A method for preparing a roxadustat intermediate

Abstract

This invention discloses a method for preparing roxadustat intermediates. Starting with a m-phenoxyacetophenone oxime derivative and a propargyl ester compound, the two react under a catalyst to undergo a cyclization reaction, synthesizing methyl 1-methyl-7-phenoxy-3-isoquinoline carboxylate. Subsequently, the roxadustat intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline carboxylate is prepared via oxidative rearrangement. This synthetic route simplifies the introduction of isoquinoline C-1 methylation, as all the starting materials and reagents are readily available or prepared. It avoids the use of highly hazardous and polluting reagents, making it safe and environmentally friendly. The reaction conditions are mild, the operation is convenient and controllable, and the prepared roxadustat intermediate has high purity and yield, offering significant cost advantages and making it suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a method for preparing a roxadustat intermediate. Background Technology

[0002] Anemia is a common condition in patients with chronic kidney disease (CKD), with high morbidity and mortality rates in both dialysis and non-dialysis CKD patients. CKD can occur at any age, but is more common in the elderly. There are approximately 120 million CKD patients in China. The number of CKD patients receiving dialysis in China exceeds 400,000, and this number is growing rapidly at a double-digit rate, leading to an increasing need for anti-anemia therapy. Current anti-anemia therapy for CKD patients primarily involves erythropoietin injections. Roxadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, offers a more convenient (oral) and safer treatment option.

[0003] Roxadustat, chemically named [(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)amino]acetic acid, traded as Allergan, is a novel oral hypoxia-inducible factor prolyl hydroxylase inhibitor developed by FibroGen (USA) and licensed to Astellas (Japan) and AstraZeneca (UK). It is a novel oral hypoxia-inducible factor prolyl hydroxylase inhibitor that induces erythropoiesis and treats renal anemia. On December 18, 2018, a domestically developed Class 1 original drug, the world's first oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), jointly developed by FibroGen China and AstraZeneca China, received marketing approval from the National Medical Products Administration (NMPA). Roxadustat is approved for the treatment of anemia in CKD dialysis patients, including those undergoing hemodialysis and peritoneal dialysis. Currently, there are several main routes for the synthesis of roxadustat:

[0004] The first synthetic route, patented by the original research company (WO2004108681), involves 11 steps, starting with 3,4-dicyanonitrobenzene, including phenol etherification, potassium hydroxide hydrolysis, glycine cyclization, methanol esterification, sodium metal and tert-butanol cyclization, phosphorus tribromide bromination, sodium hydroxide hydrolysis, n-butyllithium and iodomethane methylation, followed by sodium hydroxide hydrolysis, glycine benzyl ester amidation, and palladium on carbon debenzylation, to obtain roxadustat. This route is lengthy and has a low yield. In particular, the use of the hazardous reagent n-butyllithium in the methylation reaction limits its large-scale industrial production.

[0005]

[0006] Synthesis Route 1

[0007] Synthetic route two, based on Zhejiang Beta Pharma's world patent WO2013013609, optimizes the original drug's process. This route also uses 3,4-dicyanonitrobenzene as the starting material, proceeding sequentially through phenol etherification, potassium hydroxide hydrolysis, acetic anhydride dehydration, methyl cyanoacetate oxazolineation, hydrochloric acid cyclization, phosphorus oxychloride chlorination, palladium-catalyzed methylation, hydrolysis, and amidation to obtain roxadustat. While this route has one less reaction step than the original, it still involves numerous steps. The starting material, 2-cyano-4-nitrobenzonitrile, requires multiple reaction steps, resulting in high costs and a lack of commercially available products. In particular, the use of expensive palladium for catalytic methylation, coupled with a methylation yield of only 33%, significantly increases the cost, making large-scale industrial production difficult.

[0008]

[0009] Synthetic Route 2

[0010] Synthetic route three is a further optimization and improvement of the original research company's world patent WO2014014834. This route uses 2-bromophthalide as the starting material, proceeding sequentially through phenol etherification, thionyl chloride ring-opening chlorination, amino acid substitution, cyclization, hydroxyl alkylation, acetic anhydride acylation, and palladium-on-carbon deprotection to obtain roxadustat. This route involves numerous steps, with complex methyl group introduction requiring multiple protection and deprotection processes. In particular, the use of palladium-on-carbon catalytic deprotection necessitates specialized pressurization equipment, which is unfavorable for industrial production. Therefore, this route is difficult to implement industrially and is costly.

[0011]

[0012] Synthesis Route 3

[0013] Synthetic route four is a new route disclosed by Shanghai Xunhe Pharmaceutical Co., Ltd. in Chinese patent CN106478504A. This route uses m-bromoacetophenone as the starting material, and proceeds sequentially through phenol etherification, hydroxylamine hydrochloride and sodium borohydride reduction amination, 2-carbonylmalonate to Schiff base formation, and finally cyclization to obtain the intermediate roxadustat intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline carboxylate. The starting materials of this route are not easy to obtain and are expensive. The cyclization reaction temperature is high and the reaction conditions are harsh. At the same time, the selectivity of the reaction is poor and it is easy to generate ortho-cyclization byproducts. Therefore, the product cost is high and it is difficult to purify.

[0014]

[0015] Synthetic Route 4

[0016] Synthetic route five is a novel route proposed by Suzhou Mingrui Company in Chinese patent CN104892509. This route uses tyrosine as a starting material and proceeds sequentially through alcohol esterification, halophenyl etherification, acetaldehyde cyclization, base-catalyzed dehydrogenation, hydrogen peroxide-catalyzed hydroxylation, and finally amidation to obtain roxadustat. Compared with the aforementioned routes, this method significantly shortens the number of steps. However, the etherification reaction is prone to side reactions with the amino group, making product purification difficult. Furthermore, the yield of the hydrogen peroxide hydroxylation reaction is low. Therefore, this route requires further improvement and optimization for industrial production.

[0017]

[0018] Synthetic Route 5

[0019] In summary, there are currently many synthetic methods for roxadustat. Most of these methods first synthesize the intermediate methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate, and then proceed to roxadustat via cyclization and other reactions. However, these synthetic routes for preparing the intermediate suffer from drawbacks such as long synthetic routes leading to low yields, the use of expensive catalysts, the use of hazardous reagents, and numerous side reactions making purification difficult. These factors hinder large-scale industrial production. Therefore, developing a green, environmentally friendly, high-yield, low-cost, and highly selective process route for the roxadustat intermediate methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate is urgently needed and holds great promise. Summary of the Invention

[0020] Based on the aforementioned technical problems in the existing technology, the purpose of this application is to provide a method for preparing roxadustat intermediates.

[0021] The technical solution adopted in this invention is as follows:

[0022] A method for preparing a roxadustat intermediate includes the following steps:

[0023] S1: In organic solvent A, the phenoxyacetophenone oxime derivative shown in formula (1) (synthetic method is described in Org Lett, 2019, 21, 2863-2866.) is used as the starting material. Under the action of additives and catalysts, it undergoes a cyclization reaction with the propynyl ester compound shown in formula (2) to obtain 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid ester shown in formula (3);

[0024] S2: Subsequently, the compound of formula (3) undergoes oxidation and rearrangement reactions to obtain the roxadustat intermediate, which is the 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid ester shown in formula (5), and its reaction equation is as follows:

[0025]

[0026] In formulas (2), (3) and (5), the substituent R is a C1-C4 alkyl group, preferably methyl, ethyl or tert-butyl, etc.

[0027] The reaction route of this invention simplifies the method of introducing isoquinoline C-1 methylation, while avoiding the use of precious metal catalysts. It features simple process, convenient operation, no need for column chromatography purification, and high yield.

[0028] The catalyst of the present invention is one or more of divalent copper compounds, divalent nickel compounds, divalent cobalt compounds, trivalent cobalt compounds, and trivalent iron compounds, and is further selected as at least one of copper acetate (II), cobalt acetate tetrahydrate, nickel chloride (II), nickel nitrate hexahydrate (II), cobalt acetylacetonate (II), cobalt acetylacetonate (III), iron acetylacetonate (III), cobalt nitrate hexahydrate, cobalt chloride hexahydrate, cobalt fluoride (II), and cobalt fluoride (III), preferably cobalt acetate tetrahydrate, cobalt nitrate hexahydrate, or cobalt fluoride (II).

[0029] The additives described in this invention are one or more of acetic acid, trifluoroacetic acid, adamantane carboxylic acid, pentovalinic acid, oxalic acid, 2,2,6,6-tetramethyl-3,5-heptadecyl ketone, sodium oxalate, and acetylacetone, preferably pentovalinic acid, 2,2,6,6-tetramethyl-3,5-heptadecyl ketone, or sodium oxalate.

[0030] Further, the molar ratio of compound (1) to catalyst is 1:0.01-0.5, preferably 1:0.1-0.5; the molar ratio of compound (1) to compound (2) is 1:0.7-2.5, preferably 1:1-2; the molar ratio of compound (1) to additive is 1:0.5-2.0, preferably 1:1.

[0031] Further, in step S1, the organic solvent A is at least one of acetonitrile, dichloroethane, methanol, tetrahydrofuran, hexafluoroisopropanol, N,N-dimethylformamide, dimethylacetamide, isopropyl ether, toluene, and dimethyl sulfoxide, preferably at least one of methanol, dimethylacetamide, and toluene; the dispersion concentration of the compound of formula (1) in organic solvent A is 0.1-0.5 mol / L.

[0032] Furthermore, in step S1, the reaction temperature of the cyclization reaction is 30-150℃, preferably 40-110℃.

[0033] Further, after the reaction in step S1, the following post-processing steps are included: directly cooling to room temperature, or concentrating the reaction solution, removing the solvent, and then cooling to room temperature; adding water, and then adding ethyl acetate or dichloromethane for extraction and separation; washing the organic phase first with saturated sodium bicarbonate solution or saturated sodium chloride solution, then washing with water, drying with anhydrous sodium sulfate, concentrating, and recrystallizing the obtained concentrate with ethyl acetate and n-hexane, and drying. The volume ratio of ethyl acetate to n-hexane in the recrystallization is 1:1-5, preferably 1:2-3.

[0034] Further, in step S2, the compound of formula (3) undergoes an oxidation reaction with the oxidant in organic solvent B. The oxidant is at least one of m-chloroperoxybenzoic acid, hydrogen peroxide, peracetic acid, and ozone, preferably m-chloroperoxybenzoic acid. The molar ratio of the oxidant to the compound of formula (3) is 1.4-3.5:1.

[0035] Further, in step S2, the organic solvent B is dichloromethane, acetic acid, chloroform or 1,2-dichloroethane, preferably dichloromethane or 1,2-dichloroethane, and the dispersion concentration of the compound of formula (3) in organic solvent B is 0.1-0.5 mol / L.

[0036] Further, the rearrangement reaction in step S2 includes the following steps: the product of the compound of formula (3) after oxidation is added to a mixture of acetic acid and acetic anhydride, acetate is added, the temperature is raised to 75-85℃ and the reaction is monitored by TLC until the end, the product is concentrated under reduced pressure, water is added and the pH is adjusted to 11-12 with ammonia, the product is extracted with ethyl acetate, separated, the organic phase is washed with water, dried, filtered, concentrated and then refluxed in an acidic solution, the reaction is monitored by TLC until the end, the pH is adjusted to 7-8 with alkali, filtered, and recrystallized with isopropanol to obtain the target product.

[0037] Furthermore, the volume ratio of acetic acid to acetic anhydride is 1:1.5-3, the acetate is sodium acetate, potassium acetate or ammonium acetate, preferably sodium acetate, and the molar ratio of acetate to compound of formula (3) is 1.5 to 3:1.

[0038] Further, the acidic solution is one of the following: a hydrochloric acid-methanol mixture, a hydrochloric acid-ethanol mixture, a sulfuric acid-methanol mixture, or a sulfuric acid-ethanol mixture, with an acid concentration of 2%-10%, preferably 3%-7%; the rearrangement reaction temperature in step S2 is 65-75℃.

[0039] The beneficial effects achieved by this invention are:

[0040] This invention uses the m-phenoxyacetophenone oxime derivative shown in formula (1) and the propynate compound shown in formula (2) as starting materials to prepare methyl 1-methyl-7-phenoxyisoquinoline-3-carboxylate, an intermediate of roxadustat, shown in formula (3). Subsequently, methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate, shown in formula (5), is prepared via an oxidative rearrangement reaction. Compared with existing disclosed technologies, the synthetic route disclosed in this invention has shorter steps, uses inexpensive cobalt metal catalysis, avoids harsh reaction conditions, eliminates the need for column chromatography purification, and achieves 1-position methylation while constructing the isoquinoline core. This invention focuses on investigating the effects of catalysts, additives, organic solvents, and molar equivalents on the reaction. The selection of catalysts, additives, and organic solvents in this invention significantly improves the reaction efficiency. Detailed Implementation

[0041] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0042] The raw materials used in this invention, including the m-phenoxyacetophenone oxime derivative of formula (1) (synthetic method is described in Org Lett, 2019, 21, 2863-2866), m-phenoxyacetophenone, and propyne esters of formula (2), are all commercially available.

[0043] Example 1

[0044] To separate 50 mL three-necked flasks equipped with a magnetic stirrer and thermometer, add m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), cobalt chloride hexahydrate (0.19 g), adamantane carboxylic acid (5 mmol), methyl propynate (12.5 mmol), and toluene (15 mL). After addition, heat to 90 °C and continue reaction for 16 h. After the reaction is completed by TLC monitoring, concentrate the reaction solution to remove toluene, cool the reaction solution to room temperature, add 20 mL of water, and extract three times with ethyl acetate. Combine the organic phases, wash successively with saturated sodium bicarbonate solution and water, dry with anhydrous sodium sulfate, concentrate, and recrystallize the concentrate from ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v). Dry to obtain 1.28 g of methyl 1-methyl-7-phenoxyisoquinoline-3-carboxylate, an intermediate of roxadustat, with a yield of 87.85% and an HPLC purity of 99.7%.

[0045] Example 2

[0046] To separate 50 mL three-necked flasks equipped with a magnetic stirrer and thermometer, add m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), cobalt acetate tetrahydrate (0.49 g), trifluoroacetic acid (5 mmol), tert-butyl propargylate (10 mmol), and hexafluoroisopropanol (15 mL). After addition, heat to 40 °C and continue reaction for 15 h. After the reaction is completed by TLC monitoring, concentrate the reaction solution, cool to room temperature, add 20 mL of water, and extract three times with ethyl acetate. Combine the organic phases, wash successively with saturated sodium bicarbonate solution and water, dry with anhydrous sodium sulfate, concentrate, and recrystallize the concentrate from ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v). Dry to obtain 1.49 g of tert-butyl 1-methyl-7-phenoxyisoquinoline-3-carboxylate, an intermediate of roxadustat, with a yield of 89.31% and an HPLC purity of 99.3%.

[0047] Example 3

[0048] Add m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), acetylacetonate iron (III) (0.71 g), 2,2,6,6-tetramethyl-3,5-heptadecyl dione (10 mmol), methyl propargylate (10 mmol), and isopropyl ether (15 mL) to a 50 mL three-necked flask equipped with a magnetic stir bar and a thermometer. After the addition is complete, heat to 120 °C and reflux for 15 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated and cooled to room temperature. 20 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed successively with saturated sodium chloride and water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was recrystallized from ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v), and dried to give 0.93 g of methyl 1-methyl-7-phenoxyisoquinoline-3-carboxylate, an intermediate of roxadustat, with a yield of 63.15% and an HPLC purity of 93.4%.

[0049] Example 4

[0050] To separate 50 mL three-necked flasks equipped with a magnetic stirrer and thermometer, add m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), cobalt chloride hexahydrate (0.03 g), sodium oxalate (2.5 mmol), ethyl propargylate (10 mmol), and N,N-dimethylformamide (15 mL). After addition, heat to 110 °C and continue reaction for 16 h. After the reaction is complete as monitored by TLC, cool the reaction solution to room temperature, add 40 mL of water, extract three times with dichloromethane, combine the organic phases, wash successively with saturated sodium chloride and water, dry with anhydrous sodium sulfate, filter and concentrate. The concentrate is recrystallized from ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v), and dried to give 0.81 g of roxadustat intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylate, yield 52.89%, HPLC purity 95.5%.

[0051] Example 5

[0052] To separate 50 mL three-necked flasks equipped with a magnetic stirrer and thermometer, add m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), nickel(II) chloride (0.06 g), acetic acid (7.5 mmol), methyl propynate (5 mmol), and toluene (15 mL). After addition, heat to 120 °C and reflux for 17 h. After the reaction is complete as monitored by TLC, concentrate the reaction solution, cool to room temperature, add 20 mL of water, and extract three times with ethyl acetate. Combine the organic phases, wash successively with saturated sodium bicarbonate solution and water, dry with anhydrous sodium sulfate, concentrate, and recrystallize the concentrate from ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v). Dry to obtain 0.93 g of methyl 1-methyl-7-phenoxyisoquinoline-3-carboxylate, an intermediate of roxadustat, with a yield of 63.49% and an HPLC purity of 99.3%.

[0053] Example 6

[0054] To separate 50 mL three-necked flasks equipped with a magnetic stirrer and thermometer, add m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), cobalt(II) acetylacetonate (0.18 g), trifluoroacetic acid (7.5 mmol), tert-butyl propynate (5 mmol), and tetrahydrofuran (15 mL). After addition, heat to 40 °C and continue reaction for 17 h. After the reaction is completed by TLC monitoring, concentrate the reaction solution, cool to room temperature, add 20 mL of water, extract three times with ethyl acetate, combine the organic phases, wash successively with saturated sodium bicarbonate solution and water, dry with anhydrous sodium sulfate, concentrate, and recrystallize the concentrate from ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v), and dry to obtain 1.34 g of tert-butyl 1-methyl-7-phenoxyisoquinoline-3-carboxylate, an intermediate of roxadustat, with a yield of 80.10% and an HPLC purity of 98.5%.

[0055] Example 7

[0056] To separate 50 mL three-necked flasks equipped with a magnetic stirrer and thermometer, add m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), cobalt nitrate hexahydrate (0.22 g), acetylacetone (2.5 mmol), ethyl propynate (6 mmol), and dimethylacetamide (15 mL). After addition, heat to 90 °C and continue reaction for 14 h. After the reaction is complete as monitored by TLC, cool the reaction solution to room temperature, add 40 mL of water, extract three times with ethyl acetate, combine the organic phases, wash successively with saturated sodium chloride and water, dry with anhydrous sodium sulfate, concentrate, and recrystallize the concentrate from ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v). Dry to obtain 1.37 g of roxadustat intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylate, yield 89.13%, HPLC purity 92.1%.

[0057] Example 8

[0058] To separate 50 mL three-necked flasks equipped with a magnetic stirrer and thermometer, add m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), cobalt(II) fluoride (0.24 g), sodium oxalate (10 mmol), tert-butyl propargylate (10 mmol), and dichloroethane (15 mL). After addition, heat to 60 °C and continue reaction for 16 h. After the reaction is complete as monitored by TLC, concentrate the reaction solution, add 20 mL of water to the concentrate, extract three times with ethyl acetate, combine the organic phases, wash successively with saturated sodium chloride and water, dry with anhydrous sodium sulfate, concentrate, and recrystallize the concentrate from ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v), and dry to obtain 1.38 g of tert-butyl 1-methyl-7-phenoxyisoquinoline-3-carboxylate, an intermediate of roxadustat, with a yield of 82.33% and an HPLC purity of 98.2%.

[0059] Example 9

[0060] To separate 50 mL three-necked flasks equipped with a magnetic stirrer and thermometer, add m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), cobalt acetate tetrahydrate (0.06 g), adamantane carboxylic acid (2.5 mmol), ethyl propynate (12.5 mmol), and DMSO (15 mL). After addition, heat to 90 °C and continue reaction for 17 h. After the reaction is complete as monitored by TLC, concentrate the reaction solution, add 40 mL of water, extract three times with ethyl acetate, combine the organic phases, wash successively with saturated sodium bicarbonate solution and water, dry with anhydrous sodium sulfate, concentrate, and recrystallize the concentrate from ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v), and dry to obtain 1.31 g of roxadustat intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylate, yield 85.54%, HPLC purity 92.2%.

[0061] Example 10

[0062] To separate 50 mL three-necked flasks equipped with a magnetic stirrer and thermometer, add m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), copper(II) acetate (0.10 g), trifluoroacetic acid (2.5 mmol), methyl propargylate (7.5 mmol), and acetonitrile (15 mL). After addition, heat to 40 °C and continue reaction for 15 h. After the reaction is complete as monitored by TLC, cool the reaction solution to room temperature, concentrate the reaction solution, add 20 mL of water to the concentrate, extract three times with ethyl acetate, combine the organic phases, wash successively with sodium bicarbonate solution and water, dry with anhydrous sodium sulfate, concentrate, and recrystallize the concentrate from ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v), and dry to obtain 0.88 g of methyl 1-methyl-7-phenoxyisoquinoline-3-carboxylate, an intermediate of roxadustat, with a yield of 60.29% and an HPLC purity of 94.9%.

[0063] Example 11

[0064] To separate 50 mL three-necked flasks equipped with a magnetic stirrer and thermometer, add m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), nickel nitrate hexahydrate (II) (1.5 g), sodium oxalate (7.5 mmol), tert-butyl propargylate (5 mmol), and N,N-dimethylformamide (15 mL). After addition, heat to 120 °C and reflux for 15 h. After the reaction is complete as monitored by TLC, concentrate the reaction solution, cool to room temperature, add 20 mL of water, and extract three times with dichloromethane. Combine the organic phases, wash successively with saturated sodium bicarbonate solution and water, dry with anhydrous sodium sulfate, concentrate, and recrystallize the concentrate from ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v). Dry to obtain 0.87 g of tert-butyl 1-methyl-7-phenoxyisoquinoline-3-carboxylate, an intermediate of roxadustat, with a yield of 52.89% and an HPLC purity of 99.3%.

[0065] Example 12

[0066] To separate 50 mL three-necked flasks equipped with a magnetic stirrer and thermometer, add m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), cobalt(III) fluoride (0.07 g), acetylacetone (2.5 mmol), ethyl propynate (6 mmol), and dimethylacetamide (15 mL). After addition, heat to 150 °C and continue reaction for 14 h. After the reaction is complete as monitored by TLC, cool the reaction solution to room temperature, add 40 mL of water, extract three times with ethyl acetate, combine the organic phases, wash successively with saturated sodium chloride and water, dry with anhydrous sodium sulfate, concentrate, and recrystallize the concentrate from ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v). Dry to obtain 1.35 g of 1-methyl-7-phenoxyisoquinoline-3-carboxylate, an intermediate of roxadustat, with a yield of 88.00% and an HPLC purity of 92.1%. 1 H NMR (400MHz, DMSO-d6) δ8.45(s,1H),8.20(d,J=8.8Hz,1H),7.65(d,J=2.4Hz,1H),7.57(m 1H),7.47(m,2H),7.24(m,1H),7.20–7.08(m,2H),3.90(s,3H),2.77(s,3H). 13C NMR (101MHz, DMSO-d6) δ166.2,158.1,157.8,156.1,139.4,131.9,131.8,130.8,129.9,124.9,124.4,122.6,119.8,112.0,52.6,22.5.

[0067] Example 13

[0068] 1-Methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (1.47 g, 5 mmol) and chloroform (15 mL) were added to a 50 mL two-necked flask equipped with a magnetic stir bar and a thermometer. The system was cooled to 0 °C, and peroxybenzoic acid (7.5 mmol) was added in portions. After the addition was complete, the mixture was brought to room temperature and the reaction was monitored by TLC until it ended (12 h). Quenching with saturated sodium thiosulfate solution, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating to remove solvent, and dissolving the remaining concentrate in a mixture of acetic acid (7.5 mL) and acetic anhydride (15 mL), adding sodium acetate (15 mmol), heating to 80 °C, and monitoring the reaction by TLC until completion (2 h), concentrating under reduced pressure, adding 10 mL of water, and alkalizing the pH to 11-12 with ammonia, extracting with ethyl acetate (10 mL × 2), taking the organic phase, washing with water, drying, filtering, concentrating, and then refluxing in a 7% hydrochloric acid-methanol mixture at 70 °C, monitoring the reaction by TLC until completion (2 h), adjusting the pH to 7-8 with sodium bicarbonate solution, filtering, and recrystallizing with isopropanol to obtain 0.93 g of off-white solid methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid, yield 60.1%, HPLC purity 98.2%.

[0069] Example 14

[0070] Ethyl 1-methyl-7-phenoxyisoquinoline-3-carboxylate (1.54 g, 5 mmol) and glacial acetic acid (20 mL) were added to a 50 mL two-necked flask equipped with a magnetic stirrer and a thermometer. 30% hydrogen peroxide (1.0 mL, 10 mmol) was added dropwise while stirring at room temperature. The temperature was raised to 65–70 °C and the reaction was continued until the addition was complete. The reaction was monitored by TLC until it ended (14 h). After concentration under reduced pressure, the solution was dissolved in a mixture of acetic acid (7.5 mL) and acetic anhydride (15 mL), and potassium acetate (10 mmol) was added. The temperature was raised to 75–85 °C, and the reaction was monitored by TLC until it ended (2 h). The solution was then concentrated under reduced pressure, water was added, and the pH of the solution was adjusted to 11–12 with ammonia. The solution was extracted with ethyl acetate (10 mL × 2). The organic phase was washed with water, dried, filtered, concentrated, and then refluxed in a 10% hydrochloric acid-ethanol mixture at 70 °C. The reaction was monitored by TLC until it ended (2 h). The pH was adjusted to 7–8 with sodium bicarbonate solution, filtered, and recrystallized from isopropanol to give 1.11 g of ethyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate, a white solid, with a yield of 68.5% and an HPLC purity of 98.1%.

[0071] Example 15

[0072] 1-Methyl-7-phenoxyisoquinoline-3-carboxylic acid tert-butyl ester (1.68 g, 5 mmol) and dichloromethane (30 mL) were added to a 50 mL two-necked flask equipped with a magnetic stir bar and a thermometer. The system was cooled to 0 °C, and m-chloroperoxybenzoic acid (7 mmol) was added in portions. After the addition was complete, the mixture was brought to room temperature and the reaction was monitored by TLC until it ended (11 h). Quenching with saturated sodium thiosulfate solution, washing with saturated brine, drying, filtering and concentrating, then dissolving in a mixture of acetic acid (7.5 mL) and acetic anhydride (15 mL), adding sodium acetate (10 mmol), heating to 75–85 °C, and monitoring the reaction by TLC until completion (2 h), concentrating under reduced pressure, adding 10 mL of water and alkalizing the solution with ammonia to pH 11–12, extracting with ethyl acetate (10 mL × 2), taking the organic phase, washing with water, drying, filtering, concentrating, and then refluxing in a 6% hydrochloric acid-methanol mixture at 70 °C, monitoring the reaction by TLC until completion (2 h), adjusting the pH to 7–8 with sodium bicarbonate solution, filtering, and recrystallizing with isopropanol to obtain 1.18 g of off-white solid 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid tert-butyl ester, yield 67.2%, HPLC purity 98.7%. 1 H NMR (400MHz, DMSO-d6) δ12.53–9.36(s,1H),8.25(m,1H),7.52–7.46(m,4H),7.32–7.09(m,3H),3.97(s,3H),2.59(s,3H). 13C NMR(101MHz,DMSO-d6)δ170.9,158.9,155.8,154.6,148.2,132.0,130.9,1 26.0,125.1,123.3,122.6,120.1,118.9,112.1,52.9,21.8.HRMS(ESI):m / z calcd for C 18 H 16 NO4[M+H] + :310.1072,found:310.1057.

[0073] The contents described in this specification are merely an enumeration of the implementation forms of the inventive concept, and the scope of protection of this invention should not be regarded as limited to the specific forms described in the embodiments.

Claims

1. A method for preparing a roxadustat intermediate, characterized in that... Includes the following steps: S1: In organic solvent A, the phenoxyacetophenone oxime derivative shown in formula (1) and the propynyl ester compound shown in formula (2) undergo a cyclization reaction under the action of additives and catalysts to obtain 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid ester shown in formula (3). S2: Subsequently, the compound of formula (3) undergoes oxidation and rearrangement reactions to obtain the roxadustat intermediate, which is the 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid ester shown in formula (5), and its reaction equation is as follows: ； In formulas (2), (3) and (5), the substituent R is a C1-C4 alkyl group; The catalyst is at least one of cobalt(II) acetylacetonate, cobalt(III) acetylacetonate, cobalt acetate tetrahydrate, cobalt nitrate hexahydrate, cobalt chloride hexahydrate, cobalt(II) fluoride, and cobalt(III) fluoride; The additives are one or more of trifluoroacetic acid, adamantane carboxylic acid, sodium oxalate, and acetylacetone; In step S1, organic solvent A is at least one of methanol, dimethylacetamide, and toluene; In step S1, the reaction temperature for the cyclization reaction is 40-110℃.

2. The method for preparing a roxadustat intermediate as described in claim 1, characterized in that... The molar ratio of compound (1) to catalyst is 1:0.01~0.5; the molar ratio of compound (1) to compound (2) is 1:0.7~2.5; the molar ratio of compound (1) to additive is 1:0.5~2.

0.

3. The method for preparing a roxadustat intermediate as described in claim 2, characterized in that... The molar ratio of compound (1) to catalyst is 1:0.1-0.5; the molar ratio of compound (1) to compound (2) is 1:1-2; the molar ratio of compound (1) to additive is 1:

1.

4. The method for preparing a roxadustat intermediate as described in claim 1, characterized in that... In step S1, the dispersion concentration of compound (1) in organic solvent A is 0.1-0.5 mol / L.

5. The method for preparing a roxadustat intermediate as described in claim 1, characterized in that... After the reaction in step S1 is completed, the following post-processing steps are also included: directly cooling to room temperature, or concentrating the reaction solution to remove the solvent and then cooling to room temperature, adding water, and adding ethyl acetate or dichloromethane for extraction and separation. The organic phase is first washed with saturated sodium bicarbonate solution or saturated sodium chloride solution, then washed with water, dried with anhydrous sodium sulfate, concentrated, and the resulting concentrate is recrystallized with ethyl acetate and n-hexane, and dried. The volume ratio of ethyl acetate to n-hexane in the recrystallization is 1:1-5.

6. The method for preparing a roxadustat intermediate as described in claim 5, characterized in that... The volume ratio of ethyl acetate to n-hexane in the recrystallization is 1:2-3.

7. The method for preparing a roxadustat intermediate as described in claim 1, characterized in that... In step S2, the compound of formula (3) undergoes an oxidation reaction with the oxidant in organic solvent B. The oxidant is at least one of m-chloroperoxybenzoic acid, hydrogen peroxide, peracetic acid, and ozone. The molar ratio of the oxidant to the compound of formula (3) is 1.4-3.5:

1.

8. The method for preparing a roxadustat intermediate as described in claim 7, characterized in that... In step S2, the oxidant is m-chloroperoxybenzoic acid.

9. The method for preparing a roxadustat intermediate as described in claim 7, characterized in that... In step S2, the organic solvent B is dichloromethane, acetic acid, chloroform or 1,2-dichloroethane, and the dispersion concentration of the compound of formula (3) in organic solvent B is 0.1-0.5 mol / L.

10. The method for preparing a roxadustat intermediate as described in claim 7, characterized in that... In step S2, the organic solvent B is dichloromethane or 1,2-dichloroethane.

11. The method for preparing a roxadustat intermediate as described in claim 1, characterized in that... Step S2 rearrangement reaction includes the following steps: The product of the compound after oxidation of formula (3) is added to a mixture of acetic acid and acetic anhydride, acetate is added, the temperature is raised to 75-85℃ and the reaction is monitored by TLC until the end, the product is concentrated under reduced pressure, water is added and the pH is adjusted to 11-12 with ammonia, the product is extracted with ethyl acetate, separated, the organic phase is washed with water, dried, filtered, concentrated and then refluxed in an acidic solution, the reaction is monitored by TLC until the end, the pH is adjusted to 7-8 with alkali, filtered, and recrystallized with isopropanol to obtain the target product.

12. The method for preparing a roxadustat intermediate as described in claim 11, characterized in that... The volume ratio of acetic acid and acetic anhydride is 1:1.5-3, the acetate is sodium acetate, potassium acetate or ammonium acetate, and the molar ratio of acetate to compound of formula (3) is 1.5-3:

1.

13. The method for preparing a roxadustat intermediate as described in claim 12, characterized in that... The acetate is sodium acetate.

14. The method for preparing a roxadustat intermediate as described in claim 11, characterized in that... The acidic solution is one of the following: a mixed solution of hydrochloric acid and methanol, a mixed solution of hydrochloric acid and ethanol, a mixed solution of sulfuric acid and methanol, or a mixed solution of sulfuric acid and ethanol, with an acid concentration of 2%-10%; the temperature of the rearrangement reaction in step S2 is 65-75℃.

15. The method for preparing a roxadustat intermediate as described in claim 14, characterized in that... The acid concentration is 3%-7%.

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