Hydrogenation reduction preparation process of apatinib intermediate

Abstract

The invention provides a hydrogenation reduction preparation process of an apatinib intermediate, and relates to the technical field of pharmaceutical chemicals. According to the preparation process of the apatinib intermediate, 1-(4-nitrophenyl) cyclopentane-1-formonitrile and H2 are subjected to a hydrogenation catalytic reaction to prepare 1-(4-aminophenyl) cyclopentane formonitrile, and a used catalyst is a triphenylphosphine sulfide / raney nickel complex. The 1-(4-aminophenyl) cyclopentane formonitrile is prepared by efficiently and highly selectively catalyzing the hydrogenation of 1-(4-nitrophenyl) cyclopentane-1-formonitrile by taking a complex obtained by carrying out coordination complexation on triphenylphosphine sulfide and Raney nickel as a catalyst, and the reaction yield is high, the content of a byproduct is low, and the reaction conditions are mild. Meanwhile, the metal coordination catalyst reduces the consumption of nickel metal, greatly simplifies the process, saves the production cost, and has important industrial application value; the catalyst can be cyclically applied in a high-activity manner, and the catalyst does not need to be supplemented in the cyclically applied process.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical and chemical technology, specifically to a hydrogenation reduction process for preparing apatinib intermediates. Background Technology

[0002] Apatinib, chemically named N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridinemethyl)amino-3-pyridinecarboxamide, has the following structural formula:

[0003]

[0004] Apatinib is an oral small-molecule tyrosine kinase inhibitor whose core target is vascular endothelial growth factor receptor-2 (VEGFR-2). Clinically, apatinib was initially developed for the treatment of advanced gastric cancer, and subsequent studies have expanded its clinical application to various solid tumors such as liver cancer, lung cancer, and breast cancer. The mechanism of action of apatinib mainly revolves around its anti-angiogenic properties, and it operates through multiple pathways. Besides apatinib itself, it exists in various forms in drug development, such as pharmaceutically acceptable salt forms (like mesylate), stereoisomers, and prodrug forms.

[0005] In the preparation of apatinib, 1-(4-aminophenyl)cyclopentanecarboxynitrile is a key intermediate, and its structural formula is as follows:

[0006]

[0007] Currently, research on the synthesis of 1-(4-aminophenyl)cyclopentanecarboxynitrile involves using 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile as a raw material and Pd / C or Pt / C as a catalyst for catalytic hydrogenation; or using a combination of ferric chloride and hydrochloric acid for catalytic reduction; and using iron powder and hydrazine hydrate as reducing agents to achieve the synthesis of the target product.

[0008] For example, patent CN106243031B discloses a method for preparing apatinib. In this method, 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile is reduced to 1-(4-aminophenyl)cyclopentanecarboxynitrile. The reducing agent used in this reduction reaction is iron powder, zinc powder, or sodium dithionite (sodium hydrosulfite). Under reflux conditions, the reducing agent iron powder, in the presence of acetic acid, reduces the nitro group in 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile to an amino group, with a reaction time of 2-8 hours. However, this method, when using iron powder or zinc powder to reduce the nitro group, generates a large amount of iron sludge and zinc sludge, thus polluting the environment. Furthermore, the subsequent processing is cumbersome and complex, affecting the product yield. Patent CN1502608A discloses a method for synthesizing a hexa-aminoamide derivative with angiogenesis-inhibiting activity, in which the preparation of the key intermediate uses a Pd / C catalytic hydrogenation reaction. Patent CN112441941A reports a method for preparing 1-(4-aminophenyl)cyclopentylformonitrile using a Pd / C or Pt / C catalyst. However, the preparation of apatinib intermediates via the addition of Pt / C and Pd / C catalysts suffers from drawbacks such as the inability to reuse catalysts, gradual decrease in catalytic activity, and the need to add or replace the catalyst. Furthermore, the use of expensive precious metals like Pd or Pt results in high production costs, hindering industrial-scale production.

[0009] Therefore, developing a method for synthesizing 1-(4-aminophenyl)cyclopentaneformonitrile that is highly efficient, has high catalyst activity, is low-cost, and environmentally friendly is of great significance for reducing the production cost of apatinib, promoting its large-scale industrial production, and improving its accessibility in the field of cancer treatment. Summary of the Invention

[0010] To address the shortcomings of existing technologies, this invention discloses a hydrogenation reduction process for preparing apatinib intermediates. The aim is to develop a preparation process with high product yield, low by-product content, and the ability to achieve highly active catalyst recycling, thereby reducing catalyst consumption and effectively lowering overall process costs.

[0011] To address at least one of the aforementioned problems, in a first aspect, the present invention proposes a hydrogenation reduction preparation process for apatinib intermediate, wherein 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile is prepared by hydrogenation catalytic reaction of the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile with H2, and the catalyst used is a triphenylphosphine thiosulfate / Raney nickel complex.

[0012] The reaction formula for preparing the apatinib intermediate of this invention is as follows:

[0013]

[0014] Through extensive research and experimentation, the research team of this invention unexpectedly discovered that in the process of preparing 1-(4-aminophenyl)cyclopentanecarboxylonitrile by hydrogenation of 1-(4-nitrophenyl)cyclopentane-1-carboxylonitrile using Raney nickel as a catalyst, the relative amount of nickel to the raw materials has a significant impact on the reaction: when the amount of nickel is too high, although the reaction efficiency can be increased and the reaction time shortened, the reduction of the CN triple bond of the cyano group in 1-(4-nitrophenyl)cyclopentane-1-carboxylonitrile by Raney nickel leads to a decrease in reaction selectivity and an increase in the content of cyano reduction products; while when the amount of nickel is low, not only is the reaction efficiency reduced and the reaction time prolonged, but the reaction selectivity also decreases and the impurity content increases.

[0015] Based on this discovery, the research team further explored the use of coordination complexation to regulate the catalytic activity of nickel catalysts. They innovatively selected triphenylphosphine / Raney nickel complex as the catalyst. In this catalytic process, the phenyl group in triphenylphosphine undergoes coordination complexation with the nickel metal in Raney nickel, thereby regulating the catalytic activity of nickel. At the same time, the steric hindrance provided by the benzene ring of triphenylphosphine can effectively prevent the cyano group from directly contacting the catalyst, thus achieving precise control of the selective hydrogenation reaction process, reducing the occurrence of side reactions, and obtaining high-quality 1-(4-aminophenyl)cyclopentanecarboxynitrile.

[0016] The embodiments of the present invention demonstrate the purity and yield of the product after the hydrogenation reaction of 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile catalyzed by the triphenylphosphine / Raney nickel complex under different reaction conditions.

[0017] In some embodiments, the present invention explores and optimizes the ratio of triphenylphosphine triphenylthionate to Raney nickel in the catalyst. Optionally, the molar ratio of triphenylphosphine triphenylthionate to nickel in Raney nickel is 1:(5-10).

[0018] In some embodiments, the present invention explores and optimizes the amount of triphenylphosphine thiocyanate / Raney nickel complex added in the hydrogenation reaction. Optionally, the mass ratio of the triphenylphosphine thiocyanate / Raney nickel complex to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile is (0.05-0.1):1.

[0019] In some embodiments, the present invention explores and optimizes the control conditions for the hydrogenation reaction.

[0020] Optionally, the temperature of the hydrogenation catalytic reaction is 20–60°C.

[0021] Optionally, the pressure of the hydrogenation catalytic reaction is 0.2 to 0.6 MPa.

[0022] In some embodiments, the present invention explores and optimizes the solvent for the hydrogenation reaction. Optionally, the hydrogenation catalytic reaction is carried out in a first solvent, which includes at least one selected from ethyl acetate, methanol, ethanol, tert-butanol, and isopropanol.

[0023] And / or, the mass ratio of the first solvent to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile is (3-10):1.

[0024] In some embodiments, the preparation process of the apatinib intermediate of the present invention further includes a post-processing step: after the reaction material is depressurized, it is subjected to solid-liquid separation to obtain a catalyst and a filtrate; the catalyst can be recycled, and the filtrate is concentrated to obtain the apatinib intermediate product. In optional examples of the present invention, the catalyst and filtrate can be separated by pressure filtration, filtration, or centrifugation. It should be noted that the specific operation of concentrating the filtrate is not limited in the present invention, and those skilled in the art can choose the method of separating the first solvent and the target product as needed to obtain the 1-(4-aminophenyl)cyclopentaneformitrile product, and the separated first solvent can be recycled.

[0025] In some embodiments, the catalyst can be recycled at least 20 times. The present invention illustrates the technical effect that after the catalyst is recycled 20 times, it can still efficiently catalyze the hydrogenation reaction of 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile without the need for catalyst replenishment.

[0026] Secondly, the present invention proposes a metal coordination catalyst for the hydrogenation reduction preparation of apatinib intermediate, which is formed by coordination of triphenylthiophosphine as a ligand with nickel metal; wherein the nickel metal is Raney nickel, and the molar ratio of nickel in triphenylthiophosphine to Raney nickel is 1:(5-10).

[0027] The research and development team of this invention conducted extensive experimental explorations, the relevant experimental details of which are shown in the embodiments of this invention. In studying metal coordination catalyst systems, the team discovered that triphenylphosphine ligand coordinated with nickel metal can form such catalysts, wherein Raney nickel was selected as the nickel metal.

[0028] However, not all coordination between triphenylphosphine sulfide and nickel metal in Raney nickel yields good results. The research team hypothesized that the coordination complexation of triphenylphosphine sulfide and Raney nickel requires the use of the porous structure of Raney nickel, but this structure also presents challenges: complex and varying pore sizes make ligand molecule migration and anchoring difficult; even if anchored, the formation of a stable coordination structure is affected by various factors, making the construction of heterogeneous coordination structures difficult and requiring precise control of conditions. After repeated experiments, the team found that when the molar ratio of triphenylphosphine sulfide to nickel in Raney nickel is 1:(5-10), the product yield can be significantly improved and the by-product content reduced. It can be inferred that under this molar ratio condition, it is beneficial to promote the anchoring of ligands on the nickel surface, thereby forming a stable heterogeneous coordination structure dominated by surface complexes.

[0029] More importantly, when the metal coordination catalyst of this invention is used in the hydrogenation reduction process of apatinib intermediates, the catalyst can be recycled multiple times without reducing the catalytic activity of nickel. This reduces nickel metal consumption and enables continuous production with high selectivity and high yield without the need for catalyst replenishment. This will greatly simplify the process and reduce costs in large-scale industrial production.

[0030] In some embodiments, the present invention explores and optimizes the nickel loading in Raney nickel, optionally wherein the nickel loading in Raney nickel is 40–80 wt%.

[0031] Thirdly, the present invention proposes a method for preparing the metal coordination catalyst described in the second aspect: Raney nickel and triphenylphosphine are coordinated and complexed in a second solvent to obtain the metal coordination catalyst, wherein the second solvent includes at least one of methanol or ethanol.

[0032] In some embodiments, the present invention explores and optimizes the control conditions for coordination complexation.

[0033] Optionally, the temperature for the coordination complexation is 50–70°C;

[0034] Optionally, the coordination complexation time is 3 to 5 hours.

[0035] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0036] (1) The hydrogenation reduction preparation process of apatinib intermediate of the present invention uses the complex obtained by coordination complexation of triphenylphosphine and Raney nickel as a catalyst to catalyze the hydrogenation of 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile to prepare 1-(4-aminophenyl)cyclopentanecarboxynitrile with high efficiency and high selectivity. The reaction has high yield, low by-product content and mild reaction conditions.

[0037] (2) The metal coordination catalyst of the present invention is formed by triphenylphosphine as a ligand and nickel metal coordination, which reduces the consumption of nickel metal, greatly simplifies the process, saves production costs, and has important industrial application value.

[0038] (3) The metal coordination catalyst of the present invention can be recycled with high activity, and no catalyst needs to be added during the recycling process. Attached Figure Description

[0039] The accompanying drawings, which form part of this application, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings:

[0040] Figure 1 The liquid chromatogram of 1-(4-aminophenyl)cyclopentaneformitrile obtained by concentration and crystallization in Example 9 of the present invention is shown. Detailed Implementation

[0041] To facilitate understanding of the present invention, a more comprehensive description will be provided below, along with preferred embodiments. However, it should be understood that these embodiments are merely for more detailed explanation and should not be construed as limiting the invention in any way, i.e., not intended to limit the scope of protection of the invention.

[0042] Unless otherwise defined, the technical terms used in the following embodiments have the same meanings as commonly understood by those skilled in the art to which this invention pertains. Unless otherwise specified, the experimental reagents used in the following embodiments are all conventional commercially available biochemical reagents; and the experimental methods described are all conventional methods.

[0043] Examples 1-8

[0044] A method for preparing a metal coordination catalyst is described below: A solvent is added to a reaction flask, followed by the addition of triphenylphosphine thiocyanate, and the mixture is heated to a certain temperature and stirred to dissolve. Then, Raney nickel is added. The mixture is stirred under reflux for a certain time, cooled to room temperature, and filtered to obtain a triphenylphosphine thiocyanate / Raney nickel complex. Note that the filtered complex product is the triphenylphosphine thiocyanate / Raney nickel complex. The specific reaction parameters for Examples 1-8 are shown in Table 1.

[0045] Table 1 Specific reaction parameters for Examples 1-8

[0046]

[0047]

[0048] Example 9

[0049] A hydrogenation reduction process for preparing an apatinib intermediate is described below:

[0050] 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile (200 g, 0.925 mol) and 1.0 kg of methanol were added to a high-pressure reactor and dissolved. Then, 20 g of the triphenylphosphine thiocyanate / Raney nickel complex from Example 1 (the molar ratio of triphenylphosphine thiocyanate to nickel in Raney nickel was 1:9.4) was added. The mass ratio of the triphenylphosphine thiocyanate / Raney nickel complex to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was 0.1:1. The reaction system was purged with nitrogen three times, followed by hydrogen purging three times, ensuring the system was filled with hydrogen. The pressure was controlled at 0.4 MPa (hydrogen was maintained at a constant pressure). The reaction was carried out under pressure at 30±2℃ for 6 hours. The reaction was considered complete when the content of the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was ≤0.05%. The reaction was then subjected to reduced pressure, with nitrogen replacing hydrogen. The mixture was then filtered (the filter cake was a triphenylphosphine / Raney nickel complex, which can be reused). The filtrate was added to a rotary evaporator and concentrated to obtain 800g of solvent. 1000g of n-hexane was added, and the mixture was heated to reflux to dissolve the solid. The mixture was then cooled to 10℃, and the solid precipitated. The solid was filtered and washed to obtain 150.7g of product with a purity of 99.3% and a yield of 87.5%.

[0051] Example 10

[0052] A hydrogenation reduction process for preparing an apatinib intermediate is described below:

[0053] 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile (200 g, 0.925 mol) and 1.0 kg of methanol solvent were added to a high-pressure reactor. After dissolution, 10 g of the triphenylphosphine thiocyanate / Raney nickel complex from Example 2 (the molar ratio of triphenylphosphine thiocyanate to nickel in Raney nickel was 1:9.4) was added. The mass ratio of the triphenylphosphine thiocyanate / Raney nickel complex to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was 0.05:1. The reaction system was purged with nitrogen three times, followed by hydrogen three times, until the system was filled with hydrogen gas. The pressure was controlled at 0.4 MPa (hydrogen gas). (Pressure maintained); the temperature was raised to 40±2℃, and the reaction was completed in 8 hours under these conditions. The presence of ≤0.05% of the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile indicated the reaction was complete. The reactants were then subjected to reduced pressure, with nitrogen replacing hydrogen, and filtered (the filter cake was a triphenylphosphine / Raney nickel complex, which could be reused). The filtrate was added to a rotary evaporator and concentrated to obtain 800g of solvent. 1000g of n-hexane was added, and the mixture was heated to reflux to dissolve the solid. The temperature was lowered to 10±2℃, and the solid precipitated. The solid was then filtered and washed to obtain 138.5g of product with a purity of 99.1% and a yield of 80.4%. After up to 20 repetitions of the triphenylphosphine / Raney nickel complex, the target product yield and purity were both satisfactory.

[0054] Example 11

[0055] A hydrogenation reduction process for preparing an apatinib intermediate is described below:

[0056] 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile (200 g, 0.925 mol) and 1.0 kg of ethanol were added to a high-pressure reactor and dissolved. Then, 18 g of the triphenylphosphine thiocyanate / Raney nickel complex from Example 3 (the molar ratio of triphenylphosphine thiocyanate to nickel in Raney nickel was 2:10) was added. The mass ratio of the triphenylphosphine thiocyanate / Raney nickel complex to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was 0.09:1. The reaction system was purged with nitrogen three times, then with hydrogen three times, until the system was filled with hydrogen gas. The pressure was controlled at 0.2 MPa (hydrogen gas). (Maintain pressure); heat to 40±2℃, and react for 9 hours under these conditions. The reaction is considered complete when the content of the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile is ≤0.05%. The reactant is then subjected to reduced pressure, with nitrogen replacing hydrogen. After pressure filtration (the filter cake is a triphenylphosphine / Raney nickel complex, which can be reused), the filtrate is added to rotary evaporator and concentrated to obtain 800g of solvent. 1500g of n-hexane is added, and the mixture is heated to reflux to dissolve the solid. The mixture is then cooled to 10℃, and the solid precipitates. The solid is filtered and washed to obtain 145.5g of product with a purity of 99.2% and a yield of 84.5%.

[0057] Example 12

[0058] A hydrogenation reduction process for preparing an apatinib intermediate is described below:

[0059] 200 g (0.925 mol) of 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile and 600 g of ethyl acetate were added to a high-pressure reactor and dissolved. Then, 12 g of the triphenylphosphine thiocyanate / Raney nickel complex from Example 4 (the molar ratio of triphenylphosphine thiocyanate to nickel in Raney nickel was 1:7) was added. The mass ratio of the triphenylphosphine thiocyanate / Raney nickel complex to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was 0.06:1. The reactor was purged with nitrogen three times, then with hydrogen three times, filling the reaction system with hydrogen gas. The pressure was controlled at 0.6 MPa (hydrogen). (Gas pressure maintained); the temperature was raised to 50±2℃, and the reaction was completed in 5 hours under these conditions. The reaction was considered complete when the content of the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was ≤0.05%. The reaction material was then subjected to reduced pressure, with nitrogen replacing hydrogen. After pressure filtration (the filter cake was a triphenylphosphine / Raney nickel complex, which can be reused), the filtrate was added to rotary evaporation and concentrated to obtain 300g of solvent. 600g of n-hexane was added, and the mixture was heated to reflux to dissolve the solid. The temperature was lowered to 10℃, and the solid precipitated. The solid was then filtered and washed to obtain 153.8g of product with a purity of 98.7% and a yield of 89.3%.

[0060] Example 13

[0061] A hydrogenation reduction process for preparing an apatinib intermediate is described below:

[0062] 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile (200 g, 0.925 mol) and 1200 g of tert-butanol solvent were added to a high-pressure reactor and dissolved. Then, 12 g of the triphenylphosphine thiocyanate / Raney nickel complex from Example 5 (the molar ratio of triphenylphosphine thiocyanate to nickel in Raney nickel was 1:7) was added. The mass ratio of the triphenylphosphine thiocyanate / Raney nickel complex to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was 0.06:1. The system was purged with nitrogen three times, then with hydrogen three times, filling the reaction system with hydrogen gas. The pressure was controlled at 0.6 MPa (hydrogen gas). (Maintain pressure); heat to 50±2℃, and react for 5 hours under these conditions. The reaction is considered complete when the content of the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile is ≤0.05%. The reactant is then subjected to reduced pressure, with nitrogen replacing hydrogen. After pressure filtration (the filter cake is a triphenylphosphine / Raney nickel complex, which can be reused), the filtrate is added to rotary evaporation and concentrated to obtain 500g of solvent. 1500g of n-hexane is added, and the mixture is heated to reflux to dissolve the solid. The mixture is then cooled to 10℃, and the solid precipitates. The solid is filtered and washed to obtain 150.9g of product with a purity of 99.1% and a yield of 87.6%.

[0063] Example 14

[0064] A hydrogenation reduction process for preparing an apatinib intermediate is described below:

[0065] 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile (200 g, 0.925 mol) and 1200 g of tert-butanol solvent were added to a high-pressure reactor and dissolved. Then, 12 g of the triphenylphosphine thiocyanate / Raney nickel complex from Example 6 (the molar ratio of triphenylphosphine thiocyanate to nickel in Raney nickel was 1:8) was added. The mass ratio of the triphenylphosphine thiocyanate / Raney nickel complex to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was 0.06:1. The system was purged with nitrogen three times, then with hydrogen three times, filling the reaction system with hydrogen gas. The pressure was controlled at 0.3 MPa (hydrogen gas). (Maintain pressure); heat to 50±2℃, and react for 7 hours under these conditions. The reaction is considered complete when the content of the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile is ≤0.05%. The reactant is then subjected to reduced pressure, with nitrogen replacing hydrogen. After pressure filtration (the filter cake is a triphenylphosphine / Raney nickel complex, which can be reused), the filtrate is added to rotary evaporation and concentrated to obtain 500g of solvent. 1500g of n-hexane is added, and the mixture is heated to reflux to dissolve the solid. The mixture is then cooled to 10℃, and the solid precipitates. The solid is filtered and washed to obtain 143.3g of product with a purity of 98.4% and a yield of 83.2%.

[0066] Example 15

[0067] A hydrogenation reduction process for preparing an apatinib intermediate is described below:

[0068] 200 g (0.925 mol) of 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile and 600 g of ethyl acetate were added to a high-pressure reactor and dissolved. Then, 16 g of the triphenylphosphine thiocyanate / Raney nickel complex from Example 7 (the molar ratio of triphenylphosphine thiocyanate to nickel in Raney nickel was 1:10) was added. The mass ratio of the triphenylphosphine thiocyanate / Raney nickel complex to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was 0.08:1. The mixture was purged with nitrogen three times, then with hydrogen three times, filling the reaction system with hydrogen gas. The pressure was controlled at 0.5 MPa (hydrogen). (Gas pressure maintained); the temperature was raised to 30±2℃, and the reaction was completed in 5 hours under these conditions. The reaction was considered complete when the content of the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was ≤0.05%. The reactants were then subjected to reduced pressure, with nitrogen replacing hydrogen. The mixture was then filtered (the filter cake was a triphenylphosphine / Raney nickel complex, which can be reused). The filtrate was added to a rotary evaporator and concentrated to obtain 300g of solvent. 1500g of n-hexane was added, and the mixture was heated to reflux to dissolve the solid. The mixture was then cooled to 10℃, and the solid precipitated. The solid was filtered and washed to obtain 155.9g of product with a purity of 99.4% and a yield of 90.5%.

[0069] Example 16

[0070] A hydrogenation reduction process for preparing an apatinib intermediate is described below:

[0071] 200 g (0.925 mol) of 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile and 2000 g of methanol solvent were added to a high-pressure reactor and dissolved. Then, 16 g of the triphenylphosphine thiocyanate / Raney nickel complex from Example 8 (the molar ratio of triphenylphosphine thiocyanate to nickel in Raney nickel was 1:9) was added. The mass ratio of the triphenylphosphine thiocyanate / Raney nickel complex to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was 0.06:1. The reactor was purged with nitrogen three times, then with hydrogen three times, filling the reaction system with hydrogen gas. The pressure was controlled at 0.5 MPa (hydrogen gas). (Maintain pressure); heat to 35±2℃, and react for 5 hours under these conditions. The reaction is considered complete when the content of the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile is ≤0.05%. The reactant is then subjected to reduced pressure, with nitrogen replacing hydrogen. After pressure filtration (the filter cake is a triphenylphosphine / Raney nickel complex, which can be reused), the filtrate is added to rotary evaporation and concentrated to obtain 400g of solvent. 2000g of n-hexane is added, and the mixture is heated to reflux to dissolve the solid. The mixture is then cooled to 10℃, and the solid precipitates. The solid is filtered and washed to obtain 158.7g of product with a purity of 99.6% and a yield of 92.1%.

[0072] Example 17

[0073] A hydrogenation reduction process for preparing an apatinib intermediate is described below:

[0074] 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile (200 g, 0.925 mol) and 1000 g of isopropanol solvent were added to a high-pressure reactor and dissolved. Then, 16 g of the triphenylphosphine thiocyanate / Raney nickel complex from Example 8 (the molar ratio of triphenylphosphine thiocyanate to nickel in Raney nickel was 1:9) was added. The mass ratio of the triphenylphosphine thiocyanate / Raney nickel complex to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was 0.07:1. The reaction system was purged with nitrogen three times, then with hydrogen three times, until the system was filled with hydrogen gas. The pressure was controlled at 0.4 MPa (hydrogen gas). (Maintain pressure); heat to 40±2℃, and react for 5 hours under these conditions. The reaction is considered complete when the content of the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile is ≤0.05%. The reactant is then subjected to reduced pressure, with nitrogen replacing hydrogen. After pressure filtration (the filter cake is a triphenylphosphine / Raney nickel complex, which can be reused), the filtrate is added to rotary evaporation and concentrated to obtain 400g of solvent. 2000g of n-hexane is added, and the mixture is heated to reflux to dissolve the solid. The mixture is then cooled to 10℃, and the solid precipitates. The solid is filtered and washed to obtain 152.8g of product with a purity of 99.2% and a yield of 88.7%.

[0075] The specific parameters of the hydrogenation reduction preparation process of the apatinib intermediates in Examples 9-17 are shown in Table 2.

[0076] Table 2 Specific reaction parameters for Examples 9-16

[0077]

[0078] Comparative Example 1

[0079] Compared to Example 9, Comparative Example 1 used a Raney nickel catalyst, while other conditions were the same as in Example 9; the specific process is as follows:

[0080] 200 g (0.925 mol) of 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile and 1.0 kg of methanol were added to a high-pressure reactor and dissolved. 20 g of Raney nickel was then added, with a Raney nickel mass ratio to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile of 0.1:1. The reactor was purged with nitrogen three times, followed by hydrogen three times, ensuring the reaction system was filled with hydrogen gas. The pressure was controlled at 0.4 MPa (hydrogen pressure maintenance). The temperature was raised to 30 °C. The reaction was carried out at ±2℃ for 4 hours. The reaction was considered complete when the content of the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was ≤0.05%. The reaction mixture was then subjected to reduced pressure, with nitrogen replacing hydrogen. The filtrate obtained by pressure filtration was added to rotary evaporation and concentrated to obtain 800g of solvent. 1000g of n-hexane was added, and the mixture was heated to reflux to dissolve the solid. The mixture was then cooled to 10℃, and the solid precipitated. The solid was filtered and washed to obtain 130.2g of product with a purity of 94.3% and a yield of 75.6%.

[0081] Comparative Example 2

[0082] Compared to Example 9, the mass ratio of the triphenylphosphine thiocyanate / Raney nickel complex to the starting material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile in Comparative Example 2 was 0.04:1, and other conditions were the same as in Example 9; the specific process is as follows:

[0083] 200 g (0.925 mol) of 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile and 1.0 kg of methanol were added to a high-pressure reactor and dissolved. 8 g of the triphenylphosphine thiocyanate / Raney nickel complex from Example 1 (the molar ratio of triphenylphosphine thiocyanate to nickel in Raney nickel was 1:9.4) was then added. The mass ratio of the triphenylphosphine thiocyanate / Raney nickel complex to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was 0.04:1. The reaction system was purged with nitrogen three times, followed by hydrogen purging three times, ensuring the system was filled with hydrogen. The pressure was controlled at 0.4 MPa (hydrogen was maintained at a constant pressure). The reaction was carried out under pressure at 30±2℃ for 6 hours. The reaction was considered complete when the content of the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was ≤0.05%. The reaction was then subjected to reduced pressure, with nitrogen replacing hydrogen. The mixture was then filtered (the filter cake was a triphenylphosphine / Raney nickel complex, which can be reused). The filtrate was added to a rotary evaporator and concentrated to obtain 800g of solvent. 1000g of n-hexane was added, and the mixture was heated to reflux to dissolve the solid. The mixture was then cooled to 10℃, and the solid precipitated. The solid was filtered and washed to obtain 136.5g of product with a purity of 98.1% and a yield of 79.3%.

[0084] Comparative Example 3

[0085] Compared to Example 9, in Comparative Example 3, the molar ratio of triphenylphosphine to nickel in the triphenylphosphine / Raney nickel complex was 1:4, and other conditions were the same as in Example 9; the specific process is as follows:

[0086] 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile (200g, 0.925mol) and 1.0kg of methanol solvent were added to a high-pressure reactor and dissolved. 20g of triphenylphosphine thiocyanate / Raney nickel complex (the molar ratio of triphenylphosphine thiocyanate to nickel in Raney nickel was 1:4) was then added. The mass ratio of triphenylphosphine thiocyanate / Raney nickel complex to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was 0.1:1. The reaction system was purged with nitrogen three times and then with hydrogen three times to fill it with hydrogen. The pressure was controlled at 0.4MPa (hydrogen pressure maintenance). The temperature was raised to 30±2℃, and the reaction was completed in 6 hours under these conditions. The reaction was considered complete when the content of the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was ≤0.05%. The reactants were then subjected to reduced pressure, with nitrogen replacing hydrogen. After pressure filtration (the filter cake was a triphenylphosphine / Raney nickel complex, which can be reused), the filtrate was added to rotary evaporator and concentrated to obtain 800g of solvent. 1000g of n-hexane was added, and the mixture was heated to reflux to dissolve the solid. The mixture was then cooled to 10℃, and the solid precipitated. After filtration and washing, 134.8g of product was obtained with a purity of 98.7% and a yield of 78.3%.

[0087] In summary, under the same conditions, in the hydrogenation reduction process of apatinib intermediates, Example 9, using triphenylphosphine / Raney nickel complex as a catalyst, achieved a product purity of 99.3% and a yield of 87.5%, while Comparative Example 1, using Raney nickel as a catalyst, achieved a product purity of 94.3% and a yield of 75.6%. Therefore, the use of triphenylphosphine / Raney nickel complex as a catalyst in this invention can delay or prevent the occurrence of side reactions, thereby significantly improving the purity and yield of the product and exhibiting superior catalytic performance.

[0088] Comparing Example 9 and Comparative Example 2, in Example 9, the mass ratio of the triphenylphosphine / Raney nickel complex to the starting material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was 0.1:1, resulting in a product purity of 99.3% and a yield of 87.5%. In Comparative Example 2, the mass ratio of the triphenylphosphine / Raney nickel complex to the starting material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile was 0.04:1, resulting in a product purity of 98.1% and a yield of 79.3%. Therefore, when the apatinib intermediate is added... In the hydrogen reduction preparation process, triphenylphosphine thiocyanate / Raney nickel complex is used as a catalyst. However, the catalytic activity of the triphenylphosphine thiocyanate / Raney nickel complex to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile is higher when the mass ratio of the triphenylphosphine thiocyanate / Raney nickel complex to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile is 0.1:1, as demonstrated in Examples 9-17, is better achieved by controlling the mass ratio of the triphenylphosphine thiocyanate / Raney nickel complex to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile within the range of (0.05-0.1):1.

[0089] By comparing Example 9 and Comparative Example 3, the molar ratio of triphenylphosphine to Raney nickel in Example 9 was 1:9.4, with a product purity of 99.3% and a yield of 87.5%. In Comparative Example 3, the molar ratio of triphenylphosphine to nickel in Raney nickel was 1:4, with a product purity of 98.7% and a yield of 78.3%. Therefore, when the hydrogenation reduction process of apatinib intermediate is used, the triphenylphosphine / Raney nickel complex is used as a catalyst. The catalytic activity of the catalyst with a molar ratio of triphenylphosphine to Raney nickel of 1:9.4 is higher than that of the catalyst with a molar ratio of 1:4. Through Examples 10-17, the molar ratio of triphenylphosphine to Raney nickel needs to be controlled in the range of 1:(5-10) to achieve better catalytic performance.

[0090] In addition, the research and development team of this invention selected the material after the reaction in Example 10 for post-processing, and recovered the triphenylphosphine / Raney nickel complex by pressure filtration. They found that the recovered triphenylphosphine / Raney nickel complex can be recycled multiple times with high activity, and has excellent economic value.

[0091] It should be noted that the above description is a further detailed explanation of the present invention in conjunction with specific embodiments, and should not be construed as limiting the specific implementation of the present invention to these descriptions; the specific parameters of this embodiment do not necessarily limit the technical solution, but merely illustrate one specific working condition. For those skilled in the art, several simple improvements and modifications can be made without departing from the concept of the present invention, and all such improvements and modifications should be considered to fall within the scope of protection of the present invention.

Claims

1. A process for preparing apatinib intermediate by hydrogenation reduction, characterized in that, 1-(4-aminophenyl)cyclopentane-1-carboxynitrile was prepared by hydrogenation catalytic reaction of the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile with H2. The catalyst used was a triphenylphosphine thiosulfate / Raney nickel complex.

2. The apatinib intermediate hydrogenation reduction preparation process according to claim 1, characterized in that, In the triphenylphosphine / Raney nickel complex, the molar ratio of triphenylphosphine to nickel in Raney nickel is 1:(5-10).

3. The hydrogenation reduction preparation process for apatinib intermediates according to claim 1, characterized in that, The mass ratio of the triphenylphosphine / Raney nickel complex to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile is (0.05~0.1):

1.

4. The apatinib intermediate hydrogenation reduction preparation process according to claim 1, characterized in that, The temperature of the hydrogenation catalytic reaction is 20–60 °C.

5. The apatinib intermediate hydrogenation reduction preparation process according to claim 1, characterized in that, The pressure of the hydrogenation catalytic reaction is 0.2–0.6 MPa.

6. The apatinib intermediate hydrogenation reduction preparation process according to claim 1, characterized in that, The hydrogenation catalytic reaction is carried out in a first solvent, which includes at least one of ethyl acetate, methanol, ethanol, tert-butanol, and isopropanol. And / or, the mass ratio of the first solvent to the raw material 1-(4-nitrophenyl)cyclopentane-1-carboxynitrile is (3-10):

1.

7. A metal coordination catalyst, characterized in that, It is formed by coordination of triphenylthiophosphine as a ligand with nickel metal; wherein the nickel metal is Raney nickel, and the molar ratio of nickel in triphenylthiophosphine to Raney nickel is 1:(5-10).

8. The metal coordination catalyst according to claim 7, characterized in that, The Raney nickel has a nickel loading of 40–80 wt%.

9. A method for preparing a metal coordination catalyst as described in any one of claims 7-8, characterized in that, The metal coordination catalyst is obtained by coordinating Raney nickel with triphenylphosphine in a second solvent, wherein the second solvent includes at least one of methanol or ethanol.

10. The method for preparing the metal coordination catalyst according to claim 9, characterized in that, The temperature for coordination complexation is 50–70°C; And / or, the coordination complexation time is 3 to 5 hours.

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