Process for the preparation of a roxadustat intermediate

Abstract

The application provides a Roxadustat intermediate and a preparation method thereof, and relates to the technical field of organic synthesis. The preparation method comprises the following steps: condensation of m-phenoxybenzaldehyde and an amino acid under catalysis of an alkali to generate an imine, then reduction to obtain an amine, and then hydrolysis, substitution, Friedel-Crafts acylation, substitution and aromatization to obtain a target product. The synthesis line of the application is novel, all the raw materials and reagents used are easy to obtain or prepare, no high-risk and high-pollution reagents are used, it is safe and environmentally friendly, the reaction conditions are mild, the operation is convenient and controllable, the prepared Roxadustat intermediate has good purity, and can be applied to industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a roxadustat intermediate and its preparation method. Background Technology

[0002] Roxadustat's Chinese name is N-[(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-yl)carbonyl]glycine, and its molecular formula is C2. 19 H 16 N2O5. Roxadustat is a small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase developed by FibroGen. It can be used orally to treat anemia associated with dialysis-dependent and non-dialysis-dependent end-stage renal disease (ESRD), chronic kidney disease (CKD), and myelodysplastic syndrome (MDS). This drug was first successfully launched in China in December 2018. Roxadustat can regulate HIF, increase hemoglobin levels, and increase iron absorption and utilization by reducing hepcidin levels. It is well tolerated, therefore, roxadustat is used to treat anemia caused by chronic kidney disease (CKD) in patients undergoing dialysis.

[0003] In existing technologies, roxadustat is generally synthesized through organic synthesis, and there are multiple synthetic routes. Among them, compounds of formula A and formula B are important intermediates in the synthesis of roxadustat.

[0004]

[0005] Currently, the main routes for the synthesis of compounds of formula A and formula B are as follows:

[0006] Synthetic Route 1: Zhejiang Beta Pharmaceutical Co., Ltd. disclosed the following preparation method in WO2013013609 and CN104024227A. In the preparation of compound B, phosphorus oxychloride is used for chlorination, which poses a high safety risk for scale-up production. The methylation method uses palladium catalyst and methylborane (trimethylborane, tetra-triphenylphosphine palladium, potassium carbonate, and 1,4-dioxane as solvent), which has a low yield. Moreover, trimethylborane is a hazardous material that is prone to spontaneous combustion, which is not conducive to industrial scale-up.

[0007]

[0008] Synthetic Route 2: CN106083720A reported the use of 4-bromo-2-methylbenzoic acid as a starting material, through esterification, coupling, bromination, amination, and cyclization to obtain compound A. The starting material 4-bromo-2-methylbenzoic acid used in this route is expensive, and carbon tetrachloride is used as the reaction solvent. This solvent is a controlled substance, and the entire route uses column chromatography for purification, which is time-consuming and labor-intensive and not suitable for industrial production.

[0009]

[0010] Synthetic Route 3: Suzhou Mingrui Pharmaceutical Technology Co., Ltd. reported in CN104892509A a method for obtaining compound B from tyrosine via esterification, etherification, cyclization, dehydrogenation, and oxidative rearrangement. In the preparation of compound B, an amino acid cyclization method was used. In this method, the introduction of the phenolic hydroxyl group into the phenyl group easily generates amino substitution byproducts, which makes it difficult to purify the final product. Furthermore, the introduction of the hydroxyl group at the 4-position of the isoquinoline ring is carried out by hydrogen peroxide oxidation, which poses a significant risk in industrial production.

[0011]

[0012] Synthetic Route 4: CN103435546 reported a process of coupling with 5-bromophthalide, followed by ring-opening, amination, and cyclization to obtain the target product A. The raw material 5-bromophthalide used in this route, along with the reactants including trimethyl borate and dichlorotriphenylphosphine, are expensive. Among them, trimethyl borate is flammable, explosive, and toxic, posing a high safety risk. The entire route is costly and unsuitable for industrial production.

[0013]

[0014] In summary, the above routes are unsuitable for industrial production due to their high cost, time-consuming and labor-intensive post-processing column chromatography, high safety risks associated with the materials used, and difficulties in purifying the final product. Therefore, it is crucial to find a route with low safety risks, environmental friendliness, and good reaction selectivity suitable for industrial production. Summary of the Invention

[0015] (a) Technical problems to be solved

[0016] To address the shortcomings of existing technologies, this invention provides a roxadustat intermediate and its preparation method, solving the technical problems of high cost and high safety risk in existing roxadustat intermediate synthesis methods.

[0017] (II) Technical Solution

[0018] To achieve the above objectives, the present invention provides the following technical solution:

[0019] A method for preparing a roxadustat intermediate, the synthetic route is shown below:

[0020]

[0021] The preparation method includes the following steps:

[0022] S1. Add the compound of formula 1 and the glycine derivative to solvent 1 and react at room temperature under the catalysis of alkali and solvent 2. After the reaction is completed, add a reducing agent at low temperature. After the reaction is completed, quench, concentrate, extract, dry and concentrate to obtain the compound of formula 2.

[0023] S2. Add the compound of formula 2 to water, then add alkali and heat to react. After the reaction is complete, extract with extractant 1. Acidify the aqueous layer at low temperature, then extract with extractant 2. Dry and concentrate to obtain the compound of formula 3.

[0024] S3. Add the compound of formula 3 to water, then add alkali, heat until dissolved, then add p-toluenesulfonyl chloride. After the reaction is complete, cool down, and then acidify, extract, dry, concentrate, and crystallize to obtain the compound of formula 4.

[0025] S4. Add the compound of formula 4 to solvent 1, add a catalytic amount of DMF, then add an acylation reagent, heat the reaction, concentrate the solvent, dissolve the oily substance in solvent 2, protect it to a low temperature environment with N2, add Lewis acid, and after the reaction is completed, quench, wash with alkali, wash with water, dry, and concentrate to obtain the compound of formula 5.

[0026] S5. Compound of formula 5 and sodium hydrogen are added to dimethyl carbonate under a nitrogen atmosphere. The reaction is heated and the solvent is evaporated after the reaction is completed. The reaction is quenched with methanol at low temperature, water is added, and the mixture is extracted with an extractant. The mixture is washed with water, dried, and concentrated to obtain compound of formula 6.

[0027] S6. Add the compound of formula 6 to a solvent, add a catalyst and a base, heat the mixture to react, and after the reaction is complete, cool it down and extract it with an extractant. Dry and concentrate the mixture to obtain the compound of formula A.

[0028] Furthermore, S1 specifically includes the following steps:

[0029] The reaction equation is shown below:

[0030]

[0031] Further, the glycine derivative mentioned in S1 is glycine methyl ester, glycine methyl ester hydrochloride, glycine ethyl ester, glycine ethyl ester hydrochloride, glycine isopropyl ester, glycine isopropyl ester hydrochloride, and preferably, the amino acid is glycine methyl ester hydrochloride.

[0032] Further, the compound of formula 1 in S1 is m-phenoxybenzaldehyde, and the molar ratio of m-phenoxybenzaldehyde to glycine derivative is 1:1-3.5, preferably 1:1-1.4;

[0033] Further, solvent 1 in S1 is any one of tetrahydrofuran, dichloromethane, chloroform, and ethyl acetate, preferably dichloromethane;

[0034] Furthermore, the base mentioned in S1 is any one of sodium bicarbonate, sodium carbonate, triethylamine, diethylamine, pyridine, and 4-N,N-dimethylaminopyridine, preferably triethylamine;

[0035] Furthermore, the molar ratio of the compound of formula 1 (m-phenoxybenzaldehyde) to the base in S1 is 1:1-3.0, preferably 1:1-2.5;

[0036] Furthermore, the room temperature reaction time described in S1 is 16-30 h, preferably 18-22 h;

[0037] Furthermore, the solvent 2 mentioned in S1 is any one of tert-butanol, methanol, and ethanol, preferably methanol;

[0038] Furthermore, the reducing agent mentioned in S1 is any one of sodium borohydride, zinc borohydride, and sodium cyanoborohydride, preferably sodium borohydride;

[0039] Furthermore, the molar ratio of the compound of formula 1 (m-phenoxybenzaldehyde) to the reducing agent in S1 is 1:1-2.0, preferably 1:1-1.5;

[0040] Furthermore, the low-temperature reaction temperature described in S1 is -5℃ to 10℃, preferably 0℃ to 5℃;

[0041] Furthermore, the reagent used for extraction in S1 is one of ethyl acetate, dichloromethane, and chloroform, preferably dichloromethane.

[0042] Furthermore, after step S1, post-processing is also included: specifically, the following steps are included: quenching, extraction, drying, concentration, and column chromatography to obtain compound of formula 2.

[0043] Furthermore, S2 specifically includes the following steps:

[0044] The reaction equation is shown below:

[0045]

[0046] Furthermore, the alkali mentioned in S2 is any one of sodium carbonate, sodium hydroxide, and potassium hydroxide, preferably sodium hydroxide;

[0047] Furthermore, the molar ratio of the compound of formula 2 to the base in S2 is 1:1.1-2.5, preferably 1:1.5-2.0;

[0048] Furthermore, the extractant 1 mentioned in S2 is any one of ethyl acetate, dichloromethane, and methyl ether, preferably methyl ether;

[0049] Furthermore, the acid used for acidification in S2 is one of hydrochloric acid, sulfuric acid, and acetic acid, preferably acetic acid;

[0050] Furthermore, the extractant 2 mentioned in S2 is one of ethyl acetate, dichloromethane, and chloroform, preferably ethyl acetate.

[0051] Furthermore, step S2 is followed by post-processing: drying and concentration to obtain compound 3.

[0052] Furthermore, S3 specifically includes the following steps:

[0053] The reaction equation is shown below:

[0054]

[0055] Furthermore, the alkali mentioned in S3 is any one of sodium carbonate, sodium hydroxide, and potassium hydroxide, preferably sodium carbonate;

[0056] Furthermore, the molar ratio of the compound of formula 3 in S3 to p-toluenesulfonyl chloride is 1:1-2.0, preferably 1:1.1-1.4;

[0057] Furthermore, the molar ratio of the compound of formula 3 to the base in S3 is 1:1-2.5, preferably 1:1.2-1.6;

[0058] Furthermore, the acid used for acidification in S3 is one of hydrochloric acid, sulfuric acid, and acetic acid, preferably hydrochloric acid;

[0059] Furthermore, the reagent used for extraction in S3 is one of ethyl acetate, dichloromethane, and chloroform, preferably ethyl acetate.

[0060] Furthermore, step S3 is followed by post-processing: drying, concentration, and crystallization to obtain compound 4.

[0061] Furthermore, S4 specifically includes the following steps:

[0062] The reaction equation is shown below:

[0063]

[0064] Furthermore, solvent 1 in S4 is any one of toluene, dichloromethane, and chloroform, preferably dichloromethane;

[0065] Furthermore, the mass ratio of the compound of formula 4 to the volume of DMF in S4 is 1g:0.01-0.05mL, preferably 1g:0.03mL;

[0066] Furthermore, the acylation reagent in S4 is any one of oxalyl chloride, thionyl chloride, and phosphorus oxychloride, preferably thionyl chloride;

[0067] Furthermore, the molar ratio of the compound of formula 4 to the acylation reagent in S4 is 1:1.5-4.0, preferably 1:1.5-2.5;

[0068] Furthermore, solvent 2 in S4 is any one of toluene, dichloromethane, and chloroform, preferably dichloromethane;

[0069] Furthermore, the Lewis acid mentioned in S4 is any one of zinc chloride, ferric chloride, aluminum chloride, and boron trifluoride, preferably aluminum chloride;

[0070] Furthermore, the molar ratio of the compound of formula 4 to the Lewis acid in S4 is 1:2.0-4.0, preferably 1:2.0-2.5;

[0071] Furthermore, the alkali used for alkaline washing in S4 is any one of sodium bicarbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide, with sodium hydroxide being preferred;

[0072] Furthermore, after step S4, post-processing is also included: washing with water, drying, and concentrating to obtain compound 5.

[0073] Furthermore, S5 specifically includes the following steps:

[0074] The reaction equation is shown below:

[0075]

[0076] Furthermore, the alkali mentioned in S5 is any one of lithium tert-butoxide, LDA, and sodium hydride, preferably sodium hydride;

[0077] Furthermore, the molar ratio of the compound of formula 5 to the base in S5 is 1:2-5, preferably 1:2-4;

[0078] Furthermore, the reaction temperature of the heating reaction described in S5 is 80-95℃, preferably 85-90℃;

[0079] Furthermore, the extractant mentioned in S5 is one of diethyl ether, ethyl acetate, dichloromethane, and chloroform, preferably ethyl acetate;

[0080] Furthermore, after step S5, post-processing is also included: quenching with methanol after cooling, washing with water, drying, and concentrating to obtain compound of formula 6;

[0081] Furthermore, S6 specifically includes the following steps:

[0082] The reaction equation is shown below:

[0083]

[0084] Furthermore, the catalyst mentioned in S6 is one of CuI and Pd2(dba)3, preferably CuI;

[0085] Furthermore, the solvent mentioned in S6 is one of 1,4-dioxane, 1,4-dioxane, and acetonitrile, preferably 1,4-dioxane;

[0086] Furthermore, the alkali mentioned in S6 is one of sodium bicarbonate, cesium carbonate, sodium carbonate, and potassium carbonate, preferably potassium carbonate;

[0087] Furthermore, the molar ratio of the compound of formula 6 to the catalyst in S6 is 1:0.05-0.5, preferably 1:0.05-0.1;

[0088] Furthermore, the reaction temperature of the heating reaction described in S6 is 50-80°C, preferably 65-75°C;

[0089] Furthermore, the reaction time for the heating reaction described in S6 is 30-40 hours, preferably 34-38 hours;

[0090] Furthermore, the extractant mentioned in S6 is any one of ethyl acetate, dichloromethane, and chloroform, with ethyl acetate being preferred.

[0091] Furthermore, step S6 is followed by post-processing: drying and concentration to obtain compound A.

[0092] (III) Beneficial Effects

[0093] This invention provides a roxadustat intermediate and its preparation method. Compared with the prior art, it has the following advantages:

[0094] This invention provides a roxadustat intermediate and its preparation method. The preparation method includes the following steps: m-phenoxybenzaldehyde and a glycine derivative are condensed under alkaline catalysis to generate an imine, which is then reduced to obtain an amine. The amine is then subjected to hydrolysis, substitution, Friedel-Crafts acylation, substitution, and aromatization to obtain the target product. The synthetic route of this invention is novel, all the raw materials and reagents used are easy to obtain or prepare, and no highly hazardous or highly polluting reagents are used. It is safe and environmentally friendly, the reaction conditions are mild, the operation is convenient and controllable, and the prepared roxadustat intermediate has good purity and is suitable for industrial production. Attached Figure Description

[0095] Figure 1 This is a flowchart of the method for preparing the roxadustat intermediate of the present invention. Detailed Implementation

[0096] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0097] To better understand the above technical solution, the following will provide a detailed explanation of the technical solution in conjunction with specific implementation methods.

[0098] Please see Figure 1 The present invention provides two technical solutions: a method for preparing a roxadustat intermediate specifically includes the following embodiments:

[0099] Example 1:

[0100] A method for preparing methyl 4-hydroxy-7-phenoxy-3-isoquinoline carboxylate, an intermediate of roxadustat (Formula A), includes the following steps:

[0101]

[0102] Synthesis of compounds S1 and S2

[0103] At room temperature, m-phenoxybenzaldehyde (49.6 g, 0.25 mol) and glycine methyl ester hydrochloride (31.4 g, 0.25 mol) were added to 250 mL of dichloromethane, followed by triethylamine (50.6 g, 0.5 mol). The reaction was carried out at room temperature for 18 h, monitored by TLC (EA:PE = 1:5). After the reactants had reacted completely, the reaction solution was concentrated to dryness. The resulting oily substance was added to 300 mL of methanol, cooled to 0 °C, and sodium borohydride was added in portions. 9.5g (0.25mol) was added, the cold source was turned off, and the reaction was stirred for 1 hour. The reaction was monitored by TLC (EA:PE = 1:1). After the imine reaction was complete, water was added dropwise to quench the reaction. After quenching, most of the solvent was concentrated, 200ml of water was added, and 200ml of dichloromethane was used for extraction. The organic phases were combined, washed once with 200ml of saturated brine, dried, and concentrated to obtain 61g of red oily liquid with a purity of 98.4% and a yield of 90%. This liquid was used directly in the next step.

[0104] 1H NMR (CDCl3, 400MHz): δ = 7.40 (d, J = 7.2Hz, 1H), 7.30 (t, J = 8.0Hz, 2H), 7.24 (t, J = 7.2Hz, 1H), 7.18–7.05 (m ,2H),6.94(d,J=8.0Hz,2H),6.83(d,J=8.0Hz,1H),3.82(s,2H),3.74(s,3H),3.40(s,2H),2.12(bs,1H). 13 C NMR (CDCl3, 150MHz): δ=170.51,157.54,155.07,130.54,129.89,128.76,125.85,123.91,123.12,119.17,118.24,54.19,51.97,49.87.

[0105] Combination of S2 and Equation 3:

[0106] At room temperature, compound 2 (71.6 g, 0.264 mol) was added to 430 ml of water, followed by sodium hydroxide (15.8 g, 0.396 mol). The mixture was heated to 60 °C and reacted for 2 h. The reaction was monitored by TLC (EA:PE = 1:1) until the reactants were completely reacted. The mixture was then cooled to room temperature and extracted with 400 ml of methyl ether. The pH of the aqueous layer was adjusted to 4 with acetic acid, and then extracted with 400 ml of ethyl acetate. The organic phases were combined, dried, and concentrated to give 64.5 g of white solid with a purity of 99.4% and a yield of 95%.

[0107] 1 H NMR (CDCl3, 400MHz): δ = 11.8 (s, 1H), 7.62 (d, J = 7.6Hz, 1H), 7.50 (t, J = 8.4Hz, 2H), 7.34 (t, J = 7.6Hz, 1H), 7.28–7.12(m,2H),7.04(d,J=8.4Hz,2H),6.95(d,J=8.4Hz,1H),3.87(s,2H),3.43(s,2H),1.94(bs,1H). 13 C NMR (CDCl3, 150MHz): δ=171.21,157.50,157.18,138.80,129.93,129.83,124.45,121.96,121.86,118.77,117.88,53.07,48.64.

[0108] Synthesis of compounds S3 and Formula 4:

[0109] At room temperature, 53 g (0.206 mol) of compound 3 was added to 560 ml of water, and sodium carbonate (26.2 g, 0.247 mol) was added. The mixture was heated to 60 °C and stirred until dissolved. Then p-toluenesulfonyl chloride (43.19 g, 0.226 mol) was added. The reaction was monitored by TLC (EA:PE = 1:1) until the reactants were completely reacted. The reaction solution was cooled to room temperature, and 500 ml of ethyl acetate was added. The pH was adjusted to 2 with 3 mol / L hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with 500 ml of ethyl acetate. The organic layers were combined, dried, and concentrated to obtain an orange-yellow oil. 200 ml of petroleum ether was added, and the mixture was stirred to crystallize, yielding 72.9 g of white solid with a purity of 99.1% and a yield of 86%.

[0110] 1 H NMR (CDCl3, 400MHz): δ = 11.8 (s, 1H), 7.95 (d, J = 8.4Hz, 2H), 7.64 (d, J = 7.4Hz, 1H), 7.48 (t, J = 8.1Hz, 2H), 7.43 (d, J = 8.4Hz, 2H) ,7.32(t,J=7.4Hz,1H),7.28–7.15(m,2H),7.09(d,J=8.1Hz,2H),6.99(d,J=8.1Hz,1H),3.92(s,2H),3.87(s,3H),3.32(s,2H).

[0111] 13 C NMR (CDCl3, 150MHz): δ=172.72,158.60,156.35,144.85,137.66,136.76,132.24,13 0.13,129.55,127.62,124.54,123.43,121.73,119.17,118.54,51.48,50.63,24.36.

[0112] Synthesis of compounds S4 and S5:

[0113] At room temperature, compound 4 (50.6 g, 0.123 mol) and 1.5 ml DMF were added to 254 ml of dichloromethane. The mixture was purged with nitrogen three times. Thionyl chloride (29.3 g, 0.246 mol) was added dropwise. After the addition was complete, the mixture was heated to reflux and monitored by TLC (EA:PE = 1:1) until the reactants reacted completely. The solvent was concentrated, and 250 ml of dichloromethane was added under nitrogen protection. The mixture was cooled to -10 °C, and anhydrous aluminum trichloride (32.8 g, 0.246 mol) was added. The mixture was monitored by TLC (EA:PE = 1:1) until the reactants reacted substantially completely. The reaction solution was slowly added to 300 ml of ice water to quench the reaction. The mixture separated into layers. The organic layer was adjusted to pH 9 with 20% sodium hydroxide aqueous solution. The organic layer was washed once with 300 ml of water. The organic layer was dried and concentrated to obtain 44.1 g of yellow solid with a purity of 98.6% and a yield of 91.2%.

[0114] 1 H NMR (400MHz, CDCl3) δ=8.49 (d, J=8.6Hz, 1H), 8.15 (d, J=8.4Hz, 2H), 7.95 (d, J=8.6&2.2Hz, 1H), 7.75 (d, J=8.4Hz, 2H), 7.61 (m, J=7.5, 3H), 7.34 (t, J=7.3, 1H), 7.26 (d, J=7.5Hz, 2H), 4.83 (s, 2H), 3.82 (dd, J=10.4, 1.0Hz, 1H), 3.73 (dd, J=10.4, 1.3Hz, 1H), 2.53 (s, 3H); 13 C NMR (150MHz, CDCl3) δ=183.14,158.24,157.78,143.34,138.35,137.60,129.95,129 .91,129.82,127.49,127.14,124.54,118.58,118.17,117.87,54.34,49.83,21.34.

[0115] Synthesis of compounds S5 and Formula 6:

[0116] Under a nitrogen atmosphere, compound 5 (26.6 g, 0.05 mol) and 60% NaH (6 g, 0.15 mol) were added to 80 ml of dimethyl carbonate. The mixture was heated to 90 °C and monitored by TLC (EA:PE = 1:1) until the reactants were basically completely reacted. The solvent was evaporated, the mixture was cooled to room temperature, quenched with 6 ml of methanol, and 40 ml of water was added. The aqueous layer was extracted with 50 ml of ethyl acetate twice. The combined organic layers were washed once with 20 ml of water. The organic layer was dried and concentrated to dryness to obtain 13.2 g of product with a purity of 98.7% and a yield of 89.1%.

[0117] 1H NMR (400MHz, CDCl3) δ=8.39 (d, J=8.6Hz, 1H), 7.85 (d, J=8.6&2.2Hz, 1H), 7.52 (m, J=7.5, 3H), 7.30 (t, J=7.3, 1H), 7.21 (d, J=7.5Hz, 2H), 4.86 (s, 1H), 3.85 (dd, J=10.4, 1.0Hz, 1H), 3.83 (dd, J=10.4, 1.3Hz, 1H), 3.29 (s, 3H), 1.94 (bs, 1H); 13 C NMR (150MHz, CDCl3) δ = 185.43, 170.22, 160.13, 158.24, 137.47, 130.38, 130.24, 129.29, 124.54, 118.29, 117.53, 115.42, 61.70, 52.32, 47.16.

[0118] S6, Synthesis of Formula A:

[0119] At room temperature, compound 6 (10 g, 33.6 mmol), CuI (0.64 g, 3.36 mmol), and K2CO3 (13.9 g, 100.8 mmol) were added to 50 mL of 1,4-dioxane. The mixture was heated to 70 °C and reacted for 34 h. The reaction was monitored by TLC (EA:PE = 1:1) until the reactants were basically completely reacted. 100 mL of water was added, and the reactants were extracted with 50 mL of ethyl acetate three times. The organic layers were combined, dried, and concentrated to obtain 8.95 g of powdered solid with a purity of 98.6% and a yield of 90.2%.

[0120] 1H NMR (400MHz, CDCl3) δ = 11.61 (s, 1H), 8.73 (s, 1H), 8.31 (d, J = 9.0Hz, 1H), 7.60 (dd, J = 9.0, 2 .4Hz, 1H), 7.50 (t, J=7.9Hz, 3H), 7.29 (t, J=7.4Hz, 1H), 7.21 (d, J=7.9Hz, 2H), 3.97 (s, 3H), 13 C NMR (150MHz, CDCl3) δ=171.16, 158.30, 155.81, 154.83, 142.82, 129.93, 128.67, 124.45, 124.26, 124.17, 122.51, 119.65, 118.81, 112.30, 52.53.

[0121] Example 2:

[0122] A method for preparing methyl 4-hydroxy-7-phenoxy-3-isoquinoline carboxylate, an intermediate of roxadustat (Formula A), includes the following steps:

[0123]

[0124] Synthesis of compounds S1 and S2

[0125] At room temperature, m-phenoxybenzaldehyde (49.6 g, 0.25 mol) and glycine ethyl ester hydrochloride (41.9 g, 0.30 mol) were added to 250 ml of ethyl acetate, followed by sodium carbonate (53 g, 0.5 mol). The reaction was carried out at room temperature for 21 h under TLC monitoring (EA:PE = 1:5). After the reactants had reacted completely, the mixture was filtered, and the reaction solution was concentrated to dryness. The resulting oily substance was added to 300 ml of ethanol, cooled to 0 °C, and cyanoboron was added in portions. Sodium hydride (23.6 g, 0.375 mol) was added, the cold source was turned off, and the reaction was stirred for 1 h. The reaction was monitored by TLC (EA:PE = 1:1). After the imine reaction was complete, water was added dropwise to quench the reaction. After quenching, most of the solvent was concentrated, 200 ml of water was added, and chloroform (150 ml * 2) was extracted. The organic phases were combined, washed once with 200 ml of saturated brine, dried, and concentrated to obtain 62.9 g of red oily liquid with a purity of 98.6% and a yield of 88.2%.

[0126] Synthesis of compounds S2 and S3:

[0127] At room temperature, compound 2 (52.8 g, 0.185 mol) was added to 300 ml of water, potassium hydroxide (20.8 g, 0.37 mol) was added, the temperature was raised to 60 °C and the reaction was carried out for 2 h. The reaction was monitored by TLC (EA:PE = 1:1) until the reactants were completely reacted. The temperature was lowered to room temperature and extracted with 300 ml of ethyl acetate. The pH of the aqueous layer was adjusted to 4 with hydrochloric acid, and then extracted with 300 ml of ethyl acetate twice. The organic phases were combined, dried and concentrated to give 43.3 g of white solid with a purity of 99.2% and a yield of 91%.

[0128] Synthesis of compounds S3 and Formula 4:

[0129] At room temperature, compound 3 (40.1 g, 0.156 mol) was added to 400 ml of water, sodium hydroxide (8.7 g, 0.218 mol) was added, the mixture was heated to 60 °C and stirred until dissolved, and then p-toluenesulfonyl chloride (35.7 g, 0.187 mol) was added. The reaction was monitored by TLC (EA:PE = 1:1) until the reactants were completely reacted. The reaction solution was cooled to room temperature, 400 ml of dichloromethane was added, and the pH was adjusted to 2 with acetic acid. The organic layer was separated, and the aqueous layer was extracted with 400 ml of dichloromethane. The organic layers were combined, dried, and concentrated to obtain an orange-yellow oily substance. 200 ml of petroleum ether was added, stirred, and crystallized to obtain 52.6 g of white solid with a purity of 98.7% and a yield of 82%.

[0130] Synthesis of compounds S4 and S5:

[0131] At room temperature, compound 4 (36 g, 87.6 mmol) and 1 ml DMF were added to 180 ml toluene. The mixture was purged with nitrogen three times, and oxaloyl chloride (22.2 g, 0.175 mol) was added dropwise. After the addition was complete, the temperature was raised to 40 °C, and TLC monitoring (EA:PE = 1:1) was performed until the reactants reacted completely. The solvent was concentrated, and 180 ml toluene was added under nitrogen protection. The temperature was lowered to -10 °C, and anhydrous ferric chloride (35.5 g, 0.219 mol) was added. TLC monitoring (EA:PE = 1:1) was performed until the reactants reacted almost completely. The reaction solution was slowly added to 200 ml of ice water to quench the reaction. The mixture separated into layers. The pH of the organic layer was adjusted to 9 with 20% potassium hydroxide aqueous solution. The organic layer was washed once with 200 ml of water. The organic layer was dried and concentrated to obtain 30.8 g of yellow solid with a purity of 97.6% and a yield of 89.3%.

[0132] Synthesis of compounds S5 and Formula 6

[0133] Under a nitrogen atmosphere, compound 5 (30 g, 0.076 mol) and LDA (25 g, 0.229 mol) were added to 120 ml of dimethyl carbonate. The temperature was controlled at 0 °C and the reaction was carried out for 2 h. The temperature was then raised to room temperature and the reaction was continued. The reaction was monitored by TLC (EA:PE = 1:1) until the reactants were basically completely reacted. The solvent was evaporated, the temperature was lowered to room temperature, and ammonium chloride aqueous solution was added to quench the reaction. 60 ml of water was added, and the aqueous layer was extracted with 60 ml of dichloromethane twice. The combined organic layers were washed once with 30 ml of water, the organic layer was dried, and the solution was concentrated to dryness to obtain 19.2 g with a purity of 97.4% and a yield of 85%.

[0134] Synthesis of compound S6, Formula A:

[0135] At room temperature, compound 6 (10 g, 33.6 mmol), Pd2(dba)3 (3.1 g, 3.36 mmol), and Cs2CO3 (32.8 g, 100.8 mmol) were added to 50 mL of 1,4-dioxane. The mixture was heated to 70 °C and reacted for 38 h. The reaction was monitored by TLC (EA:PE = 1:1) until the reactants were basically completely reacted. 100 mL of water was added, and the reactants were extracted with 50 mL of dichloromethane three times. The combined organic layers were dried and concentrated to obtain 8.7 g of powdered solid with a purity of 98% and a yield of 87.6%.

[0136] Furthermore, any content not described in detail in this specification is existing technology known to those skilled in the art.

[0137] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0138] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a roxadustat intermediate, characterized in that, The synthesis route is shown below: ； In the compound of formula 2, R is one of methyl, ethyl, or isopropyl. The method for preparing the roxadustat intermediate includes the following steps: S1 and compound 1 react with glycine derivatives under the action of alkali, and then are reduced by sodium borohydride to obtain compound 2. S2 and compound 2 are hydrolyzed under the action of alkali, and then acidified to obtain compound 3. S3 and compound 3 undergo substitution under the action of an acid-binding agent, and are then acidified to obtain compound 4. S4 and compound 4 were acylated by Friedel-Crafts to give compound 5; S5 and compound 5 undergo substitution under the action of a base to obtain compound 6; S6 and compound 6 were aromatized to give compound A; S3 specifically includes the following steps: Compound of Formula 3 was added to water, followed by the addition of alkali. The mixture was heated until it dissolved, and then p-toluenesulfonyl chloride was added. After the reaction was completed, the mixture was cooled, acidified, extracted, dried, concentrated, and crystallized to obtain compound of Formula 4. S4 specifically includes the following steps: Compound of Formula 4 was added to solvent 1, a catalytic amount of DMF was added, and an acylation reagent was added. The reaction was heated and the solvent was concentrated. The oily substance was dissolved in solvent 2. The mixture was protected with N2 at a low temperature and Lewis acid was added. After the reaction was completed, the mixture was quenched, washed with alkali, washed with water, dried, and concentrated to obtain compound of Formula 5. S5 specifically includes the following steps: Sodium hydrogen was added to dimethyl carbonate under a nitrogen atmosphere, the temperature was raised, compound of formula 5 was added to the reaction solution, the temperature was raised to react, after the reaction was completed, the temperature was lowered to a low temperature, quenched with methanol, acidified, extracted with an extractant, washed with alkaline water, washed with brine, washed with water, dried, and concentrated to obtain compound of formula 6. S6 specifically includes the following steps: Compound of Formula 6 is added to a solvent, along with a catalyst and a base. The mixture is heated to react, and after the reaction is complete, the temperature is lowered. The mixture is then extracted with an extractant, dried, and concentrated to obtain compound of Formula A. The solvent is 1,4-dioxane, the catalyst is CuI, the base is K2CO3, and the extractant is ethyl acetate.

2. The method for preparing a roxadustat intermediate according to claim 1, characterized in that, S1 specifically includes the following steps: Compound of Formula 1 and glycine derivative were added to solvent 1 and reacted at room temperature under the catalysis of alkali and solvent 2. After the reaction was completed, a reducing agent was added at low temperature. After the reaction was completed, the compound of Formula 2 was obtained by quenching, concentration, extraction, drying and concentration.

3. The method for preparing a roxadustat intermediate according to claim 1, characterized in that, S2 specifically includes the following steps: Compound of Formula 2 was added to water, then alkali was added and the temperature was raised to react. After the reaction was completed, it was extracted with extractant 1. The aqueous layer was acidified at low temperature and then extracted with extractant 2. The mixture was dried and concentrated to obtain compound of Formula 3.

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