Preparation method of rosaxostat intermediate

Abstract

The invention provides a preparation method of a rosaxostat intermediate, which is characterized in that 2-bromo-4-fluorobenzoate is used as an initial raw material, and the rosaxostat isoquinoline intermediate is prepared through the reaction processes of coupling, substitution, hydrolysis, condensation and the like. According to the method, low-price initial raw materials are used, and reaction processes which are difficult to control, such as precious metal catalysis, hydrogenation and oxidation, are not needed. The method is simple in process route, simple to operate, low in cost and suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a key intermediate of roxadustat. Background Art

[0002] Roxadustat is a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor developed by FibroGen. By stimulating erythropoiesis, regulating iron metabolism, and reducing hepcidin, it treats renal anemia. It has shown good efficacy in both dialysis-dependent chronic kidney disease (DD-CKD) anemia and non-dialysis-dependent chronic kidney disease (NDD-CKD) anemia, and no increased risk of cardiovascular events has been found. The listing of this drug provides a new treatment option for anemia patients caused by chronic kidney disease.

[0003] The chemical name of roxadustat is: N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinyl)carbonyl]glycine, and its structural formula is as follows:

[0004] The synthetic route of roxadustat reported in the original PCT patent WO2004108681A is as follows:

[0005] Patent WO2014014834A improved the synthetic route of roxadustat. Starting from 5-bromophthalide, after obtaining the isoquinoline ring, it reacts with tetramethylmethanediamine, and then through acetylation, reduction and other steps to complete the methylation reaction of the isoquinoline ring to obtain the key intermediate of roxadustat, methyl 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinecarboxylate. Finally, it undergoes an ammonolysis reaction with glycine to obtain the product. The synthesis process is as follows:

[0006] There are also many domestic enterprises that have applied for patents on the synthesis of roxadustat and its intermediates, including the method for the rearrangement of the oxazole ring intermediate to construct an isoquinoline ring by Beda Pharmaceutical (CN104024227B), the method of Mingrui Medicine to oxidize tetrahydroisoquinoline to isoquinoline starting from 4-hydroxyphenylalanine (CN104892509A), the method of Nanfang Jimin Medicine to prepare an isoquinoline intermediate starting from 4-phenoxyphenol through acetylation, rearrangement, oxidation and other processes (CN109776415A), the method of Cavendish Biotech to prepare an isoquinoline intermediate starting from methyl 4-fluoro-2-bromobenzoate through substitution, catalytic coupling and other processes (CN108794397A), etc. The key point of all the above routes lies in how to rapidly prepare the intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline carboxylate. However, the routes are all relatively long and require dangerous operations such as noble metal catalysis or oxidation, making it difficult to achieve industrialization. The method of Keechao Biotech to synthesize an isoquinoline intermediate starting from 4-phenoxyphthalic anhydride through ring opening with a Grignard reagent and then ring closing (CN110526813A) is currently the shortest route with fewer dangerous reactions. However, its disadvantage is that the starting materials and amine sources are expensive, and its synthesis cost is much higher than that of the original research patent, which is not suitable for large-scale production.

[0007] Summary of the Invention

[0008] To solve the deficiencies of the prior art, the present invention provides a new method for synthesizing Intermediate V. This process uses inexpensive starting materials and does not involve difficult-to-control reaction processes such as noble metal catalysis, hydrogenation, and oxidation. The process route is simple, the operation is straightforward, the cost is low, and it is suitable for large-scale industrial production.

[0009] The solution provided by the present invention is as follows:

[0010] A method for synthesizing a roxadustat intermediate, the synthesis route is as follows:

[0011] Specifically, a method for preparing a roxadustat intermediate includes the following steps:

[0012] 1. Using 2-bromo-4-fluorobenzoate as a starting material, reacting with acetic anhydride in the presence of a metal reagent and a catalyst to obtain Compound II;

[0013] 2. Reacting Compound II with phenol under alkaline conditions to obtain Compound III;

[0014] 3. Compound III reacts with a protecting group removal reagent to obtain Compound IV;

[0015] 4. Compound IV is first prepared into an acyl chloride compound and then undergoes a condensation reaction with methyl diphenylmethylidene glycinate to obtain Intermediate V;

[0016] R1 is methyl, ethyl, isopropyl, or tert-butyl, and R2 is methyl, ethyl, isopropyl, or tert-butyl.

[0017] Furthermore, in Step 1, the reaction temperature is -30 - 0 °C; the reaction solvent is tetrahydrofuran, 2-methyltetrahydrofuran, or toluene.

[0018] Furthermore, in Step 1, the catalyst is one of cuprous chloride, copper chloride, cuprous bromide, cuprous iodide, and copper acetate.

[0019] Furthermore, in Step 1, the reaction metal reagent is one of methylmagnesium bromide, methylmagnesium chloride, isopropylmagnesium bromide, lithium diisopropylamide, and butyllithium.

[0020] Furthermore, in Step 2, the reaction temperature is 25 - 60 °C.

[0021] Furthermore, in Step 2, the reaction solvent is one of DMF, NMP, DMSO, toluene, and ethanol.

[0022] Furthermore, in Step 2, the base is one of potassium carbonate, sodium carbonate, cesium carbonate, and potassium hydroxide.

[0023] Furthermore, in Step 3, the protecting group removal reagent is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, 10% sulfuric acid aqueous solution, 10% hydrochloric acid aqueous solution, and trifluoroacetic acid.

[0024] Furthermore, in Step 4, Compound IV is prepared into an acyl chloride compound with N,N-dimethylformamide and an acylating reagent.

[0025] Preferably, the acylating reagent in Step 4 is thionyl chloride, phosphorus oxychloride, or oxalyl chloride.

[0026] Furthermore, in Step 4, the condensation reaction temperature is 0 - 40 °C.

[0027] Furthermore, in Step 4, the base used in the condensation reaction is potassium tert-butoxide, and the acid is hydrochloric acid ethanol or p-toluenesulfonic acid.

[0028] Advantages of the present invention: The present invention provides a new method for synthesizing intermediate (V). The raw materials are cheap and easily available, the synthesis route is simple, the reaction steps are few, the product can meet the production requirements after slurrying, the yield is high, the use of difficult-to-control reactions such as noble metal catalysis, oxidation, and hydrogenation is avoided, the pollution is small, the production cost is low, and it is suitable for industrial production. Detailed implementation manners

[0029] The present invention will be further described in conjunction with specific embodiments, but the content of the present invention is not limited thereto.

[0030] Example 1

[0031] (1) Synthesis of methyl 2-acetyl-4-fluorobenzoate (II-1)

[0032] In reactor 1, dissolve methyl 2-bromo-4-fluorobenzoate (462.9 g, 2.0 mol) in anhydrous tetrahydrofuran (2.3 L). After complete dissolution, add copper(I) iodide (3.8 g, 0.02 mol) to the reaction system, and cool the reaction system to -30°C. Control the reaction temperature not higher than -25°C, and dropwise add iPrMgCl·LiCl (1.3 M, THF) (1.7 L, 2.2 mol). After the dropping is completed, maintain the reaction at -20°C for 3 hours. In reactor 2, add acetic anhydride (510.0 g, 5.0 mol) and anhydrous tetrahydrofuran (1.0 L), stir the system evenly and cool it to -30°C. After stabilization, slowly drop the materials in reactor 1 into reactor 2, and control the temperature not higher than -20°C during this period. After the dropping is completed, maintain the reaction at -30°C for 0.5 h. After detecting the completion of the reaction by liquid phase, slowly drop water (2.3 L) into the reaction system. After the dropping is completed, heat the system to room temperature. Separate the liquid, concentrate the organic phase until no liquid flows out, and recrystallize the residue with ethyl acetate / n-heptane to obtain methyl 2-acetyl-4-fluorobenzoate (II-1) (350.0 g, 90%). MS (ESI) m / z = 197.1; NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 8.4, 5.0 Hz, 1H), 7.61 (dd, J = 8.0, 2.7 Hz, 1H), 7.25 (td, J = 8.4, 2.7 Hz, 1H), 3.92 (s, 3H), 2.67 (s, 3H).

[0033] Here, the tetrahydrofuran can be replaced by 2-methyltetrahydrofuran or toluene, and the copper(I) iodide can be replaced by copper(I) chloride, copper(II) chloride, copper(I) bromide or copper(II) acetate.

[0034] (2) Synthesis of methyl 2-acetyl-4-phenoxybenzoate (Ⅲ-1)

[0035] Methyl 2-acetyl-4-fluorobenzoate (Ⅱ-1) (350.0 g, 1.8 mol) was added to DMF (1.7 L). After stirring until clear, potassium carbonate (166.0 g, 2.2 mol) and phenol (178.1 g, 1.9 mol) were added. After replacing the reaction system with nitrogen, the temperature was raised to 60 °C and the reaction was carried out for 5 h. After the reaction was completed, the temperature was lowered to 10 °C, and water (5 L) was added dropwise to the reaction system. After the addition was completed, the mixture was stirred at room temperature for 3 h. The system was filtered, and the filter cake was washed with water (1.5 L×3). The filter cake was dried in vacuo to obtain methyl 2-acetyl-4-phenoxybenzoate (Ⅲ-1) (443.6 g, 91.2%). MS (ESI) m / z = 271.1; NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 2.7 Hz, 1H), 7.40 - 7.32 (m, 2H), 7.12 (tt, J = 7.5, 1.5 Hz, 1H), 7.06 - 6.98 (m, 2H), 6.89 (dd, J = 8.4, 2.7 Hz, 1H).

[0036] Here, DMF can be replaced by DMSO, NMP, toluene or ethanol, and potassium carbonate can be replaced by sodium carbonate, cesium carbonate or potassium hydroxide.

[0037] (3) Synthesis of 2-acetyl-4-phenoxybenzoic acid (Ⅳ-1)

[0038] Methyl 2-acetyl-4-phenoxybenzoate (Ⅲ-1) (432.1 g, 1.6 mol) was suspended in methanol / water (1:1, 2.5 L), and while maintaining the temperature not higher than 20 °C, sodium hydroxide (120.0 g, 3.2 mol) was added in batches. After the addition was completed, the reaction was carried out at room temperature until completely dissolved, and the reaction was monitored by liquid phase. Most of the methanol was concentrated under reduced pressure, and 2 M dilute hydrochloric acid was added dropwise to the residue to adjust the pH to 4 - 5, and a large amount of solid precipitated. The mixture was stirred at a constant temperature for 3 h, and after filtration, the filter cake was washed with water (0.5 L×3). The filter cake was dried to obtain 2-acetyl-4-phenoxybenzoic acid (Ⅳ-1, 383.5 g, 93.6%). MS (ESI) m / z = 256.0; 1HNMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 1H), 7.47 (q, J = 7.7 Hz, 2H), 7.31 (d, J = 6.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 3H), 7.09 (s, J = 12.6 Hz, 1H), 1.93 (s, 3H).

[0039] Here, sodium hydroxide can be replaced by potassium hydroxide, lithium hydroxide, 10% sulfuric acid aqueous solution, 10% hydrochloric acid aqueous solution.

[0040] (4) Synthesis of intermediate methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (Ⅴ-1)

[0041] Suspend 2-acetyl-4-phenoxybenzoic acid (Ⅳ-1, 358.5 g, 1.4 mol) in dichloromethane (1.8 L) in reactor 1, add N,N-dimethylformamide (1.0 g, 0.014 mol), and cool the reaction system to 0 °C. Keep the temperature not exceeding 5 °C, and dropwise add thionyl chloride (178.5 g, 1.5 mol). After the addition is completed, heat up to reflux and react for 5 h. After the raw materials are completely reacted, concentrate the reaction system. After no liquid flows out, add anhydrous tetrahydrofuran (0.3 L) to the residue for azeotropic distillation. After distilling to dryness again, add anhydrous tetrahydrofuran (0.5 L) to dissolve. Add tetrahydrofuran (1.2 L) to reactor 2, cool to 0 °C, and successively add potassium tert-butoxide (188.5 g, 1.7 mol) and methyl diphenylmethyleneglycinate (354.6 g, 1.4 mol). Then slowly drop the solution in reactor 1 into reactor 2. Keep the reaction at 0 °C for 3 h. After the reaction is completed, filter the system. Dropwise add 4 N hydrochloric acid methanol solution to the filtrate until pH = 1 - 2, and heat up to 40 °C to react for 4 h. After the reaction is completed, concentrate the reaction system to dryness, add 600 mL of ethyl acetate to the residue to dissolve, and add 200 mL * 3 of water to wash the ethyl acetate solution. Separate the organic phase and concentrate it until no more liquid flows out. Add ethyl acetate / n-heptane (1:2, 1 L) to slurry. Filter, wash the filter cake with n-heptane (0.5 L), and dry to obtain intermediate methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (Ⅴ-1, 390.2 g, yield 90.3%, purity 98%). MS(ESI) m / z = 210.1; 1HNMR (500 MHz, CDCl3) δ 8.05 (d, J =8.4 Hz, 1H), 7.56 (d, J = 2.8 Hz, 1H), 7.37-7.33 (m, 3H), 7.14-7.07 (m, 3H),7.02-6.99 (m, 3H), 3.93 (s, 3H), 2.95 (s, 3H).

[0042] Thionyl chloride here can be replaced by phosphorus oxychloride or oxalyl chloride.

[0043] Example 2

[0044] (1) Synthesis of tert-butyl 2-acetyl-4-fluorobenzoate (Ⅱ-2)

[0045] Dissolve tert-butyl 2-bromo-4-fluorobenzoate (548.0 g, 2.0 mol) in anhydrous tetrahydrofuran (2.7 L) in reactor 1. After complete dissolution, add copper(I) chloride (2.0 g, 0.02 mol) to the reaction system, and cool the reaction system to -30 °C. Control the reaction temperature not higher than -25 °C, and drip iPrMgCl·LiCl (1.3 M, THF) (1.7 L, 2.2 mol). After the dripping is completed, keep the reaction at -20 °C for 3 hours. Add acetic anhydride (510.0 g, 5.0 mol) and anhydrous tetrahydrofuran (1.0 L) to reactor 2, stir the system evenly and cool it to -30 °C. After stabilization, slowly drip the materials in reactor 1 into reactor 2, and control the temperature not higher than -10 °C during this period. After the dripping is completed, keep the reaction at -20 °C for 0.5 h. After detecting the completion of the reaction by liquid phase, slowly drip water (2.3 L) into the reaction system. After the dripping is completed, heat the system to room temperature. Separate the liquid, concentrate the organic phase until no liquid flows out, and recrystallize the residue with ethyl acetate / n-heptane to obtain tert-butyl 2-acetyl-4-fluorobenzoate (Ⅱ-2) (442.8 g, 93%). MS (ESI) m / z = 239.1; 1 HNMR (500 MHz, CDCl3) δ 7.90 (dd, J = 8.4,5.0 Hz, 1H), 7.61 (dd, J = 8.0, 2.7 Hz, 1H), 7.28 (td, J = 8.2, 2.7 Hz, 1H),2.67 (s, 3H), 1.54 (s, 9H).

[0046] Here, tetrahydrofuran can be replaced by 2-methyltetrahydrofuran or toluene, and copper(I) chloride can be replaced by copper(I) iodide, copper(II) chloride, copper(I) bromide or copper(II) acetate.

[0047] (2) Synthesis of tert-butyl 2-acetyl-4-phenoxybenzoate (Ⅲ-2)

[0048] Add tert-butyl 2-acetyl-4-fluorobenzoate (Ⅱ-2) (428.6 g, 1.8 mol) to DMSO (2.2 L). After stirring until it becomes clear, add cesium carbonate (717.2 g, 2.2 mol) and phenol (178.1 g, 1.9 mol). After purging the reaction system with nitrogen, heat it to 60 °C and react for 5 h. After the reaction is completed, cool it to 10 °C and add water (6 L) dropwise to the reaction system. After the addition is complete, stir at room temperature for 3 h. Filter the system and wash the filter cake with water (1.5 L×3). The filter cake is dried under vacuum to obtain tert-butyl 2-acetyl-4-phenoxybenzoate (Ⅲ-2) (508.5 g, 90.5%). MS (ESI) m / z = 313. 1 HNMR (400 MHz, CDCl3) δ7.93 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 2.7 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.12(tt, J = 7.3, 1.4 Hz, 1H), 7.06 - 7.00 (m, 2H), 6.89 (dd, J = 8.4, 2.7 Hz, 1H),2.66 (s, 3H), 1.55 (s, 9H).

[0049] Here, DMSO can be replaced by DMF, NMP, toluene or ethanol, and cesium carbonate can be replaced by potassium carbonate, cesium carbonate or potassium hydroxide.

[0050] (3) Synthesis of 2-acetyl-4-phenoxybenzoic acid (Ⅳ-2)

[0051] Dissolve tert-butyl 2-acetyl-4-phenoxybenzoate (Ⅲ-2) (499.4 g, 1.6 mol) in dichloromethane (2 L), and keep the temperature not higher than 10 °C. Drop trifluoroacetic acid (729.7 g, 4.8 mol) into the reaction system. After the addition is complete, heat it to room temperature and react for 5 h. Monitor the reaction by liquid phase until it is completed. Concentrate it to dryness under reduced pressure, and slurry the residue with ethyl acetate / n-heptane (1:3 = 1.0 L). Stir at room temperature for 3 h and then filter. Wash the filter cake with n-heptane (0.5 L×3). The filter cake is dried to obtain 2-acetyl-4-phenoxybenzoic acid (Ⅳ-2) (340.9 g, 83.2%). MS(ESI) m / z=256.01; 11H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 1H), 7.47 (q, J = 7.7 Hz, 2H), 7.31 (d, J = 6.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 3H), 7.09 (s, J = 12.6 Hz, 1H), 1.93 (s, 3H).

[0052] (4) Synthesis of intermediate ethyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (Ⅴ-2)

[0053] Suspend 2-acetyl-4-phenoxybenzoic acid (Ⅳ-2) (332.9 g, 1.3 mol) in dichloromethane (1.8 L) in reactor 1, add N,N-dimethylformamide (1.0 g, 0.014 mol), and cool the reaction system to 0 °C. Keep the temperature not exceeding 5 °C and add oxalyl chloride (177.8 g, 1.4 mol) dropwise. After the dropwise addition is completed, heat up to reflux and react for 5 h. After the raw materials are reacted completely, concentrate the reaction system. After no liquid flows out, add anhydrous tetrahydrofuran (0.3 L) to the residue for azeotropic distillation. After distilling to dryness again, add anhydrous tetrahydrofuran (0.5 L) to dissolve. Add tetrahydrofuran (1.1 L) to reactor 2, cool to 0 °C, and successively add potassium tert-butoxide (179.5 g, 1.6 mol) and ethyl diphenylmethylglycinate (347.5 g, 1.3 mol). Then slowly add the solution in reactor 1 to reactor 2. Keep the reaction at 0 °C for 3 h. After the reaction is completed, filter the system. Add p-toluenesulfonic acid (447.7 g, 2.6 mol) to the filtrate and heat up to 60 °C to react for 4 h. After the reaction is completed, concentrate the reaction system to dryness, add 600 mL of ethyl acetate to the residue to dissolve, and add 200 mL × 3 of water to wash the ethyl acetate solution. Separate the organic phase and concentrate it until no more liquid flows out. Add ethyl acetate / n-heptane (1:2, 1 L) to slurry. Filter, wash the filter cake with n-heptane (0.5 L), and dry to obtain intermediate ethyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (Ⅴ-2) (370.9 g, yield 88.3%, purity 98.6%). MS(ESI) m / z = 324.1; 11H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 2.8 Hz, 1H), 7.39 - 7.31 (m, 2H), 7.15 - 7.06 (m, 3H), 7.04 - 6.96 (m, 2H), 4.36 (q, J = 7.0 Hz, 2H), 2.96 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H).

[0054] Here, oxalyl chloride can be replaced by phosphorus oxychloride or thionyl chloride.

[0055] The scope of protection of the present invention includes but is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the technical scope protected by the present invention shall be included within the scope of protection of the invention.

Claims

1. A preparation method of roxadustat intermediate, characterized in that , including the following steps: (1) Using 2-bromo-4-fluorobenzoate as the starting material, reacting with acetic anhydride in the presence of a metal reagent and a catalyst to obtain Compound II ； (2) Reacting Compound II with phenol under alkaline conditions to obtain Compound III ； (3) Reacting Compound III with a protecting group removing reagent to obtain Compound IV ； (4) First preparing Compound IV into an acyl chloride compound and then performing a condensation reaction with methyl diphenylmethylglycinate to obtain Intermediate V 。 2. The R1 is methyl, ethyl, isopropyl or tert-butyl, and the R2 is methyl, ethyl, isopropyl or tert-butyl.

3. The preparation method according to claim 1, characterized in that: The reaction temperature in step (1) is -30 - 0 °C; the reaction solvent is one of tetrahydrofuran, 2-methyltetrahydrofuran, and toluene.

4. The preparation method according to claim 1, wherein: The catalyst in step (1) is one of copper(I) chloride, copper(II) chloride, copper(I) bromide, copper(I) iodide, and copper(II) acetate.

5. The preparation method according to claim 1, characterized in that: The reaction metal reagent in step (1) is one of methylmagnesium bromide, methylmagnesium chloride, isopropylmagnesium bromide, lithium diisopropylamide, and butyllithium.

6. The preparation method according to claim 1, characterized in that: The reaction temperature in step (2) is 25 - 60 °C, the reaction solvent is one of DMF, NMP, DMSO, toluene, and ethanol, and the base in the reaction is one of potassium carbonate, sodium carbonate, cesium carbonate, and potassium hydroxide.

7. The preparation method according to claim 1, wherein: The protecting group removing reagent in step (3) is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, 10% sulfuric acid aqueous solution, 10% hydrochloric acid aqueous solution, and trifluoroacetic acid.

8. The preparation method according to claim 1, characterized in that: In step (4), Compound IV is prepared into an acyl chloride compound with N,N-dimethylformamide and an acylating reagent.

9. The preparation method according to claim 7, wherein: The acylating reagent in step (4) is thionyl chloride, phosphorus oxychloride, or oxalyl chloride.

10. The preparation method according to claim 1, characterized in that: The condensation reaction temperature in step (4) is 0 - 40 °C, the base used in the condensation reaction in step (4) is potassium tert-butoxide, and the acid is hydrochloric acid ethanol or p-toluenesulfonic acid.

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