and the ferrous nitrate solution is 1 g: 1 mL: 0.5 mL; the mass concentration of the aqueous solution of 3-mercaptopropyltriethoxysilane is 20-30%; and the mass concentration of the ferrous nitrate solution is 15-20%.

[0013] Preferably, in step (2), the nano-titanium dioxide and the aqueous solution of 3-mercaptopropyltriethoxysilane are mixed and ball-milled at a speed of 300-500 rpm for 20-30 min, and then dried; then ferrous nitrate solution is added and mixed and ball-milled at a speed of 100-300 rpm for 20-30 min, and then air-dried naturally in the dark.

[0014] Preferably, in step (3), the mass ratio of the modified nano-titanium dioxide, tetraborate, initiator, tetramethylethylenediamine and water is 1-3:0.1-0.2:0.05-0.07:0.2-0.3:10.

[0015] Preferably, in step (3), the tetraborate is sodium tetraborate; the initiator is persulfate, more preferably ammonium persulfate or sodium persulfate.

[0016] Preferably, in step (4), the first solution and the second solution are mixed such that the mass ratio of water in each solution is 3:1; the reaction is carried out in a water bath at 30-40°C for 1-2 hours.

[0017] Preferably, in step (4), the post-treatment of immersion in acid solution is to immerse the gel in acid solution to remove carbonates and form a porous structure.

[0018] Preferably, in step two, the Ni-Al alloy comprises 30-50% nickel and 50-70% aluminum by mass fraction, with a total mass percentage of 100%; the alloy powder has a particle size of 100-200 mesh.

[0019] Preferably, in step three, the mass-to-volume ratio of the alloy powder, porous acrylamide gel carrier, and alkaline solution is 10g:2-4g:100mL; the alkaline solution is a sodium hydroxide aqueous solution with a mass concentration of 10-25%; and the ultrasonic treatment is performed at 70-80℃ for 1-2 hours.

[0020] Secondly, the present invention also provides a modified Raney nickel catalyst prepared by the above preparation method.

[0021] Compared with the prior art, the present invention has the following beneficial effects: (1) By loading Ni-Al alloy powder onto a porous acrylamide gel carrier, the high mechanical strength of the gel carrier can bind and adsorb more Ni-Al alloy powder, thereby improving the enrichment effect of the alloy. The porous structure also improves the diffusion efficiency of the reactants. (2) By utilizing the nano-titanium dioxide modified by iron ions in the support, more metal catalytic active centers are formed. The Ni-Al alloy, together with iron and titanium, can exert a better catalytic effect. At the same time, the porous structure increases the specific surface area, thereby further improving the catalytic selectivity. (3) It can not only reduce the amount of catalyst added and shorten the reaction time, but also improve the yield and conversion rate of the product, and can be recycled multiple times. Detailed Implementation

[0022] The technical solution of the present invention is illustrated below with specific embodiments, but the scope of protection of the present invention is not limited thereto: The preparation of modified Raney nickel catalysts includes the following steps: Step 1: Preparation of porous acrylamide gel carrier; (1) Dissolve maleimide, acrylamide, sodium acrylate, N,N'-methylenediacrylamide and porogen (carbonate) in water so that the mass ratio of maleimide, acrylamide, sodium acrylate, N,N'-methylenediacrylamide, porogen and water is 2~3:2~3:0.5~1:0.05~0.08:5~6:30 to obtain the first solution.

[0023] (2) Nano-titanium dioxide (average particle size 50-200 nm) was mixed with an aqueous solution of 3-mercaptopropyltriethoxysilane with a mass concentration of 20-30%, and then ball-milled at a speed of 300-500 rpm for 20-30 min, and then dried at 50-60 °C; then mixed with a ferrous nitrate solution with a mass concentration of 15-20%, and ball-milled at a speed of 100-300 rpm for 20-30 min, and then air-dried in the dark. The ratio of the amount of nano-titanium dioxide, the aqueous solution of 3-mercaptopropyltriethoxysilane and the ferrous nitrate solution added was 1 g: 1 mL: 0.5 mL, to obtain modified nano-titanium dioxide.

[0024] (3) A second solution is obtained by mixing modified nano-titanium dioxide, tetraborate (sodium tetraborate), initiator (persulfate), tetramethylethylenediamine and water in a mass ratio of 1~3:0.1~0.2:0.05~0.07:0.2~0.3:10.

[0025] (4) Mix the first solution and the second solution (the mass ratio of water in the first solution and the second solution is 3:1) and react in a water bath at 30-40℃ for 1-2 hours; then immerse in an acid solution for post-treatment to remove carbonates from the gel until the gel mass no longer changes significantly. Then take out the gel, freeze dry it, and obtain a porous acrylamide gel carrier.

[0026] Step 2: Prepare Ni-Al alloy, which includes 30-50% nickel and 50-70% aluminum by mass fraction, with a total mass percentage of 100%, and then grind it into alloy powder of 100-200 mesh.

[0027] Step 3: Add the alloy powder to an alkaline solution (sodium hydroxide aqueous solution with a mass concentration of 10-25%), and then add a porous acrylamide gel carrier. The ratio of alloy powder, porous acrylamide gel carrier and alkaline solution is 10g:2-4g:100mL. Sonicate at 70-80℃ and 80-100kHz for 1-2 hours. After filtration, wash with anhydrous ethanol, freeze dry to obtain the modified Raney nickel catalyst, and store it in anhydrous ethanol.

[0028] Example 1 The preparation of modified Raney nickel catalysts includes the following steps: Step 1: Preparation of porous acrylamide gel carrier; (1) Dissolve maleimide, acrylamide, sodium acrylate, N,N'-methylenediacrylamide and porogen (sodium carbonate) in water so that the mass ratio of maleimide, acrylamide, sodium acrylate, N,N'-methylenediacrylamide, porogen and water is 2:2:0.8:0.05:5:30 to obtain the first solution.

[0029] (2) Nano-titanium dioxide (average particle size 100 nm) was mixed with an aqueous solution of 3-mercaptopropyltriethoxysilane with a mass concentration of 25%, and then ball-milled at 400 rpm for 30 min, and then dried at 60 °C; then it was mixed with a ferrous nitrate solution with a mass concentration of 15%, and ball-milled at 200 rpm for 20 min, and then air-dried in the dark. The ratio of the amount of nano-titanium dioxide, the aqueous solution of 3-mercaptopropyltriethoxysilane and the ferrous nitrate solution added was 1 g: 1 mL: 0.5 mL, thus obtaining modified nano-titanium dioxide.

[0030] (3) The modified nano-titanium dioxide, tetraborate (sodium tetraborate), initiator (ammonium persulfate), tetramethylethylenediamine and water in a mass ratio of 1:0.1:0.06:0.25:10 are mixed to obtain the second solution.

[0031] (4) After mixing the first solution and the second solution (the mass ratio of water in the first solution and the second solution is 3:1), react in a water bath at 30°C for 1 hour; then immerse in an acid solution (0.1 mol / L hydrochloric acid solution) for post-treatment to remove carbonates from the gel. Treat until the gel mass no longer changes significantly, then take out the gel, freeze dry, and obtain a porous acrylamide gel carrier.

[0032] Step 2: Prepare Ni-Al alloy, which includes 40% nickel and 60% aluminum by mass fraction, with a total mass percentage of 100%, and then grind it into alloy powder of 150-200 mesh.

[0033] Step 3: Add the alloy powder to an alkaline solution (20% sodium hydroxide aqueous solution), and then add a porous acrylamide gel carrier. The ratio of alloy powder, porous acrylamide gel carrier and alkaline solution is 10g:3g:100mL. Sonicate at 70℃ and 90kHz for 1h. After filtration, wash with anhydrous ethanol, freeze dry to obtain the modified Raney nickel catalyst, and store it in anhydrous ethanol.

[0034] Example 2 The difference from Example 1 is that the preparation of the porous acrylamide gel carrier is different.

[0035] Includes the following steps: (1) Dissolve maleimide, acrylamide, sodium acrylate, N,N'-methylenediacrylamide and porogen (sodium carbonate) in water so that the mass ratio of maleimide, acrylamide, sodium acrylate, N,N'-methylenediacrylamide, porogen and water is 3:2:1:0.08:5:30 to obtain the first solution.

[0036] (2) Nano-titanium dioxide (average particle size 100 nm) was mixed with an aqueous solution of 3-mercaptopropyltriethoxysilane with a mass concentration of 25%, and then ball-milled at 400 rpm for 30 min, and then dried at 60 °C; then it was mixed with a ferrous nitrate solution with a mass concentration of 20%, and ball-milled at 200 rpm for 30 min, and then air-dried in the dark. The ratio of the amount of nano-titanium dioxide, the aqueous solution of 3-mercaptopropyltriethoxysilane and the ferrous nitrate solution added was 1 g: 1 mL: 0.5 mL, thus obtaining modified nano-titanium dioxide.

[0037] (3) The modified nano-titanium dioxide, tetraborate (sodium tetraborate), initiator (ammonium persulfate), tetramethylethylenediamine and water in a mass ratio of 2:0.2:0.06:0.3:10 are mixed to obtain the second solution.

[0038] (4) After mixing the first solution and the second solution (the mass ratio of water in the first solution and the second solution is 3:1), react in a water bath at 30°C for 1.5 h; then immerse in an acid solution (0.1 mol / L hydrochloric acid solution) for post-treatment to remove carbonates from the gel. Treat until the gel mass no longer changes significantly, then take out the gel, freeze dry, and obtain a porous acrylamide gel carrier.

[0039] Example 3 The difference from Example 1 is that the preparation of the porous acrylamide gel carrier is different.

[0040] Includes the following steps: (1) Dissolve maleimide, acrylamide, sodium acrylate, N,N'-methylenediacrylamide and porogen (sodium carbonate) in water so that the mass ratio of maleimide, acrylamide, sodium acrylate, N,N'-methylenediacrylamide, porogen and water is 3:3:1:0.08:6:30 to obtain the first solution.

[0041] (2) Nano-titanium dioxide (average particle size 100 nm) was mixed with an aqueous solution of 30% 3-mercaptopropyltriethoxysilane and ball-milled at 400 rpm for 30 min, and then dried at 60 °C; then it was mixed with a 20% ferrous nitrate solution and ball-milled at 200 rpm for 30 min, and then air-dried in the dark. The ratio of the amount of nano-titanium dioxide, the aqueous solution of 3-mercaptopropyltriethoxysilane and the ferrous nitrate solution added was 1 g: 1 mL: 0.5 mL, thus obtaining modified nano-titanium dioxide.

[0042] (3) The modified nano-titanium dioxide, tetraborate (sodium tetraborate), initiator (ammonium persulfate), tetramethylethylenediamine and water in a mass ratio of 3:0.2:0.07:0.2:10 are mixed to obtain the second solution.

[0043] (4) After mixing the first solution and the second solution (the mass ratio of water in the first solution and the second solution is 3:1), react in a water bath at 35°C for 2 hours; then immerse in an acid solution (0.1 mol / L hydrochloric acid solution) for post-treatment to remove carbonates from the gel. Treat until the gel mass no longer changes significantly, then take out the gel, freeze-dry it, and obtain a porous acrylamide gel carrier.

[0044] Example 4 The preparation of modified Raney nickel catalysts includes the following steps: Step 1: Prepare a porous acrylamide gel carrier using the same preparation process as in Example 1.

[0045] Step 2: Prepare Ni-Al alloy, which includes 30% nickel and 70% aluminum by mass fraction, with a total mass percentage of 100%, and then grind it into alloy powder of 100-150 mesh.

[0046] Step 3: Add the alloy powder to an alkaline solution (20% sodium hydroxide aqueous solution), and then add a porous acrylamide gel carrier. The ratio of alloy powder, porous acrylamide gel carrier and alkaline solution is 10g:4g:100mL. Sonicate at 70℃ and 100kHz for 1.5h. After filtration, wash with anhydrous ethanol, freeze dry to obtain the modified Raney nickel catalyst, and store it in anhydrous ethanol.

[0047] Comparative Example 1 The difference from Example 1 is that no modified nano-titanium dioxide is added during the preparation of the porous acrylamide gel carrier.

[0048] Includes the following steps: (1) Dissolve maleimide, acrylamide, sodium acrylate, N,N'-methylenediacrylamide and porogen (sodium carbonate) in water so that the mass ratio of maleimide, acrylamide, sodium acrylate, N,N'-methylenediacrylamide, porogen and water is 2:2:0.8:0.05:5:30 to obtain the first solution.

[0049] (3) Mix tetraborate (sodium tetraborate), initiator (ammonium persulfate), tetramethylethylenediamine and water in a mass ratio of 0.1:0.06:0.25:10 to obtain a second solution.

[0050] (4) After mixing the first solution and the second solution (the mass ratio of water in the first solution and the second solution is 3:1), react in a water bath at 30°C for 1 hour; then immerse in an acid solution (0.1 mol / L hydrochloric acid solution) for post-treatment to remove carbonates from the gel. Treat until the gel mass no longer changes significantly, then take out the gel, freeze dry, and obtain a porous acrylamide gel carrier.

[0051] Comparative Example 2 The difference from Example 1 is that titanium dioxide that has not been modified with ferrous nitrate was added during the preparation of the porous acrylamide gel carrier.

[0052] Includes the following steps: (1) Dissolve maleimide, acrylamide, sodium acrylate, N,N'-methylenediacrylamide and porogen (sodium carbonate) in water so that the mass ratio of maleimide, acrylamide, sodium acrylate, N,N'-methylenediacrylamide, porogen and water is 2:2:0.8:0.05:5:30 to obtain the first solution.

[0053] (2) Nano-titanium dioxide (average particle size 100nm) was mixed with an aqueous solution of 3-mercaptopropyltriethoxysilane with a mass concentration of 25%, and then ball-milled at 400rpm for 30min, and then dried at 60℃. The ratio of the amount of nano-titanium dioxide to the aqueous solution of 3-mercaptopropyltriethoxysilane was 1g:1mL, and modified nano-titanium dioxide was obtained.

[0054] (3) The modified nano-titanium dioxide, tetraborate (sodium tetraborate), initiator (ammonium persulfate), tetramethylethylenediamine and water in a mass ratio of 1:0.1:0.06:0.25:10 are mixed to obtain the second solution.

[0055] (4) After mixing the first solution and the second solution (the mass ratio of water in the first solution and the second solution is 3:1), react in a water bath at 30°C for 1 hour; then immerse in an acid solution (0.1 mol / L hydrochloric acid solution) for post-treatment to remove carbonates from the gel. Treat until the gel mass no longer changes significantly, then take out the gel, freeze dry, and obtain a porous acrylamide gel carrier.

[0056] Comparative Example 3 The difference from Example 1 is that the amount of modified nano-titanium dioxide added during the preparation of the porous acrylamide gel carrier is too small.

[0057] Includes the following steps: (1) Dissolve maleimide, acrylamide, sodium acrylate, N,N'-methylenediacrylamide and porogen (sodium carbonate) in water so that the mass ratio of maleimide, acrylamide, sodium acrylate, N,N'-methylenediacrylamide, porogen and water is 2:2:0.8:0.05:5:30 to obtain the first solution.

[0058] (2) Nano-titanium dioxide (average particle size 100 nm) was mixed with an aqueous solution of 3-mercaptopropyltriethoxysilane with a mass concentration of 25%, and then ball-milled at 400 rpm for 30 min, and then dried at 60 °C; then it was mixed with a ferrous nitrate solution with a mass concentration of 15%, and ball-milled at 200 rpm for 20 min, and then air-dried in the dark. The ratio of the amount of nano-titanium dioxide, the aqueous solution of 3-mercaptopropyltriethoxysilane and the ferrous nitrate solution added was 1 g: 1 mL: 0.5 mL, thus obtaining modified nano-titanium dioxide.

[0059] (3) The modified nano-titanium dioxide, tetraborate (sodium tetraborate), initiator (ammonium persulfate), tetramethylethylenediamine and water in a mass ratio of 0.5:0.1:0.06:0.25:10 are mixed to obtain the second solution.

[0060] (4) After mixing the first solution and the second solution (the mass ratio of water in the first solution and the second solution is 3:1), react in a water bath at 30°C for 1 hour; then immerse in an acid solution (0.1 mol / L hydrochloric acid solution) for post-treatment to remove carbonates from the gel. Treat until the gel mass no longer changes significantly, then take out the gel, freeze dry, and obtain a porous acrylamide gel carrier.

[0061] Comparative Example 4 The difference from Example 1 is that maleimide was not added during the preparation of the porous acrylamide gel carrier.

[0062] Includes the following steps: (1) Dissolve acrylamide, sodium acrylate, N,N'-methylenediacrylamide and porogen (sodium carbonate) in water so that the mass ratio of acrylamide, sodium acrylate, N,N'-methylenediacrylamide, porogen and water is 4:0.8:0.05:5:30 to obtain the first solution.

[0063] (2) Nano-titanium dioxide (average particle size 100 nm) was mixed with an aqueous solution of 3-mercaptopropyltriethoxysilane with a mass concentration of 25%, and then ball-milled at 400 rpm for 30 min, and then dried at 60 °C; then it was mixed with a ferrous nitrate solution with a mass concentration of 15%, and ball-milled at 200 rpm for 20 min, and then air-dried in the dark. The ratio of the amount of nano-titanium dioxide, the aqueous solution of 3-mercaptopropyltriethoxysilane and the ferrous nitrate solution added was 1 g: 1 mL: 0.5 mL, thus obtaining modified nano-titanium dioxide.

[0064] (3) The modified nano-titanium dioxide, tetraborate (sodium tetraborate), initiator (ammonium persulfate), tetramethylethylenediamine and water in a mass ratio of 1:0.1:0.06:0.25:10 are mixed to obtain the second solution.

[0065] (4) After mixing the first solution and the second solution (the mass ratio of water in the first solution and the second solution is 3:1), react in a water bath at 30°C for 1 hour; then immerse in an acid solution (0.1 mol / L hydrochloric acid solution) for post-treatment to remove carbonates from the gel. Treat until the gel mass no longer changes significantly, then take out the gel, freeze dry, and obtain a porous acrylamide gel carrier.

[0066] Application examples 50 mL of 200 g / L (S)-3-cyano-5-methylhexanoic acid aqueous solution was placed in a reaction vessel, and the modified Raney nickel catalysts from Examples 1-4 and Comparative Examples 1-4 were added respectively. The pressure was controlled at 2 MPa at room temperature, the stirring speed was 600 rpm, and the reaction was carried out for 2 h.

[0067] The modified Raney nickel catalyst can be reused by filtering it after the reaction is completed, washing it with anhydrous ethanol, freeze-drying it, and then putting it back into the above reaction.

[0068] After the reaction was completed, samples were taken, and the conversion rate of (S)-3-cyano-5-methylhexanoic acid and the yield of (S)-3-aminomethyl-5-methylhexanoic acid (pregabalin intermediate II) were determined by HPLC. The HPLC detection conditions were as follows: column C-18; mobile phase A was pH 7.5 phosphate buffer: acetonitrile = 950:50 (v / v); mobile phase B was acetonitrile.

[0069] Table 1 As shown in Table 1, the modified Raney nickel catalyst of this invention exhibits catalytic activity and selectivity, and also demonstrates good catalytic effect in the catalytic hydrogenation reaction of (S)-3-cyano-5-methylhexanoic acid. Ultimately, it can reduce the amount of catalyst added while obtaining (S)-3-aminomethyl-5-methylhexanoic acid (pregabalin intermediate II) with high conversion and high yield, and can also be recycled multiple times. Comparative Examples 1-3 show that due to surface modification, the modified titanium dioxide exhibits synergistic catalysis with iron and titanium and Ni-Al. Therefore, the amount added and the effect of surface modification both affect the catalytic effect of the catalyst, and also affect the cross-linking within the gel support and the loading stability of the Ni-Al alloy. Consequently, compared to Example 1, the product yield and the yield after repeated use are both reduced. Comparative Example 4 shows that maleimide, due to its C=O content, is beneficial in improving cross-linking stability in the gel support, thus ensuring a high yield even after multiple cycles.

[0070] The above are merely preferred embodiments of the present invention and do not limit the patent scope of the present invention. Any equivalent structural or procedural transformations made using the present invention specification, or direct or indirect applications in other related technical fields, are similarly included within the patent protection scope of the present invention.

Claims

1. A method for preparing a modified Raney nickel catalyst for the synthesis of pregabalin intermediate II, characterized in that, Pregabalin intermediate II is (S)-3-aminomethyl-5-methylhexanoic acid, and the preparation of the catalyst includes the following steps: Step 1: Preparation of porous acrylamide gel carrier; (1) Dissolve maleimide, acrylamide, sodium acrylate, N,N'-methylenediacrylamide and porogen in water to obtain the first solution; (2) The nano-titanium dioxide was mixed with an aqueous solution of 3-mercaptopropyltriethoxysilane and ball-milled, then dried; then it was mixed with a ferrous nitrate solution and ball-milled, and dried again to obtain modified nano-titanium dioxide; (3) The modified nano-titanium dioxide, tetraborate, initiator, tetramethylethylenediamine and water in a mass ratio of 1~3:0.1~0.2:0.05~0.07:0.2~0.3:10 are mixed to obtain a second solution; (4) Mix the first solution and the second solution and react them; then immerse them in an acid solution for further treatment; Step 2: Prepare Ni-Al alloy, then grind it into alloy powder; Step 3: Add the alloy powder to an alkaline solution, then add a porous acrylamide gel carrier, and sonicate; then remove and freeze-dry to obtain the modified Raney nickel catalyst.

2. The method for preparing the modified Raney nickel catalyst for the synthesis of pregabalin intermediate II according to claim 1, characterized in that, In step (1), the mass ratio of maleimide, acrylamide, sodium acrylate, N,N'-methylenediacrylamide, porogen and water is 2~3:2~3:0.5~1:0.05~0.08:5~6:30; the porogen is a carbonate.

3. The method for preparing the modified Raney nickel catalyst for the synthesis of pregabalin intermediate II according to claim 1, characterized in that, In step (2), the mass-volume ratio of the nano-titanium dioxide, the aqueous solution of 3-mercaptopropyltriethoxysilane, and the ferrous nitrate solution is 1g:1mL:0.5mL; the mass concentration of the aqueous solution of 3-mercaptopropyltriethoxysilane is 20~30%; and the mass concentration of the ferrous nitrate solution is 15~20%.

4. The method for preparing the modified Raney nickel catalyst for the synthesis of pregabalin intermediate II according to any one of claims 1-3, characterized in that, In step (3), the initiator is persulfate.

5. The method for preparing the modified Raney nickel catalyst for the synthesis of pregabalin intermediate II according to any one of claims 1-3, characterized in that, In step (4), the first solution and the second solution are mixed such that the mass ratio of water in each solution is 3:1; the reaction is carried out in a water bath at 30~40℃ for 1~2 hours.

6. The method for preparing the modified Raney nickel catalyst for the synthesis of pregabalin intermediate II according to claim 1, characterized in that, The Ni-Al alloy comprises 30-50% nickel and 50-70% aluminum by mass fraction, with a total mass percentage of 100%; the alloy powder has a particle size of 100-200 mesh.

7. The method for preparing the modified Raney nickel catalyst for the synthesis of pregabalin intermediate II according to claim 1 or 6, characterized in that, The mass-to-volume ratio of the alloy powder, porous acrylamide gel carrier, and alkaline solution is 10g:2~4g:100mL; the alkaline solution is a sodium hydroxide aqueous solution with a mass concentration of 10~25%.

8. The method for preparing the modified Raney nickel catalyst for the synthesis of pregabalin intermediate II according to claim 1 or 6, characterized in that, The ultrasonic treatment is performed at 70-80℃ for 1-2 hours.

9. A modified Raney nickel catalyst prepared by the preparation method according to any one of claims 1-8.

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