A Raney nickel metal alloy catalyst and its preparation method and application in hydrogenation preparation of pregabalin

Abstract

The invention discloses a Raney nickel metal alloy catalyst and a preparation method thereof and an application thereof in hydrogenation preparation of pregabalin, wherein the Raney nickel metal alloy catalyst uses Raney nickel as a carrier to load metal elements, and the Raney nickel mass composition is Ni45-50wt%, Al50-55wt%, and the total amount is 100%; the metal mass loading is 0.1-3wt%. The non-precious metal Raney‑Ni‑X catalyst preparation method provided by the present invention is simple, low in cost, high in activity, and good in selectivity. When catalyzing (S)‑3‑cyano‑5‑methylhexanoic acid hydrogenation to prepare pregabalin, the reaction conditions are mild, the catalyst dosage is reduced by 83%, and the yield is increased from 85% to more than 99%, which can realize industrial production.

Description

(I) Technical field

[0001] The present invention relates to the field of industrial catalysis, and in particular to a Raney nickel metal alloy (Raney-Ni-XY) catalyst for preparing pregabalin by catalytic hydrogenation, and the preparation and application thereof. (II) Background technology

[0002] Pregabalin, chemical name (S)-3-aminomethyl-5-methylhexanoic acid, is a new type of γ-aminobutyric acid (GABA) receptor agonist and a first-line drug for the treatment of postherpetic neuralgia, diabetic peripheral neuropathy, epilepsy, fibromyalgia and other diseases. Compared with traditional drugs such as carbamazepine and phenytoin sodium, pregabalin has the advantages of good efficacy, low dosage and few side effects. After its launch, it quickly became a "blockbuster" drug. In 2019, the global market sales reached US$7.8 billion, ranking among the top best-selling drugs in the world.

[0003] Due to the huge market demand for pregabalin, its synthesis method has also become a research hotspot. For example, patent CN106748850A discloses a method for obtaining pregabalin by Hofmann rearrangement of R-3-(carbamoylmethyl)-5-methylhexanoic acid under the action of sodium hypochlorite and alkali metal hydroxide. However, the hydrogenation process of this method uses a noble metal palladium carbon catalyst, which has the defects of high industrial production cost, long hydrogenation time (15-25h), and low efficiency. Patent CN109942446A reports a method for preparing pregabalin using R-1-(dibenzylamino)-4-methyl-2-chloropentane as a raw material, but its hydrogenation process also requires the use of a noble metal palladium carbon catalyst, and the catalyst dosage is large (47.4% of the raw material mass), which cannot be applied to industrial production.

[0004] Racemic isobutylsuccinonitrile is efficiently hydrolyzed by nitrilase to synthesize (S)-3-cyano-5-methylhexanoic acid (ZL202011383565.4), and the compound can be hydrogenated in one step to prepare pregabalin. This route has fewer steps, high atom economy, and is environmentally friendly. However, the commercial Raney nickel catalyst currently used in this process has a low hydrogenation yield (<85%), many impurities, and a large amount of catalyst (60% of the mass of the raw material) (ZL202110204296.9).

[0005] Therefore, the creation of efficient non-precious metal hydrogenation catalysts is of great significance for the realization of industrial production of pregabalin by chemical-enzymatic method. (III) Summary of the invention

[0006] The present invention aims to provide a Raney nickel metal alloy (Raney-Ni-XY) catalyst and a preparation method thereof and application thereof in hydrogenation preparation of pregabalin. The present invention starts from a cheap Raney-type Ni-based catalyst and obtains a hydrogenation catalyst that can efficiently catalyze (S)-3-cyano-5-methylhexanoic acid to synthesize pregabalin by constructing different metal alloys, thereby laying a foundation for the industrialization of the chemical-enzymatic synthesis process of pregabalin.

[0007] The technical solution adopted by the present invention is:

[0008] The invention provides a Raney nickel metal alloy catalyst, which has a structural formula of Raney-Ni-X, wherein X represents a metal. The Raney nickel metal alloy catalyst uses Raney nickel as a carrier to load metal elements, wherein the mass composition of the Raney nickel is Ni45-50wt%, Al50-55wt%, and the total amount is 100%; and the mass loading of the metal is 0.1-3wt%.

[0009] Preferably, the metal includes any one or two of Mo, Gr, and Fe.

[0010] Preferably, the metal is Gr or Fe, wherein the mass loading of Gr is 2% and the mass loading of Fe is 1%; or the metal is Mo or Gr, wherein the mass loading of Mo is 2% and the mass loading of Gr is 1%.

[0011] The percentage contents of nickel, aluminum and metal in the catalyst prepared by the method of the present invention are measured based on the total amount of nickel and aluminum added.

[0012] The present invention also provides a method for preparing the Raney nickel metal alloy catalyst, which is carried out according to the following steps:

[0013] (1) According to the mass composition, Ni powder, Al powder and metal powder are placed in a graphite crucible, heated to melt, stirred evenly with a graphite rod, and smelted at 1000-2000°C for 1-2 hours, poured into an iron plate, cooled naturally, crushed with a metal crusher, and sieved with 100-200 mesh to obtain alloy powder;

[0014] (2) The alloy powder is added in batches to a sodium hydroxide aqueous solution with a mass concentration of 10-25%, and the powder is stirred at room temperature for activation for 1-3 hours. After activation, the powder is kept at 80-90° C. for 2-3 hours, and then washed with clean water for 3-10 times to obtain a Raney nickel metal alloy catalyst, which is stored in a 0.1 mol / L sodium hydroxide aqueous solution.

[0015] Preferably, step (1) is carried out by melting at 1000° C. for 1 h.

[0016] Preferably, in step (1), the amount of nickel powder added is 45-50% of the total mass of nickel powder and aluminum powder; the amount of aluminum powder added is 50-55% of the total mass of nickel powder and aluminum powder; and the amount of metal powder added is 0.1-3% of the total mass of nickel powder and aluminum powder.

[0017] Preferably, the volume amount of the 10-25% sodium hydroxide aqueous solution in step (2) is 1-5 mL / g, preferably 4 mL / g, based on the mass of the alloy powder.

[0018] Preferably, after activation in step (2), the mixture is kept at 80° C. for 2 h.

[0019] The present invention also provides an application of a Raney nickel metal alloy catalyst in the hydrogenation of (S)-3-cyano-5-methylhexanoic acid to prepare pregabalin. The application method comprises the following steps: placing an aqueous solution of (S)-3-cyano-5-methylhexanoic acid in a hydrogenation reactor, adding the Raney nickel metal alloy catalyst, reacting under the conditions of a reaction pressure of 1-3 MPa, a reaction temperature of room temperature (25-30° C.), and a stirring speed of 300-600 rpm, separating and purifying the reaction liquid after the reaction is complete, and obtaining (S)-3-aminomethyl-5-methylhexanoic acid (pregabalin).

[0020] Preferably, the concentration of the (S)-3-cyano-5-methylhexanoic acid aqueous solution is 200 g / L, and the volume dosage is 10-20 mL / g, preferably 25 mL / g, based on the mass of the catalyst. The reaction pressure is 2 MPa, and the stirring speed is 600 rpm.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] 1) The present invention prepares a non-precious metal Raney-Ni-X catalyst, in particular a four-element catalyst, which has a simple preparation method, low cost, high activity and good selectivity.

[0023] 2) When catalyzing the hydrogenation of (S)-3-cyano-5-methylhexanoic acid to prepare pregabalin, the reaction conditions are mild, the amount of catalyst used is reduced by 83%, and the yield is increased from 85% to more than 99%, which can realize industrial production. (IV) Description of the drawings

[0024] Figure 1 This is the reaction process of synthesizing pregabalin by catalytic hydrogenation of Raney-Ni-Mo-Cr (dosage is 20wt%) in Example 6.

[0025] Figure 2 This is the reaction process of synthesizing pregabalin by catalytic hydrogenation of Raney-Ni-Mo-Cr (dosage is 10 wt%) in Example 7. (V) Specific implementation methods

[0026] The present invention is further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto:

[0027] The percentages of nickel, aluminum and metal in the catalysts of the embodiments of the present invention are measured based on the total amount of nickel and aluminum added.

[0028] Example 1: Preparation of Raney-Ni catalyst and catalytic hydrogenation of (S)-3-cyano-5-methylhexanoic acid

[0029] 1. Raney-Ni catalyst

[0030] (1) Weigh 90 g of Ni powder and 100 g of Al powder respectively and place them in a graphite crucible, heat until molten, stir evenly with a graphite rod, keep melting at 1000°C for 1 hour, pour into an iron plate and cool naturally. After cooling, crush them with a metal crusher and sieve with 100 mesh to obtain 186 g of Ni-Al alloy powder.

[0031] (2) Weigh 20 g of Ni-Al alloy powder and add it in batches to 80 mL of 25% sodium hydroxide aqueous solution, keep stirring at room temperature for 1 hour, keep it at 80°C for 2 hours after activation, and then wash it with clean water 3 times to obtain 12.5 g of Raney-Ni catalyst with a Ni mass fraction of 47.4% and an Al mass fraction of 52.6%, which is stored in 0.1 mol / L sodium hydroxide aqueous solution.

[0032] 2. Application

[0033] 50 mL of 200 g / L (S)-3-cyano-5-methylhexanoic acid aqueous solution was placed in a hydrogenation reactor, and 2 g of the above-prepared hydrogenation catalyst was added. The reaction was carried out for 10 h under the conditions of a reaction pressure of 2 MPa, a reaction temperature of room temperature, and a stirring speed of 600 rpm. Samples were taken and the conversion rate of (S)-3-cyano-5-methylhexanoic acid and the yield of pregabalin were detected by HPLC. The general HPLC detection conditions were: chromatographic column C-18 column; mobile phase A was pH 7.5 phosphate buffer: acetonitrile = 950:50 (v / v); mobile phase B was acetonitrile.

[0034] The results showed that the conversion rate of (S)-3-cyano-5-methylhexanoic acid was 100%, and the yield of pregabalin was 85%.

[0035] Example 2: Preparation of Raney-Ni-Mo Catalyst and Catalytic Hydrogenation of (S)-3-Cyano-5-Methylhexanoic Acid

[0036] 1. Raney-Ni-Mo catalyst

[0037] (1) 90 g of Ni powder, 100 g of Al powder and 3.8 g of Mo powder were weighed and placed in a graphite crucible, heated to melt, stirred evenly with a graphite rod, and melted at 1000°C for 1 h, then poured into an iron plate and cooled naturally. After cooling, the powder was crushed with a metal crusher and sieved with 100 mesh to obtain 189 g of Ni-Al-Mo alloy powder.

[0038] (2) Weigh 20g of Ni-Al-Mo alloy powder and add it to 80mL of 25% sodium hydroxide aqueous solution in batches, keep stirring at room temperature for 1h, keep it at 80℃ for 2h after activation, and then wash the catalyst with water 3 times to obtain 13.1g of Raney-Ni-Mo catalyst, with Ni mass fraction of 47.4%, Al mass fraction of 52.6% and Mo mass loading of 2%. The catalyst was stored in 0.1mol / L sodium hydroxide aqueous solution.

[0039] 2. Application

[0040] 50 mL of 200 g / L (S)-3-cyano-5-methylhexanoic acid aqueous solution was placed in a hydrogenation reactor, 2 g of the above-prepared hydrogenation catalyst was added, and the reaction was carried out for 4 h under the conditions of a reaction pressure of 2 MPa, a reaction temperature of room temperature, and a stirring speed of 600 rpm. The method of Example 1 was used for detection, and the results showed that the conversion rate of (S)-3-cyano-5-methylhexanoic acid was 100%, and the yield of pregabalin was 96.4%.

[0041] Example 3: Construction of Raney-Ni-Cr Catalyst and Catalytic Hydrogenation of (S)-3-Cyano-5-Methylhexanoic Acid

[0042] 1. Raney-Ni-Cr catalyst

[0043] (1) 90 g of Ni powder, 100 g of Al powder and 3.8 g of Cr powder were weighed and placed in a graphite crucible, heated to melt, stirred evenly with a graphite rod, and melted at 1000°C for 1 h, then poured into an iron plate and cooled naturally. After cooling, the powder was crushed with a metal crusher and sieved with 100 mesh to obtain 188.7 g of Ni-Al-Cr alloy powder.

[0044] (2) Weigh 20g of Ni-Al-Cr alloy powder and add it to 80mL of 25% sodium hydroxide aqueous solution in batches, keep stirring at room temperature for 1h, keep it at 80℃ for 2h after activation, and then wash the catalyst with water for 3 times to obtain 12.3g of Raney-Ni-Cr catalyst, with Ni mass fraction of 47.4%, Al mass fraction of 52.6% and Cr mass loading of 2%. The catalyst was stored in 0.1mol / L sodium hydroxide aqueous solution.

[0045] 2. Application

[0046] 50 mL of 200 g / L (S)-3-cyano-5-methylhexanoic acid aqueous solution was placed in a hydrogenation reactor, 2 g of the above-prepared hydrogenation catalyst was added, and the reaction was carried out for 4 h under the conditions of a reaction pressure of 2 MPa, a reaction temperature of room temperature, and a stirring speed of 600 rpm. The method of Example 1 was used for detection, and the results showed that the conversion rate of (S)-3-cyano-5-methylhexanoic acid was 100%, and the yield of pregabalin was 94.8%.

[0047] Example 4: Construction of Raney-Ni-Fe catalyst and catalysis of (S)-3-cyano-5-methylhexanoic acid hydrogenation

[0048] 1. Raney-Ni-Fe catalyst

[0049] (1) 90 g of Ni powder, 100 g of Al powder and 3.8 g of Fe powder were weighed and placed in a graphite crucible, heated to melt, stirred evenly with a graphite rod, and melted at 1000°C for 1 h. The mixture was poured into an iron plate and cooled naturally. After cooling, the mixture was crushed with a metal crusher and sieved with 100 mesh to obtain 188.5 g of Ni-Al-Fe alloy powder.

[0050] (2) Weigh 20g of Ni-Al-Fe alloy powder and add it to 80mL of 25% sodium hydroxide aqueous solution in batches, keep stirring at room temperature for 1h, keep it at 80℃ for 2h after activation, and then wash the catalyst with water for 3 times to obtain 12.0g of Raney-Ni-Fe catalyst, with Ni mass fraction of 47.4%, Al mass fraction of 52.6% and Fe mass loading of 2%. The catalyst was stored in 0.1mol / L sodium hydroxide aqueous solution.

[0051] 2. Application

[0052] 50 mL of 200 g / L (S)-3-cyano-5-methylhexanoic acid aqueous solution was placed in a hydrogenation reactor, 2 g of the above-prepared hydrogenation catalyst was added, and the reaction was carried out for 4 h under the conditions of a reaction pressure of 2 MPa, a reaction temperature of room temperature, and a stirring speed of 600 rpm. The results of the detection using the method of Example 1 showed that the conversion rate of (S)-3-cyano-5-methylhexanoic acid was 100%, and the yield of pregabalin was 95.4%.

[0053] Example 5: Construction of Raney-Ni-Cr-Fe catalyst and catalysis of (S)-3-cyano-5-methylhexanoic acid hydrogenation

[0054] 1. Raney-Ni-Cr-Fe catalyst

[0055] (1) 90 g of Ni powder, 100 g of Al powder, 3.8 g of Cr powder and 1.9 g of Fe powder were weighed and placed in a graphite crucible, heated to melt, stirred evenly with a graphite rod, and melted at 1000°C for 1 h, then poured into an iron plate and cooled naturally. After cooling, the mixture was crushed with a metal crusher and sieved with 100 mesh to obtain 191.0 g of Ni-Al-Cr-Fe alloy powder.

[0056] (2) Weigh 20g of Ni-Al-Cr-Fe alloy powder and add it to 80mL of 25% sodium hydroxide aqueous solution in batches, keep stirring at room temperature for 1h, keep it at 80℃ for 2h after activation, and then wash the catalyst with clean water 3 times to obtain 12.8g of Raney-Ni-Cr-Fe catalyst, with Ni mass fraction of 47.4%, Al mass fraction of 52.6%, Cr mass loading of 2%, and Fe mass loading of 1%. The catalyst was stored in 0.1mol / L sodium hydroxide aqueous solution.

[0057] 2. Application

[0058] 50 mL of 200 g / L (S)-3-cyano-5-methylhexanoic acid aqueous solution was placed in a hydrogenation reactor, 2 g of the above-prepared hydrogenation catalyst was added, and the reaction was carried out for 2 h under the conditions of a reaction pressure of 2 MPa, a reaction temperature of room temperature, and a stirring speed of 600 rpm. The method of Example 1 was used for detection, and the results showed that the conversion rate of (S)-3-cyano-5-methylhexanoic acid was 100%, and the yield of pregabalin was 96.2%.

[0059] Example 6: Construction of Raney-Ni-Mo-Cr Catalyst and Catalytic Hydrogenation of (S)-3-Cyano-5-Methylhexanoic Acid

[0060] 1. Raney-Ni-Mo-Cr catalyst

[0061] (1) 90 g of Ni powder, 100 g of Al powder, 3.8 g of Mo powder and 1.9 g of Cr powder were weighed and placed in a graphite crucible, heated to melt, stirred evenly with a graphite rod, and melted at 1000°C for 1 h, then poured into an iron plate and cooled naturally. After cooling, the powder was crushed with a metal crusher and sieved with 100 mesh to obtain 191.3 g of Ni-Al-Mo-Cr alloy powder.

[0062] (2) Weigh 20g of Ni-Al-Mo-Cr alloy powder and add it to 80mL of 25% sodium hydroxide aqueous solution in batches, keep stirring at room temperature for 1h, keep it at 80°C for 2h after activation, and then wash the catalyst with clean water 3 times to obtain 12.8g of Raney-Ni-Mo-Cr catalyst, with Ni mass fraction of 47.4%, Al mass fraction of 52.6%, Mo mass loading of 2%, and Cr mass loading of 1%. The catalyst was stored in 0.1mol / L sodium hydroxide aqueous solution.

[0063] 2. Application

[0064] 50 mL of 200 g / L (S)-3-cyano-5-methylhexanoic acid aqueous solution was placed in a hydrogenation reactor, and 2 g of the above-prepared hydrogenation catalyst was added. The reaction was carried out for 2 h at a reaction pressure of 2 MPa, a reaction temperature of room temperature, and a stirring speed of 600 rpm. The method of Example 1 was used for detection, and the results were ( Figure 1 ) showed that the conversion rate of (S)-3-cyano-5-methylhexanoic acid was 100% and the yield of pregabalin was 99.8%.

[0065] Example 7: Construction of Raney-Ni-Mo-Cr catalyst and catalytic hydrogenation of (S)-3-cyano-5-methylhexanoic acid to prepare pregabalin

[0066] 1. Raney-Ni-Mo-Cr catalyst

[0067] (1) 90 g of Ni powder, 100 g of Al powder, 3.8 g of Mo powder and 1.9 g of Cr powder were weighed and placed in a graphite crucible, heated to melt, stirred evenly with a graphite rod, and melted at 1000°C for 1 h, then poured into an iron plate and cooled naturally. After cooling, the powder was crushed with a metal crusher and sieved with 100 mesh to obtain 192.3 g of Ni-Al-Mo-Cr alloy powder.

[0068] (2) Weigh 20g of alloy powder and add it to 80mL of 25% sodium hydroxide aqueous solution in batches, keep stirring at room temperature for 1h, keep it at 80°C for 2h after activation, and then wash the catalyst with clean water 3 times to obtain 13.0g of Raney-Ni-Mo-Cr catalyst, with Ni mass fraction of 47.4%, Al mass fraction of 52.6%, Mo mass loading of 2%, and Cr mass loading of 1%. The catalyst was stored in 0.1mol / L sodium hydroxide aqueous solution.

[0069] 2. Application

[0070] 50 mL of 200 g / L (S)-3-cyano-5-methylhexanoic acid aqueous solution was placed in a hydrogenation reactor, and 1 g of the hydrogenation catalyst prepared above was added. The reaction was carried out for 4 h under the conditions of a reaction pressure of 2 MPa, a reaction temperature of room temperature, and a stirring speed of 600 rpm. The method of Example 1 was used for detection, and the results were ( Figure 2 ) showed that the conversion rate of (S)-3-cyano-5-methylhexanoic acid was 100% and the yield of pregabalin was 99.9%.

Claims

1. Use of a Raney nickel metal alloy catalyst in the hydrogenation of (S)-3-cyano-5-methylhexanoic acid to prepare pregabalin, characterized in that: The application method is: placing an aqueous solution of (S)-3-cyano-5-methylhexanoic acid in a hydrogenation reactor, adding a Raney nickel metal alloy catalyst, reacting under the conditions of a reaction pressure of 1-3 MPa, a reaction temperature of room temperature, and a stirring speed of 300-600 rpm, separating and purifying the reaction liquid after the reaction is complete, and obtaining (S)-3-aminomethyl-5-methylhexanoic acid; The Raney nickel metal alloy catalyst uses Raney nickel as a carrier to load metal elements, wherein the mass composition of the Raney nickel is Ni45-50wt%, Al50-55wt%, and the total amount is 100%; the metal is Cr or Fe, wherein the mass loading of Cr is 2% and the mass loading of Fe is 1%; or the metal is Mo or Cr, wherein the mass loading of Mo is 2% and the mass loading of Cr is 1%.

2. The use according to claim 1, characterized in that The Raney nickel metal alloy catalyst is prepared according to the following steps: (1) According to the mass composition, Ni powder, Al powder and metal powder are placed in a graphite crucible, heated to melt, stirred evenly with a graphite rod, and smelted at 1000-2000° C. for 1-2 hours, poured into an iron plate, cooled naturally, crushed with a metal crusher, and sieved with 100-200 mesh to obtain alloy powder; (2) The alloy powder is added in batches to a sodium hydroxide aqueous solution with a mass concentration of 10-25%, and the powder is stirred at room temperature for activation for 1-3 hours. After activation, the powder is kept at 80-90° C. for 2-3 hours, and then washed with clean water for 3-10 times to obtain a Raney nickel metal alloy catalyst, which is stored in a 0.1 mol / L sodium hydroxide aqueous solution.

3. The use according to claim 2, characterized in that Step (1) is to heat and smelt at 1000°C for 1 hour.

4. The use according to claim 2, characterized in that In step (1), the amount of nickel powder added is 45-50% based on the total mass of nickel powder and aluminum powder; the amount of aluminum powder added is 50-55% based on the total mass of nickel powder and aluminum powder; and the amount of metal powder added is 0.1-3% based on the total mass of nickel powder and aluminum powder.

5. The use according to claim 2, characterized in that Step (2) The volume amount of 10-25% sodium hydroxide aqueous solution is 1-5 mL / g based on the mass of the alloy powder.

6. The use according to claim 1, characterized in that The concentration of the (S)-3-cyano-5-methylhexanoic acid aqueous solution is 200 g / L, and the volume usage is 10-20 mL / g based on the mass of the catalyst.

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