Roxadustat intermediates and processes for their preparation

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, reduction of the imine to obtain an amine, ring formation of the amine, hydrolysis, Friedel-Crafts acylation, ring opening, oxidation and esterification 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, the application is safe, environment-friendly, the reaction condition is mild, the operation is convenient and controllable, the Roxadustat intermediate prepared has high purity and high yield, has obvious cost advantage, and is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, in particular to a Roxadustat intermediate and a preparation method thereof. BACKGROUND

[0002] Roxadustat belongs to 4-hydroxyisoquinoline derivatives, and is a small molecule HIF-PH enzyme inhibitor. HIF is an important transcription factor for adapting to oxygen changes in vivo. Under normal oxygen conditions, HIF-PH enzyme promotes the degradation of HIF. When the body is in a hypoxic state, the activity of HIF-PH enzyme is inhibited, and the accumulation of HIF increases, thereby inducing the expression of corresponding genes, adapting to the changes in the body. Roxadustat stabilizes HIF, inhibits its degradation, activates the transcription of related genes, produces corresponding physiological reactions, moderately increases the concentration of erythropoietin, improves the sensitivity of erythropoietin (EPO) receptor, coordinates the generation of red blood cells, reduces the level of hepcidin, increases the content and activity of transferrin receptor, promotes the absorption and utilization of iron, and has good tolerance. Therefore, roxadustat is used for treating anemia caused by chronic kidney disease (CKD) in patients undergoing dialysis treatment.

[0003] In the prior art, roxadustat is generally synthesized by organic synthesis, and there are multiple synthesis paths. The compound of formula A is an important intermediate for synthesizing roxadustat.

[0004]

[0005] Currently, the synthesis of I mainly has the following routes:

[0006] Synthesis route one: CN106083720A reports that 4-bromo-2-methylbenzoic acid is used as a raw material, and through esterification, coupling, bromination, amination, and cyclization, compound I is obtained. The raw material 4-bromo-2-methylbenzoic acid used in this route is expensive, and carbon tetrachloride is used as a reaction solvent. The solvent is a controlled substance. The post-treatment of the entire route uses column chromatography purification method, which is time-consuming and laborious, and is not suitable for industrial production.

[0007]

[0008] Synthesis route two: CN103435546 reports that 5-bromophthalide is used as a raw material, and through coupling with phenol, ring opening, amination, and cyclization, the target product 1 is obtained. The raw material 5-bromophthalide used in this route is expensive, and the reaction materials include trimethyl borate and dichlorotriphenylphosphine, which are expensive. Trimethyl borate is flammable, explosive, and toxic, and has a high safety risk coefficient. The entire route is expensive and is not suitable for industrial production.

[0009]

[0010] In summary, the above route or because of high cost, post-processing column chromatography time-consuming and labor-consuming, the use of material safety risk coefficient is high, are not suitable for industrial production. Therefore, it is particularly important to find a cost suitable, green, good reaction selectivity, high yield, suitable for industrial production route. SUMMARY

[0011] (I) Technical problems to be solved

[0012] In view of the deficiencies in the prior art, the present application provides a roxadustat intermediate and a preparation method thereof, which solves the technical problems of high cost and high safety risk coefficient of the synthesis method of the existing roxadustat intermediate.

[0013] (II) Technical solutions

[0014] In order to achieve the above purpose, the present application is realized by the following technical solutions:

[0015] A preparation method of a roxadustat intermediate, the synthesis route is as follows:

[0016]

[0017] The preparation method comprises the following steps:

[0018] S1, the compound of formula 1 and amino acid are added to solvent 1, and the reaction is carried out at room temperature under the catalysis of base. After the reaction is completed, it is concentrated to dryness. The oil is dissolved in solvent 2, a reducing agent is added, and the reaction is carried out at low temperature. After the reaction is completed, it is quenched, extracted, dried and concentrated to obtain the compound of formula 2;

[0019] S2, the compound of formula 2 is added to a solvent, and a condensing agent is added. N2 protection, heating reaction, after the reaction is completed, concentrated to dryness, extracted, dried, concentrated to obtain the compound of formula 3;

[0020] S3, the compound of formula 3 is added to water, and a base is added. After the reaction is completed, it is extracted with extractant 1, the water layer is acidified at low temperature, and then extracted with extractant 2. After drying and concentrating, the compound of formula 4 is obtained;

[0021] S4, the compound of formula 4 is added to solvent 1, a catalytic amount of DMF is added, and an acylating agent is added. After heating reaction and solvent concentration, the oil is dissolved in solvent 2, and N2 protection is carried out in a low temperature environment. A Lewis acid is added, and after the reaction is completed, it is quenched, washed with base, washed with water, dried and concentrated to obtain the compound of formula 5;

[0022] S5, the compound of formula 5 is added to a solvent and water, and a base is added. After heating reaction, the reaction is completed, and the temperature is lowered to room temperature. The compound of formula 6 is obtained by filtration;

[0023] S6, the compound of formula 6 and a catalyst are added to water, an oxidizing agent is added, a base is added to the reaction system, the reaction is warmed, after the reaction is completed, acidification is used, an extracting agent is used for extraction, drying, concentration to obtain the compound of formula 7;

[0024] S7, the compound of formula 7 is added to a solvent, an acid is added, the reaction is warmed, after the reaction is completed, the temperature is lowered to crystallize, filtration, drying to obtain the compound A;

[0025] Further, the S1 specifically comprises the following steps:

[0026] The reaction equation is as follows:

[0027]

[0028] Further, the amino acid in S1 is serine methyl ester, serine methyl ester hydrochloride, serine ethyl ester, serine ethyl ester hydrochloride, serine isopropyl ester, serine isopropyl ester hydrochloride, preferably the amino acid is serine methyl ester hydrochloride.

[0029] Further, the molar ratio of the m-phenoxybenzaldehyde to the amino acid in S1 is 1:1-3.5, preferably 1:1-1.4;

[0030] Further, the solvent 1 in S1 is any one of tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, preferably dichloromethane;

[0031] Further, the base in S1 is any one of sodium bicarbonate, sodium carbonate, triethylamine, diethylamine, pyridine, 4-N, N-dimethylaminopyridine, preferably triethylamine;

[0032] Further, the molar ratio of the m-phenoxybenzaldehyde to the base in S1 is 1:1-3.0, preferably 1:1-2.5;

[0033] Further, the room temperature reaction time in S1 is 16-30h, preferably 18-22h;

[0034] Further, the solvent 2 in S1 is any one of tert-butyl alcohol, methanol, ethanol, preferably methanol;

[0035] Further, the reducing agent in S1 is any one of sodium borohydride, zinc borohydride, lithium borohydride, preferably sodium borohydride;

[0036] Further, the molar ratio of the m-phenoxybenzaldehyde to the reducing agent in S1 is 1:1-2.0, preferably 1:1-1.5;

[0037] Further, the low temperature reaction temperature in S1 is -5℃-10℃, preferably 0℃-5℃;

[0038] Further, the extraction solvent in S1 is one of ethyl acetate, dichloromethane, chloroform, preferably dichloromethane.

[0039] Further, after step S1, there is further post-treatment, which specifically includes the following steps: quenching, extraction, drying, and concentration to obtain the compound of formula 2.

[0040] Further, the S2 specifically includes the following steps:

[0041] The reaction equation is as follows:

[0042]

[0043] Further, the solvent in S2 is one of tetrahydrofuran, ethyl acetate, acetonitrile, preferably acetonitrile;

[0044] Further, the condensing agent in S2 is carbonyldiimidazole (CDI), N, N'-diisopropyl carbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI), preferably CDI;

[0045] Further, the molar ratio of the compound of formula 2 to the condensing agent in S2 is 1:1.2-3.5, preferably 1:1-1.5;

[0046] Further, the reaction temperature in S2 is 50-100°C, preferably 75-90°C, and the reaction time is 2-28h, preferably 2-12h;

[0047] Further, the extraction solvent is one of ethyl acetate, dichloromethane, chloroform, preferably ethyl acetate;

[0048] Further, after step S2, there is further post-treatment: drying and concentration to obtain the compound of formula 3.

[0049] Further, the S3 specifically includes the following steps:

[0050]

[0051] Further, the base in S3 is any one of sodium carbonate, sodium hydroxide, potassium hydroxide, preferably sodium hydroxide;

[0052] Further, the molar ratio of the compound of formula 3 to the base in S3 is 1:1.2-3.5, preferably 1:1.5-2.0;

[0053] Further, the extraction agent 1 in S3 is any one of ethyl acetate, dichloromethane, chloroform, preferably ethyl acetate;

[0054] Further, the acid used in the acidification in S3 is one of hydrochloric acid and sulfuric acid, preferably hydrochloric acid;

[0055] Further, the extractant 2 in S3 is one of ethyl acetate, dichloromethane, chloroform, preferably ethyl acetate.

[0056] Further, the step S3 is followed by post-treatment: drying, concentration to obtain the compound of formula 3.

[0057] Further, the S4 specifically comprises the following steps:

[0058]

[0059] Further, the solvent 1 in S4 is any one of toluene, dichloromethane, chloroform, preferably dichloromethane;

[0060] Further, the volume ratio of the compound of formula 4 to DMF in S4 is 1 g: 0.01-0.05 mL, preferably 1 g: 0.03 mL;

[0061] Further, the acylating agent in S4 is any one of oxalyl chloride, sulfurous chloride, phosphorus oxychloride, preferably sulfurous chloride;

[0062] Further, the molar ratio of the compound of formula 4 to the acylating agent in S4 is 1: 1.5-4.0, preferably 1: 1.5-2.5;

[0063] Further, the solvent 2 in S4 is any one of toluene, dichloromethane, chloroform, preferably dichloromethane;

[0064] Further, the Lewis acid in S4 is any one of zinc chloride, ferric chloride, aluminum chloride, boron trifluoride, preferably aluminum chloride;

[0065] Further, the molar ratio of the compound of formula 4 to the Lewis acid in S4 is 1: 1.5-4.0, preferably 1: 1.5-2.5;

[0066] Further, the base used in the base washing in S4 is any one of sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, preferably sodium hydroxide;

[0067] Further, the step S4 is followed by post-treatment: water washing, drying, concentration to obtain the compound of formula 5.

[0068] Further, the S5 specifically comprises the following steps:

[0069]

[0070] Further, the solvent in S5 is any one of tetrahydrofuran, acetone, acetonitrile, 1,4 dioxane, preferably 1,4 dioxane;

[0071] Further, the base in S5 is any one of cesium carbonate, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, preferably sodium bicarbonate.

[0072] Further, the molar ratio of the compound of formula 5 to the base in S5 is 1:4-8, preferably 1:4-6;

[0073] Further, the reaction temperature in S5 is 40-80°C, preferably 50-60°C;

[0074] Further, after the step S5, the process further comprises post-treatment: cooling to room temperature, and filtering to obtain the compound of formula 6.

[0075] Further, the S6 specifically comprises the following steps:

[0076]

[0077] Further, the catalyst in S6 is any one of sodium chloride, potassium chloride, NCS, sodium bromide, preferably sodium chloride;

[0078] Further, the molar ratio of the compound of formula 6 to the catalyst in S6 is 1:0.15-0.35, preferably 1:0.20-0.25;

[0079] Further, the oxidant in S6 is any one of 30% hydrogen peroxide, 30% TBHP, preferably 30% TBHP;

[0080] Further, the molar ratio of the compound of formula 6 to the oxidant in S6 is 1:3-8, preferably 1:4-6;

[0081] Further, the base in S6 is any one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, preferably sodium hydroxide;

[0082] Further, the molar ratio of the compound of formula 6 to the base in S6 is 1:3-8, preferably 1:4-6;

[0083] Further, the reaction temperature in S6 is 40-90°C, preferably 70-80°C;

[0084] Further, the reaction time in S6 is 10-26h, preferably 12-14h;

[0085] Further, the extractant in S6 is any one of ethyl acetate, dichloromethane, chloroform, preferably ethyl acetate.

[0086] Further, the step S6 further comprises post-treatment: drying and concentrating to obtain the compound of formula 7.

[0087] Further, the step S7 comprises the following steps:

[0088]

[0089] Further, the solvent in S7 is any one of methanol, ethanol and isopropanol, preferably methanol.

[0090] Further, the acid in S7 is concentrated sulfuric acid, concentrated hydrochloric acid or thionyl chloride, preferably concentrated sulfuric acid.

[0091] Further, the reaction time in S7 is 6-14h, preferably 8-10h.

[0092] Further, the crystallization temperature in S7 is-10-0℃, preferably-5-0℃.

[0093] Further, the step S6 further comprises post-treatment: filtering and drying to obtain the compound A.

[0094] (III) Beneficial effects

[0095] The present application provides a Roxadustat intermediate and a preparation method thereof.

[0096] The present application provides a Roxadustat intermediate and a preparation method thereof, the preparation method comprising the following steps: condensation of m-phenoxybenzaldehyde and amino acid under catalysis of a base to generate an imine, then reduction to obtain an amine, and then ring formation, hydrolysis, Friedel-Crafts acylation, ring opening, oxidation and esterification to obtain the target product, the synthesis route of the present application is novel, all the raw materials and reagents used are easy to obtain or prepare, and no high-risk and high-pollution reagents are used, which is safe, environmentally friendly, has mild reaction conditions, is easy and controllable to operate, and the prepared Roxadustat intermediate has good purity, high yield, obvious cost advantage and is suitable for industrial production. DETAILED DESCRIPTION

[0097] In order to make the purpose, technical scheme and advantages of the embodiments of the present application more clear, the technical scheme in the embodiments of the present application is described clearly and completely, obviously, the described embodiments are part of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor belong to the scope of protection of the present application.

[0098] In order to better understand the above technical scheme, the above technical scheme will be described in detail in combination with specific embodiments.

[0099] Example 1

[0100] A process for preparing a Roxadustat intermediate, methyl 4-hydroxy-7-phenoxy-3- isoquinolinecarboxylate (Formula A), comprising the following steps:

[0101]

[0102] S1, synthesis of compound of Formula 2

[0103] Into 250 ml dichloromethane, add m-phenoxybenzaldehyde (50 g, 0.25 mol) and serine methyl ester hydrochloride (38.9 g, 0.25 mol), then add triethylamine (63.2 g, 0.63 mol), react at room temperature for 18 h, monitor by TLC (EA: PE = 1:5), after the raw material is completely reacted, concentrate the reaction solution to dryness, add 300 ml of methanol, cool to 0°C, and add sodium borohydride (10 g, 0.25 mol) in batches, after the addition is completed, turn off the cooling source, stir for 1 h, monitor by TLC (EA: PE = 1:1), after the imine reaction is completed, quench the reaction by dropwise adding water, after the quenching is completed, concentrate most of the solvent, add 200 ml of water, extract with 200 ml of dichloromethane twice, wash the combined organic phase with 200 ml of saturated brine once, dry, and concentrate to obtain 70.1 g of red oily liquid, with a purity of 99.2% and a yield of 93.1%; Formula 2 is C 17 H 19 NO4, LC-MS measured molecular ion peak m / z is 302.1, [M+H]+ is consistent with the theoretical value, elemental analysis C.67.74; H.6.35; N.4.65; O.21.26; 1 HNMR (400MHz, CDCl3) δ 7.39 (m, 3H), 7.30 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 7.3 Hz, 2H), 7.04 (d, J = 8.0, 1H), 6.92 (d, J = 8.0, 1H), 6.83 (m, 1H), 6.25 (s, 1H), 4.92 (s, 1H), 3.88 (m, 2H), 3.74 (m, 1H), 3.66 (m, 2H), 3.25 (s, 3H); 13 CNMR (150MHz, CDCl3) δ 173.07, 157.50, 157.14, 139.26, 129.93, 129.84, 124.45, 121.96, 121.50, 118.77, 117.65, 69.79, 62.20, 52.17, 52.07.

[0104] S2, synthesis of Formula 3:

[0105] The compound of formula 2 (60.2 g, 0.20 mol) and CDI (48.65 g, 0.3 mol) were added into 360 ml of acetonitrile at room temperature, and the mixture was heated to 80 °C for 2 h, and TLC monitoring (EA: PE = 1:1) was performed until the raw material was completely reacted. The solvent was concentrated to dryness, 250 ml of water was added, and 250 ml*2 of ethyl acetate was extracted. The organic phase was combined, washed once with 250 ml of saturated brine, dried, and concentrated to give 62.2 g of a light red oil with a purity of 99.4% and a yield of 95%; formula 3 is C 18 H 17 The molecular ion peak m / z of LC-MS was 328.2, [M+H]+, which was consistent with the theoretical value, and the elemental analysis C.66.04; H.5.24; N.4.28; O.24.44; 1 HNMR (400 MHz, CDCl3 δ 7.32 (m, 3H), 7.30 (t, J = 8.1 Hz, 1H), 7.10 (d, J = 7.9 Hz, 2H), 7.04 (d, J = 8.1, 1H), 6.96 (d, J = 8.1, 1H), 6.92 (t, J = 7.3 Hz, 1H), 4.67 (t, J = 4.0 Hz, 1H), 4.54 (dt, J = 1.9, 1.0 Hz, 2H), 4.35 (dd, J = 12.3, 3.9 Hz, 1H), 4.31 (dd, J = 12.3, 3.9 Hz, 1H), 3.68 (s, 3H). 13 CNMR (150 MHz, CDCl3) δ 171.24, 160.13, 157.50, 156.96, 137.18, 130.06, 129.93, 124.45, 121.93, 121.78, 118.77, 118.01, 64.46, 60.36, 52.26, 47.35.

[0106] S3, synthesis of compound of formula 4:

[0107] The compound of formula 3 (65.5 g, 0.2 mol) was added into 300 ml of water at room temperature, and sodium hydroxide (12 g, 0.3 mol) was added. The mixture was stirred and reacted, and TLC monitoring (EA: PE = 1:1) was performed until the raw material was completely reacted. The reaction solution was cooled to room temperature, 300 ml*2 of ethyl acetate was added, the water layer was cooled to 0 °C, hydrochloric acid was added to adjust the pH to 2, 200 ml*2 of ethyl acetate was added, the organic layer was combined, dried, and concentrated to give 59 g of a yellow oil with a purity of 99.1% and a yield of 94.3%; formula 4 is C 17 H 15NO5, LC-MS showed that the molecular ion peak m / z was 314.1, [M+H]+consistent with the theoretical value, elemental analysis C.65.16; H.4.84; N.4.46; O.25.54; 1 HNMR (400 MHz, CDC13) δ 13.25 (s, 1H), 7.39 (m, 3H), 7.31 (t, J = 8.2 Hz, 1H), 7.10 (d, J = 7.9 Hz, 2H), 7.02 (d, J = 8.2 Hz, 1H), 6.96 (J = 8.2 Hz, 1H), 6.92 (t, J = 7.4 Hz, 1H), 4.71 (t, J = 4.0 Hz, 1H), 4.58 (dt, J = 1.9, 1.0 Hz, 2H), 4.38 (dd, J = 12.3, 4.0 Hz, 1H), 4.30 (dd, J = 12.3, 4.0 Hz, 1H). 13 CNMR (125 MHz, CDC13) δ 173.52, 158.37, 157.50, 156.96, 137.19, 130.06, 129.93, 124.45, 121.93, 121.78, 118.77, 118.01, 64.64, 60.89, 47.46.

[0108] S4, synthesis of compound of formula 5:

[0109] The compound of formula 4 (62.7 g, 0.2 mol) and 1.9 ml DMF were put into 450 ml dichloromethane at room temperature, replaced by nitrogen for 3 times, dropwise added with sulfoxide chloride (35.7 g, 0.3 mol), after dropwise addition, warmed to reflux, monitored by TLC (EA: PE = 1:1) until the raw material was completely reacted, concentrated the solvent, added with 450 ml dichloromethane under nitrogen protection, cooled to -10°C, added with anhydrous aluminum chloride (75.7 g, 0.5 mol), monitored by TLC (EA: PE = 1:1) until the raw material was completely reacted, slowly added the reaction liquid into 400 ml ice water for quenching, separated the layers, adjusted the pH of the organic layer to 9 with 20% sodium hydroxide aqueous solution, separated the layers, washed the organic layer with 400 ml water once, dried the organic layer, concentrated to obtain 54.5 g of oil, the purity was 99%, the yield was 92.2%, and formula 5 was C 17 H 13 NO4, LC-MS showed that the molecular ion peak m / z was 296.2, [M+H]+consistent with the theoretical value, elemental analysis C.69.14; H.4.46; N.4.75; O.21.65; 1HNMR (400 MHz, CDC13) δ 7.99 (d, J = 8.6 Hz, IH), 7.65 (d, J = 8.6 Hz, IH), 7.32 (m, J = 7.5, 3H), 7.10 (t, J = 7.3, IH), 6.97 (m, 2H), 6.95 (d, J = 2.0 Hz, IH), 4.86 (dd, J = 12.4, 1.0 Hz, IH), 4.64 (dd, J = 12.4, 1.0 Hz, IH), 4.37 (dd, J = 12.5, 3.3 Hz, IH), 4.29 (dd, J = 12.5, 3.5 Hz, IH). 13 CNMR (125 MHz, CDC13) δ 192.62, 159.59, 157.78, 156.87, 135.39, 129.93, 129.89, 129.17, 124.45, 118.92, 117.92, 117.37, 64.56, 58.71, 42.34.

[0110] S5, synthesis of compound of formula 6:

[0111] The compound of formula 5 (11.8 g, 40 mmol) was added to a mixture of 50 ml 1,4 dioxane and 120 ml water at room temperature, then sodium bicarbonate (13.4 g, 160 mmol) was added, the temperature was raised to 60 °C, and the reaction was monitored by TLC (EA:PE = 1:1) until the starting material was substantially consumed. The mixture was filtered, and the filter cake was washed with a small amount of ice methanol to give 9.3 g of solid with a purity of 99.5% and a yield of 87% of compound of formula 6. 16 H 13 NO3, LC-MS measured molecular ion peak m / z 268.3, [M+H]+consistent with the theoretical value, elemental analysis C.71.92; H.4.90; N.5.22; O.17.96; 1 HNMR (400 MHz, CDC13) δ 11.94 (s, IH), 8.59 (s, IH), 7.91 (d, J = 8.0 Hz, IH), 7.63 (d, J = 8.0, IH), 7.32 (t, J = 7.4, 3H), 6.97 (d, J = 7.4, 2H), 6.87 (t, J = 7.2, IH), 5.39 (s, IH), 4.76 (d, J = 5.6 Hz, 2H); 13 CNMR (125 MHz, CDC13) δ 158.30, 155.85, 147.78, 143.46, 142.52, 129.93, 127.32, 124.45, 123.67, 123.22, 118.88, 118.81, 111.36, 59.71.

[0112] S6, synthesis of formula 7:

[0113] The compound of formula 6 (20 g, 75 mmol) and sodium chloride (0.87 g, 15 mmol) were added to 30% TBHP (90.1 g, 0.3 mol) at room temperature, and then sodium hydroxide (12 g, 0.3 mol) was added to the reaction mixture, which was heated to 70°C and kept for 14 h, and TLC monitoring (EA: PE = 1:1) was performed until the raw material was completely reacted. The reaction solution was cooled to 0°C, acidified with hydrochloric acid to pH = 2, extracted with 100 ml*2 of ethyl acetate, the organic layers were combined, dried, and concentrated to obtain a solid 18.8 g with a purity of 98.8% and a yield of 89%, and formula 7 was C 16 H 11 The molecular ion peak m / z of LC-MS was 282.1, [M+H]+, which was consistent with the theoretical value, and the elemental analysis C.68.35; H.3.95; N.4.97; O.22.73, 1 HNMR (400MHz, CDCl3) δ 13.4 (s, 1H), 11.9 (s, 1H), δ 8.70 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.30 (t, J = 7.5 Hz, 3H), 7.03 (d, J = 7.2 Hz, 2H), 6.89 (t, J = 7.4 Hz, 1H). 13 CNMR (125MHz, CDCl3) δ 171.21, 164.01, 158.30, 155.81, 142.23, 129.93, 128.54, 125.35, 124.45, 124.18, 121.88, 119.63, 118.81, 112.30.

[0114] S7, synthesis of formula A:

[0115] The compound of formula 7 (16.9 g, 60 mmol) was added to 80 ml of methanol at room temperature, and then 0.6 g of concentrated sulfuric acid was added, and the reaction was heated to reflux and kept for 8 h, and TLC monitoring (EA: PE = 1:1) was performed until the raw material was completely reacted. The reaction solution was cooled to -5°C to crystallize, filtered and dried to obtain a white powdery solid 15.4 g with a purity of 99.4% and a yield of 87%, and formula A was C 17 H 13NO4, LC-MS measured molecular ion peak m / z is 296.1, [M+H]+ with the same theoretical value, elemental analysis C.69.16; H.4.43; N.4.73; O.21.68; 1HNMR (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 CNMR (125MHz, 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..

[0116] Example 2

[0117] A method for preparing a Roxadustat intermediate, methyl 4-hydroxy-7-phenoxy-3- isoquinolinecarboxylate (Formula A), comprising the following steps:

[0118]

[0119] S1, synthesis of compound of formula 2

[0120] Phenylphenoxybenzaldehyde (50 g, 0.25 mol) and isopropyl serinate (38.9 g, 0.35 mol) were added to 200 ml of ethyl acetate at room temperature, and sodium carbonate (26.5 g, 0.25 mol) was added. The reaction was carried out at room temperature for 22 h, and TLC monitoring (EA: PE = 1:5) was performed. After the raw material was completely reacted, filtration was performed, and the reaction liquid was concentrated to dryness. The obtained oil was added to 300 ml of ethanol, and the temperature was lowered to 0°C. Lithium borohydride (8.3 g, 0.38 mol) was added in batches, the cold source was turned off after addition, and the reaction was stirred for 1 h. TLC monitoring (EA: PE = 1:1) was performed. After the imine reaction was completed, water was added dropwise to quench the reaction. After quenching was completed, most of the solvent was concentrated, 150 ml of water was added, and 100 ml of chloroform was extracted twice. The organic phase was combined and washed once with 200 ml of saturated brine, dried, and concentrated to obtain 79.16 g of red oily liquid with a purity of 98.9% and a yield of 92.2%. The formula 2 is C 20 H 25 NO4, LC-MS measured molecular ion peak m / z is 344.2, [M+H]+ with the same theoretical value, elemental analysis C.69.94; H.7.35; N.4.06; O.18.65; 1HNMR (400 MHz, CDC13) δ 7.39 (m, 3H), 7.30 (t, J = 8.0 Hz, IH), 7.10 (d, J = 7.2 Hz, 2H), 6.96 (d, J = 8.0 Hz, IH), 6.83 (m, IH), 6.92 (d, J = 8.0 Hz, IH), 6.23 (s, IH), 4.95 (s, IH), 3.84 (m, 2H), 3.79 (m, IH), 3.56 (m, 2H), 3.27 (s, 9H); 13 CNMR (125 MHz, CDC13) δ 170.50, 157.50, 157.14, 139.26, 129.93, 129.84, 124.45, 121.96, 121.50, 118.77, 117.65, 82.77, 62.77, 62.01, 52.07, 28.38.

[0121] S2, synthesis of compound of formula 3:

[0122] The compound of formula 2 (68.7 g, 0.20 mol) and DIC (25.24 g, 0.2 mol) were added into 200 ml THF at room temperature, and the mixture was heated to 80 °C for 5 h, and TLC monitoring (EA: PE = 1:1) until the starting material was completely reacted. The solvent was concentrated to dryness, 350 ml water was added, and 200 ml dichloromethane was extracted twice. The combined organic phase was washed with 300 ml saturated brine once, dried, and concentrated to give 69.2 g of light red oil with a purity of 99.1% and a yield of 93.7%. Formula 3 is C 21 H 23 NO5, LC-MS measured molecular ion peak m / z is 370.1, [M+H]+ is consistent with the theoretical value, elemental analysis C.68.27; H.6.28; N.3.80; O.21.65; 1 HNMR (400 MHz, CDC13) δ 7.39 (m, 3H), 7.30 (t, J = 8.0 Hz, IH), 7.10 (d, J = 7.2 Hz, 2H), 6.96 (d, J = 8.0 Hz, IH), 6.83 (m, IH), 6.92 (d, J = 8.0 Hz, IH), 6.23 (s, IH), 4.95 (s, IH), 3.84 (m, 2H), 3.79 (m, IH), 3.56 (m, 2H), 3.27 (s, 9H); 13CNMR (125 MHz, CDC13) δ 169.11, 160.13, 157.50, 156.96, 137.19, 130.06, 129.93, 124.45, 121.93, 121.78, 118.77, 118.01, 82.09, 64.30, 61.19, 47.33, 27.59.

[0123] S3, synthesis of compound of formula 4:

[0124] The compound of formula 3 (73.9 g, 0.2 mol) was added into 200 ml water at room temperature, potassium hydroxide (22.4 g, 0.4 mol) was added, the reaction was stirred and monitored by TLC (EA: PE = 1:1) until the raw material was completely reacted. The reaction solution was cooled to room temperature, extracted with dichloromethane 200 ml*2, the water layer was cooled to 0°C, adjusted to PH 2 with sulfuric acid, extracted with dichloromethane 200 ml*2, combined organic layer, dried, concentrated to get 57.6 g yellow oil, purity 98.8%, yield 92.0%.

[0125] S4, synthesis of compound of formula 5:

[0126] The compound of formula 4 (62.7 g, 0.2 mol) and 3.2 ml DMF were added into 300 ml toluene at room temperature, replaced with nitrogen for 3 times, added dropwise oxalyl chloride (63.5 g, 0.5 mol), after dropwise, warmed to reflux, monitored by TLC (EA: PE = 1:1) until the raw material was completely reacted, concentrated the solvent, added 450 ml toluene under nitrogen protection, cooled to -10°C, added anhydrous zinc chloride (40.9 g, 0.3 mol), monitored by TLC (EA: PE = 1:1) until the raw material was completely reacted, the reaction solution was slowly added into 500 ml ice water to quench, separated, the organic layer was adjusted to PH = 9 with sodium carbonate aqueous solution, separated, the organic layer was washed with 300 ml water twice, dried, concentrated to get 53.8 g oil, purity 98.5%, yield 91%.

[0127] S5, synthesis of compound of formula 6

[0128] The compound of formula 5 (11.8 g, 40 mmol) was added into 150 ml tetrahydrofuran (THF) and 120 ml water at room temperature, added cesium carbonate (78 g, 240 mmol), warmed to 50°C, monitored by TLC (EA: PE = 1:1) until the raw material was completely reacted, filtered, the filter cake was washed with a small amount of ice methanol to get solid 9.15 g, purity 99.0%, yield 85.5%.

[0129] S6, synthesis of compound of formula 7:

[0130] Compound of formula 6 (20 g, 75 mmol) and sodium bromide (1.95 g, 19 mmol) were added to 30% hydrogen peroxide (51 g, 0.45 mol) at room temperature. To the reaction mixture, sodium carbonate (47.69 g, 0.45 mol) was added. The reaction mixture was warmed to 80 °C and maintained for 22 h. The reaction was monitored by TLC (EA: PE = 1:1). The reaction mixture was cooled to 0 °C and acidified with hydrochloric acid to pH = 2. The reaction mixture was extracted with dichloromethane (100 ml x 2). The organic layers were combined, dried and concentrated to obtain a solid 18.5 g with 98.5% purity and 88% yield.

[0131] S7, Synthesis of compound of formula A:

[0132] Compound of formula 7 (16.9 g, 60 mmol) was added to 100 ml of isopropyl alcohol at room temperature. 1.0 g of concentrated hydrochloric acid was added. The reaction was warmed to reflux and maintained for 8 h. The reaction was monitored by TLC (EA: PE = 1:1). The reaction mixture was cooled to 0 °C and the crystals were filtered and dried to obtain a white powder 15.1 g with 99.2% purity and 85% yield.

[0133] Example 3

[0134] A process for the preparation of a Roxadustat intermediate, methyl 4-hydroxy-7- phenoxy-3-isoquinolinecarboxylate (formula A) comprising the steps of:

[0135]

[0136] S1, Synthesis of compound of formula 2

[0137] M-phenoxybenzaldehyde (50 g, 0.25 mol) and serine ethyl ester (39.9 g, 0.3 mol) were added to 200 ml of tetrahydrofuran at room temperature. N, N dimethyl amino pyridine (76.9 g, 0.63 mol) was added. The reaction was stirred at room temperature for 22 h. The reaction was monitored by TLC (EA: PE = 1:5). After the completion of the reaction, the reaction mixture was filtered and concentrated to dryness. The obtained oil was dissolved in 200 ml of tert-butyl alcohol. Borane zinc hydride (28.52 g, 0.3 mol) was added portion wise at 0 °C. The reaction was stirred for 1 h. The reaction was monitored by TLC (EA: PE = 1:1). After the completion of the reaction, the reaction was quenched by the drop wise addition of water. The reaction was concentrated to remove most of the solvent. 350 ml of water was added. The reaction was extracted with ethyl acetate (150 ml x 2). The organic layers were combined and washed with 200 ml of saturated brine. The organic layer was dried and concentrated to obtain 78.56 g of a red colored oily liquid with 99.0% purity and 91.5% yield. Formula 2 is C 19 H 23NO4, LC-MS shows [M+H]+ at m / z 330.2, consistent with the molecular weight, elemental analysis C. 69.28; H. 7.04; N. 4.25; O. 19.43; 1 HNMR (400 MHz, CDC13) δ 7.37 (m, 3H), 7.32 (d, J = 8.0 Hz, IH), 7.10 (d, J = 7.2 Hz, 2H), 7.00 (d, J = 8.0 Hz, IH), 6.92 (d, J = 8.0 Hz, IH), 6.83 (m, IH), 6.23 (s, IH), 5.01 (s, IH), 3.88 (ddt, J = 5.3, 4.0, 0.9 Hz, 2H), 3.77 (dd, J = 6.2, 5.3 Hz, IH), 3.66 (m, 2H), 3.55 (dt, J = 8.5, 4.4 Hz, IH), 1.29 (d, J = 5.7 Hz, 3H), 1.24 (d, J = 5.7 Hz, 3H). 13 CNMR (125 MHz, CDC13) δ 171.91, 157.50, 157.14, 139.26, 129.93, 129.84, 124.45, 121.96, 121.50, 118.77, 117.65, 70.09, 62.88, 62.22, 52.07, 21.77.

[0138] S2, synthesis of compound of formula 3:

[0139] The compound of formula 2 (65.9 g, 0.20 mol) and EDCl (25.24 g, 0.3 mol) were added into 300 ml of ethyl acetate at room temperature, and the mixture was heated to 75 °C for 15 h, and TLC monitoring (EA: PE = 1:1) until the raw material was completely reacted. The solvent was concentrated to dryness, 250 ml of water was added, and 100 ml of chloroform was extracted twice. The combined organic phase was washed with 300 ml of saturated brine once, dried, and concentrated to give 64.8 g of light red oil with a purity of 98.5% and a yield of 91.2%. Formula 3 is C 20 H 21 NO5, LC-MS shows [M+H]+ at m / z 356.1, consistent with the molecular weight, elemental analysis C. 67.59; H. 5.96; N. 3.94; O. 22.5; 1HNMR (400 MHz, CDC13) δ 7.34 (m, 3H), 7.30 (t, J = 8.1 Hz, IH), 7.10 (d, J = 7.2, 2H), 7.05 (d, J = 8.1 Hz, IH), 7.00 (d, J = 8.1 Hz, IH), 6.92 (m, IH), 5.03 (m, IH), 4.68 (t, J = 4.1 Hz, IH), 4.54 (dt, J = 1.7, 1.2 Hz, 2H), 4.42 (dd, J = 12.4, 1.1 Hz, IH), 4.34 (dd, J = 12.4, 1.1 Hz, IH), 1.29 (d, J = 1.9 Hz, 3H), 1.24 (d, J = 1.7 Hz, 3H). 13 CNMR (125 MHz, CDC13) δ 170.34, 160.13, 157.50, 156.96, 137.19, 130.06, 129.93, 124.45, 121.93, 121.78, 118.77, 118.01, 69.31, 64.48, 60.51, 47.35, 21.32.

[0140] S3, synthesis of compound of formula 4:

[0141] The compound of formula 3 (71 g, 0.2 mol) was added into 200 ml water at room temperature, sodium carbonate (21.2 g, 0.36 mol) was added, the reaction was stirred, and TLC (EA:PE = 1:1) was used to monitor the reaction until the raw material was completely reacted. The reaction liquid was cooled to room temperature, 100 ml*2 chloroform was added for extraction, the water layer was cooled to 0°C, hydrochloric acid was used to adjust the pH to 2, 200 ml*2 chloroform was added for extraction, the organic layers were combined, dried, and concentrated to obtain 57.6 g of yellow oil, with a purity of 98.8% and a yield of 92.0%.

[0142] S4, synthesis of compound of formula 5:

[0143] The compound of formula 4 (62.7 g, 0.2 mol) and 2.6 ml DMF were added into 200 ml chloroform at room temperature, nitrogen was replaced for 3 times, phosphorus oxychloride (61.3 g, 0.4 mol) was added dropwise, after the dropwise addition was completed, the temperature was increased to reflux, TLC (EA:PE = 1:1) was used to monitor the reaction until the raw material was completely reacted, the solvent was concentrated, 250 ml chloroform was added under the protection of nitrogen, the temperature was cooled to -10°C, ferric chloride (81.1 g, 0.5 mol) was added, TLC (EA:PE = 1:1) was used to monitor the reaction until the raw material was completely reacted, the reaction liquid was slowly added into 400 ml ice water for quenching, the layers were separated, the organic layer was adjusted to pH = 9 with potassium hydroxide aqueous solution, the layers were separated, the organic layer was washed with 300 ml water twice, the organic layer was dried and concentrated to obtain 52.9 g of oil, with a purity of 98.9% and a yield of 89.5%.

[0144] S5, synthesis of compound of formula 6:

[0145] The compound of formula 5 (11.8 g, 40 mmol) was added into 250 ml acetonitrile and 220 ml water at room temperature, and then sodium hydroxide (8 g, 200 mmol) was added. The temperature was raised to 60 °C, and TLC monitoring (EA: PE = 1:1) was performed until the raw material was substantially completely reacted. Filtration was performed, and the filter cake was washed with a small amount of ice methanol to obtain a solid 9.17 g with a purity of 99.2% and a yield of 85.8%.

[0146] S6, synthesis of compound of formula 7:

[0147] The compound of formula 6 (20 g, 75 mmol) and NCS (2.3 g, 17.3 mmol) were added into 30% TBHP (114 g, 0.38 mol) at room temperature, and then sodium acetate (31.2 g, 0.38 mol) was added into the reaction mixture. The temperature was raised to 90 °C and was kept for 12 h, and TLC monitoring (EA: PE = 1:1) was performed until the raw material was completely reacted. The reaction liquid was cooled to 0 °C, and was acidified with hydrochloric acid until the pH was 2. 150 ml chloroform was added for extraction twice, and the combined organic layer was dried and concentrated to obtain a solid 18.4 g with a purity of 98.9% and a yield of 87%.

[0148] S7, synthesis of compound of formula A:

[0149] The compound of formula 7 (16.9 g, 60 mmol) was added into 100 ml ethanol at room temperature, and then 5.0 g of thionyl chloride was added. The reaction was raised to reflux and was kept for 8 h, and TLC monitoring (EA: PE = 1:1) was performed until the raw material was completely reacted. The reaction liquid was cooled to 0 °C to crystallize, and was filtered and dried to obtain a white powder solid 15.1 g with a purity of 99.0% and a yield of 85.5%.

[0150] It should be noted that the relational terms herein such as first and second and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any such actual relationship or order between such entities or actions. Moreover, the terms "comprises", "comprising", or any other variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but can include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without more limitations, an element defined by an "comprising" statement is not excluded from a process, method, article, or apparatus that includes the element - even if the same process, method, article, or apparatus also includes other elements not mentioned in the "comprising" statement.

[0151] The above examples are only used to illustrate the technical solutions of the present application, and are not intended to limit the present application; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that the technical solutions recorded in the foregoing examples can be modified, or some technical features can be replaced by equivalent features; and these modifications or replacements 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 application.

Claims

1. A process for the preparation of a roxadustat intermediate characterized in that, The synthetic route is shown as follows: ， R in the compound of formula 2 and formula 3 is one of methyl, ethyl and isopropyl; The preparation method comprises the following steps: S1, the compound of formula 1 is reacted with amino acid ester under the action of a base, and then reduced by sodium borohydride to obtain the compound of formula 2; S2, the compound of formula 2 is cyclized and protected to obtain the compound of formula 3; S3, the compound of formula 3 is hydrolyzed under the action of a base, and then acidified to obtain the compound of formula 4; S4, the compound of formula 4 is subjected to Friedel-Crafts acylation to obtain the compound of formula 5; S5, the compound of formula 5 is ring-opened under the action of a base to obtain the compound of formula 6; S6, the compound of formula 6 is oxidized to obtain the compound of formula 7; S7, the compound of formula 7 is esterified to obtain the compound of formula A.

2. A process for the preparation of a roxadustat intermediate according to claim 1, characterized in that, The S1 specifically comprises the following steps: The compound of formula 1 and the amino acid ester are added into solvent 1, and reacted at room temperature under the catalysis of a base; after the reaction is completed, the mixture is concentrated to dryness, the oil is dissolved in solvent 2, a reducing agent is added, and the mixture is reacted at low temperature; after the reaction is completed, the mixture is quenched, extracted, dried and concentrated to obtain the compound of formula 2.

3. A process for the preparation of a roxadustat intermediate according to claim 1, characterized by, The S2 specifically comprises the following steps: The compound of formula 2 is added into a solvent, and then a condensing agent is added; the mixture is reacted under heating under the protection of N2; after the reaction is completed, the mixture is concentrated to dryness, extracted, dried and concentrated to obtain the compound of formula 3.

4. A process for the preparation of a roxadustat intermediate according to claim 1, characterized by, The S3 specifically comprises the following steps: The compound of formula 3 is added into water, and then a base is added; after the reaction is completed, the mixture is extracted with extractant 1, the water layer is acidified at low temperature, and then extracted with extractant 2; the mixture is dried and concentrated to obtain the compound of formula 4.

5. The method for preparing a roxadustat intermediate according to claim 1, characterized in that, The S4 specifically comprises the following steps: The compound of formula 4 is added into solvent 1, a catalytic amount of DMF is added, and then an acylating reagent is added; the mixture is reacted under heating, the solvent is concentrated, the oil is dissolved in solvent 2, and the mixture is placed in a low-temperature environment under the protection of N2; a Lewis acid is added, and after the reaction is completed, the mixture is quenched, washed with a base, washed with water, dried and concentrated to obtain the compound of formula 5.

6. A process for the preparation of a roxadustat intermediate according to claim 1, characterized by, The S5 specifically comprises the following steps: The compound of formula 5 is added into a solvent and water, a base is added, and the mixture is reacted under heating; after the reaction is completed, the mixture is cooled to room temperature, and filtered to obtain the compound of formula 6.

7. A process for the preparation of a roxadustat intermediate according to claim 1, characterized by, The S6 specifically comprises the following steps: The compound of formula 6 and a catalyst are added into water, an oxidizing agent is added, and then a base is added into the reaction system; the mixture is reacted under heating; after the reaction is completed, the mixture is acidified with an acid, extracted with an extractant, dried and concentrated to obtain the compound of formula 7.

8. A process for the preparation of a roxadustat intermediate according to claim 1, characterized by, The S7 specifically comprises the following steps: The compound of formula 7 is added into a solvent, an acid is added, and the mixture is reacted under heating; after the reaction is completed, the mixture is cooled to precipitate crystals, and filtered to obtain the compound of formula A.

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