A roxadustat intermediate compound and a preparation method and application thereof

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a Roxadustat intermediate compound and a preparation method and application thereof. The compound is prepared by ring formation of acryloyl glycine methyl ester and m-phenoxyphenylacetone oxime; the reaction condition is mild, and the yield and purity are relatively high. The compound is used for preparing a key intermediate (1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) glycine methyl ester of Roxadustat, and has relatively high reaction stability, and the obtained product has relatively high yield and purity, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a roxadustat intermediate compound, its preparation method, and its application. Background Technology

[0002] Roxadustat (FG-4592), chemically named N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline)carbonyl]glycine, was originally developed by FibroGen, a US company, as a small molecule inhibitor that inhibits the activity of hypoxia-inducible factor prolyl hydroxylase (HIF-PH). It stabilizes HIF-2 and induces erythropoietin (EPO) expression. In April 2006, Astellas of Japan entered into a licensing agreement with FibroGen, acquiring development rights in Europe, the CIS, the Middle East, and South Africa. On July 31, 2013, AstraZeneca of the UK and FibroGen entered into a strategic collaboration agreement, acquiring development rights in the US, China, and other major markets outside the aforementioned Astellas licensing territories. It was first approved for marketing in China on December 18, 2018, for the treatment of anemia caused by chronic kidney disease (CKD) in patients undergoing dialysis. Roxadustat is marketed as a capsule, available in 20mg and 50mg strengths, under the brand name [Brand Name Missing]. Its chemical structural formula is:

[0003]

[0004] Currently, there are several methods for synthesizing roxadustat and its key intermediates. Among them, Chinese patent application CN104892509A uses L-tyrosine as the starting material, concentrated sulfuric acid as the catalyst, and methanol as the solvent. Refluxing for 16–20 h yields L-tyrosine methyl ester. Under nitrogen protection, a potassium salt is formed in a methanol-potassium methoxide solution. Then, using freshly prepared copper powder as a catalyst and dimethyl sulfoxide as the solvent, it undergoes an Ullmann coupling reaction with bromobenzene to give methyl 2-amino-3-(4-phenoxyphenyl)propionate. Subsequently, under concentrated hydrochloric acid conditions, it undergoes a Pictet-Spengler reaction with acetaldehyde, cyclizing to generate methyl 1-methyl-7-phenoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate. Then, in the presence of potassium carbonate, it reacts with p-toluenesulfonyl chloride to generate an N-p-toluenesulfonyl compound to improve dehydrogenation selectivity. Finally, in the presence of 30% sodium hydroxide, p-toluenesulfonic acid is eliminated to achieve the dehydrogenation reaction. 1-Methyl-7-phenoxyisoquinoline-3-carboxylate was converted into oxynitrides in the presence of glacial acetic acid and hydrogen peroxide to enhance the positive charge at the C-4 position of the isoquinoline ring. An oxidative rearrangement reaction was then carried out with the participation of p-toluenesulfonyl chloride to achieve C-4 hydroxylation, yielding 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate. Finally, the product was amidated with glycine under sodium methoxide-methanol conditions. This synthetic route has certain advantages and is relatively close to the principles of green synthesis. The construction of the isoquinoline ring adopts a synthesis reaction similar to that of Pictet-Spengler tetrahydroisoquinoline, while simultaneously solving the problem of C-1 methylation of the isoquinoline. The C-4 hydroxylation uses a HOAc / H2O2 and TsCl system, which also yields a relatively high yield. However, the Ullmann coupling reaction introduces byproducts from the reaction of the amino group with bromobenzene, and two steps use dimethyl sulfoxide as a solvent, leading to higher costs for industrial production. The overall yield of the six steps is approximately 20%. The synthetic route is shown below:

[0005]

[0006] Reference J. Org. Chem., 2018, 83(10): 15415-15425 uses 4-phenoxybenzaldehyde as the starting material. Under the action of sodium hydride, it undergoes a condensation reaction with methyl isocyanate, while the isocyanate is amidated to form (Z)-2-formamido-3-(4-phenoxyphenyl)acrylate methyl acrylate. Subsequently, under the action of POCl3, the formamido group dehydrates to form (Z)-2-isocyano-3-(4-phenoxyphenyl)acrylate methyl acrylate. In the presence of DBU, the nitrate anion generated by the deionization of 2-nitropropane reacts with iodophenyldiacetic acid [PhI(OAc)2] to form an iodoanion radical. After the radical loses iodobenzene, it releases a molecule of carbon dioxide, generating a methyl radical. Subsequently, it reacts with the methyl radical to form an imino radical, which undergoes intramolecular cyclization to generate methyl 1-methyl-7-phenoxyisoquinoline-3-carboxylate methyl ester. Then, the C-4 hydroxylation was completed using the same HOAc / H2O2 and TsCl system. Finally, the product was prepared by amidation with glycine. This method is concise, with an overall yield of approximately 17%. Its core step is a radical cyclization reaction to form isoquinoline. The main products of this radical reaction are methyl 1-methyl-7-phenoxyisoquinoline-3-carboxylate and iodobenzene, resulting in low atom utilization. The synthetic route is shown below:

[0007]

[0008] Chinese patent application CN108794397A uses 2-bromo-4-fluorobenzoic acid as a starting material. It is first chlorinated with thionyl chloride, then esterified with methanol, and subsequently undergoes a nucleophilic substitution reaction with phenol under alkaline conditions to obtain methyl 2-bromo-4-phenoxybenzoate. Then, under the action of Pd(OAc)2, tri-o-tolylphosphine, and DIPEA, it undergoes a Heck coupling reaction with n-butyl vinyl ether to generate methyl 4-phenoxy-2-(1-propoxyvinyl)benzoate, which is then hydrolyzed with 10% hydrochloric acid and 20% sulfuric acid to 2-acetyl-4-phenoxybenzoic acid, with a two-step yield of 82%. Subsequently, under the action of sodium acetate, it reacts with hydroxylamine hydrochloride to generate an oxime, which then reacts with a carboxyl group to form an intramolecular cyclization to generate 4-methyl-6-phenoxy-1H-benzo[d][1,2]azin-1-one. Then, it undergoes a Wittig reaction with methyl 2-(triphenyl-1,5-phosphine)acetate, breaking the NO bond and forming a β-dicarbonyl compound after tautomerism. This compound then undergoes intramolecular cyclization to generate methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate. Finally, it is amidated with glycine to obtain the target product. This method has high yields at each step, with an overall yield of approximately 27%. However, the Wittig reaction has low atom utilization, and the organophosphorus reagent causes significant environmental pollution. The synthetic route is shown below:

[0009]

[0010] Furthermore, patent WO2013013609 describes the preparation of 4-phenoxyphthalic acid from 4-nitrophthalonitrile as a starting material. This was followed by reflux and dehydration cyclization in acetic anhydride / acetic acid to yield 5-phenoxyphthalic anhydride. Then, under conditions with 1,8-diazabicycloundec-7-ene (DBU) as a base, it was reacted with methyl isocyanate in tetrahydrofuran at room temperature to give 2-[4-(methoxycarbonyl)azol-5-yl]-4-phenoxybenzoic acid. The yields of the first two steps were not specified in the literature. Subsequently, under acidic conditions, cyclization was performed to generate methyl 1,4-dihydroxy-7-phenoxyisoquinoline-3-carboxylate, with a yield of only 22% for this step. Then, using phosphorus oxychloride (POCl3) as the chlorination reagent, the hydroxyl group at the C-1 position of the isoquinoline ring is chlorinated, and then coupled with trimethylborane under Pd(PPh3)4 catalysis to generate methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate. After alkaline hydrolysis, it is then reacted with glycine methyl ester hydrochloride to generate (1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine methyl ester (I), which is finally hydrolyzed to give roxadustat. This method requires six steps, with an overall yield of less than 14%. The purification of several intermediates requires column chromatography, and the single-step yield of C-1 methylation is approximately 25%, making it unsuitable for large-scale industrial production. The synthetic route is shown below:

[0011]

[0012] Chinese patent application CN107954931A uses methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate as the starting material, and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) as the brominating agent. The reaction is first carried out at low temperature followed by reflux to obtain methyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate. Then, in a system of ethylene glycol monomethyl ether and potassium phosphate, methyl methyl ester is coupled with Pd(PPh3)4 as a catalyst and hydrolyzed to obtain 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid. This is then amidated with glycine methyl ester hydrochloride to obtain I, and finally hydrolyzed to obtain roxadustat. This preparation method consists of four steps with an overall yield of approximately 48%. The method is simple and has a high yield; however, its drawback lies in the unavailability of the starting materials and the relatively high difficulty of synthesis. The synthetic route is shown below:

[0013]

[0014] As shown above, methyl glycine (1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) can be prepared via different routes, followed by hydrolysis to prepare roxadustat. The hydrolysis conditions are milder than those of other routes, making it more suitable for industrial production. The synthetic routes are shown below:

[0015]

[0016] Therefore, I, as a key intermediate in the preparation of roxadustat, can directly affect the production, market supply, and quality of this drug. Its chemical structure is as follows:

[0017]

[0018] As can be seen from the above, the current processes for preparing roxadustat or its intermediate (1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine methyl ester (I) have many shortcomings. Therefore, finding a process suitable for the industrial production of (1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine methyl ester (I) with mild reaction conditions, simple operation, and high product yield and purity remains a problem that needs to be solved. Summary of the Invention

[0019] To address the problems existing in the current preparation technology of (1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine methyl ester (I), this invention provides a novel intermediate compound of roxadustat, the structure of which is shown in Formula I-2; and provides a method for preparing (1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine methyl ester (I) using this method. This method has mild reaction conditions, simple operation, and the target product obtained has high purity and yield.

[0020] The specific technical solution of the present invention is as follows:

[0021] A first aspect of the present invention provides a novel intermediate compound of roxadustat, the structure of which is shown in Formula I-2:

[0022]

[0023] A second aspect of the present invention provides a method for preparing a novel intermediate compound I-2 of roxadustat, the method comprising the following steps:

[0024] Compound I-1, methyl acryloylglycinate (SM-2), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer {[Cp*RhCl2]2}, trimethylacetic acid (PivOH), and silver salt were added to acetonitrile, and the temperature was controlled at T. B After the reaction was detected as complete, the intermediate compound I-2 was obtained through post-processing. The reaction route is as follows:

[0025]

[0026] Preferably, the silver salt is selected from one or a combination of AgOAc, AgBF4, Ag2O, and Ag2CO3, with Ag2CO3 being the most preferred.

[0027] Preferably, the molar ratio of compound I-1 and SM-2 to [Cp*RhCl2]2, PivOH, and silver salt is 1:1.1-1.8:1.0%-5.0%:1.5-4.0:1.5-4.0, more preferably 1:1.3:2.0%:2.0:2.0.

[0028] Preferably, the reaction temperature T B The temperature range is 0–30℃, with 20–25℃ being preferred.

[0029] In a preferred embodiment, a post-processing operation is required after the reaction is completed. Specifically, the reaction liquid is filtered through diatomaceous earth, and the resulting filtrate is concentrated under reduced pressure to dryness and then recrystallized through an ethyl acetate / n-hexane system to obtain intermediate I-2.

[0030] The preferred volume ratio of the ethyl acetate / n-hexane system is 1:1 to 3; more preferably 1:2.

[0031] Compound I-1 can be prepared using existing technologies or by the following methods.

[0032] Preparation method of compound I-1:

[0033] Compound SM-1, hydroxylamine hydrochloride, and a base were added to reaction solvent A, and the temperature was controlled at T. A After the reaction was completed and detected, the mixture was filtered. The resulting filter cake was purified with water, slurried, and dried under reduced pressure to obtain intermediate compound I-1. The reaction route is as follows:

[0034]

[0035] Preferably, the alkali is selected from sodium acetate, potassium acetate, triethylamine, and sodium carbonate, with sodium acetate being the most preferred.

[0036] Preferably, the reaction solvent A is selected from one or a combination of methanol, ethanol, tetrahydrofuran, acetonitrile, 1,4-dioxane, and water.

[0037] Preferably, the molar ratio of compound SM-1 to hydroxylamine hydrochloride and alkali is 1:1.2-1.8:1.2-1.8, more preferably 1:1.5:1.5.

[0038] Preferably, the reaction temperature T A The temperature range is 60–90℃, with 75–80℃ being preferred.

[0039] The third aspect of this invention provides the use of a novel roxadustat intermediate compound I-2 in the preparation of the key intermediate of roxadustat, (1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine methyl ester (I).

[0040] A novel roxadustat intermediate compound I-2 is used in the preparation of roxadustat key intermediate (1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine methyl ester (I). The preparation method includes the following steps:

[0041] Compound I-2 undergoes nitrogen oxidation of the isoquinoline ring, followed by a rearrangement reaction catalyzed by p-toluenesulfonyl chloride, and is then post-treated to yield compound (I).

[0042] The reaction route is as follows:

[0043]

[0044] Preferably, the oxidant is hydrogen peroxide, peroxybenzoic acid, m-chloroperoxybenzoic acid, peracetic acid, sodium hypochlorite, or ozone, with m-chloroperoxybenzoic acid being the most preferred.

[0045] Preferably, the solvent for the oxidation reaction is glacial acetic acid.

[0046] Preferably, the oxidation reaction is carried out at a temperature of 60–70°C.

[0047] The rearrangement reaction is carried out at a temperature of 25–61°C, preferably 35–45°C.

[0048] Preferably, the ratio of I-2 to the oxidant and p-toluenesulfonyl chloride is 1:1.2-4.0:1.2-3.0, more preferably 1:2.5:2.0.

[0049] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0050] 1. This invention provides a novel intermediate compound I-2 for roxadustat, which is used to prepare the key intermediate compound I for roxadustat through oxidative rearrangement. The preparation has high purity and yield, demonstrating the unique structural advantages of this intermediate compound.

[0051] 2. The preparation of the new intermediate compound I-2 is carried out under mild reaction conditions, is safer to operate, and has high purity and yield, making it suitable for industrial production. Detailed Implementation

[0052] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection of the present invention.

[0053] This invention uses HPLC to determine the purity of methyl glycine (I), a key intermediate of roxadustat, under the following chromatographic conditions:

[0054] Column: YMC Triart-C 18 Column (4.6 mm × 250 mm, 5.0 μm) or equivalent performance column;

[0055] Mobile phase: A. 0.1 mol / L formic acid solution; B. Acetonitrile;

[0056] Gradient elution: (0–25 min: A 80%–30%, 25–50 min: A 30%);

[0057] Column temperature: 30℃;

[0058] Detection wavelength: 260nm;

[0059] Flow rate: 1.0 ml / min;

[0060] Injection volume: 10 μl;

[0061] The retention time is approximately 29.9 minutes.

[0062] The structural confirmation data of compound I-2 obtained in this invention are as follows:

[0063]

[0064] ESI-HRMS (m / z): 351.1068 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ: 8.53 (s, 1H), 7.80 (d, J = 8.95Hz, 1H), 7.70 (dd, J = 2.38, 8.94Hz, 2H), 7.62 (d, J = 2.34Hz, 1H), 7.5 0(d,J=2.41Hz,2H),7.37(t,J=8.86Hz,1H),7.12~7.14(m,1H),7.01~7.03(m,1H),4.02(s,2H),3.77(s,3H),2.86(s,3H); 13 C NMR (125MHz, DMSO-d6) δ: 170.73, 168.52, 156.43, 154.08, 151.65, 140.01, 130.67, 13 0.06,127.98,127.45,123.88,123.34,122.46,119.24,113.10,51.82,45.85,25.15.

[0065] The structural confirmation data for compound I obtained in this invention are as follows:

[0066]

[0067] ESI-HRMS (m / z): 367.1294 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ: 13.21 (s, 1H), 9.22 (t, J = 5.58Hz, 1H), 8.29 (d, J = 9.00Hz, 1H), 7.61 (d, J = 2.34Hz, 1H), 7.53 (dd, J = 2.40, 9 .00Hz,1H),7.46~7.50(m,2H),7.26(tt,J=0.90,7.44Hz,1H),7.17~7.19(m,2H),4.14(d,J=6.24Hz,2H),3.69(s,3H),2.70(s,3H); 13 C NMR (151MHz, DMSO-d6) δ: 170.08, 169.90, 157.84, 155.53, 152.87, 146.99, 131.45, 13 0.38,125.26,124.56,123.46,122.42,119.49,119.38,112.13,51.93,45.83,25.93.

[0068] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0069] Synthesis of compound I-1

[0070] Example 1

[0071] At room temperature, compound SM-1 (42.45 g, 0.20 mol), hydroxylamine hydrochloride (20.85 g, 0.30 mol), and sodium acetate (24.61 g, 0.30 mol) were added to ethanol (250 ml). The mixture was refluxed under controlled temperature. After the reaction was completed, the mixture was filtered. The resulting filter cake was purified by water, slurryed, and dried under reduced pressure to obtain intermediate compound I-1, with a yield of 95.3% and an HPLC purity of 99.73%.

[0072] Example 2

[0073] At room temperature, compound SM-1 (42.45 g, 0.20 mol), hydroxylamine hydrochloride (16.68 g, 0.24 mol), and potassium acetate (23.55 g, 0.24 mol) were added to acetonitrile (250 ml). The mixture was refluxed under controlled temperature. After the reaction was completed, the mixture was filtered. The resulting filter cake was purified by water, slurryed, and dried under reduced pressure to obtain intermediate compound I-1, with a yield of 93.8% and an HPLC purity of 99.72%.

[0074] Example 3

[0075] At room temperature, compound SM-1 (42.45 g, 0.20 mol), hydroxylamine hydrochloride (25.02 g, 0.36 mol), and sodium acetate (24.61 g, 0.36 mol) were added to tetrahydrofuran (250 ml). The mixture was refluxed under controlled temperature. After the reaction was completed, the mixture was filtered. The resulting filter cake was purified by water, slurryed, and dried under reduced pressure to obtain intermediate compound I-1, with a yield of 94.2% and an HPLC purity of 99.55%.

[0076] Synthesis of compound I-2

[0077] Example 4

[0078] Compounds I-1 (22.73 g, 0.10 mol), SM-2 (18.60 g, 0.13 mol), [Cp*RhCl2]2 (1.24 g, 2.0 mmol), PivOH (20.43 g, 0.20 mol), and Ag2CO3 (55.15 g, 0.20 mol) were added to acetonitrile (200 ml) and reacted at a controlled temperature of 20–25 °C. After the reaction was completed, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure and recrystallized from ethyl acetate / n-hexane (volume ratio 1:2) to obtain intermediate I-2, with a yield of 96.5% and an HPLC purity of 99.75%.

[0079] Example 5

[0080] Compound I-1 (22.73 g, 0.10 mol), SM-2 (15.74 g, 0.11 mol), [Cp*RhCl2]2 (1.24 g, 2.0 mmol), PivOH (20.43 g, 0.20 mol), and Ag2CO3 (55.15 g, 0.20 mol) were added to acetonitrile (200 ml) and reacted at a controlled temperature of 25–30 °C. After the reaction was completed, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure and recrystallized from ethyl acetate / n-hexane (volume ratio 1:2) to obtain intermediate I-2, with a yield of 94.6% and an HPLC purity of 99.73%.

[0081] Example 6

[0082] Compounds I-1 (22.73 g, 0.10 mol), SM-2 (25.75 g, 0.18 mol), [Cp*RhCl2]2 (1.24 g, 2.0 mmol), PivOH (20.43 g, 0.20 mol), and AgOAc (33.38 g, 0.20 mol) were added to acetonitrile (200 ml) and reacted at a controlled temperature of 10–15 °C. After the reaction was completed, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure and recrystallized from ethyl acetate / n-hexane (volume ratio 1:2) to obtain intermediate I-2, with a yield of 93.6% and an HPLC purity of 99.67%.

[0083] Example 7

[0084] Compound I-1 (22.73 g, 0.10 mol), SM-2 (18.60 g, 0.13 mol), [Cp*RhCl2]2 (0.62 g, 1.0 mmol), PivOH (20.43 g, 0.20 mol), and Ag2O (46.35 g, 0.20 mol) were added to acetonitrile (200 ml) and reacted at a controlled temperature of 25–30 °C. After the reaction was completed, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure and recrystallized from ethyl acetate / n-hexane (volume ratio 1:2) to obtain intermediate I-2, with a yield of 94.5% and an HPLC purity of 99.70%.

[0085] Example 8

[0086] Compounds I-1 (22.73 g, 0.10 mol), SM-2 (18.60 g, 0.13 mol), [Cp*RhCl2]2 (3.09 g, 5.0 mmol), PivOH (20.43 g, 0.20 mol), and AgBF4 (38.93 g, 0.20 mol) were added to acetonitrile (200 ml) and reacted at a controlled temperature of 15–20 °C. After the reaction was completed, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure and recrystallized from ethyl acetate / n-hexane (volume ratio 1:2) to obtain intermediate I-2, with a yield of 96.3% and an HPLC purity of 99.56%.

[0087] Example 9

[0088] Compound I-1 (22.73 g, 0.10 mol), SM-2 (18.60 g, 0.13 mol), [Cp*RhCl2]2 (1.24 g, 2.0 mmol), PivOH (15.32 g, 0.15 mol), and Ag2CO3 (41.36 g, 0.15 mol) were added to acetonitrile (200 ml) and reacted at a controlled temperature of 25–30 °C. After the reaction was completed, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure and recrystallized from ethyl acetate / n-hexane (volume ratio 1:2) to obtain intermediate I-2, with a yield of 93.4% and an HPLC purity of 99.59%.

[0089] Example 10

[0090] Compound I-1 (22.73 g, 0.10 mol), SM-2 (18.60 g, 0.13 mol), [Cp*RhCl2]2 (1.24 g, 2.0 mmol), PivOH (40.85 g, 0.40 mol), and Ag2CO3 (110.30 g, 0.40 mol) were added to acetonitrile (300 ml) and reacted at a controlled temperature of 5–10 °C. After the reaction was completed, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure and recrystallized from ethyl acetate / n-hexane (volume ratio 1:2) to obtain intermediate I-2, with a yield of 94.6% and an HPLC purity of 99.67%.

[0091] Synthesis of Compound I

[0092] Example 11

[0093] At room temperature, compound I-2 (21.02 g, 0.06 mol) and m-chloroperoxybenzoic acid (17.26 g, 0.10 mol) were added to glacial acetic acid (80 ml) and stirred until homogeneous. The temperature was maintained at 60–70 °C, and the remaining m-chloroperoxybenzoic acid (8.63 g, 0.05 mol) in glacial acetic acid (40 ml) was slowly added dropwise to the reaction system (over approximately 7–10 hours). After the addition was complete and the reaction was finished, the reactants were concentrated under reduced pressure (and ethanol was added for further concentration under reduced pressure to remove any remaining glacial acetic acid). The concentrated residue was dissolved in dichloromethane (50 ml), washed with saturated sodium bicarbonate solution (20 ml × 2), washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate in the organic phase. Then, p-toluenesulfonyl chloride (19.06 g, 0.10 mol) was added to the organic layer and the mixture was refluxed under controlled temperature. After the reaction was detected to be complete, the reactants were concentrated to dryness under reduced pressure, and methanol was added for cooling and crystallization. The resulting solid was dried under reduced pressure to obtain compound I, with a yield of 93.9% and an HPLC purity of 99.76%.

[0094] Example 12

[0095] At room temperature, compound I-2 (21.02 g, 0.06 mol) and m-chloroperoxybenzoic acid (17.26 g, 0.048 mol) were added to glacial acetic acid (80 ml) and stirred until homogeneous. The temperature was maintained at 60–70 °C, and the remaining m-chloroperoxybenzoic acid (8.63 g, 0.024 mol) in glacial acetic acid (40 ml) was slowly added dropwise to the reaction system (over approximately 7–10 hours). After the addition was complete and the reaction was finished, the reactants were concentrated under reduced pressure (and ethanol was added for further concentration under reduced pressure to remove any remaining glacial acetic acid). The concentrated residue was dissolved in chloroform (50 ml), washed with saturated sodium bicarbonate solution (20 ml × 2), washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate in the organic phase. Then, p-toluenesulfonyl chloride (19.06 g, 0.10 mol) was added to the organic layer and the mixture was refluxed under controlled temperature. After the reaction was confirmed to be complete, the reactants were concentrated to dryness under reduced pressure, and methanol was added for cooling and crystallization. The resulting solid was dried under reduced pressure to obtain compound I, with a yield of 92.6% and an HPLC purity of 99.64%.

[0096] Example 13

[0097] At room temperature, compound I-2 (21.02 g, 0.06 mol) and peracetic acid (12.17 g, 0.16 mol) were added to glacial acetic acid (80 ml) and stirred until homogeneous. The temperature was maintained at 60–70 °C, and the remaining peracetic acid (6.08 g, 0.08 mol) in glacial acetic acid (40 ml) was slowly added dropwise to the reaction system (over approximately 7–10 hours). After the addition was complete and the reaction was finished, the reactants were concentrated under reduced pressure (and ethanol was added for further concentration under reduced pressure to remove any remaining glacial acetic acid). The concentrated residue was dissolved in dichloromethane (50 ml), washed with saturated sodium bicarbonate solution (20 ml × 2), washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate in the organic phase. Then, p-toluenesulfonyl chloride (19.06 g, 0.10 mol) was added to the organic layer and the reaction was carried out at a controlled temperature of 30–35 °C. After the reaction was detected to be complete, the reactants were concentrated to dryness under reduced pressure, and methanol was added for cooling and crystallization. The resulting solid was dried under reduced pressure to obtain compound I, with a yield of 93.2% and an HPLC purity of 99.70%.

[0098] Example 14

[0099] At room temperature, compound I-2 (21.02 g, 0.06 mol) and 30% hydrogen peroxide (11.34 g, 0.10 mol) were added to glacial acetic acid (80 ml) and stirred until homogeneous. The temperature was maintained at 60–70 °C, and the remaining 30% hydrogen peroxide (5.67 g, 0.05 mol) solution in glacial acetic acid (40 ml) was slowly added dropwise to the reaction system (over approximately 7–10 hours). After the addition was complete and the reaction was finished, the reactants were concentrated under reduced pressure (and ethanol was added for further concentration under reduced pressure to remove any remaining glacial acetic acid). The concentrated residue was dissolved in chloroform (50 ml), washed with saturated sodium bicarbonate solution (20 ml × 2), washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate in the organic phase. Then, p-toluenesulfonyl chloride (13.73 g, 0.072 mol) was added to the organic layer and the mixture was refluxed under controlled temperature. After the reaction was confirmed to be complete, the reactants were concentrated to dryness under reduced pressure, and methanol was added for cooling and crystallization. The resulting solid was dried under reduced pressure to obtain compound I, with a yield of 92.8% and an HPLC purity of 99.64%.

[0100] Example 15

[0101] At room temperature, compound I-2 (21.02 g, 0.06 mol) and perbenzoic acid (13.81 g, 0.10 mol) were added to glacial acetic acid (80 ml) and stirred until homogeneous. The temperature was maintained at 60–70 °C, and the remaining perbenzoic acid (6.91 g, 0.05 mol) in glacial acetic acid (40 ml) was slowly added dropwise to the reaction system (over approximately 7–10 hours). After the addition was complete and the reaction was finished, the reactants were concentrated under reduced pressure (and ethanol was added for further concentration under reduced pressure to remove any remaining glacial acetic acid). The concentrated residue was dissolved in dichloromethane (50 ml), washed with saturated sodium bicarbonate solution (20 ml × 2), washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate in the organic phase. Then, p-toluenesulfonyl chloride (34.32 g, 0.18 mol) was added to the organic layer and the reaction was carried out at a controlled temperature of 30–35 °C. After the reaction was detected to be complete, the reactants were concentrated to dryness under reduced pressure, methanol was added, and the mixture was cooled to crystallize. The resulting solid was dried under reduced pressure to obtain compound I, with a yield of 93.5% and an HPLC purity of 99.72%.

Claims

1. A method for preparing roxadustat intermediate compound I, characterized in that, Its preparation method includes the following steps: Step 1: Add compound I-1, acryloylglycine methyl ester SM-2, [Cp*RhCl2]2, trimethylacetic acid, and silver salt to acetonitrile, and control the temperature T. B After the reaction was detected as complete, the intermediate compound I-2 was obtained through post-processing. The reaction route is as follows: ； Step 2: Compound I-2 undergoes nitrogen oxidation of the isoquinoline ring, followed by a rearrangement reaction catalyzed by p-toluenesulfonyl chloride, and is then post-treated to obtain compound I; The reaction route is as follows: ； The silver salt mentioned in step 1 is Ag2CO3; The molar ratio of compounds I-1 and SM-2 to [Cp*RhCl2]2, trimethylacetic acid, and silver salt in step 1 is 1:1.3:2.0%:2.0:2.

0. The reaction temperature T mentioned in step 1 B The temperature is 20–25℃. The oxidant in the nitrogen oxidation reaction described in step 2 is m-chloroperoxybenzoic acid; The solvent for the nitrogen oxidation reaction in step 2 is glacial acetic acid; The temperature of the nitrogen oxidation reaction in step 2 is 60–70°C; the temperature of the rearrangement reaction is 25–61°C.

2. The preparation method according to claim 1, characterized in that, After the reaction in step 1 is completed, post-processing is required. Specifically, the reaction solution is filtered through diatomaceous earth, and the resulting filtrate is concentrated under reduced pressure to dryness. After recrystallization through an ethyl acetate / n-hexane system, intermediate I-2 is obtained.

3. The preparation method according to claim 1, characterized in that, The rearrangement reaction in step 2 is carried out at a temperature of 35–45°C.

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