A method for preparing roxadustat

Abstract

The application discloses a preparation method of Roxadustat, which comprises the following steps: firstly, condensing compound 1 with a condensing agent under the action of an organic base to obtain a hydroxyl acylation intermediate; and secondly, directly coupling the hydroxyl acylation intermediate with methyl boronic acid under the catalysis of a catalyst to obtain a key intermediate compound 2. The improvement avoids the use of phosphorus oxychloride or phosphorus tribromide, effectively reduces the generation of three wastes, shortens the reaction steps, and improves the reaction yield. In the condensation step with a glycine segment, glycine sodium is used to replace glycine, and the amidation reaction of the glycine sodium with the intermediate compound 2 is studied to obtain the final product roxadustat 3. The improvement also greatly reduces the alkaline decomposition by-product of the intermediate compound 2, improves the reaction yield and the purity of the finished product.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical industry and relates to a method for preparing roxadustat. Background Technology

[0002] Roxadustat (FG-4592) has the chemical name N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline)carbonyl]glycine, with the following structural formula:

[0003]

[0004] Roxadustat is a small molecule oral inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase, jointly developed by Febrogans, Astellas, and AstraZeneca. This drug has shown significant efficacy in treating anemia associated with chronic kidney disease and end-stage renal disease. It has been approved by the FDA and marketed in Europe and the United States, and is particularly effective in treating renal anemia in non-dialysis patients, demonstrating great market potential.

[0005] PCT patent WO2004108681 reports the intermediate of roxadustat and the synthetic route for preparing roxadustat. The key intermediate 1,4-dihydroxy-7-phenoxyisoquinoline-3-carboxylic acid ester is first brominated and hydrolyzed, then alkylated by the reaction of butyllithium with iodomethane and benzyl bromide, followed by hydrolysis to obtain the key intermediate 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid ester. Finally, it is condensed with glycine tert-benzyl ester and debenzinated to obtain the final product roxadustat.

[0006]

[0007] PCT patent WO2014014834 also reports an improved synthetic route for roxadustat. This route utilizes the intermediate 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid ester to react with tetramethylmethanediamine, followed by a substitution reaction with acetic anhydride. Then, methylation of the isoquinoline ring is achieved using palladium on carbon hydrogenation to obtain the key intermediate 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid ester. Finally, it undergoes ammonolysis with glycine to obtain the product. The route is shown below:

[0008]

[0009] In general, the method of introducing a methyl group onto isoquinoline is more cumbersome and lengthy, with Method 1 having a low yield and Method 2 requiring palladium hydrogenation on carbon. Both methods are not very atom-economical, generate significant post-processing waste, and have high costs. Furthermore, regarding the docking strategy between the key intermediate and the glycine fragment in subsequent reactions, Patent Route 1, utilizing glycine benzyl ester, requires an additional deprotection reaction, and this debenzylation requires palladium hydrogenation on carbon. While Patent Route 2 involves a direct one-step reaction, the strong basicity of sodium alkoxide leads to more side reactions and increases the likelihood of alkaline hydrolysis impurities, making final product purification more difficult. Overall, these methods for synthesizing roxadustat are generally too long, have low overall yields, high costs, and are difficult to scale up. There is still a need to find a simpler, lower-cost method suitable for industrial production. Summary of the Invention

[0010] To address the shortcomings of existing technologies, the purpose of this invention is to provide a method for preparing roxadustat. The preparation process of this invention is simple, low-cost, and suitable for industrial production.

[0011] To achieve the purpose of this invention, the following technical solution is adopted:

[0012] A method for preparing roxadustat includes reacting intermediate compound 2 with sodium glycine to obtain roxadustat 3;

[0013]

[0014] In compound 2, R is selected from methyl, ethyl, isopropyl, n-butyl, or benzyl.

[0015] Furthermore, the reaction solvent is selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, or acetonitrile; the reaction temperature is -10 to 130℃.

[0016] Further, after the reaction is completed, the mixture is cooled to room temperature, and the pH is adjusted to weakly acidic by adding acid. The mixture is then pulped, filtered, and the crude product is recrystallized using an organic mixed solvent. The crude product can be selected from a benign solvent or a homogeneous mixture of an inert solvent and a benign solvent: the inert solvent is selected from n-heptane, n-hexane, petroleum ether, or water, and the benign solvent is selected from acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, or toluene.

[0017] As a preferred method for synthesizing compound 2, compound 1 is first condensed with a condensing agent under the action of an organic base to obtain an intermediate state, and then coupled with methylboronic acid in a one-pot reaction under the combined action of a catalyst and an alkali metal salt to obtain compound 2.

[0018]

[0019] In compounds 1 and 2, R is selected from methyl, ethyl, isopropyl, n-butyl, or benzyl.

[0020] Further, the organic base is selected from triethylamine, DIPEA, N,N-dimethylaniline, DBU, or DABCO; the catalyst is selected from palladium on carbon, palladium hydroxide, sodium palladiumate, palladium acetate, palladium chloride, bis(triphenylphosphine)dichloride, or Pd(dppf)Cl2; no ligand is added, or the ligand is selected from triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, S-Phos, X-Phos, XantPhos, or di-tert-butylphenylphosphine; the alkali metal salt is selected from... Sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide, or sodium tert-butoxide; the condensing agent is selected from p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, DCC, EDCI, DIC, BOP, BrOP, or PyBroP; the reaction solvent is selected from 1,4-dioxane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or DMSO; the reaction temperature is 40–130 °C.

[0021] Further, after the reaction is completed, the mixture is cooled to room temperature, water is added to quench the reaction, the mixture is extracted and separated, the organic phase is washed with water, and the crude product is concentrated to obtain a uniform mixture of an inert solvent and a benign solvent for crystallization: the inert solvent is selected from n-heptane, n-hexane, petroleum ether or water, and the benign solvent is selected from acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile or toluene.

[0022] More specifically, a method for preparing roxadustat according to the present invention includes the following steps:

[0023] (1) Under the action of a catalyst, compound 1 is first condensed with a condensing agent under the action of an organic base to obtain an intermediate state, and then coupled with methylboronic acid in a one-pot reaction under the combined action of the catalyst and the alkali metal salt to obtain compound 2.

[0024]

[0025] (2) The compound 2 obtained in step (1) was reacted with sodium glycine to obtain roxadustat 3;

[0026]

[0027] In this compound, R is selected from methyl, ethyl, isopropyl, n-butyl, or benzyl.

[0028] In step (1), the organic base is characterized by being selected from triethylamine, DIPEA, N,N-dimethylaniline, DBU, or DABCO; the catalyst is selected from palladium on carbon, palladium hydroxide, sodium palladiumate, palladium acetate, palladium chloride, bis(triphenylphosphine)dichloride, or Pd(dppf)Cl2; no ligand is added, or the ligand is selected from triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, S-Phos, X-Phos, XantPhos, or di-tert-butylphenylphosphine; The metal salt is selected from sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide, or sodium tert-butoxide; the condensing agent is selected from p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, DCC, EDCI, DIC, BOP, BrOP, or PyBroP; the reaction solvent is selected from 1,4-dioxane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or DMSO; the reaction temperature is 40–130 °C.

[0029] In step (2), the reaction solvent is selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, or acetonitrile; the reaction temperature is -10 to 130°C. The product crystallization solvent is selected from a homogeneous mixture of one inert solvent and one benign solvent: wherein the inert solvent is selected from n-heptane, n-hexane, petroleum ether, or water, and the benign solvent is selected from acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, or toluene.

[0030] This invention relates to a method for preparing roxadustat. The method involves first condensing 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid ester compound 1 with a condensing agent under the action of an organic base to obtain a hydroxylated acylated intermediate. Then, in a one-pot process under catalysis, it is directly coupled with methylboric acid to obtain the key intermediate 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid ester compound 2. This improvement avoids the use of phosphorus oxychloride or phosphorus oxybromide, effectively reducing the generation of waste, shortening the reaction steps, and increasing the reaction yield. In the condensation step with the glycine fragment, sodium glycinate was used to replace glycine, and its amidation reaction with intermediate compound 2 was studied to obtain the final product, roxadustat 3. This improvement also significantly reduces the alkaline hydrolysis byproducts of intermediate compound 2, improving the reaction yield and the purity of the final product. Overall, this method reduces the number of reaction steps, greatly improves the route efficiency, reduces process costs, and reduces the generation of byproducts, which is beneficial for improving the purity of the final product. This route is simple to operate, has a high overall yield, and yields a high-purity product, making it suitable for scale-up production. Detailed Implementation

[0031] The embodiments of the present invention are described in detail below. These embodiments are implemented based on the technical solution of the present invention, and provide detailed implementation methods and specific operation processes. However, the scope of protection of the present invention is not limited to the following embodiments.

[0032] Example 1

[0033]

[0034] Compound 1a (31.13 g, 100 mmol) was added to a three-necked flask, followed by 150 mL of L-MAC and triethylamine (25.30 g, 250 mmol). After stirring to dissolve, BrOP (42.69 g, 110 mmol) was added, and the mixture was reacted at room temperature for 2–3 hours. Methylboric acid (8.98 g, 150 mmol) was added, followed by palladium chloride (177 mg, 1 mmol) and tricyclohexylphosphine ligand (560 mg, 2 mmol) under nitrogen protection. The mixture was then subjected to three vacuum cycles with alternating nitrogen atmospheres. Potassium carbonate (41.46 g, 300 mmol) was added, and 15 mL of deionized water was injected. The mixture was then heated to 100–105 °C for 6–8 hours. After the reaction was completed, the mixture was cooled and quenched with water (150 mL). The mixture was extracted three times with ethyl acetate (150 mL), and the combined organic phases were washed twice with water (150 mL). The mixture was dried over sodium sulfate, filtered through diatomaceous earth, concentrated, and recrystallized from ethyl acetate and n-heptane to give compound 2a (23.92 g, 77.3%).

[0035] In Example 1, the solvent DMAC N,N-dimethylacetamide can be replaced by 1,4-dioxane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, or DMSO; the organic base triethylamine can be replaced by DIPEA, N,N-dimethylaniline, DBU, or DABCO; the condensing agent BrOP can be replaced by p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, DCC, EDCI, DIC, BOP, or PyBroP; the catalyst palladium chloride can be replaced by palladium on carbon, palladium hydroxide, sodium palladiumate, palladium acetate, bis(triphenylphosphine)dichloride, or Pd(dppf)Cl2; the ligand tricyclohexylphosphine can be omitted or replaced by triphenylphosphine, tri-tert-butylphosphine, S-Phos, X-Phos, XantPhos, or di-tert-butylphenylphosphine; and potassium carbonate can be replaced by sodium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide, or sodium tert-butoxide.

[0036] In recrystallization, n-heptane can be replaced by n-hexane, petroleum ether, or water, and ethyl acetate can be replaced by acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, or toluene.

[0037] Example 2

[0038]

[0039] Compound 1b (32.53 g, 100 mmol) was added to a three-necked flask, followed by 160 mL of 1,4-dioxane and triethylamine (25.30 g, 250 mmol). After stirring to dissolve, PyBrOP (51.28 g, 110 mmol) was added, and the mixture was reacted at room temperature for 2–3 hours. Methylboric acid (8.98 g, 150 mmol) was added, followed by palladium acetate (0.225 g, 1 mmol) and the ligand di-tert-butylphenylphosphine (445 mg, 2 mmol) under nitrogen protection. The mixture was then subjected to three vacuum cycles with alternating nitrogen atmospheres. Potassium carbonate (41.46 g, 300 mmol) was added, and 16 mL of deionized water was injected. The mixture was then heated to 100–105 °C and reacted for 6–8 hours. After the reaction was completed, the mixture was cooled and 160 mL of water was added. The mixture was extracted three times with 160 mL of ethyl acetate. The combined organic phases were washed twice with water (160 mL each), dried over sodium sulfate, filtered through diatomaceous earth, concentrated, and recrystallized from ethyl acetate and n-heptane to give compound 2a (27.52 g, 85.1%).

[0040] In Example 2, the solvent 1,4-dioxane can be replaced by N,N-dimethylacetamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, or DMSO; the organic base triethylamine can be replaced by DIPEA, N,N-dimethylaniline, DBU, or DABCO; the condensing agent PyBroP can be replaced by BrOP, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, DCC, EDCI, DIC, or BOP; the catalyst palladium acetate can be replaced by palladium chloride, palladium on carbon, palladium hydroxide, sodium palladiumate, bis(triphenylphosphine)dichloride, or Pd(dppf)Cl2; the ligand di-tert-butylphenylphosphine can be omitted or replaced by tricyclohexylphosphine, triphenylphosphine, tri-tert-butylphosphine, S-Phos, X-Phos, or XantPhos; and potassium carbonate can be replaced by sodium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide, or sodium tert-butoxide.

[0041] In recrystallization, n-heptane can be replaced by n-hexane, petroleum ether, or water, and ethyl acetate can be replaced by acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, or toluene.

[0042] Example 3

[0043]

[0044] Compound 1c (33.93 g, 100 mmol) was added to a three-necked flask, followed by 170 mL of 1,4-dioxane and diisopropylethylamine (32.31 g, 250 mmol). After stirring to dissolve, BrOP (42.69 g, 110 mmol) was added, and the mixture was reacted at room temperature for 2–3 hours. Methylboric acid (8.98 g, 150 mmol) was added, followed by the addition of bis(triphenylphosphine)palladium dichloride (0.702 g, 1 mmol) under nitrogen protection. The nitrogen atmosphere was then switched three times under vacuum. Potassium phosphate (63.68 g, 300 mmol) was added, and 17 mL of deionized water was injected. The mixture was then heated to 100–105 °C and reacted for 6–8 hours. After the reaction was completed, the mixture was cooled and 170 mL of water was added. The mixture was extracted three times with ethyl acetate (170 mL), and the combined organic phases were washed twice with water (170 mL). The mixture was dried over sodium sulfate, filtered through diatomaceous earth, concentrated, and recrystallized from isopropanol and water to give compound 2c (28.17 g, 83.5%).

[0045] In Example 3, the solvent 1,4-dioxane can be replaced by N,N-dimethylacetamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, or DMSO; the organic base diisopropylethylamine (DIPEA) can be replaced by triethylamine, N,N-dimethylaniline, DBU, or DABCO; and the condensing agent BrOP can be replaced by PyBroP, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, DCC, etc. EDCI, DIC, or BOP can be used instead; the catalyst palladium acetate can be replaced by palladium chloride, palladium on carbon, palladium hydroxide, sodium palladium, bis(triphenylphosphine)dichloride palladium, or Pd(dppf)Cl2; the ligand di-tert-butylphenylphosphine can be omitted or replaced by tricyclohexylphosphine, triphenylphosphine, tri-tert-butylphosphine, S-Phos, X-Phos, or XantPhos; potassium phosphate can be replaced by potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, or sodium tert-butoxide.

[0046] Water can be replaced by n-heptane, n-hexane, or petroleum ether as the recrystallization solvent, and ethyl acetate can be replaced by acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, or toluene.

[0047] Example 4

[0048]

[0049] Compound 1d (35.34 g, 100 mmol) was added to a three-necked flask, followed by 176 mL of 1,4-dioxane and triethylamine (25.30 g, 250 mmol). After stirring to dissolve, PyBrOP (51.28 g, 110 mmol) was added, and the mixture was reacted at room temperature for 2–3 hours. Methylboric acid (8.98 g, 150 mmol) was added, followed by palladium acetate (0.225 g, 1 mmol) and the ligand di-tert-butylphenylphosphine (445 mg, 2 mmol) under nitrogen protection. The mixture was then subjected to three vacuum cycles with alternating nitrogen atmospheres. Potassium carbonate (41.46 g, 300 mmol) was added, and 18 mL of deionized water was injected. The mixture was then heated to 100–105 °C and reacted for 6–8 hours. After the reaction was completed, the mixture was cooled and 176 mL of water was added. The mixture was extracted three times with 176 mL of ethyl acetate. The combined organic phases were washed twice with water (176 mL each), dried over sodium sulfate, filtered through diatomaceous earth, concentrated, and recrystallized from ethyl acetate and n-heptane to give compound 2d (30.68 g, 87.3%).

[0050] In Example 4, the solvent 1,4-dioxane can be replaced by N,N-dimethylacetamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, or DMSO; the organic base triethylamine can be replaced by diisopropylethylamine (DIPEA), N,N-dimethylaniline, DBU, or DABCO; and the condensing agent PyBroP can be replaced by BrOP, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, DCC, etc. EDCI, DIC, or BOP can be used instead; the catalyst palladium acetate can be replaced by palladium chloride, palladium on carbon, palladium hydroxide, sodium palladium, bis(triphenylphosphine)dichloride palladium, or Pd(dppf)Cl2; the ligand di-tert-butylphenylphosphine can be omitted or replaced by tricyclohexylphosphine, triphenylphosphine, tri-tert-butylphosphine, S-Phos, X-Phos, or XantPhos; potassium phosphate can be replaced by potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, or sodium tert-butoxide.

[0051] In recrystallization, n-heptane can be replaced by water, n-hexane, or petroleum ether, and ethyl acetate can be replaced by acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, or toluene.

[0052] Example 5

[0053]

[0054] In a three-necked flask, compound 1e (38.74 g, 100 mmol) was added, followed by 194 mL of toluene and triethylamine (25.30 g, 250 mmol). After stirring to dissolve, BOP (48.68 g, 110 mmol) was added, and the mixture was reacted at room temperature for 2–3 hours. Methylboric acid (8.98 g, 150 mmol) was added, followed by the addition of Pd(dppf)Cl2 (0.732 g, 1 mmol) and the ligand Xantphos (0.578 g, 1 mmol) under nitrogen protection. The mixture was then subjected to three separate nitrogen-vacuum reactions. Potassium phosphate (63.68 g, 300 mmol) was added, and 19 mL of deionized water was injected. The mixture was then heated to 100–105 °C and reacted for 6–8 hours. After the reaction was completed, the mixture was cooled and 194 mL of water was added. The mixture was extracted three times with ethyl acetate (194 mL), and the combined organic phases were washed twice with water (194 mL). The mixture was dried over sodium sulfate, filtered through diatomaceous earth, concentrated, and recrystallized from ethyl acetate and n-heptane to give compound 2e (32.90 g, 85.4%).

[0055] In Example 5, the solvent toluene can be replaced by 1,4-dioxane, N,N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, or DMSO; the organic base triethylamine can be replaced by diisopropylethylamine (DIPEA), N,N-dimethylaniline, DBU, or DABCO; and the condensing agent PyBroP can be replaced by BrOP, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, DCC, etc. EDCI, DIC, or BOP can be used instead; the catalyst Pd(dppf)Cl2 can be replaced by palladium acetate, palladium chloride, palladium on carbon, palladium hydroxide, sodium palladium, or bis(triphenylphosphine)dichloride palladium; the ligand XantPhos can be omitted or replaced by di-tert-butylphenylphosphine, tricyclohexylphosphine, triphenylphosphine, tri-tert-butylphosphine, S-Phos, or X-Phos; potassium phosphate can be replaced by potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, or sodium tert-butoxide.

[0056] In recrystallization, n-heptane can be replaced by water, n-hexane, or petroleum ether, and ethyl acetate can be replaced by acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, or toluene.

[0057] Example 6

[0058]

[0059] Compound 2a (30.93 g, 100 mmol) and DMF (155 mL) were added to a three-necked flask and stirred until homogeneous. Sodium glycinate (14.56 g, 150 mmol) was then added. The mixture was heated to 90–95 °C and reacted for 18–24 hours. After the reaction was completed, the mixture was cooled to room temperature, and dilute hydrochloric acid (5% (309 mL)) was slowly added. The mixture was then slowly cooled and stirred to form a slurry. After filtration, the crude product was recrystallized from ethyl acetate and n-heptane to obtain roxadustat product 3 (32.55 g, 92.1%, purity 99.7%).

[0060] In Example 6, the solvent N,N-dimethylacetamide can be replaced by methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, toluene, N,N-dimethylformamide, N-methylpyrrolidone, DMSO, or acetonitrile; the recrystallization solvent n-heptane can be replaced by n-hexane, petroleum ether, or water; and ethyl acetate can be replaced by acetone, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, or toluene.

[0061] Example 7

[0062]

[0063] Compound 2b (32.33 g, 100 mmol) and DMSO (160 mL) were added to a three-necked flask and stirred until homogeneous. Sodium glycinate (14.56 g, 150 mmol) was then added. The mixture was heated to 90–95 °C and reacted for 18–24 hours. After the reaction was completed, the mixture was cooled to room temperature, and dilute hydrochloric acid (5%, 323 mL) was slowly added dropwise. The mixture was then slowly cooled and stirred to form a slurry. After filtration, the crude product was recrystallized from MTBE and n-heptane to obtain roxadustat product 3 (33.79 g, 95.8%, purity 99.9%).

[0064] In Example 7, the solvent DMSO can be replaced by methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or acetonitrile. The recrystallization solvent n-heptane can be replaced by n-hexane, petroleum ether, or water, and MTBE can be replaced by ethyl acetate, acetone, isopropyl acetate, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, or toluene.

[0065] Example 8

[0066]

[0067] Compound 2c (33.64 g, 100 mmol) and N-methylpyrrolidone (168 mL) were added to a three-necked flask and stirred until homogeneous. Sodium glycinate (14.56 g, 150 mmol) was then added. The mixture was heated to 90–95 °C and reacted for 18–24 hours. After the reaction was completed, the mixture was cooled to room temperature, and dilute hydrochloric acid (5%, 336 mL) was slowly added dropwise. The mixture was then slowly cooled and stirred to form a slurry. After filtration, the crude product was recrystallized from isopropanol and n-heptane to obtain roxadustat product 3 (32.61 g, 92.4%, purity 99.8%).

[0068] In Example 8, the solvent N-methylpyrrolidone can be replaced by methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, DMSO, or acetonitrile. The recrystallization solvent n-heptane can be replaced by n-hexane, petroleum ether, or water, and isopropanol can be replaced by ethyl acetate, acetone, isopropyl acetate, MTBE, methanol, ethanol, tetrahydrofuran, acetonitrile, or toluene.

[0069] Example 9

[0070]

[0071] Compound 2d (35.14 g, 100 mmol) and n-butanol (175 mL) were added to a three-necked flask and stirred until homogeneous. Sodium glycinate (14.56 g, 150 mmol) was then added. The mixture was heated to 90–95 °C and reacted for 16–18 hours. After the reaction was completed, the mixture was cooled to room temperature, and dilute hydrochloric acid (5% (351 mL)) was slowly added dropwise. The mixture was then slowly cooled and stirred to form a slurry. After filtration, the crude product was recrystallized from tetrahydrofuran and n-heptane to obtain roxadustat product 3 (30.63 g, 86.6%, purity 99.6%).

[0072] In Example 9, the solvent n-butanol can be replaced by methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, or acetonitrile. The recrystallization solvent n-heptane can be replaced by n-hexane, petroleum ether, or water, and tetrahydrofuran can be replaced by ethyl acetate, acetone, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, acetonitrile, or toluene.

[0073] Example 10

[0074]

[0075] Compound 2e (38.54 g, 100 mmol) and toluene (192 mL) were added to a three-necked flask and stirred until homogeneous. Sodium glycinate (14.56 g, 150 mmol) was then added. The mixture was heated to 90–95 °C and reacted for 18–24 hours. After the reaction was completed, the mixture was cooled to room temperature, and dilute hydrochloric acid (5%, 385 mL) was slowly added dropwise. Most of the solvent was removed by vortexing, and the mixture was slowly cooled and stirred into a slurry. The slurry was filtered, and the crude product was recrystallized from toluene and n-heptane to obtain roxadustat product 3 (29.42 g, 83.2%, purity 99.6%).

[0076] In Example 10, the solvent toluene can be replaced by methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, or acetonitrile. The recrystallization solvent n-heptane can be replaced by n-hexane, petroleum ether, or water, and toluene can be replaced by ethyl acetate, acetone, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, or acetonitrile.

Claims

1. A method for preparing roxadustat, characterized in that... Includes the following steps: 1) Compound 1 is condensed with a condensing agent under the action of an organic base to obtain an intermediate state, and then coupled with methylboronic acid under the combined action of a catalyst and an alkali metal salt to obtain compound 2; ； 2) This includes reacting intermediate compound 2 with sodium glycine to obtain roxadustat compound 3; ； In compounds 1 and 2, R is selected from methyl, ethyl, isopropyl, n-butyl, or benzyl. The catalyst described in step 1) is selected from palladium acetate, palladium chloride, bis(triphenylphosphine)palladium dichloride, or Pd(dppf)Cl2; no ligand is added or the ligand is selected from triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, S-Phos, X-Phos, XantPhos, or di-tert-butylphenylphosphine; the condensing agent is selected from BOP, BrOP, or PyBroP; the reaction solvent is selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, or acetonitrile; Step 2) After the reaction is complete, cool to room temperature, add acid to adjust the pH to weakly acidic, slurry, filter, and recrystallize the crude product using an organic mixed solvent. The organic mixed solvent is selected from a homogeneous mixture of an inert solvent and a benign solvent. The inert solvent is selected from n-heptane, n-hexane, petroleum ether, or water, and the benign solvent is selected from acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, or toluene. The organic base in step 1) is selected from triethylamine, DIPEA, N,N-dimethylaniline, DBU or DABCO; the alkali metal salt is selected from sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide or sodium tert-butoxide. After the reaction in step 1) is completed, the mixture is cooled to room temperature, water is added to quench the reaction, the mixture is extracted and separated, the organic phase is washed with water, and the crude product is concentrated to obtain a uniform mixture of inert and benign solvents for crystallization: the inert solvent is selected from n-heptane, n-hexane, petroleum ether or water, and the benign solvent is selected from acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile or toluene.

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