Synthesis method for roxadustat intermediate

Abstract

Disclosed in the present invention are a synthesis method for a Roxadustat intermediate, comprising the following steps: (1) under the action of an acidic catalyst, reacting compound II p-bromo-α-phenylethylamine with 2-oxomalonic acid to obtain compound III; (2) under the action of a Cu(I) compound, a ligand, and a base, carrying out Ullmann reaction on compound III and phenol to obtain compound IV; (3) under the action of TfOH / TFAA, carrying out ring-closing reaction on compound IV to obtain compound V; and (4) carrying out esterification reaction on compound V and an alcohol to obtain target compound I. The synthesis method of the present invention has a short process route, cheap and easily-available raw materials, mild reaction conditions, a high total yield, and a low production cost, and is applicable to industrial production.

Description

A synthetic method for roxadustat intermediate Technical Field

[0001] The present invention relates to a method for synthesizing a rosuvastatin intermediate, and belongs to the technical field of drug synthesis. Background Art

[0002] Roxadustat (the compound represented by Formula A), chemically known as N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinolyl)carbonyl]glycine and in English as Roxadustat, is an oral, small-molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase, developed by Phibrogen (USA) and licensed by Astellas and AstraZeneca. The drug stabilizes HIF-2 and induces EPO expression, primarily in clinical practice for the treatment of anemia caused by chronic kidney disease. In December 2018, the CFDA approved roxadustat capsules, a Class 1 new drug, for marketing in China under the trade name Aerezhuo.

[0003]

[0004] FibroGen reported a representative synthesis process for roxadustat in patents WO 2014014835 and CN103435546. This process uses 5-bromoisobenzofuran-1(3H)-one as the starting material. After an Ullmann coupling reaction, transesterification and chlorination, nucleophilic substitution, intramolecular Claisen ester condensation, elimination, and subsequent secondary substitution and reduction reactions, the key intermediate, Formula I, methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate, is obtained. This Formula I compound then undergoes an amidation reaction with glycine to produce roxadustat. The specific synthetic route is as follows:

[0005]

[0006]

[0007]

[0008] Therefore, the compound of formula I is a key intermediate for the synthesis of roxadustat and is of great significance for the synthesis of roxadustat.

[0009] Numerous synthetic processes have been reported in the literature for the synthesis of the compound of Formula I. Route 1, described in the aforementioned roxadustat route, uses 5-bromoisobenzofuran-1(3H)-one as a starting material and proceeds through seven steps. This process is lengthy, yields low overall yield, and utilizes expensive reagents such as dichlorotriphenylphosphine, methyl p-toluenesulfonylglycine, and tetramethylmethanediamine, most of which are toxic and hazardous. Furthermore, the reaction involves high-pressure hydrogenation, which compromises process safety and makes it unsuitable for industrial production.

[0010] Route 2 is a method for preparing the compound of formula I reported in document CN106478503. This method uses 5-bromo-3-methylisobenzofuran-1(3H)-one as the starting material. The specific synthetic route is as follows:

[0011]

[0012] The synthetic idea of ​​this method is basically the same as that of Route 1. Although the route is shorter and the total yield is higher, in addition to some of the defects of Route 1, the starting material 5-bromo-3-methylisobenzofuran-1(3H)-one is difficult to prepare and difficult to purchase.

[0013] Route 3 is a method for preparing the compound of formula I reported in document EP3305769. The specific synthetic route is as follows:

[0014]

[0015] The method uses methyl 2-bromo-4-fluorobenzoate as a starting material, undergoes a nucleophilic substitution reaction with phenol, and then undergoes hydrolysis and acidification to obtain an intermediate, which first reacts with N,N'-carbonyldiimidazole (CDI) to form an acyl imidazole. The intermediate then undergoes a nucleophilic substitution and cyclization reaction with methyl isocyanoacetate under the action of DBU. The obtained intermediate then undergoes a condensation reaction with n-butyl vinyl ether using Pd(OAc)2 as a catalyst, bis(2-diphenylphosphinophenyl) ether (DPEPhos) as a phosphine ligand, and N,N-diisopropylethylamine (DIPEA) as an acid-binding agent to obtain an enol ether intermediate. The enol ether is converted into an enol and then into an acetyl group at 60°C in concentrated hydrochloric acid, and the oxazole ring is simultaneously opened. Finally, a condensation ring-closure reaction occurs to obtain the compound of formula I. This process involves complex processes such as ring closure, ring opening, and re-ring closure. The process conditions are harsh and difficult to control. Impurities that are difficult to separate are easily produced during the reaction, resulting in a low overall yield and difficult purification of the product. In addition, the route uses expensive and environmentally harmful reagents such as Pd(OAc)2, DPEpHos, CDI, and n-butyl vinyl ether, making it unsuitable for industrial production.

[0016] Route 4 is a method for preparing the compound of Formula I reported in document CN104892509. This method uses L-tyrosine as the starting material. After esterification, the L-tyrosine undergoes an Ullmann coupling reaction with bromobenzene using fresh copper powder as a catalyst and DMSO as a solvent. The reaction then undergoes a Pictet-Spengle cyclization reaction with acetaldehyde in the presence of concentrated hydrochloric acid. The cyclization product first reacts with p-toluenesulfonyl chloride (TsCl) to form an N-toluenesulfonyl compound. The compound is then dehydrogenated in DMSO using 30% sodium hydroxide to eliminate the p-toluenesulfonic acid. The dehydrogenation product is then reacted with glacial acetic acid and hydrogen peroxide to form the nitrogen oxide of the compound of Formula I. This is then subjected to an oxidative rearrangement reaction in the presence of TsCl to produce the compound of Formula I. The specific synthetic route is as follows:

[0017]

[0018] This process route is relatively short, and the raw materials are relatively cheap and readily available, but the overall yield is not high. A more serious drawback is that in the second step of the process, the Ullmann coupling reaction, in addition to the Ullmann coupling reaction between the phenolic hydroxyl group and bromobenzene to obtain the main product, a by-product is also produced when the amino group in the molecule undergoes an Ullmann coupling reaction with bromobenzene. This by-product has a similar structure to the main product and is difficult to remove. The third step of the process, the Pictet-Spengle ring-closure reaction, is carried out in concentrated hydrochloric acid under reflux conditions with acetaldehyde. Acetaldehyde is highly oxidized under heating, so the process is prone to produce impurities and is difficult to control. Technical issues

[0019] Purpose of the invention: The purpose of the present invention is to provide a method for synthesizing a rosuvastatin intermediate with a short process route, cheap and readily available raw materials, mild reaction conditions, high total yield, low production cost and suitable for industrial production. Technical Solutions

[0020] Technical solution: The method for synthesizing the rosuvastatin intermediate of the present invention comprises the following steps:

[0021] Compound II p-bromo-α-phenylethylamine is reacted with 2-oxomalonate in the presence of an acidic catalyst to obtain compound III 2-((1-(3-bromophenyl)ethyl)iminomalonic acid;

[0022] (2) Compound III and phenol undergo Ullmann reaction in the presence of a Cu(I) compound, a ligand, and a base to obtain compound IV 2-((1-(3-phenoxyphenyl)ethyl)iminomalonic acid;

[0023] (3) Compound IV undergoes a ring-closure reaction under the action of TfOH / TFAA to obtain compound V 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid;

[0024] (4) Compound V is subjected to an esterification reaction with an alcohol to obtain the target compound I 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate; the synthetic route is:

[0025]

[0026] Wherein, R1 is a C1~C4 alkyl group.

[0027] The solvent used in the reaction of step (1) is toluene, and the reaction temperature is the reflux temperature in toluene (110-120°C).

[0028] Wherein, in step (1), the acidic catalyst is a sulfonic acid compound, and the sulfonic acid compound is an alkylsulfonic acid or an arylsulfonic acid; and the molar ratio of the sulfonic acid compound to compound II is 5-15:100.

[0029] In the step (1) reaction, a water separation device is installed, which can timely separate the water generated in the reaction, thereby better promoting the reaction and improving the reaction yield.

[0030] Wherein, in step (2), the Cu(I) compound is one of Cu2O, CuBr, CuI or CuCl; and the molar ratio of the Cu(I) compound to compound III is 5-10:100.

[0031] Wherein, in step (2), the ligand is a binary Schiff base compound containing a pyridine ring, and its structural formula is:

[0032]

[0033] Wherein, R2 is H, C1~C3 alkyl, C1~C3 alkoxy or halogen;

[0034] The molar ratio of the ligand to compound III is 15-20: 100. The binary Schiff base compound selected as the ligand of the present invention is obtained by condensing 2-pyridine formaldehyde compounds and trans-cyclohexanediamine.

[0035] Wherein, in step (2), the base is Cs2CO3 or K2PO4, and the molar ratio of the base to compound III is 1.25~2:1.

[0036] Wherein, the solvent selected in the reaction of step (2) is acetonitrile or toluene.

[0037] Wherein, in step (2), the reaction temperature is 60~110°C.

[0038] Among them, adding 4Å molecular sieves in the reaction of step (2) can better promote the reaction.

[0039] Wherein, in step (3), compound IV undergoes a ring-closure reaction at room temperature under the action of TfOH (trifluoromethanesulfonic acid) and TFAA (trifluoroacetic anhydride) to prepare compound V in high yield; wherein, the molar ratio of TfOH to compound IV is 0.25~0.3:1; the molar ratio of TFAA to compound IV is 4.5~6:1.

[0040] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: the synthesis method of the present invention has the advantages of short process route, simple operation steps, cheap and easy-to-obtain raw materials, mild reaction conditions, easy-to-control impurities, high total yield and low production cost, and can be applied to industrial production. Implementation Method Example 1

[0041] Preparation of compound III 2-((1-(3-bromophenyl)ethyl)iminomalonic acid:

[0042] 100 mmol of compound II, 100 mmol of 2-oxomalonate, 15 mmol of p-toluenesulfonic acid, and 250 mL of toluene were added to a reaction flask. The reaction system was heated to reflux with stirring. The reaction progress was monitored by TLC. After completion of the reaction, heating was stopped and the mixture was cooled to room temperature. 250 mL of ice water was added to the reaction solution, which was stirred and allowed to stand. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The solid was dried under reduced pressure to obtain compound III in a yield of 77%. The crude solid was directly carried into the next reaction without purification. Example 2

[0043] Preparation of compound III 2-((1-(3-bromophenyl)ethyl)iminomalonic acid:

[0044] 100 mmol of compound II, 100 mmol of 2-oxomalonate, 12 mmol of p-toluenesulfonic acid, and 250 mL of toluene were added to a reaction flask. A water separator was installed and the reaction system was heated to reflux with stirring. The generated water was continuously separated during the experiment. The reaction progress was monitored by TLC. After the reaction was completed, heating was stopped and the mixture was cooled to room temperature. 250 mL of ice water was added to the reaction solution, which was stirred and allowed to stand. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The solid was dried under reduced pressure to obtain compound III in a yield of 90%. The crude solid was directly carried into the next reaction without purification.

[0045] Based on Example 2, the catalyst can be replaced by benzenesulfonic acid, methanesulfonic acid or ethanesulfonic acid instead of p-toluenesulfonic acid. The molar ratio of the sulfonic acid compound to Compound II can be adjusted arbitrarily between 5 and 15:100. Other reaction conditions remain unchanged to obtain Compound III 2-((1-(3-bromophenyl)ethyl)iminomalonic acid. Example 3

[0046] Preparation of compound IV 2-((1-(3-phenoxyphenyl)ethyl)iminomalonic acid:

[0047] Under nitrogen protection, 55 mmol of phenol, 100 mmol of Cs2CO3, and 100 mL of acetonitrile were added to a reaction flask. After stirring for 10 min, 50 mmol of compound III prepared in Example 2, 10 mmol of ligand (R2 = H), and 5 mmol of Cu2O were added to the reaction flask. The temperature was raised to 80°C with stirring, and the reaction was stirred and maintained overnight. The reaction progress was monitored by TLC (developing solvent: n-hexane:ethyl acetate = 5:1). After the reaction was completed, the filtrate was cooled to room temperature and filtered. The solvent was distilled off the filtrate under reduced pressure. 100 mL of water was added and stirred at room temperature for 0.5 h. The precipitated solid was filtered and the filter cake was washed with water. The solid was dissolved in 100 mL of dichloromethane, washed with 50 mL of 1N hydrochloric acid solution, and then washed with 100 mL of water. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The solid was dried under reduced pressure to obtain compound IV in a yield of 63% (based on compound II). Example 4

[0048] Preparation of compound IV 2-((1-(3-phenoxyphenyl)ethyl)iminomalonic acid:

[0049] Under nitrogen protection, 55 mmol of phenol, 62.5 mmol of Cs2CO3, and 100 mL of acetonitrile were added to a reaction flask. After stirring for 10 min, 50 mmol of compound III prepared in Example 2, 7.5 mmol of ligand (R2 = H), 2.5 mmol of Cu2O, and 15 g of 4Å molecular sieves were added to the reaction flask. The temperature was raised to 80°C with stirring, and the reaction was stirred and maintained overnight. The reaction progress was monitored by TLC (developing solvent: n-hexane:ethyl acetate = 5:1). After the reaction was completed, the filtrate was cooled to room temperature and filtered. The solvent was evaporated under reduced pressure from the filtrate. 100 mL of water was added, and the mixture was stirred at room temperature for 0.5 h. The precipitated solid was filtered, and the filter cake was washed with water. The solid was dissolved in 100 mL of dichloromethane, washed with 50 mL of 1N hydrochloric acid solution, and then washed with 100 mL of water. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The solid was dried under reduced pressure to obtain compound IV in a yield of 65% (based on compound II). Example 5

[0050] Preparation of compound IV 2-((1-(3-phenoxyphenyl)ethyl)iminomalonic acid:

[0051] Under nitrogen protection, 55 mmol of phenol, 100 mmol of Cs2CO3, and 100 mL of acetonitrile were added to a reaction flask. After stirring for 10 min, 50 mmol of compound III prepared in Example 2, 10 mmol of ligand (R2 = H), 5 mmol of Cu2O, and 15 g of 4Å molecular sieves were added to the reaction flask. The temperature was raised to 80°C with stirring, and the reaction was stirred and maintained overnight. The reaction progress was monitored by TLC (developing solvent: n-hexane:ethyl acetate = 5:1). After the reaction was completed, the filtrate was cooled to room temperature and filtered. The solvent was distilled off the filtrate under reduced pressure. 100 mL of water was added, and the mixture was stirred at room temperature for 0.5 h. The precipitated solid was filtered, and the filter cake was washed with water. The solid was dissolved in 100 mL of dichloromethane, washed with 50 mL of 1N hydrochloric acid solution, and then washed with 100 mL of water. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The solid was dried under reduced pressure to obtain compound IV in a yield of 84% (based on compound II). ESI-LRMS m / z: 314.1836 [M+H] + , 1 H NMR (500 MHz, DMSO-d6) δ: 1.25 (d, J= 2.4 Hz, 3H), 2.99 (q, 1H), 6.89 (s, 1H), 6.98~7.13 (m, 4H), 7.16~7.24 (m, 2H), 7.41~7.52 (m, 2H), 12.4(s, 2H).

[0052] On the basis of Example 5, the base can be replaced by K2CO3, K3PO4, or Na2CO3 in place of Cs2CO3; the catalyst can be replaced by CuBr, CuI, or CuCl in place of Cu2O; R2 in the ligand can be replaced by a C1-C4 alkyl group, a C1-C3 alkoxy group, or a halogen in place of H; the solvent can be replaced by toluene or DMF in place of acetonitrile; the reaction temperature is adjusted between 40 and 110°C; other reaction conditions remain unchanged. Some experimental results are shown in Table 1, and the yields of the prepared compound IV are all calculated based on compound II.

[0053] Table 1 shows the conditions and results for preparing compound IV in Examples 6 to 26

[0054] No. R2 Catalyst Base Temperature / °C Solvent Yield / % Example 6 Methyl Cu2OCs2CO3 80 Acetonitrile 81 Example 7 Ethyl Cu2OCs2CO3 80 Acetonitrile 77 Example 8 n-Propyl Cu2OCs2CO3 80 Acetonitrile 71 Example 9 n-Butyl Cu2OCs2CO3 80 Acetonitrile 61 Example 10 Methoxy Cu2OCs2CO3 80 Acetonitrile 80 Example 11 Ethoxy Cu2OCs2CO3 80 Acetonitrile 75 Example 12 Propoxy Cu2OCs2CO3 80 Acetonitrile 64 Example 13 Bromine Cu2OCs2CO3 80 Acetonitrile 66 Example 14 Chlorine Cu2OCs2CO3 80 Acetonitrile 70 Example 15 Hydrogen CuClCs2CO3 80 Ethyl Nitrile 64 Example 16 Hydrogen CuBrCs2CO3 80 Acetonitrile 76 Example 17 Hydrogen CuICs2CO3 80 Acetonitrile 79 Example 18 Hydrogen Cu2OK2CO3 80 Acetonitrile 47 Example 19 Hydrogen Cu2ONa2CO3 80 Acetonitrile 35 Example 20 Hydrogen Cu2OK3PO4 80 Acetonitrile 68 Example 21 Hydrogen Cu2OCs2CO3 80 Toluene 71 Example 22 Hydrogen Cu2OCs2CO3 80 DMF 47 Example 23 Hydrogen Cu2OCs2CO3 90 Toluene 74 Example 24 Hydrogen Cu2OCs2CO3 110 Toluene 77 Example 25 Hydrogen Cu2OCs2CO3 40 Acetonitrile 50 Example 26 Hydrogen Cu2OCs2CO3 60 Acetonitrile 69 Example 27

[0055] Preparation of compound V 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid:

[0056] 50 mmol of compound IV prepared in Example 5, 300 mmol of TFAA, and 60 mL of dichloromethane were added to a reaction flask. After stirring at room temperature for 15 minutes, 15 mmol of TfOH was added and the reaction was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC (developing solvent: n-hexane: ethyl acetate = 5:1). After the reaction was completed, the reaction solution was placed in an ice-water bath. 200 mL of water and 60 mL of dichloromethane were added to the reaction solution and stirred for 20 minutes. The aqueous layer was separated and extracted with 40 mL of dichloromethane. The organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The solid was dried under reduced pressure to obtain compound V in a yield of 93%. The structure of compound V is shown in FIG. 1 H NMR and 13 The structure was confirmed by C NMR. 1H NMR (500 MHz, DMSO-d6) δ:8.39 (d, J = 9.0 Hz, 1H), 7.67 (s, 1H), 7.59-7.53 (m, 1H), 7.48 (d, J=7.7 Hz, 2H), 7.18-7.28(m, 2H), 7.18 (d, J=7.8 Hz, 2H), 2.78 (s, 3H); 13 C NMR (126 MHz, DMSO-d6) δ: 168.8, 161.7, 158.4, 156.1, 142.4, 131.1, 130.9, 127.9, 127.0, 125.0, 123.8, 119.8, 113.6, 18.6. Example 28

[0057] Preparation of compound V 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid:

[0058] 50 mmol of compound IV prepared in Example 5, 150 mmol of TFAA, and 60 mL of dichloromethane were added to a reaction flask. The reaction was stirred at room temperature for 15 min, and then 7.5 mmol of TfOH was added. The reaction was stirred at room temperature for 3 h. The reaction progress was monitored by TLC (developing solvent: n-hexane:ethyl acetate = 5:1). After the reaction was completed, the reaction solution was placed in an ice-water bath, and 200 mL of water and 60 mL of dichloromethane were added to the reaction solution. The mixture was stirred for 20 min, the aqueous layer was separated, and the aqueous layer was extracted with 40 mL of dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The solid was dried under reduced pressure to obtain compound V in a yield of 60%. Example 29

[0059] Preparation of compound V 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid:

[0060] 50 mmol of compound IV prepared in Example 5, 225 mmol of TFAA, and 60 mL of dichloromethane were added to a reaction flask. The reaction was stirred at room temperature for 15 min, and then 12.5 mmol of TfOH was added. The reaction was stirred at room temperature for 3 h. The reaction progress was monitored by TLC (developing solvent: n-hexane:ethyl acetate = 5:1). After the reaction was completed, the reaction solution was placed in an ice-water bath, and 200 mL of water and 60 mL of dichloromethane were added to the reaction solution. The mixture was stirred for 20 min, the aqueous layer was separated, and the aqueous layer was extracted with 40 mL of dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The solid was dried under reduced pressure to obtain compound V in a yield of 85%. Example 30

[0061] Preparation of target compound I 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester:

[0062] 50 mmol of compound V prepared in Example 27, 50 mL of methanol, and 4 mL of concentrated sulfuric acid were added to a reaction flask, stirred uniformly at room temperature, heated to reflux, and stirred for 3 hours. The reaction was stopped, the methanol was evaporated under reduced pressure, and 30 mL of dichloromethane was added to the residue. The mixture was washed twice with 40 mL of saturated sodium bicarbonate and then twice with 60 mL of water under stirring. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The solid was dried under reduced pressure to obtain the target compound I, 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester, in a yield of 88%. The structure is shown in FIG. 1 H NMR and 13 C NMR was used for confirmation. 1 H NMR (500 MHz, DMSO-d6) δ:11.50 (s, 1H), 8.33 (d, J=9.0 Hz, 1H), 7.59 (d, J=2.3 Hz, 1H), 7.49-7.54 (m, 3H), 7.28 (t, J=7.4 Hz, 1H), 7.20 (d, J=7.7 Hz, 2H), 2.64 (s, 3H), 2.53(s, 3H); 13 C NMR (126 MHz, DMSO-d6) δ: 170.9, 158.9, 155.8, 154.6, 148.4, 132.1, 130.9, 126.1, 125.1, 123.4, 122.8, 120.1, 119.0, 112.3, 52.9, 21.9.

[0063] Based on Example 30, ethanol, propanol and n-butanol can be used instead of methanol, and other reaction conditions remain unchanged to obtain a series of compounds, namely, 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid ethyl ester, 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid propyl ester and 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid butyl ester.

Claims

1. A method for synthesizing a roxadustat intermediate, characterized in that: The steps include: (1) reacting compound II with 2-oxomalonate in the presence of an acidic catalyst to obtain compound III 2-((1-(3-bromophenyl)ethyl)imidomalonic acid; the acidic catalyst is a sulfonic acid compound, and the sulfonic acid compound is an alkylsulfonic acid or an arylsulfonic acid; (2) Compound III and phenol undergo Ullmann reaction in the presence of a Cu(I) compound, a ligand and a base to obtain compound IV 2-((1-(3-phenoxyphenyl)ethyl)imidomalonic acid; a 4Å molecular sieve is added during the reaction; Wherein, the Cu(I) compound is one of Cu2O, CuBr, CuI or CuCl; The ligand is a binary Schiff base compound containing a pyridine ring, and its structural formula is: ； Wherein, R2 is H, C1~C3 alkyl, C1~C3 alkoxy or halogen; The base is Cs2CO3 or K2PO4; (3) Compound IV undergoes a ring-closing reaction at room temperature under the action of TfOH and TFAA to obtain compound V 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid; (4) Compound V is subjected to an esterification reaction with an alcohol to obtain the target compound I 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate; the synthetic route is: ； Wherein, R1 is a C1~C4 alkyl group.

2. The method for synthesizing a roxadustat intermediate according to claim 1, characterized in that: The solvent used in the reaction of step (1) is toluene, and the reaction temperature is the temperature at which the reaction mixture refluxes in toluene.

3. The method for synthesizing a roxadustat intermediate according to claim 1, characterized in that: In step (1), the molar ratio of the sulfonic acid compound to compound II is 5-15:

100.

4. The method for synthesizing a roxadustat intermediate according to claim 1, characterized in that: A water separation device is installed in the reaction of step (1).

5. The method for synthesizing a roxadustat intermediate according to claim 1, characterized in that: In step (2), the molar ratio of the Cu (I) compound to the compound III is 5-10:

100.

6. The method for synthesizing a roxadustat intermediate according to claim 1, characterized in that: In step (2), the molar ratio of the ligand to compound III is 15-20:

100.

7. The method for synthesizing a roxadustat intermediate according to claim 1, characterized in that: In step (2), the molar ratio of the base to compound III is 1.25-2:

1.

8. The method for synthesizing a roxadustat intermediate according to claim 1, characterized in that: In step (2), the reaction temperature is 60-110°C.

9. The method for synthesizing a roxadustat intermediate according to claim 1, characterized in that: In step (3), the molar ratio of TfOH to compound IV is 0.25-0.3:1; the molar ratio of TFAA to compound IV is 4.5-6:1.

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