Method for preparing multi-substituted isoquinoline compounds

Abstract

The present invention application relates to a preparation method and application of a pharmaceutical intermediate of a multi-substituted isoquinoline compound. The synthesis method involved in the present invention application is simple, efficient, economical, environmentally friendly and suitable for industrial production.

Description

Technical Field

[0001] The invention relates to pharmaceutical intermediates, their preparation methods and applications. Background Art

[0002] Renal anemia is one of the main complications in the decompensated stage of chronic kidney disease (CKD). With the progression of CKD, the prevalence and severity of CKD-related anemia gradually increase. Patients have severe fatigue and low quality of life. Currently, the standard treatment for renal anemia is the replacement of erythropoietin (EPO hormone).

[0003] Roxadustat is the world's first developed small molecule hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) drug for the treatment of renal anemia. The physiological effect of hypoxia-inducible factor (HIF) not only increases the expression of erythropoietin, but also increases the expression of erythropoietin receptor and proteins that promote iron absorption and circulation. Roxadustat inhibits the PH enzyme by mimicking one of the substrates of prolyl hydroxylase (PH), α-ketoglutaric acid, and affects the role of the PH enzyme in maintaining the balance of HIF production and degradation rates, thereby achieving the purpose of correcting anemia.

[0004] On December 18, 2018, the National Medical Products Administration (NMPA) of China approved the listing of the first-class innovative drug Roxadustat Capsules (trade name: Aeriduo, INN generic name: Roxadustat, research and development code: FG-4592) through the priority review and approval process for the treatment of anemia caused by chronic kidney disease (CKD) in patients receiving dialysis treatment.

[0005] Roxadustat was discovered by FibroGen and developed in cooperation with the Japanese pharmaceutical company Astellas for the treatment of CKD-related anemia in dialysis patients and non-dialysis patients. In addition, FibroGen has also cooperated with AstraZeneca to develop Roxadustat in the United States, China and other markets.

[0006] The synthetic method of the compound patent published by the original research FibroGen can be seen in patents US 8765956 B2 and CN102977016 B. This route uses 3,4-dicyanonitrobenzene as the raw material, constructs the isoquinoline ring through ring closure and ring-opening rearrangement, introduces a methyl group through halogenation and coupling reactions, and finally introduces the glycine side chain to obtain roxadustat. This route has problems such as poor selectivity in the ring formation reaction, the need to use precious metal catalysts in the methyl group introduction reaction, and a relatively long overall reaction route.

[0007] Subsequently, the originator company optimized the synthesis route. The process patent routes disclosed by it can be seen in Patent US9340511 B and CN 103435546 B. This route uses 5-bromophthalide as the starting material, introduces methyl glycinate through a ring-opening reaction, then constructs an isoquinoline ring through a ring-closing reaction, and then introduces a methyl group through the reduction of an amine, followed by protection and deprotection reactions. The whole process is relatively long, and a palladium-carbon is required for the deprotection reaction.

[0008] After researching the existing technologies for synthesizing roxadustat, one obvious feature is that after constructing the isoquinoline ring, a methyl group is introduced through a halogenation and coupling scheme. For example: the patent WO2013013609 A1 of Zhejiang Betta Pharmaceutical Co., Ltd., the patents WO 2018072662 A1 and WO 2019174631 A1 of Shanghai Pharmaceutical Group, the patent CN 107602466 A of Sun Tingting, and the patent CN 108383787 A of Wang Zhaoju, etc. All these technologies have the problems that the coupling reaction for introducing a methyl group requires the participation of precious metals, the reaction conditions are harsh, and the cost is high.

[0009] In addition, there are also reports on the route for introducing a methyl group on the isoquinoline ring in advance. The route of the patent CN106478503 A of Shanghai Xunhe uses methyl-substituted phthalide as the starting material and synthesizes a key intermediate of methyl-substituted isoquinoline through ring-opening, substitution, and ring-closing reactions. This route has the problems that the starting material is not easily available and needs to be synthesized through 3 steps. Another patent CN 106478504 A applied by Shanghai Xunhe synthesizes an isoquinoline structure intermediate through an intramolecular high-temperature ring-closing reaction solution. Since its reaction temperature is about 200°C, there are safety problems and it is difficult to realize in production.

[0010] The patent CN 104892509 B applied by Suzhou Mingrui uses tyrosine as the starting material, constructs an isoquinoline ring through etherification, cyclization and other reactions, and finally introduces a hydroxyl group. The whole route is simple and efficient. However, there are selectivity problems in its etherification reaction, and the reaction for introducing a hydroxyl group requires the use of hydrogen peroxide, which has safety problems and is difficult to realize large-scale production.

[0011] Aiming at the defects of the existing technologies, developing a simple, efficient, economical, environmentally friendly and industrially applicable process technology has important practical significance for improving the economic and social benefits of this drug. Summary of the Invention

[0012] One of the purposes of the present invention is to provide a method for synthesizing the roxadustat intermediate compound VI:

[0013]

[0014] Wherein R is a C1-20 hydrocarbon group; PG is a protecting group for N.

[0015] Specifically, the reaction conditions of the reaction steps are described in detail as follows:

[0016] The method for preparing compound VI from compound V, wherein PG is benzyloxycarbonyl, p-toluenesulfonyl, benzenesulfonyl, acetyl or propoxycarbonyl.

[0017] The method for preparing compound VI from compound V includes generating compound VI from compound V under oxidation conditions, and the oxidant is ammonium cerium nitrate.

[0018] Another object of the present invention is to provide a method for synthesizing the intermediate compound VII of roxadustat:

[0019]

[0020] Wherein R is a C1-20 hydrocarbon group; PG is a protecting group for N.

[0021] Specifically, the reaction conditions of the reaction steps are described in detail as follows:

[0022] The method for preparing compound VII from compound VI, wherein PG is benzyloxycarbonyl, p-toluenesulfonyl, benzenesulfonyl, acetyl or propoxycarbonyl.

[0023] The method for preparing compound VII from compound VI includes obtaining compound VII through a deprotection reaction of compound VI under acidic conditions, and the acid is selected from one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, formic acid and other acids.

[0024] Another object of the present invention is to provide a method for synthesizing the intermediate compound IV of roxadustat:

[0025] Wherein R is a C1-20 hydrocarbon group.

[0026] Specifically, the reaction conditions of the reaction steps are described in detail as follows:

[0027] The method for preparing compound IV from compound I includes the following steps:

[0028] (1) Compound I reacts with oxalyl chloride and iron(III) chloride to obtain compound II;

[0029] (2) Compound II is deprotected under acidic conditions to obtain compound III;

[0030] (3) Compound III undergoes a reduction reaction to obtain compound IV.

[0031] The acid in step (2) is selected from one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, formic acid, etc. The reduction reaction conditions in step (3) are selected from one or more of sodium borohydride, lithium borohydride, palladium carbon / hydrogen, Raney nickel / hydrogen.

[0032] Another object of the present invention is to provide a method for preparing compound VII using compound I as a starting material:

[0033]

[0034] wherein R is a C1-20 hydrocarbon group; PG is a protecting group for N.

[0035] Specifically, the reaction conditions of the reaction steps are described in detail as follows:

[0036] In the method for preparing compound VII from compound I, PG is benzyloxycarbonyl, p-toluenesulfonyl, benzenesulfonyl, acetyl or propyloxycarbonyl.

[0037] The method for preparing compound VII from compound I includes the following steps:

[0038] (1) Compound I reacts with oxalyl chloride and iron(III) chloride to obtain compound II;

[0039] (2) Compound II is deprotected under acidic conditions to obtain compound III;

[0040] (3) Compound III undergoes a reduction reaction to obtain compound IV;

[0041] (4) The amino group in compound IV is protected to obtain compound V;

[0042] (5) Compound V undergoes an oxidation reaction to obtain compound VI;

[0043] (6) Compound VI undergoes a reaction to remove the protecting group under acidic conditions to obtain compound VII.

[0044] The acid in step (2) is selected from one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, formic acid, etc. The reduction reaction conditions in step (3) are selected from one or more of sodium borohydride, lithium borohydride, palladium carbon / hydrogen, Raney nickel / hydrogen. The protecting group in step (4) is selected from one of benzyloxycarbonyl, p-toluenesulfonyl, benzenesulfonyl, acetyl or propyloxycarbonyl. The oxidizing agent in step (5) is ammonium cerium(IV) nitrate. The acid in step (6) is selected from one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, formic acid, etc.

[0045] Another object of the present invention is to provide an intermediate compound II for the synthesis of roxadustat:

[0046]

[0047] Wherein R is a C1-20 hydrocarbyl group, and the compound of formula II is a single configuration of (5S, 10bR), (5R, 10bR), (5S, 10bS), (5R, 10bS) or a mixture thereof.

[0048] Another object of the present invention is to provide an intermediate compound or its salt III for synthesizing roxadustat:

[0049]

[0050] Wherein R is a C1-20 hydrocarbyl group, and the compound of formula III is a single configuration of (3S), (3R) or a mixture thereof.

[0051] Another object of the present invention is to provide an intermediate compound V for synthesizing roxadustat:

[0052]

[0053] Wherein the compound of formula V is a single configuration of (1S,3S), (1R,3S), (1S,3R), (1R,3R) or a mixture thereof, and R is a C1-20 hydrocarbyl group; PG is a protecting group for N, and further, PG is benzenesulfonyl, p-toluenesulfonyl, acetyl, benzoyl, benzyloxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl.

[0054] Another object of the present invention is to provide an intermediate compound VI for synthesizing roxadustat:

[0055]

[0056] Wherein the compound of formula VI is a single configuration of (1S,3S), (1R,3S), (1S,3R), (1R,3R) or a mixture thereof, and R is a C1-20 hydrocarbyl group; PG is a protecting group for N, and further, PG is benzenesulfonyl, p-toluenesulfonyl, acetyl, benzoyl, benzyloxycarbonyl, propoxycarbonyl.

[0057] Compared with the prior art, the method for synthesizing the roxadustat intermediate in the present application has the following advantages:

[0058] 1. Directly introduce a methyl group, with a simple and efficient route;

[0059] 2. The reaction conditions are mild and suitable for large-scale production.

[0060] Specific embodiments

[0061] The embodiments of the present application will be described below through examples. Those skilled in the art should recognize that these specific examples only represent the implementation technical solutions selected to achieve the purpose of the present application, and do not limit the technical solutions. According to the teachings of the present application, it is obvious to improve the technical solutions of the present application in combination with the prior art, and all belong to the scope protected by the present application.

[0062] The implementation conditions adopted in the examples can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in conventional experiments. Among them, the chemical reagents used in the following examples are all commercially available chemical reagents.

[0063] Example 1:

[0064] Synthesis of methyl 2-acetamido-3-(4-phenoxyphenyl)propionate (6)

[0065]

[0066] Add 134.0 g of compound 1 and 212.3 g of compound 2 into a reaction flask, add 675 mL of DCM, start stirring, control the temperature at 5 - 15 °C, dropwise add 133.8 g of DBU, react for 2 h, monitor the complete conversion of raw materials by HPLC, add 804 mL of water to quench the reaction, dropwise add acetic acid to adjust the pH to 6 - 7, stir for 10 min, then separate the layers, extract the aqueous phase with 402 mL of DCM twice. Combine the organic phases and concentrate under reduced pressure at 35 °C to 1 vol, white solid precipitates, add 536 mL of MTBE for slurrying for 1 h, filter by suction, wash the filter cake with 134 mL of MTBE, and obtain 199.2 g of off-white solid compound 3, with a yield of 94.6% and a purity of 96.0%.

[0067] The NMR data of compound 3 are as follows:

[0068] 1 H NMR (400 MHz, CDCl3) δ 7.47 – 7.35 (m, 2H), 7.40 – 7.34 (m, 4H),7.22 – 7.13 (m, 1H), 7.06 – 7.02 (m, 2H), 6.98 – 6.92 (m, 2H), 3.82 (s, 3H),2.12 (s, 3H).

[0069] The mass spectrometry data of compound 3 are as follows: M+H molecular ion peak 312.3.

[0070] Add 100 g of compound 3, 1000 mL of methanol, and 1 g of catalyst (Rc, Sp-Duenphos) (NBD)BF4 to the hydrogenation kettle. Replace the air with hydrogen, repeat three times, and finally pressurize to 3 - 4 Mpa. React overnight and monitor the complete reaction of the raw materials by LC-MS. Concentrate the reaction solution to dryness, add 150 mL of EA, heat to 60 - 65 °C, then dropwise add 200 mL of Hept. After the addition is complete, start to slowly cool down. Solids precipitate at about 50 °C. After cooling to room temperature, transfer it to an ice-water bath and stir for 1 h. Filter by suction, and wash the filter cake with 100 mL of n-heptane to obtain 92.0 g of compound 6 with a yield of 91.5% and a purity of 100%.

[0071] The NMR data of compound 6 are as follows:

[0072] 1 H NMR (400 MHz, DMSO- d 6) δ 8.38 – 8.36 (m, 1H), 7.41 – 7.36 (m, 2H),7.25 – 7.21 (m, 2H), 7.15 – 7.11 (m, 1H), 6.99 – 6.93 (m, 4H), 4.47 – 4.41(m, 1H), 3.60 (s, 3H), 3.02 – 2.84 (m, 2H), 1.81 (s, 3H).

[0073] The MS data of compound 6 are as follows: M+H molecular ion peak 314.3.

[0074] Example 2

[0075] Synthesis of methyl 10b-methyl-2,3-dioxo-9-phenoxy-3,5,6,10b-tetrahydro-2H-oxazolo[2,3-a]isoquinoline-5-carboxylate (8)

[0076]

[0077] Add 2.8 g of compound 6 and 28 mL of DCM to the reaction flask, start stirring, and add 1.3 g of oxalyl chloride dropwise while controlling the temperature at 20 - 30 °C. React for 1 - 2 h, add 1.7 g of FeCl3 in batches while controlling the temperature at -15 - -10 °C, keep stirring for 0.5 h, then transfer to room temperature and react overnight. Monitor the complete conversion of the raw materials by HPLC. Add water to quench the reaction, stir for 10 min, then separate the layers. The organic phase is concentrated to dryness under reduced pressure at 35 °C to obtain the crude product. The crude product is purified by column chromatography (n-heptane / ethyl acetate = 10:1 to 3:1) to obtain 2.4 g of a pale yellow solid product 8 with a yield of 62.5% and an HPLC purity of 97.0%.

[0078] The NMR data of Compound 8 are as follows:

[0079] 1 H NMR (400 MHz, DMSO- d 6) δ 7.44 – 7.38 (m, 3H), 7.20 – 7.15 (m, 1H),7.09 – 7.08 (m, 1H), 7.06 – 7.01 (m, 3H), 4.91 – 4.87 (m, 1H), 3.79 (s, 3H),3.53 – 3.47 (m, 1H), 3.30 – 3.24 (m, 1H), 1.87 (s, 3H).

[0080] The MS data of Compound 8 are as follows: M+H molecular ion peak 368.3.

[0081] Example 4

[0082] Synthesis of methyl 1-methyl-7-phenoxy-3,4-dihydroisoquinoline-3-carboxylate (9)

[0083]

[0084] 1.4 g of Compound 8 was added to a reaction flask, 14 mL of ethanol and 1.4 mL of concentrated sulfuric acid were added, and the mixture was heated to reflux. The reaction was monitored by HPLC until completion. The reaction solution was poured into saturated sodium bicarbonate solution for quenching, extracted twice with EA, and the combined organic phases were concentrated to dryness. The residue was purified by column chromatography (n-heptane / ethyl acetate = 10:1 to 6:1) to obtain 0.9 g of a pale yellow solid product 9, with a yield of 80% and an HPLC purity of 97.3%.

[0085] The NMR data of Compound 9 are as follows:

[0086] 1 H NMR (400 MHz, CDCl3) δ7.38 – 7.34 (m, 2H), 7.21 – 7.18 (m, 2H),7.13 (s, 1H), 7.05 – 7.00 (m, 3H), 4.26 – 4.20 (m, 1H), 3.84 (s, 3H), 2.98 –2.92 (m, 2H), 2.41 (s, 3H).

[0087] The MS data of Compound 9 are as follows: M+H molecular ion peak 296.3.

[0088] Example 5

[0089] Synthesis of Methyl 1-methyl-7-phenoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (10)

[0090]

[0091] Add 1.6 g of compound 9, 0.16 g of palladium on carbon, and 16 mL of methanol into a 250 mL hydrogenation autoclave. Replace the air with hydrogen, repeat three times, pressurize to 4 - 5 Mpa, and react at room temperature for 3 h. Monitor the reaction by HPLC until the raw materials are completely reacted. Then, perform suction filtration, concentrate the filtrate to dryness, and purify by column chromatography (n-heptane / ethyl acetate = 10:1 to 6:1) to obtain 970 mg of oily product 10 with a yield of 60.0% and a purity of 98.5%.

[0092] The mass spectrometry data of compound 10 are as follows: the molecular ion peak of M + H is 298.3.

[0093] Example 6

[0094] Synthesis of Methyl 1-methylene-4-oxo-7-phenoxy-2-p-toluenesulfonyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (12)

[0095]

[0096] Add 0.6 g of compound 11 into a reaction flask, add 6 mL of MeCN and 6 mL of water, slowly add 3.65 g of ammonium cerium(IV) nitrate, and stir the reaction at room temperature. Monitor the reaction by HPLC until the raw materials are completely converted. Then, add 30 mL of ethyl acetate, stir and separate the layers. The organic phase is concentrated to obtain the crude product, and the crude product is purified by column chromatography (n-heptane / ethyl acetate = 20:1 to 8:1) to obtain 150 mg of pale yellow solid product 12 with a yield of 21%.

[0097] The mass spectrometry data of compound 12 are as follows: the molecular ion peak of M - H2O + H is 464.2.

[0098] Example 7

[0099] Synthesis of Methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (13)

[0100]

[0101] 0.13 g of compound 12 was added to a reaction flask, 1 mL of an AcOH solution containing 30% HBr was added, and then 26 mg of phenol was added. The reaction was stirred at room temperature and monitored by HPLC until the raw materials were completely converted. 20 mL of ethyl acetate was added, and the solution was added to a 20% potassium carbonate solution. After stirring and liquid separation, the organic phase was concentrated to obtain a crude product. The crude product was purified by column chromatography (n - heptane / ethyl acetate = 20:1 to 5:1) to obtain 10 mg of a pale yellow solid product, with a yield of 11% and an HPLC purity of 98.0%.

[0102] The NMR data of compound 13 is as follows:

[0103] 1 H NMR (400 MHz, CDCl3) δ 11.71 (s, 1H), 8.42 - 8.40 (m, 1H), 7.52 - 7.42(m, 4H), 7.28 - 7.23 (m, 1H), 7.16 - 7.13 (m, 2H), 4.10 (s, 3H), 2.77 (s, 3H).

[0104] The mass spectrometry data of compound 13 is as follows: The molecular ion peak of M + H is 310.1.

[0105] Example 8:

[0106] Synthesis of ethyl 2 - acetamido - 3-(4 - phenoxyphenyl)propionate (7)

[0107]

[0108] 225 mL of DCM, 45 g of compound 1 and 60.4 g of compound 4 were successively added to a reaction flask. The temperature was lowered to 0 - 10 °C, and 44.4 g of DBU was added dropwise. After slowly raising the temperature to room temperature, the reaction was carried out for 1 h. The reaction was monitored by HPLC until it ended. 225 mL of water was added to quench the reaction. After liquid separation, the organic phase was concentrated to dryness to obtain a crude product. 180 mL of MTBE was added, and the mixture was slurried at room temperature for 1 h, filtered, and rinsed with 90 mL of MTBE to obtain 566.8 g of a white solid product 5, with a yield of 90.4% and a purity of 100%.

[0109] The NMR data of compound 5 is as follows:

[0110] 1 H NMR (400 MHz, CDCl3) δ 7.48 – 7.37 (m, 4H), 7.20 – 7.13 (m, 2H),7.09 – 7.06 (m, 2H), 6.98 – 6.96 (m, 2H), 4.31 (q, J= 7.1 Hz, 2H), 2.16 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H).

[0111] The mass spectrometry data of Compound 5 are as follows: M+1 molecular ion peak 326.3.

[0112] 1.0 L of ethanol, 65 g of Compound 5 and 0.5 g of catalyst (Rc, Sp-Duenphos) (NBD)BF4 were successively added into the hydrogenation kettle. The hydrogenation kettle was sealed, and hydrogen was replaced 3 times. Finally, the hydrogen pressure was pressurized to 1.8 Mpa, and the temperature was raised to 40 - 50 °C. The reaction was carried out overnight. The raw material conversion was monitored by HPLC until it was complete. The mixture was concentrated to dryness, dissolved in 65 mL of ethyl acetate, and 195 mL of n-heptane was added dropwise. A solid precipitated out. The mixture was stirred for 2 h, filtered by suction, washed with 65 mL of n-heptane / ethyl acetate = 3 / 1, and dried to obtain 59.5 g of a white solid product 7 with a yield of 91.0% and a purity of 100%.

[0113] The NMR data of Compound 7 are as follows:

[0114] 1H NMR (400 MHz, DMSO- d 6) δ 8.37 – 8.35 (m, 1H), 7.40 – 7.36 (m, 2H), 7.25 – 7.23 (m, 2H), 7.14 – 7.11 (m, 1H), 6.99 – 6.92 (m, 4H), 4.46 – 4.40 (m, 1H), 4.07 – 4.02 (m, 2H), 3.00 – 2.86 (m, 2H), 1.82 (s, 3H), 1.12 (t, J = 7.1 Hz, 3H).

[0115] The mass spectrometry data of Compound 7 are as follows: M+1 molecular ion peak 328.3.

[0116] Example 9:

[0117] Synthesis of Ethyl 1-Methyl-7-phenoxy-3,4-dihydroisoquinoline-3-carboxylate (15)

[0118]

[0119] Add 1.28 L of DCM and 160.0 g of Compound 7 to a reaction flask. Dropwise add 69.0 g of oxalyl chloride at room temperature and stir for 1 h. Detect by HPLC, and no raw materials remain. Cool down to -10~-15 °C, add 96.1 g of FeCl3 in batches, slowly warm up to room temperature for reaction, detect by HPLC until the reaction ends. Add 800 mL of water and 1600 mL of DCM, separate the organic phase by liquid separation, wash it once with 480 mL of water, take out 1 / 8 of the organic phase, concentrate it to dryness, add 200 mL of ethanol for pulping, filter by suction to obtain 8.1 g of light yellow solid Product 14, with a yield of 34.8% and a purity of 95.5%; concentrate the remaining organic phase to dryness, add 1.4 L of ethanol / sulfuric acid = 10 / 1, warm up to 70~80 °C, monitor by HPLC until the raw materials are completely converted, pour the reaction solution into saturated sodium bicarbonate to quench the reaction solution, adjust the pH to 7, separate the liquid by liquid separation, concentrate, and purify by column chromatography (n-heptane / ethyl acetate = 50:1 to 20:1) to obtain 110 g of brown-yellow oily Product Compound 15, with a yield of 83.0% and a purity of 98.0%.

[0120] The mass spectrometry data of Compound 14 are as follows: M+1 molecular ion peak 382.2.

[0121] The NMR data of Compound 15 are as follows:

[0122] 1 H NMR (400 MHz, CDCl3) δ 7.37 – 7.33 (m, 2H), 7.20 – 7.17 (m, 2H),7.14 – 7.11 (m, 1H), 7.04 – 6.99 (m, 3H), 4.29 (q, J J = 7.1 Hz, 2H), 4.26 –4.19 (m, 1H), 3.03 – 2.86 (m, 2H), 2.40 (d, J J = 2.0 Hz, 3H), 1.32 (t, J J = 7.1Hz, 3H).

[0123] The mass spectrometry data of Compound 15 are as follows: M+1 molecular ion peak 310.2.

[0124] Example 10:

[0125] Synthesis of Ethyl 1-methyl-7-phenoxy-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylate (16)

[0126]

[0127] Add 120 mL of ethanol, 15 g of Compound 15, and 1.5 g of palladium carbon into a hydrogenation autoclave. Seal the autoclave, replace the hydrogen three times, and finally pressurize the hydrogen to 5 MPa. React at room temperature for 2 h. Monitor the reaction of the raw materials to completion by LCMS, filter by suction, concentrate to dryness, and obtain 13.8 g of a brown liquid product 16 with a yield of 91.3% and a purity of 95.4%.

[0128] The NMR data of Compound 16 are as follows:

[0129] 1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.29 (m, 2H), 7.09 – 7.05 (m, 2H), 6.99 – 6.96 (m, 2H), 6.88 – 6.87 (m 1H), 6.82 – 6.79 (m, 1H), 4.28 – 4.22 (m, 2H), 4.13 – 4.11 m, 1H), 3.74 – 3.70 (m, 1H), 3.07 – 2.92 (m, 2H), 2.02 (s, 1H), 1.46 (d, J J = 6.5 Hz, 3H), 1.32 (t, J J = 7.1 Hz, 3H).

[0130] The MS data of Compound 16 are as follows: M+1 molecular ion peak 312.3.

[0131] Example 11:

[0132] Synthesis of Ethyl 1-Methyl-7-phenoxy-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (17)

[0133]

[0134] Add 150 mL of DCM, 22.4 g of Compound 17, 10.2 g of triethylamine, and 19.24 g of p-toluenesulfonyl chloride into a reaction flask in sequence. Heat up to 40 - 50 °C and react overnight. Monitor the reaction of the raw materials to be basically completely converted by HPLC. Add 100 mL of water to quench the reaction, separate the layers, concentrate, and purify by a chromatography column (n-heptane / ethyl acetate = 100:1 to 8:1) to obtain 25.1 g of a white solid Compound 17 with a yield of 74.1% and a purity of 99.3%.

[0135] The NMR data of Compound 17 are as follows:

[0136] 11H NMR (400 MHz, CDCl3) δ 7.67– 7.65 (m, 2H), 7.35 – 7.31 (m, 2H),7.21 – 7.19 (m, 2H), 7.13 – 7.09 (m, 1H), 7.03 – 7.01 (m, 1H), 6.93 – 6.90(m, 2H), 6.78 – 6.75 (m, 1H), 6.65 – 6.64 (m, 1H), 4.93 (q, J J = 7.0 Hz, 1H),4.56 – 4.53 (m, 1H), 4.23 (q, J J = 7.1 Hz, 2H), 3.01 – 2.96 (m, 2H), 2.38 (s,3H), 1.48 (d, J J = 7.0 Hz, 3H), 1.29 (t, J J = 7.1 Hz, 3H).

[0137] The mass spectrometry data of compound 17 is as follows: M+1 molecular ion peak 466.3.

[0138] Example 12:

[0139] Synthesis of ethyl 1-methylene-4-oxo-7-phenoxy-2-(p-toluenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (18)

[0140]

[0141] 1.6 g of compound 17 was added to a reaction flask, 16 mL of MeCN and 16 mL of water were added, 9.44 g of ammonium cerium(IV) nitrate was slowly added, and the reaction was stirred at room temperature. The conversion of the starting material was monitored by HPLC until complete. 100 mL of ethyl acetate was added, and the mixture was stirred and separated. The organic phase was concentrated to obtain a crude product, which was purified by column chromatography (n-heptane / ethyl acetate = 20:1 to 8:1) to give 0.95 g of the product as a pale yellow solid, with a yield of 58%.

[0142] The NMR data of compound 18 is as follows:

[0143] 1 1H NMR (400 MHz, CDCl3) δ 7.94-7.92 (m, 3H), 7.48-7.44 (m, 2H), 7.34-7.26 (m, 3H), 7.13-7.10 (m, 2H), 6.99-6.96 (m, 1H), 6.71-6.70 (m, 1H), 4.86(q,J = 6.8 Hz, 1H), 4.35 - 4.29 (m, 2H), 2.46 (s, 3H), 1.27 (d, J = 6.8 Hz, 3H), 1.24 (t, J = 6.8 Hz, 3H).

[0144] The mass spectrometry data of Compound 18 is as follows: M - H2O + H molecular ion peak 478.2.

[0145] Example 13:

[0146] Synthesis of Ethyl 4 - hydroxy - 1 - methyl - 7 - phenoxyisoquinoline - 3 - carboxylate (30)

[0147]

[0148] 0.2 g of Compound 18 was added to a reaction flask, 2 mL of AcOH solution containing 33% HBr was added, and then 39.4 mg of phenol was added. The reaction was stirred at room temperature and monitored by HPLC until the raw materials were completely converted. 20 mL of ethyl acetate was added, and the solution was added to 20% potassium carbonate solution. After stirring and liquid - separation, the organic phase was concentrated to obtain the crude product. The crude product was purified by column chromatography (n - heptane / ethyl acetate = 20:1 to 5:1) to obtain 90 mg of the product as a pale - yellow solid, with a yield of 67% and an HPLC purity of 95.0%.

[0149] The NMR data of Compound 30 is as follows:

[0150] 1 H NMR (400 MHz, DMSO - d 6) δ 11.61 (s, 1H), 8.31 - 8.29 (m, 1H), 7.57 - 7.56 (m, 1H), 7.53 - 7.47 (m, 3H), 7.29 - 7.25 (s, 1H), 7.20 - 7.18 (m, 2H), 4.45 (d, J = 7.1 Hz, 2H), 2.63 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H).

[0151] The mass spectrometry data of Compound 30 is as follows: M + H molecular ion peak 324.1.

[0152] Example 14:

[0153] Synthesis of Ethyl 1 - methyl - 7 - phenoxy - 2 - carbobenzyloxy - 1,2,3,4 - tetrahydroisoquinoline - 3 - carboxylate (19)

[0154]

[0155] Add 80 mL of THF, 80 mL of water, 8.01 g of compound 16 and 3.9 g of potassium bicarbonate to the reaction flask. Cool the temperature to 0 - 10 °C, and add 5.33 g of benzyl chloroformate in batches. React at room temperature for 1 h. Detect by HPLC that the raw materials are completely converted. Separate the liquid, dry with anhydrous sodium sulfate, concentrate, and purify by column chromatography (n - heptane / ethyl acetate = 50:1 to 15:1) to obtain 7.7 g of an oily substance with a yield of 70% and a purity of 99.05%.

[0156] The NMR data of compound 19 are as follows:

[0157] 1 H NMR (400 MHz, CDCl3) δ 7.40 – 7.34 (m, 7H), 7.17 – 7.11 (m, 2H),7.03 – 7.01 (m, 2H), 6.89 – 6.81 (m, 2H), 5.33 – 5.10 (m, 3H), 4.74 – 4.22(m, 2H), 4.07 – 4.04 (m, 1H), 3.19 – 3.12 (m, 2H), 1.52 (d, J J = 6.9 Hz, 3H),1.32 – 1.15 (m, 3H).

[0158] The MS data of compound 19 are as follows: M+H molecular ion peak 446.3.

[0159] Example 15:

[0160] Synthesis of 2 - benzyl - 3 - ethyl - 1 - hydroxy - 1 - methyl - 4 - oxo - 7 - phenoxy - 3,4 - dihydroisoquinoline - 2,3(1 H ) - dicarbonate (20)

[0161]

[0162] Add 6 g of compound 19 to the reaction flask, add 60 mL of MeCN and 60 mL of water, slowly add 36.9 g of ammonium cerium(IV) nitrate, stir and react at room temperature. Monitor by HPLC until the raw materials are completely converted. Add 200 mL of ethyl acetate, stir and separate the liquid. The organic phase is concentrated to obtain the crude product. The crude product is purified by column (n - heptane / ethyl acetate = 20:1 to 5:1) to obtain 3.65 g of a pale yellow solid product with a yield of 56% and an HPLC purity of 95.0%.

[0163] The NMR data of compound 20 are as follows:

[0164] 1 1H NMR (400 MHz, CDCl3) δ 7.94 - 7.78 (m, 1H), 7.51 - 7.46 (m, 2H), 7.41 - 7.27 (m, 7H), 7.24 - 7.15 (m, 3H), 7.02 - 6.97 (m, 1H), 5.47 - 5.46 (m, 1H), 5.27 - 5.19 (m, 2H), 4.06 - 4.01 (m, 2H), 1.49 - 1.34 (m, 3H), 1.10 - 1.06 (m, 3H).

[0165] The mass spectrometry data of Compound 19 is as follows: M - H2O + H molecular ion peak 458.3.

[0166] Example 16:

[0167] Synthesis of Ethyl 4 - hydroxy - 1 - methyl - 7 - phenoxyisoquinoline - 3 - carboxylate (30)

[0168]

[0169] 3.5 g of Compound 20 was added to a reaction flask, 12 mL of AcOH was added, and the mixture was stirred until dissolved. Then 12 mL of an AcOH solution containing 30% HBr was added, and the reaction was stirred at room temperature. The conversion of the starting material was monitored by HPLC until complete. 100 mL of ethyl acetate was added, and the solution was added to a 20% potassium carbonate solution. After stirring and liquid separation, the organic phase was concentrated to obtain a crude product. The crude product was purified by column chromatography (n - heptane / ethyl acetate = 20:1 to 5:1) to give 2.05 g of the product as a pale yellow solid, with a yield of 86% and an HPLC purity of 99.5%.

[0170] The NMR data of Compound 30 is as follows:

[0171] 1 1H NMR (400 MHz, CDCl3) δ 11.61 (s, 1H), 8.31 - 8.29 (m, 1H), 7.57 - 7.56 (m, 1H), 7.53 - 7.47 (m, 3H), 7.29 - 7.25 (s, 1H), 7.20 - 7.18 (m, 2H), 4.45 (d, J = 7.1 Hz, 2H), 2.63 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H).

[0172] The mass spectrometry data of Compound 30 is as follows: M + H molecular ion peak 324.1.

[0173] Example 17:

[0174] Synthesis of Ethyl 1-Methyl-7-phenoxy-2-phenylsulfonyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (21)

[0175]

[0176] Add 80 mL of DCM, 8.0 g of compound 16, 5.2 g of triethylamine and 6.9 g of phenylsulfonyl chloride to a reaction flask. Heat the mixture to 40 °C and react overnight. Monitor the reaction by HPLC until the raw materials are completely reacted. Then add 80 mL of water to quench the reaction. Separate the layers and concentrate the organic layer to dryness. Purify the residue by column chromatography (n-heptane / ethyl acetate = 50:1 to 9:1) to obtain 8.9 g of an oily substance with a yield of 77.3% and a purity of 100%.

[0177] The NMR data of compound 21 are as follows:

[0178] 1 H NMR (400 MHz, CDCl3) δ 7.79 – 7.77 (m, 2H), 7.53 – 7.48 (m, 1H),7.42– 7.40 (m, 2H), 7.33 – 7.31 (m, 2H), 7.11 – 7.10 (m, 1H), 7.02 – 7.00 (m,1H), 6.91 – 6.89 (m, 2H), 6.78 – 6.75 (m, 1H), 6.64 – 6.63 (m, 1H), 4.97 –4.92 (m, 1H), 4.57 – 4.53 (m, 1H), 4.26 – 4.20 (m, 2H), 3.16 – 2.97 (m, 2H),1.50 – 1.47 (m, 3H), 1.31 – 1.26 (m, 3H).

[0179] The MS data of compound 21 are as follows: M+H molecular ion peak 452.7.

[0180] Example 18:

[0181] Synthesis of Ethyl 1-Methylene-4-oxo-7-phenoxy-2-phenylsulfonyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (22)

[0182]

[0183] 6 g of compound 21 was added to a reaction flask, 60 mL of MeCN and 60 mL of water were added, 36.9 g of ammonium cerium(IV) nitrate was added slowly, and the reaction was stirred at room temperature. The conversion of the raw materials was monitored by HPLC until it was complete. 60 mL of ethyl acetate was added, and the mixture was stirred and separated. The organic phase was concentrated to obtain a crude product, which was purified by column chromatography (n-heptane / ethyl acetate = 20:1 to 8:1) to obtain 2.9 g of a pale yellow solid product, with a yield of 47.0% and an HPLC purity of 93.0%.

[0184] The mass spectrometry data of compound 22 is as follows: the molecular ion peak of M-H2O+H is 464.3.

[0185] Example 19:

[0186] Synthesis of ethyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (30)

[0187]

[0188] 2.9 g of compound 22 was added to a reaction flask, 12 mL of an AcOH solution containing 30% HBr was added, and then 0.59 g of phenol was added. The reaction was stirred at room temperature. The conversion of the raw materials was monitored by HPLC until it was complete. 30 mL of ethyl acetate was added, and the solution was added to a 20% potassium carbonate solution. The mixture was stirred and separated. The organic phase was concentrated to obtain a crude product, which was purified by column chromatography (n-heptane / ethyl acetate = 20:1 to 5:1) to obtain 1.51 g of a pale yellow solid product, with a yield of 74.0% and a purity of 96.2%.

[0189] The NMR data of compound 30 is as follows:

[0190] 1 H NMR (400 MHz, CDCl3) δ 11.61 (s, 1H), 8.31 - 8.29 (m, 1H), 7.57 - 7.56(m, 1H), 7.53 - 7.47 (m, 3H), 7.29 - 7.25 (s, 1H), 7.20 - 7.18 (m, 2H), 4.45 (d, J = 7.1 Hz, 2H), 2.63 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H).

[0191] The mass spectrometry data of compound 30 is as follows: the molecular ion peak of M+H is 324.1.

[0192] Example 20:

[0193] Synthesis of Ethyl 1-Methyl-7-phenoxy-2-acetyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (23)

[0194]

[0195] Add 6.0 g of compound 15 into a hydrogenation kettle, add 60 mL of ethanol, 3.96 g of acetic anhydride, and then 0.6 g of 10% Pd / C. Seal the hydrogenation kettle, replace the hydrogen 3 times, and finally fill it to 3 - 4 MPa. Stir the reaction at room temperature, monitor the complete conversion of the raw materials by HPLC, filter, wash the filter cake with 30 mL of ethanol, concentrate the filtrate to obtain the crude product, and purify the crude product by column chromatography to obtain 4.2 g of white solid product, with a yield of 57.0% and an HPLC purity of 97.5%.

[0196] The NMR data of compound 23 are as follows:

[0197] 1 H NMR (400 MHz, CDCl3) δ 7.39 - 7.34 (m, 2H), 7.19 - 7.14 (m, 2H), 7.04 - 7.01 (m, 2H), 6.91 - 6.82 (m, 2H), 5.64 - 4.22 (m, 2H), 4.26 - 4.22 (m, 2H), 3.17 - 3.14 (m, 2H), 2.26 - 2.17 (m, 3H), 1.58 - 1.42 (m, 3H), 1.44 - 1.31 (m, 3H).

[0198] The MS data of compound 23 are as follows: M + H molecular ion peak 354.3.

[0199] Example 21:

[0200] Synthesis of Ethyl 2-Acetyl-1-hydroxy-1-methyl-4-oxo-7-phenoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (24)

[0201]

[0202] Add 1 g of compound 23 into a reaction flask, add 10 mL of MeCN and 10 mL of water, slowly add 7.8 g of ammonium cerium nitrate, stir the reaction at room temperature, monitor the complete conversion of the raw materials by HPLC, add 30 mL of ethyl acetate, stir and separate the liquid. Concentrate the organic phase to obtain the crude product, and purify the crude product by column chromatography (n - heptane / ethyl acetate = 20:1 to 5:1) to obtain 0.6 g of light yellow solid product, with a yield of 55% and an HPLC purity of 98.0%.

[0203] The NMR data of Compound 24 are as follows:

[0204] 1 H NMR (400 MHz, CDCl3) δ 7.99 - 7.97 (m, 1H), 7.47 - 7.43 (m, 2H), 7.27 - 7.25 (m, 1H), 7.13 - 7.11 (m, 2H), 7.00 - 6.98 (m, 1H), 6.81 - 6.80 (m, 1H), 5.20(s, 1H), 5.05 - 5.04 (m, 1H), 4.22 - 4.19 (m, 2H), 5.64 - 4.22 (m, 2H), 4.26 - 4.22(m, 2H), 3.17 - 3.14 (m, 2H), 2.26 - 2.17 (m, 3H), 1.58 - 1.42 (m, 3H), 1.44 - 1.31(m, 3H).

[0205] The mass spectrometry data of Compound 24 are as follows: M +H molecular ion peak 384.6.

[0206] Example 22:

[0207] Synthesis of Ethyl 4 - hydroxy - 1 - methyl - 7 - phenoxyisoquinoline - 3 - carboxylate (30)

[0208]

[0209] Add 30 mg of Compound 24 into a reaction flask, add it to 2 mL of THF, then add 15 mg of p - toluenesulfonic acid, heat up to 60 - 70 °C, stir the reaction. HPLC detection shows the formation of the target product, and LC - MS detects the molecular signal of the target compound.

[0210] The mass spectrometry data of Compound 30 are as follows: M+H molecular ion peak 324.1.

[0211] Example 23:

[0212] Synthesis of Ethyl 1 - methyl - 7 - phenoxy - 2 - benzoyl - 1,2,3,4 - tetrahydroisoquinoline - 3 - carboxylate (25)

[0213]

[0214] 12 g of Compound 16 was added into a reaction flask, followed by the addition of 120 mL of DCM, 5.8 g of triethylamine and 8.2 g of benzoyl chloride. The reaction was stirred at room temperature and monitored by HPLC until the raw materials were completely converted. Then 30 mL of water was added, and the mixture was stirred and separated by liquid-liquid extraction. The organic phase was concentrated to obtain the crude product, which was purified by column chromatography (n-heptane / ethyl acetate = 20:1 to 5:1) to give 14.5 g of a white solid product with a yield of 89.7% and an HPLC purity of 97.5%.

[0215] The NMR data of Compound 25 are as follows:

[0216] 1 H NMR (400 MHz, DMSO- d 6) δ 7.48 - 7.22 (m, 8H), 7.13 - 6.78 (m, 5H), 5.54 - 4.72 (m, 2H), 4.24 - 3.98 (m, 2H), 3.38 - 3.32 (m, 1H), 3.19 - 3.10 (m, 1H), 1.48 - 1.35 (m, 3H), 1.29 - 1.08 (m, 3H).

[0217] The MS data of Compound 25 are as follows: the molecular ion peak of M+H is 416.3.

[0218] Example 24:

[0219] Synthesis of ethyl 1-methyl-7-phenoxy-2-propoxycarbonyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (26)

[0220]

[0221] 10 g of Compound 16 was added into a reaction flask, followed by the addition of 150 mL of THF and 150 mL of water, 4.0 g of sodium bicarbonate and 4.7 g of propyl chloroformate. The reaction was stirred at room temperature and monitored by HPLC until the raw materials were completely converted. Then 200 mL of ethyl acetate was added, and the mixture was stirred and separated by liquid-liquid extraction. The organic phase was concentrated to obtain the crude product, which was purified by column chromatography (n-heptane / ethyl acetate = 20:1 to 8:1) to give 9.9 g of a pale yellow oily product with a yield of 77.0% and an HPLC purity of 99.8%.

[0222] The NMR data of Compound 26 are as follows:

[0223] 11H NMR (400 MHz, CDCl3) δ 7.38 - 7.33 (m, 2H), 7.16 - 7.10 (m, 2H), 7.03 - 7.00 (m, 2H), 6.89 - 6.84 (m, 2H), 5.30 - 5.13 (m, 1H), 4.70 - 4.49 (m, 1H), 4.26 - 4.18 (m, 2H), 4.11 - 4.02 (m, 2H), 3.17 - 3.12 (m, 2H), 1.75 - 1.60 (m, 2H), 1.52 - 1.45 (m, 3H), 1.33 - 1.26 (m, 3H), 1.01 - 0.92 (m, 3H).

[0224] The mass spectrometry data of Compound 26 is as follows: M+H molecular ion peak 398.3.

[0225] Example 27:

[0226] 2 - propyl - 3 - ethyl - 1 - hydroxy - 1 - methyl - 4 - oxo - 7 - phenoxy - 3,4 - dihydroisoquinoline - 2,3(1 H ) - dicarbonate (27) synthesis

[0227]

[0228] 6 g of Compound 26 was added to a reaction flask, 60 mL of MeCN and 60 mL of water were added, 41.4 g of ammonium cerium(IV) nitrate was slowly added, and the reaction was stirred at room temperature. The conversion of the raw material was monitored by HPLC until it was complete. 100 mL of ethyl acetate was added, and the mixture was stirred and separated. The organic phase was concentrated to obtain a crude product, and the crude product was purified by column chromatography (n - heptane / ethyl acetate = 20:1 to 8:1) to obtain 4.9 g of a pale yellow solid product with a yield of 76.3% and an HPLC purity of 75.0%.

[0229] The NMR data of Compound 27 is as follows:

[0230] 11H NMR (400 MHz, CDCl3) δ 8.02 - 7.90 (m, 1H), 7.48 - 7.43 (m, 2H), 7.30 - 7.26 (m, 1H), 7.14 - 7.10 (m, 2H), 7.01 - 6.98 (m, 1H), 6.83 - 6.81 (m, 1H), 5.38 - 5.32 (m, 1H), 4.27 - 4.26 (m, 2H), 4.20 - 4.09 (m, 2H), 1.76 - 1.66 (m, 2H), 1.57 - 1.54 (m, 3H), 1.23 - 1.19 (m, 2H), 1.01 - 0.97 (m, 3H).

[0231] The mass spectrometry data of Compound 27 is as follows: The molecular ion peak of M - H2O + H is 410.3.

[0232] Example 28:

[0233] Synthesis of N - [(4 - hydroxy - 1 - methyl - 7 - phenoxy - 3 - isoquinolinyl)carbonyl]glycine (roxadustat)

[0234]

[0235] Add 2 g of Compound 30 into a reactor, add 20 mL of methanol, then add 1.4 g of glycine and 1.0 g of sodium methoxide. Seal the reactor, stir, and heat up to 110 - 120 °C for reaction for 4 hours. Cool down to room temperature. Monitor the reaction by HPLC to ensure complete conversion of the raw materials. The target compound roxadustat is confirmed by HPLC and LC - MS.

[0236] The mass spectrometry data of Compound roxadustat is as follows: The molecular ion peak of M - H is 351.1.

Claims

1. A method for preparing a compound of formula VII from a compound of formula I: wherein R is a C1-20 hydrocarbyl group; PG is a protecting group for a nitrogen atom.

2. The method for preparing a compound of formula VII according to claim 1, wherein the PG protecting group is benzyloxycarbonyl, p-toluenesulfonyl, benzenesulfonyl, acetyl or propyloxycarbonyl.

3. The method for preparing the compound of formula VII according to claim 1, characterized in that: The preparation of compound VII from a compound of formula I comprises the following steps: (1) Reacting the compound of formula I with oxalyl chloride and iron(III) chloride to obtain a compound of formula II; (2) Deprotecting the compound of formula II under acidic conditions to obtain a compound of formula III; (3) Subjecting the compound of formula III to a reduction reaction to obtain a compound of formula IV; (4) Protecting the amino group in the compound of formula IV with a protecting group to obtain a compound of formula V; (5) Oxidizing the compound of formula V to obtain a compound of formula VI; (6) Under acidic conditions, obtaining the compound of formula VII by a reaction of removing the protecting group from the compound of formula VI.

4. The method for preparing Compound VII according to claim 3, wherein: The acid in the acidic conditions of step (2) is selected from one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, formic acid.

5. The method for preparing Compound VII according to claim 3, wherein: The reducing reagent for the reduction reaction in step (3) is selected from one or more of sodium borohydride, lithium borohydride, palladium on carbon / hydrogen, Raney nickel / hydrogen.

6. The method for preparing compound VII according to claim 3, characterized in that: The protecting group in step (4) is selected from one of benzyloxycarbonyl, p-toluenesulfonyl, benzenesulfonyl, acetyl or propyloxycarbonyl.

7. The method for preparing Compound VII according to claim 3, characterized in that: The oxidizing agent for the oxidation reaction in step (5) is ammonium cerium(IV) nitrate.

8. The method for preparing Compound VII according to claim 3, wherein: The acid in the acidic conditions of step (6) is selected from one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, formic acid.

9. The compound of formula VII prepared by the method for preparing a compound of formula VII according to claim 1 can be further used for preparing the pharmaceutical active molecule roxadustat: wherein R is a C1-20 hydrocarbyl group.

10. A method for preparing a compound of formula VI from a compound of formula V: wherein R is a C1-20 hydrocarbyl group; PG is a protecting group for a nitrogen atom.

11. The method for preparing a compound of formula VI from the compound of formula V according to claim 10, wherein the protecting group PG is benzyloxycarbonyl, p-toluenesulfonyl, benzenesulfonyl, acetyl or propyloxycarbonyl.

12. A method for preparing a compound of formula VI from the compound of formula V according to claim 10, characterized in that: The compound of formula V is oxidized to obtain a compound of formula VI.

13. A method for preparing a compound of formula VI from the compound of formula V according to claim 12, characterized in that: The oxidation reaction uses ammonium cerium(IV) nitrate as the oxidizing agent.

14. A method for preparing a compound of formula VII from a compound of formula VI: wherein R is a C1-20 hydrocarbyl group; PG is a protecting group for a nitrogen atom.

15. The method for preparing a compound of formula VII from the compound of formula VI according to claim 14, wherein the protecting group PG is benzyloxycarbonyl, p-toluenesulfonyl, benzenesulfonyl, acetyl or propyloxycarbonyl.

16. A method for preparing a compound of formula VII from the compound of formula VI according to claim 14, characterized in that: The compound of formula VI is obtained under acidic conditions to obtain a compound of formula VII.

17. A method for preparing a compound of formula VII from the compound of formula VI according to claim 16, characterized in that: The acid in the said acidic conditions is selected from one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, formic acid.

18. A method for preparing a compound of formula IV from a compound of formula I: wherein R is a C1-20 hydrocarbyl group.

19. The method for preparing the compound of formula IV according to claim 18, wherein: The preparation of compound IV from a compound of formula I comprises the following steps: (1) Reacting the compound of formula I with oxalyl chloride and iron(III) chloride to obtain a compound of formula II; The compound of formula II is deprotected under acidic conditions to obtain the compound of formula III; The compound of formula III is subjected to a reduction reaction to obtain the compound of formula IV.

20. The method for preparing the compound of formula IV according to claim 19, characterized in that: The acid in the acidic condition in step (2) is selected from one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, and formic acid.

21. The method for preparing the compound of formula IV according to claim 19, wherein: The reducing reagent for the reduction reaction in step (3) is selected from one or more of sodium borohydride, lithium borohydride, palladium on carbon / hydrogen, and Raney nickel / hydrogen.

22. A compound of formula II: , wherein R is a C1-20 hydrocarbyl group, and the compound of formula II is a single configuration of (5S, 10bR), (5R, 10bR), (5S, 10bS), (5R, 10bS) or a mixture thereof.

23. A compound of formula III or a salt thereof: , where R is a C1-20 hydrocarbyl group, and the compound of formula III is a single configuration of (3S), (3R) or a mixture thereof.

24. A compound of formula V: , where R is a C1-20 hydrocarbyl group, PG is a protecting group for the nitrogen atom, and the compound of formula V is a single configuration of (1S,3S), (1R,3S), (1S,3R), (1R,3R) or a mixture thereof.

25. The compound according to claim 24, wherein the PG protecting group is benzenesulfonyl, p-toluenesulfonyl, acetyl, benzoyl, benzyloxycarbonyl, tert-butoxycarbonyl, or propoxycarbonyl.

26. A compound of formula VI: , where R is a C1-20 hydrocarbyl group, PG is a protecting group for the nitrogen atom, and the compound of formula VI is a single configuration of (1S,3S), (1R,3S), (1S,3R), (1R,3R) or a mixture thereof.

27. The compound according to claim 26, wherein PG is p-toluenesulfonyl, benzenesulfonyl, acetyl, benzoyl, benzyloxycarbonyl, or propoxycarbonyl.

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