A process for the preparation of roxadustat and intermediates thereof

Abstract

The application provides a preparation method of a key intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline formate (LT-D3) of roxadustat, which is prepared from 3-oxo-3-(4-phenoxyphenyl) propionate (MQC) through aldehyde groupization, imidization and reduction reaction. The method is novel, the synthesis line is relatively simple, all raw materials and reagents used are easy to obtain or prepare, the reagent used in the imidization step, substituted aniline, can be obtained through a reduction reaction, the cyclic utilization of the aniline reagent can be realized, the atomic economy of green chemistry is realized, no high-risk and high-pollution reagent is used in the preparation method, the method is safe, environment-friendly, the reaction condition is mild, the operation is convenient and controllable, the prepared roxadustat intermediate LT-D3 has good purity and yield, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a method for preparing roxadustat and its intermediates. Background Technology

[0002] Roxadustat, developed by Fibrogen, is the world's first small-molecule hypoxia-inducible factor prolyl hydroxylase inhibitor, used to treat anemia caused by chronic disease in patients undergoing dialysis. Roxadustat was first approved for marketing in China in December 2018, providing a new treatment option for patients with anemia caused by chronic kidney disease.

[0003] Roxadustat has an isoquinoline skeleton structure, with the chemical name 2-(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamido)acetic acid, and its structural formula is shown below:

[0004]

[0005] The isoquinoline compound with the following structural formula LT-D3 has the chemical name methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid. It is a key intermediate in the synthesis of roxadustat, and the synthesis of this intermediate is also a difficult point in the synthesis of roxadustat active pharmaceutical ingredient.

[0006]

[0007] In the prior art, the original research company disclosed a synthesis process for roxadustat intermediate LT-D3 in Chinese patent application CN103435546A. This route involves the etherification process of 5-bromophthalide and phenol. This process has high requirements for moisture content and is prone to ring-opening, generating a large number of by-products, resulting in unsatisfactory yield and purity of roxadustat intermediate LT-D3.

[0008] Beijing Bemettop New Drug R&D Co., Ltd. disclosed a method for synthesizing LT-D3, an intermediate of roxadustat, in Chinese patent application CN104024227A. The reaction conditions for generating the isoquinoline ring are mild, but it requires a large number of experimental steps to introduce the methyl group at the 1-position of the isoquinoline ring, and the introduction process usually requires ultra-low temperature conditions. In addition, the yield of some reaction steps in this synthesis method is low, and column chromatography is required for purification, which is costly and not easy to scale up.

[0009] Shenzhen Tajirui Biopharmaceutical Co., Ltd. disclosed a method for synthesizing the roxadustat intermediate LT-D3 in Chinese patent application CN106083720A. This patented method features mild reaction conditions, high selectivity, no isomer formation, and no need for column purification. However, the method uses carbon tetrachloride, a solvent that generates the genotoxic impurity benzenesulfonate; furthermore, the intermediates in multiple steps are not purified before being fed into the reaction, which is detrimental to quality control.

[0010] Shanghai Xunhe Pharmaceutical Technology Co., Ltd. disclosed a method for synthesizing LT-D3, an intermediate of roxadustat, in Chinese patent application CN106478503A. The patented method has a short reaction step, but the keto-malonic acid dimethyl ester used is not easy to obtain, and the cyclization reaction requires a high temperature of nearly 200°C, making industrialization difficult.

[0011] Given the importance of treating and preventing HIF-related diseases, there is always interest in the industry for cost-effective and novel methods for preparing roxadustat, especially its key intermediate LT-D3. Developing a synthetic method for roxadustat's key intermediate LT-D3 with a simple process route, mild reaction conditions, and suitability for industrial production is of great significance. Summary of the Invention

[0012] To address the shortcomings of existing technologies, this invention provides a method for preparing LT-D3, an intermediate of roxadustat, which features mild reaction conditions, low heavy metal content, high product purity and yield, strong operability, and suitability for industrial production.

[0013] The present invention provides a method for preparing the roxadustat intermediate LT-D3, the synthetic route of which is as follows:

[0014]

[0015] R is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and halogen.

[0016] The preparation method of the above-mentioned roxadustat intermediate LT-D3 specifically includes the following steps:

[0017] (1) Compound LT-D1 was prepared by aldehyde reaction using compound MQC as the starting material;

[0018] (2) The compound LT-D1 from step (1) was subjected to an imidization reaction to prepare compound LT-D2;

[0019] (3) The compound LT-D2 from step (2) was reduced to prepare the intermediate LT-D3 of roxadustat.

[0020] In the preparation process, the aldehyde reaction product LT-D1 in step (1) can be purified before proceeding to step (2); or it can be directly proceeded to step (2) without purification.

[0021] In the preparation process, step (2) also includes a process of purifying the imidization reaction product LT-D2.

[0022] Preferably, in step (1), the reaction route is as follows:

[0023]

[0024] The reaction process is as follows: starting with compound MQC, it undergoes an aldehyde reaction with compound B1 in an aprotic reaction solvent A1 under the action of a phase transfer catalyst, and the reaction product is LT-D1.

[0025] Wherein, the compound B1 in step (1) is selected from paraformaldehyde and trioxane; preferably, the compound B1 is trioxane.

[0026] Furthermore, the aldehyde reaction in step (1) also includes the addition of an oxidizing agent to activate compound B1; the oxidizing agent is selected from one or more of sodium persulfate and potassium persulfate; preferably, the oxidizing agent is sodium persulfate.

[0027] The phase transfer catalyst in step (1) is selected from quaternary ammonium salt phase transfer catalysts; specifically, the quaternary ammonium salt phase transfer catalyst is tetrabutylammonium chloride.

[0028] In step (1), the aprotic reaction solvent A1 is selected from one or more of tetrahydrofuran, 1,2-dichloroethane, and acetonitrile; preferably, the reaction solvent A1 is acetonitrile.

[0029] Further, in step (1), the molar ratio of starting material MQC to catalyst is 1:1.5 to 3.5; preferably, the molar ratio of starting material MQC to catalyst is 1:2.5; even further, in step (1), the molar ratio of starting material MQC to oxidant is 1:1.5 to 3.5; preferably, the molar ratio of starting material MQC to oxidant is 1:1.5.

[0030] Preferably, in step (2), the reaction route is as follows:

[0031]

[0032] R is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and halogen.

[0033] The reaction process is as follows: the reaction product LT-D1 obtained in step (1) undergoes an imidization reaction with compound B2 in an aprotic reaction solvent A2, and the reaction product is LT-D2; further, step (2) also includes a process of purifying the reaction product LT-D2.

[0034] Wherein, the compound B2 in step (2) is selected from aniline, p-methoxyaniline, p-bromoaniline or p-toluidine.

[0035] In step (2), the aprotic reaction solvent A2 is selected from one or more of ethyl acetate, acetonitrile, N,N-dimethylformamide, and dichloromethane; preferably, the reaction solvent A2 is dichloromethane.

[0036] Further, the purification process of the reaction product LT-D2 in step (2) includes processes such as vacuum concentration, extraction, and crystallization; preferably, the purification process of the reaction product LT-D2 in step (2) is vacuum concentration and recrystallization of the concentrate; more specifically, the purification process of the reaction product LT-D2 in step (2) is: concentrating the reaction product LT-D2 under reduced pressure until there are no fractions, and crystallizing the concentrate with ethyl acetate / n-heptane; or crystallizing the concentrate with ethyl acetate / petroleum ether, etc.

[0037] It should be noted that the purification process in steps (1) and (2) above can take various measures, including but not limited to common purification methods such as filtration, washing, extraction, purification, and drying. Other auxiliary steps can also be taken to collect products, increase yield, improve product purity, and remove impurities.

[0038] Preferably, in step (3), the reaction route is as follows:

[0039]

[0040] R is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and halogen.

[0041] The reaction process is as follows: the reaction product LT-D2 obtained after purification in step (2) is reduced in a non-protic reaction solvent A3 under the action of a metal catalyst by introducing hydrogen gas to generate roxadustat intermediate LT-D3.

[0042] In step (3), the aprotic reaction solvent A3 is selected from one or more of tetrahydrofuran, ethyl acetate, ethanol, and 1,4-dioxane; preferably, the reaction solvent A3 is ethyl acetate.

[0043] In step (3), the metal catalyst is selected from one or more of palladium on carbon, palladium acetate, and Raney nickel; preferably, the catalyst is palladium on carbon; more preferably, the catalyst is 10% palladium on carbon, where 10% refers to the molar percentage of palladium metal in the palladium on carbon catalyst.

[0044] Further, in step (3), the molar ratio of LT-D2 to catalyst is 1:0.05 to 0.2; preferably, the molar ratio of LT-D2 to catalyst is 1:0.1.

[0045] In another aspect, this invention also provides a method for preparing roxadustat, the specific synthetic route of which is as follows:

[0046]

[0047] R is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and halogen.

[0048] Specifically, the method for preparing roxadustat includes a process of further acylation reaction of the key intermediate LT-D3 synthesized above to obtain roxadustat; specifically, the acylation reaction is the reaction of LT-D3 with glycine in the presence of catalyst DBU to obtain roxadustat.

[0049] The present invention also provides a compound LT-D1 prepared by the above step (1), the structural formula of which is as follows:

[0050]

[0051] The present invention also provides a compound LT-D2 prepared by step (2) above, the structural formula of which is as follows:

[0052]

[0053] R is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and halogen.

[0054] Furthermore, the compound LT-D2 described in this invention can specifically be:

[0055]

[0056] The compounds LT-D1 and LT-D2 of this invention can be used as intermediates in the synthesis of roxadustat.

[0057] The present invention also provides the use of compounds LT-D1 and LT-D2 as described above in the preparation of roxadustat key intermediates LT-D3 and roxadustat.

[0058] The present invention has the following beneficial effects:

[0059] This invention proposes a method for preparing 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline carboxylate (LT-D3), a key intermediate of roxadustat. The method uses 3-oxo-3-(4-phenoxyphenyl)propionate (MQC) as a starting material, and proceeds through aldehyde sizing, imidization, and reduction reactions. This invention features a novel and relatively simple synthetic route. All the raw materials and reagents used are readily available or easily prepared. The reagent used in the imidization step—substituted aniline—can be reduced to unsubstituted aniline, enabling the recycling of aniline reagents and achieving atom economy in green chemistry. Furthermore, the preparation method avoids the use of highly hazardous and polluting reagents, making it safe and environmentally friendly. The reaction conditions are mild, and the operation is convenient and controllable. The prepared roxadustat intermediate exhibits high purity and yield, making it suitable for industrial production. Detailed Implementation

[0060] The technical solution of this application is further described below with reference to specific embodiments, but this does not limit the application.

[0061] The above description is only a preferred embodiment of this application and is not intended to limit this application. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

[0062] Example 1: A method for preparing the roxadustat intermediate LT-D3, the specific synthetic route of which is as follows:

[0063] 1.1 The aldehyde alkylation reaction generates LT-D1, and the reaction equation is as follows:

[0064]

[0065] Add 250.00 g of acetonitrile (reaction solvent), 50.00 g of MQC (starting material), 94.12 g of tetrabutylammonium chloride (phase transfer catalyst), 60.48 g of sodium persulfate (oxidant), and 152.53 g of trioxane to a reaction flask. Heat to 70–80 °C and stir for 5 hours. Add 2500.00 g of water to the reaction solution and cool to room temperature to allow crystallization. Filter the solution. Purify the filter cake with 500.00 g of tetrahydrofuran and 1000.00 g of water to obtain 47.30 g of a pale yellow solid, namely compound LT-D1, with a yield of 86.4% and an HPLC purity of 95.169%.

[0066] Compound LT-D1: Melting point 174.0–174.8 °C; LCMS: [M+H] + (m / z: 324.05); NMR data 1H NMR (400MHz, DMSO): δ12.086 (s, 1H), 9.910 (s, 1H), 8.429 (d, J = 69.6Hz, 1H), 7.638 ~ 7.249 (m, 6H), 4.019 (s, 3H).

[0067] 1.2 Imine reaction to generate LT-D4, the reaction equation is as follows:

[0068]

[0069] 40 ml of dichloromethane, 2.00 g of LT-D1, and 1.14 g of p-methoxyaniline were added to the reaction flask. The mixture was stirred at room temperature for 20 hours. The reaction endpoint was detected by TLC. The mixture was concentrated under reduced pressure until no fraction was obtained. The concentrate was crystallized with ethyl acetate / petroleum ether to give 2.29 g of yellow crystals, namely compound LT-D4, with a yield of 86.4% and an HPLC purity of 99.405%.

[0070] Compound LT-D4: Melting point 167.5–168.8 °C; LCMS: [M+H] + (m / z: 429.16); NMR data 1 H NMR (400MHz, DMSO): δ11.792(s,1H),9.313(s,1H),8.719(s,1H),8.399(d,J=8.8Hz,1H),7.712(dd,J=2.0,9.2Hz,1H),7 .587~7.548(m,2H),7.403(t,J=7.2Hz,1H),7.303(d,J=8.0Hz,2H),6.957(d,J=8.8Hz,2H),3.999(s,3H),3.796(s,3H).

[0071] 1.3 The reduction reaction produces the roxadustat intermediate LT-D3, and the reaction equation is as follows:

[0072]

[0073] Add 2.00 g of LT-D4, 50 ml of ethanol as solvent, and 0.10 g of palladium acetate as metal catalyst to a reaction flask. Purge with hydrogen gas as reducing agent, pressurize to 0.3–0.4 MPa, and heat to 50–60 °C for 8 hours. Filter, wash the filtrate twice with water, concentrate under reduced pressure, and slurry with methanol to obtain 1.22 g of a pale yellow solid, namely compound LT-D3, with a yield of 84.7% and an HPLC purity of 96.381%.

[0074] Example 2: A method for preparing the roxadustat intermediate LT-D3, the specific synthetic route of which is as follows:

[0075] 2.1 The aldehyde alkylation reaction generates LT-D1, and the reaction equation is as follows:

[0076]

[0077] Add 250.00 g of tetrahydrofuran, 50.00 g of MQC, 133.56 g of tetrabutylammonium fluoride phase transfer catalyst, 68.66 g of potassium persulfate oxidant, and 228.82 g of paraformaldehyde to the reaction flask. Heat to 70-80℃ and stir for 5 hours. Add 2500.00 g of water to the reaction solution and cool to room temperature to crystallize. Filter to obtain 45.22 g of pale yellow solid, which is compound LT-D1, with a yield of 82.6% and an HPLC purity of 93.524%.

[0078] 2.2 Imine reaction to generate LT-D5, the reaction equation is as follows:

[0079]

[0080] Add 40 ml of ethyl acetate, 2.00 g of LT-D1, and 0.87 g of aniline to the reaction flask. React at room temperature for 20 hours. Concentrate under reduced pressure until no fraction remains. Crystallize the concentrate with ethyl acetate / n-heptane to obtain 2.08 g of yellow powder, which is compound LT-D5. The yield is 84.6%, and the HPLC purity is 97.461%.

[0081] Compound LT-D5: Melting point 113.8–115.9 °C; LCMS: [M+H] + (m / z: 399.16); NMR data 1 H NMR (400MHz, DMSO): δ11.402(s,1H), 9.089(s,1H), 8.500(s,1H), 8.175(d,J=9.2Hz,1H), 7.549 ~7.492(m,3H), 7.395~7.336(m,3H), 7.284~7.210(m,3H), 7.022(d,J=6.8Hz,2H), 3.954(s,3H).

[0082] 2.3 The reduction reaction produces the roxadustat intermediate LT-D3, and the reaction equation is as follows:

[0083]

[0084] Add 2.00 g of LT-D2, 40 ml of tetrahydrofuran as the reaction solvent, and 0.20 g of 10% palladium on carbon as the metal catalyst to the reaction flask. Purge with hydrogen gas as the reducing agent, pressurize to 0.3–0.4 MPa, heat to 50–60 °C, and react for 8 hours. Filter, wash the filtrate twice with water, concentrate under reduced pressure, and slurry with methanol to obtain 1.32 g of a pale yellow solid, which is LT-D3. The yield is 85.2%, and the HPLC purity is 96.134%.

[0085] Example 3: A method for preparing the roxadustat intermediate LT-D3, the specific synthetic route of which is as follows:

[0086] 3.1 The aldehyde alkylation reaction generates LT-D1, and the reaction equation is as follows:

[0087]

[0088] Add 500.00 g of 1,2-dichloroethane, 50.00 g of MQC, 141.18 g of tetrabutylammonium chloride (phase transfer catalyst), 100.79 g of sodium persulfate, and 152.53 g of trioxane to a reaction flask. Heat to 50–60 °C and stir for 12 hours. After the reaction is complete, cool to room temperature. Wash the reaction solution three times with water (300.00 g × 3), once with saturated sodium bicarbonate solution (100.00 g), and once with saturated brine solution (100.00 g). Concentrate the organic phase under reduced pressure until no fraction remains. Crystallize the residue with ethyl acetate and petroleum ether to obtain 46.91 g of a pale yellow solid, which is compound LT-D1, with a yield of 85.7% and an HPLC purity of 91.342%.

[0089] 3.2 Imine reaction to generate LT-D6, the reaction equation is as follows:

[0090]

[0091] 40 ml of acetonitrile, 2.00 g of LT-D1, and 1.60 g of p-bromoaniline were added to the reaction flask. The mixture was stirred at room temperature for 20 hours, and a solid gradually precipitated. The reaction endpoint was detected by TLC. The mixture was concentrated under reduced pressure until no fraction was distilled off. The concentrate was crystallized with ethyl acetate / petroleum ether to give 2.48 g of light yellow crystals, namely compound LT-D6, with a yield of 84.1% and an HPLC purity of 93.919%.

[0092] Compound LT-D6: Melting point 209.4–210.5 °C; ESI: [M+H] + (m / z: 477.0443, 479.0422); NMR data 1H NMR (400MHz, DMSO): δ11.944(s,1H),9.243(d,J=2.8Hz,1H),8.734(s,1H),8.446(d,J=9.2Hz,1H),7.739(dd,J=2.4, 9.2Hz, 1H), 7.605~7.541(m,4H), 7.411~7.374(m,1H), 7.297(d,J=8.0Hz,2H), 7.090(d,J=8.4Hz,2H), 4.006(s,3H).

[0093] 3.3 The reduction reaction produces the roxadustat intermediate LT-D3, and the reaction equation is as follows:

[0094]

[0095] Add 2.00 g of LT-D6, 50 ml of 1,4-dioxane as the reaction solvent, and 0.40 g of Raney nickel as the metal catalyst to the reaction flask. Purge with hydrogen gas as the reducing agent, pressurize to 0.3–0.4 MPa, and heat to 50–60 °C for 8 hours. Filter, wash the filtrate twice with water, concentrate under reduced pressure, and slurry with methanol to obtain 1.08 g of a pale yellow solid, which is LT-D3. The yield is 83.1%, and the HPLC purity is 97.864%.

[0096] Example 4: A method for preparing the roxadustat intermediate LT-D3, the specific synthetic route of which is as follows:

[0097] 4.1 The aldehyde alkylation reaction generates LT-D1, and the reaction equation is as follows:

[0098]

[0099] Add 250.00 g of acetonitrile (reaction solvent), 50.00 g of MQC (raw material), 117.65 g of tetrabutylammonium chloride (phase transfer catalyst), 60.48 g of sodium persulfate (oxidant), and 152.53 g of trioxane to a reaction flask. Heat to 70–80 °C and stir for 5 hours. Add 2500.00 g of water to the reaction solution and cool to room temperature to allow crystallization. Filter the solution. Purify the filter cake with 500.00 g and 1000.00 g of acetonitrile to obtain 49.1 g of a pale yellow solid, namely compound LT-D1, with a yield of 89.7% and an HPLC purity of 96.341%.

[0100] 4.2 Imine reaction to generate LT-D7, the reaction equation is as follows:

[0101]

[0102] Add 40 ml of N,N-dimethylformamide, the reaction solvent, to the reaction flask and stir. Add 2.00 g of LT-D1 and 0.99 g of p-toluidine and stir at room temperature for 20 hours. Detect the reaction endpoint by TLC. Add 50 ml of water to the reaction solution and extract three times with ethyl acetate (50 ml × 3). Crystallize the concentrate with ethyl acetate / petroleum ether to give 2.16 g of a light yellow solid, which is compound LT-D7. The yield is 84.7% and the HPLC purity is 99.342%.

[0103] Compound LT-D7: Melting point 147.8–149.2 °C; LCMS: [M+H] + (m / z: 413.17); NMR data 1 H NMR (400MHz, DMSO): δ11.749(s,1H),9.272(s,1H),8.678(s,1H),8.375(d,J=9.2Hz,1H),7.690(d,J=8.4Hz,1H),7.550(t,J=7.6H z, 2H), 7.376 (t, J = 7.2Hz, 1H), 7.291 (d, J = 7.6Hz, 2H), 7.199 (d, J = 8.0Hz, 2H), 7.010 (d, J = 7.6Hz, 2H), 3.992 (s, 3H), 2.327 (s, 3H).

[0104] 4.3 The reduction reaction produces the roxadustat intermediate LT-D3, and the reaction equation is as follows:

[0105]

[0106] Add 2.00 g of LT-D7, 40 ml of ethyl acetate as the reaction solvent, and 0.10 g of 10% palladium on carbon as the metal catalyst to the reaction flask. Purge with hydrogen gas as the reducing agent, pressurize to 0.3–0.4 MPa, heat to 50–60 °C, and react for 8 hours. Filter, wash the filtrate twice with water, concentrate under reduced pressure, and slurry with methanol to obtain 1.30 g of a pale yellow solid, which is LT-D3. The yield is 86.7%, and the purity is 98.352%.

[0107] Example 5: A method for preparing roxadustat

[0108] Based on the synthesized roxadustat key intermediate LT-D3, roxadustat was further prepared by acylation reaction, and the reaction equation is as follows:

[0109]

[0110] 20 g of anhydrous ethanol, 2.00 g of LT-D3, 14.00 g of anhydrous sodium thiosulfate and 0.82 g of glycine were added to a reaction flask under nitrogen protection. The catalyst DBU (1,8-diazacyclo[5,4,0]undecene-7) was added. After the addition was complete, the temperature was controlled at 70–80 °C and the mixture was stirred. After the reaction was complete, the temperature was lowered to room temperature, and 6.00 g of 10% hydrochloric acid was added. The mixture was stirred, filtered, and dried to obtain 2.15 g of a yellow solid, namely roxadustat, with a yield of 94.4% and an HPLC purity of 96.876%.

[0111] Roxadustat: Melting point 219.9–223.4 °C; LCMS: [M+H] + (m / z: 353.11); NMR data 1 H NMR (400MHz, DMSO): δ13.298(s,1H), 12.788(br,1H), 9.095(t,J=6.0Hz,1H), 8.283(d,J=9.0Hz,1H), 7.606(d,J=2.4Hz,1H), 7.521(dd, J1=9.0Hz, J2=2.4Hz, 1H), 7.470 (t, J=7.8Hz, 2H), 7.246 (t, J=7.2Hz, 1H), 7.171 (d, J=7.8Hz, 2H), 4.042 (d, J=6.0Hz, 2H), 2.693 (s, 3H).

[0112] It should be noted that in the above synthesis of roxadustat intermediate LT-D3, the purification process in the aldehyde reaction step and the imine reaction step can take various measures, including but not limited to common purification methods such as filtration, washing, extraction, purification, and drying. Other auxiliary steps can also be taken to collect the product, increase the yield, improve the purity of the product, and remove impurities.

[0113] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A process for the preparation of a Roxadustat intermediate, LT-D3, characterized by, The synthetic route is as follows: R is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy and halogen; Specifically comprising the following steps: (1) Compound MQC is used as a starting material, and an aldehyde group is prepared to obtain compound LT-D1 through aldehyde group reaction; (2) Compound LT-D1 of step (1) is prepared to obtain compound LT-D2 through imination reaction; (3) Compound LT-D2 of step (2) is prepared to obtain Roxadustat intermediate LT-D3 through reduction reaction; The reaction process of step (1) is specifically as follows: Compound MQC is used as a starting material, and aldehyde group reaction is carried out with compound B1 in aprotic reaction solvent A1 under the action of a phase transfer catalyst, and the reaction product is LT-D1; compound B1 is selected from one of polyformaldehyde and trioxane; the aldehyde group reaction of step (1) also includes the process of adding an oxidizing agent.

2. The process for the preparation of Roxadustat intermediate LT-D3 according to claim 1, characterized in that, The step (2) also includes the process of refining the imination reaction product LT-D2.

3. A process for the preparation of Roxadustat intermediate LT-D3 according to claim 1, characterized by, The oxidizing agent of step (1) is selected from one or more of sodium persulfate and potassium persulfate.

4. A process for the preparation of Roxadustat intermediate LT-D3 according to claim 1, characterized by, The phase transfer catalyst in step (1) is selected from a quaternary ammonium salt phase transfer catalyst.

5. The process for the preparation of Roxadustat intermediate LT-D3 according to claim 1, characterized in that, The aprotic reaction solvent A1 of step (1) is selected from one or more of tetrahydrofuran, 1,2-dichloroethane and acetonitrile.

6. The process for the preparation of Roxadustat intermediate LT-D3 according to claim 1, characterized in that, The reaction route of step (2) is as follows: R is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy and halogen; The reaction process is specifically as follows: the reaction product LT-D1 obtained in step (1) is subjected to imination reaction with compound B2 in aprotic reaction solvent A2, and the reaction product is LT-D2.

7. The process for the preparation of Roxadustat intermediate LT-D3 according to claim 6, characterized in that, Compound B2 in step (2) is selected from aniline, p-methoxyaniline, p-bromoaniline or p-toluidine.

8. A process for the preparation of a roxadustat intermediate LT-D3 according to claim 6, characterized by, The aprotic reaction solvent A2 of step (2) is selected from one or more of ethyl acetate, acetonitrile, N,N-dimethylformamide and dichloromethane.

9. A process for the preparation of a roxadustat intermediate LT-D3 according to claim 1, characterized by, The reaction route of step (3) is as follows: R is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy and halogen; The reaction process is specifically as follows: the reaction product LT-D2 obtained after step (2) is subjected to reduction reaction in aprotic reaction solvent A3 under the action of a metal catalyst, hydrogen is introduced, and Roxadustat intermediate LT-D3 is generated.

10. The process for the preparation of Roxadustat intermediate LT-D3 according to claim 9, characterized in that, The aprotic reaction solvent A3 of step (3) is selected from one or more of tetrahydrofuran, ethyl acetate, ethanol and 1,4-dioxane.

11. The method of claim 9, wherein the preparation of the intermediate LT-D3 of Roxadustat is characterized by, The metal catalyst in step (3) is selected from one or more of palladium on carbon, palladium acetate and Raney nickel.

12. A method of preparing roxadustat, characterized by, The synthetic route is as follows: R is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy and halogen; Specifically comprising the following steps: (1) Roxadustat intermediate LT-D3 is prepared by the preparation method according to any one of claims 1-11; (2) Roxadustat intermediate LT-D3 is prepared to obtain Roxadustat through acylation reaction; the acylation reaction is that LT-D3 is reacted with glycine in the presence of catalyst DBU to obtain Roxadustat.

13. A compound LT-D2, characterized by, The specific structural formula is as follows: R is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy and halogen.

14. The compound of claim 13, LT-D2, wherein, The compound LT-D2 is:

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