A process for the preparation of a roxadustat intermediate III

Abstract

The application provides a method for preparing roxadustat intermediate III, i.e. 3-methyl-5-phenoxyisobenzofuran-1(3H)-one, which comprises the following steps: generating 5-bromo-3-methylisobenzofuran-1(3H)-one through self-cyclization by taking 4-bromo-2-ethylbenzoic acid as a raw material; and generating roxadustat intermediate III through carbon-oxygen coupling reaction of 5-bromo-3-methylisobenzofuran-1(3H)-one and phenol. The method can significantly shorten the reaction time, improve the reaction yield, and simplify the reaction conditions, and is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a preparation method of Roxadustat intermediate III. BACKGROUND

[0002] Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.

[0003] 3-methyl-5-phenoxyisobenzofuran-1(3H)-one is an important organic compound, which is an intermediate for treating chronic anemia drug Roxadustat. Roxadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, the chemical name is N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinyl) carbonyl] glycine, which can treat patients with chronic kidney disease combined with anemia. It inhibits hypoxia-inducible factor prolyl hydroxylase, simulates the physiological response under hypoxic conditions, and induces the increase of endogenous erythropoietin, thereby increasing the hemoglobin level. Roxadustat has better safety and effectiveness than existing treatment options, does not require intravenous iron supplementation, and does not significantly increase erythropoietin levels. Roxadustat has been marketed in China, Japan and the European Union.

[0004] At present, there are many methods reported for the preparation of 3-methyl-5-phenoxyisobenzofuran-1(3H)-one, but the existing methods have many problems, such as more reaction steps, lower yield, harsh reaction conditions, and the need to use expensive metal catalysts. SUMMARY

[0005] The present application provides the use of 4-bromo-2-ethylbenzoic acid in the preparation of Roxadustat or Roxadustat intermediates, and provides a method for preparing Roxadustat intermediate III, i.e. 3-methyl-5-phenoxyisobenzofuran-1(3H)-one, from 4-bromo-2-ethylbenzoic acid. The method provided by the present application is simple and efficient, greatly shortens the reaction time and improves the reaction yield, and is particularly suitable for industrial production.

[0006] Specifically, the present application provides the following technical solutions.

[0007] In the first aspect of the present application, the use of 4-bromo-2-ethylbenzoic acid in the preparation of Roxadustat or Roxadustat intermediates is provided.

[0008] In some embodiments of the present application, the Roxadustat intermediate is Roxadustat intermediate III, i.e. 3-methyl-5-phenoxyisobenzofuran-1(3H)-one.

[0009] In a second aspect of the invention, a method for preparing roxadustat intermediate III is provided, comprising:

[0010] 5-Bromo-3-methylisobenzofuran-1(3H)-one was generated from 4-bromo-2-ethylbenzoic acid via self-cyclization.

[0011] 5-Bromo-3-methylisobenzofuran-1(3H)-one undergoes a carbon-oxygen coupling reaction with phenol to generate roxadustat intermediate III;

[0012] The roxadustat intermediate III is 3-methyl-5-phenoxyisobenzofuran-1(3H)-one.

[0013] The self-cyclization reaction of 4-bromo-2-ethylbenzoic acid according to the present invention occurs in the presence of a solvent and a catalyst.

[0014] In some embodiments of the present invention, the solvent for the self-cyclization reaction of 4-bromo-2-ethylbenzoic acid is selected from one or more of 1,2-dichloroethane, acetonitrile, trifluoroethanol and ethyl acetate.

[0015] In an embodiment of the present invention, the catalyst is a non-metallic catalyst containing diethyl iodophenyl ester.

[0016] In some embodiments of the present invention, the catalyst is composed of diethyl iodophenyl ester, an inorganic salt containing bromide ions, and an oxidant.

[0017] In some embodiments of the present invention, the inorganic salt containing bromide ions is selected from at least one of potassium bromide, sodium bromide, ammonium bromide, and tetrabutylammonium bromide.

[0018] In some embodiments of the present invention, the oxidant is selected from at least one of sodium bromate, sodium periodate, sodium persulfate, benzoyl peroxide, and elemental iodine.

[0019] In some embodiments of the present invention, the catalyst includes diethyl iodophenyl ester, any one selected from potassium bromide, sodium bromide, ammonium bromide and tetrabutylammonium bromide, and any one selected from sodium bromate, sodium periodate, sodium persulfate, benzoyl peroxide and elemental iodine.

[0020] In this invention, the self-cyclization reaction of 4-bromo-2-ethylbenzoic acid is a free radical substitution reaction. The reaction process is simple and easy to control, requiring no harsh reaction conditions or complex equipment. It has a good reaction rate, short reaction time (only 4-8 hours), and high reaction yield.

[0021] In particular, in some embodiments of the present invention, when the solvent for the self-cyclization reaction of 4-bromo-2-ethylbenzoic acid is 1,2-dichloroethane or acetonitrile, the reaction yield can reach 76% or more, especially when the solvent is 1,2-dichloroethane, the reaction yield can reach 91.5% or more.

[0022] In particular, in some embodiments of the present invention, the catalyst is selected from the following combinations: potassium bromide, sodium bromate and diethyl iodophthalate; sodium bromide, sodium bromate and diethyl iodophthalate; ammonium bromide, sodium bromate and diethyl iodophthalate; tetrabutylammonium bromide, sodium bromate and diethyl iodophthalate; sodium bromide, sodium periodate and diethyl iodophthalate; sodium bromide, sodium persulfate and diethyl iodophthalate; sodium bromide, benzoyl peroxide and diethyl iodophthalate; sodium bromide, elemental iodine and diethyl iodophthalate. In such embodiments, the reaction yield can be 56% or higher; in particular, when the oxidant in the catalyst combination is sodium bromate, sodium periodate, sodium persulfate, or benzoyl peroxide, the reaction yield can reach 72% or higher; especially, when the catalyst is a combination of potassium bromide, sodium bromate, and diethyl iodophthalate, or a combination of sodium bromide, sodium bromate, and diethyl iodophthalate, or a combination of sodium bromide, benzoyl peroxide, and diethyl iodophthalate, the reaction yield can reach 86% or higher; and, more preferably, when the catalyst is a combination of potassium bromide, sodium bromate, and diethyl iodophthalate, or a combination of sodium bromide, sodium bromate, and diethyl iodophthalate, the reaction yield can reach 91% or higher.

[0023] In some embodiments of the present invention, the molar ratio of diethyl iodophenyl ester, bromide-containing inorganic salt and oxidant in the catalyst is 1-3:1-3:1-3.

[0024] In some embodiments of the present invention, the molar ratio of diethyl iodophthalate, the bromide-containing inorganic salt, and the oxidant in the catalyst is 2-3:1-3:2-3. In such embodiments, the reaction yield can reach 75% or more. In still other embodiments of the present invention, the molar ratio of diethyl iodophthalate, the bromide-containing inorganic salt, and the oxidant in the catalyst is 2-3:2-3:2 or 2-3:2-3:3, and the reaction yield can reach 90% or more. In still other embodiments of the present invention, the molar ratio of diethyl iodophthalate, the bromide-containing inorganic salt, and the oxidant in the catalyst is 1-1.5:1:1-1.5, with preferred ratios such as 1:1:1, 1.5:1:1, or 1:1:1.5, etc. In such embodiments, the reaction yield can reach 91% or more.

[0025] In some embodiments of the present invention, the reaction temperature for the self-cyclization reaction of 4-bromo-2-ethylbenzoic acid is 50-80°C, preferably 75-80°C. The reaction process of the present invention is simple and easy to control, requiring no harsh reaction conditions or complex equipment.

[0026] Specifically, in some embodiments of the present invention, the self-cyclization reaction of 4-bromo-2-ethylbenzoic acid includes: dissolving 4-bromo-2-ethylbenzoic acid, an inorganic salt containing bromide ions, an oxidant, and diethyl iodophenyl ester in a solvent to form a reaction mixture; heating the reaction mixture to between 75-85°C under nitrogen protection and maintaining the temperature for 4-8 hours; separating and purifying the mixture; and recrystallizing it with petroleum ether to obtain 5-bromo-3-methylisobenzofuran-1(3H)-one.

[0027] In some embodiments of the present invention, the separation and purification include: after the reaction is completed, cooling the reaction solution to room temperature, adding saturated sodium carbonate solution, stirring and allowing it to stand for separation, taking the aqueous phase, extracting it with dichloromethane, combining the organic phases, washing it with saturated sodium sulfite solution and purified water, drying, filtering, and concentrating under reduced pressure.

[0028] The carbon-oxygen coupling reaction of 5-bromo-3-methylisobenzofuran-1(3H)-one with phenol according to the present invention, in embodiments of the present invention, is carried out under alkaline conditions in the presence of a solvent, a catalyst and a ligand.

[0029] In some embodiments of the present invention, the ligand is an amine compound, preferably N,N'-dimethylethylenediamine or L-proline.

[0030] In some embodiments of the present invention, the solvent is selected from one or more of N,N-dimethylacetamide, tert-butanol, and xylene.

[0031] In some embodiments of the present invention, the catalyst is a copper salt selected from one or more of anhydrous copper acetate, cuprous oxide, and cuprous bromide.

[0032] In some embodiments of the present invention, the alkaline conditions can be achieved by adding an alkaline compound selected from one or more of potassium phosphate, potassium tert-butoxide, and potassium carbonate.

[0033] In some embodiments of the present invention, the molar ratio of 5-bromo-3-methylisobenzofuran-1(3H)-one, phenol, catalyst, ligand and basic compound is 1:1.1-1.5:0.1-0.2:0.15-0.25:1.2-1.8.

[0034] In some embodiments of the present invention, the reaction temperature is 80-110°C.

[0035] Specifically, in some embodiments of the present invention, the carbon-oxygen coupling reaction of 5-bromo-3-methylisobenzofuran-1(3H)-one with phenol includes the following steps: adding 5-bromo-3-methylisobenzofuran-1(3H)-one, phenol, catalyst, ligand and basic substance to a solvent in proportion to form a reaction mixture, heating to 80-110°C, maintaining the temperature for reaction, and obtaining a solid product containing roxadustat intermediate III, which is then separated and purified to obtain roxadustat intermediate III compound.

[0036] In some embodiments of the present invention, the separation and purification operation includes: washing the solid product with water, dissolving it in dichloromethane, washing it with an acidic solution and water, concentrating it under reduced pressure, adding it to methanol, stirring it at 5-10°C, filtering it, washing it with cold methanol, and drying it under vacuum to obtain roxadustat intermediate III compound.

[0037] In a third aspect of the invention, a method for preparing roxadustat is provided, comprising:

[0038] 5-Bromo-3-methylisobenzofuran-1(3H)-one was generated from 4-bromo-2-ethylbenzoic acid via self-cyclization.

[0039] 5-Bromo-3-methylisobenzofuran-1(3H)-one undergoes a carbon-oxygen coupling reaction with phenol to generate roxadustat intermediate III;

[0040] The roxadustat intermediate III is 3-methyl-5-phenoxyisobenzofuran-1(3H)-one;

[0041] Roxadustat was then prepared using roxadustat intermediate III.

[0042] Roxadustat can be prepared from roxadustat intermediate III according to conventional methods in the art.

[0043] In some embodiments of the present invention, a method for preparing roxadustat from roxadustat intermediate III includes:

[0044] Roxadustat intermediate III (3-methyl-5-phenoxyisobenzofuran-1(3H)-one) was refluxed with thionyl chloride, boric acid, dichlorotriphenylphosphine and potassium carbonate in toluene to give methyl 2-(1-chloroethyl)-4-phenoxybenzoate.

[0045] Methyl 2-(1-chloroethyl)-4-phenoxybenzoate was reacted with methyl p-toluenesulfonylglycine, sodium iodide and potassium carbonate in N,N-dimethylacetamide (DMAC) to give methyl 2-(1-(N-methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino)ethyl)-4-phenoxybenzoate.

[0046] Methyl 2-(1-(N-methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino)ethyl)-4-phenoxybenzoate was reacted with sodium methoxide in DMAC to give methyl 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline carboxylate.

[0047] 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline carboxylate methyl ester was reacted with glycine methyl ester hydrochloride, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP) and N,N-diisopropylethylamine in anhydrous dichloromethane to give N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline)carbonyl]glycine methyl ester;

[0048] Roxadustat was obtained by reacting N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline)carbonyl]glycine methyl ester with sodium hydroxide under reflux in methanol.

[0049] The present invention provides a method for preparing roxadustat using Formula III as a raw material, which has the advantages of simple operation, few steps, high yield, and low cost.

[0050] The various specific technical features described in the embodiments of the above aspects of the present invention can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

[0051] Unless otherwise specified, the numerical range described in this invention includes all values ​​within this range, and also includes the range value formed by any two values ​​within this range. For example, 1 to 3, this numerical range includes all values ​​between 1 and 3, and also includes the range value (1.5 to 2.5) formed by any two values ​​within this range (e.g., 1.5, 2.5); different values ​​of the same indicator appearing in all embodiments of this invention can be arbitrarily combined to form a range value.

[0052] Compared with existing technologies, the advantages of this invention include:

[0053] This invention provides a method for preparing roxadustat intermediate III from 4-bromo-2-ethylbenzoic acid and a method for preparing roxadustat. In the method of this invention, 5-bromo-3-methylisobenzofuran-1(3H)-one is generated by self-cyclization from 4-bromo-2-ethylbenzoic acid. The self-cyclization of 4-bromo-2-ethylbenzoic acid is achieved through a free radical substitution reaction in the presence of a specific solvent (e.g., 1,2-dichloroethane) and a non-metallic catalyst (including or composed of diethyl iodophenyl ester, an inorganic salt containing bromide ions, and an oxidant). This reaction process is simple and easy to control, requiring no harsh reaction conditions or complex equipment, thus greatly improving the reaction rate and significantly shortening the reaction time. The reaction time for this step can be reduced to 4–8 hours. Simultaneously, this step also exhibits good yield, reaching up to 91.5%. Furthermore, 5-bromo-3-methylisobenzofuran-1(3H)-one undergoes a carbon-oxygen coupling reaction with phenol to generate roxadustat intermediate III. In this invention, N,N'-dimethylethylenediamine is used as a ligand, and anhydrous copper acetate, cuprous oxide, or cuprous bromide is used as a catalyst, significantly improving the yield. Detailed Implementation

[0054] The present application is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the application. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer.

[0055] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of skill in the art. All reagents and materials used in this application are readily available through conventional means, and unless otherwise specified, they are used in accordance with conventional methods in the art or as per the product instructions. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this application. The preferred embodiments and materials described herein are for illustrative purposes only.

[0056] Preparation of Intermediate III (3-methyl-5-phenoxyisobenzofuran-1 (3H)-one) H 1. Preparation of Intermediate II (5-bromo-3-methylisobenzofuran-1 (3H)-one)

[0057]

[0058] Example 1

[0059] Example 2

[0060] 1,2-Dichloroethane (250 mL), 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), potassium bromide (23.8 g, 0.2 mol, 1.0 eq.), sodium bromate (30.2 g, 0.2 mol, 1.0 eq.), and diethyl iodophenyl ester (64.4 g, 0.2 mol, 1.0 eq.) were added sequentially to a three-necked flask. The mixture was purged with nitrogen three times. Under nitrogen protection, the temperature was raised to 80 °C and the reaction was maintained for 6 h. After cooling to room temperature, 250 mL of saturated sodium bicarbonate solution was added. The mixture was stirred for 20 minutes and allowed to stand to separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized from petroleum ether and dried under vacuum at 50 °C to obtain intermediate II (41.3 g, 91%). MS m / z 228 [M+H] + 249[M+Na] + .

[0061] Example 3

[0062] Add 250 mL of 1,2-dichloroethane, 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), sodium bromide (20.6 g, 0.2 mol, 1.0 eq.), sodium bromate (30.2 g, 0.2 mol, 1.0 eq.), and diethyl iodophenyl ester (64.4 g, 0.2 mol, 1.0 eq.) to a three-necked flask in sequence. Purge the flask three times with nitrogen. Under nitrogen protection, heat to 80 °C. The reaction was carried out at ℃ for 6 hours, then cooled to room temperature. A saturated sodium bicarbonate solution (250 mL) was added, and the mixture was stirred for 20 minutes. The mixture was allowed to stand and separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized with petroleum ether and dried under vacuum at 50℃ to obtain intermediate II (41.7 g, 91.5%).

[0063] Example 4

[0064] 1,2-Dichloroethane (250 mL), 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), ammonium bromide (19.6 g, 0.2 mol, 1.0 eq.), sodium bromate (30.2 g, 0.2 mol, 1.0 eq.), and diethyl iodophenyl ester (64.4 g, 0.2 mol, 1.0 eq.) were added sequentially to a three-necked flask. The mixture was purged with nitrogen three times, and under nitrogen protection, the temperature was raised to 80 °C and maintained for 6 h. After cooling to room temperature, 250 mL of saturated sodium bicarbonate solution was added. The mixture was stirred for 20 minutes and allowed to stand to separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized from petroleum ether and dried under vacuum at 50 °C to obtain intermediate II (32.7 g, 72%).

[0065] Example 5

[0066] Add 250 mL of 1,2-dichloroethane, 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), tetrabutylammonium bromide (64.4 g, 0.2 mol, 1.0 eq.), sodium bromate (30.2 g, 0.2 mol, 1.0 eq.), and diethyl iodophenyl ester (64.4 g, 0.2 mol, 1.0 eq.) to a three-necked flask in sequence. Purge the mixture three times with nitrogen. Under nitrogen protection, heat to [temperature missing]. The reaction was carried out at 80℃ for 6 hours, then cooled to room temperature. A saturated sodium bicarbonate solution (250 mL) was added, and the mixture was stirred for 20 minutes. The mixture was allowed to stand and separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized with petroleum ether and dried under vacuum at 50℃ to obtain intermediate II (34.1 g, 75%).

[0067] Example 6

[0068] 1,2-Dichloroethane (250 mL), 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), sodium bromide (20.6 g, 0.2 mol, 1.0 eq.), sodium periodate (42.8 g, 0.2 mol, 1.0 eq.), and diethyl iodophenyl ester (64.4 g, 0.2 mol, 1.0 eq.) were added sequentially to a three-necked flask. The mixture was purged with nitrogen three times. Under nitrogen protection, the temperature was raised to 80 °C and the reaction was maintained for 6 h. After cooling to room temperature, 250 mL of saturated sodium bicarbonate solution was added. The mixture was stirred for 20 minutes and allowed to stand to separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized from petroleum ether and dried under vacuum at 50 °C to obtain intermediate II (34.5 g, 76%).

[0069] Example 7

[0070] 1,2-Dichloroethane (250 mL), 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), sodium bromide (20.6 g, 0.2 mol, 1.0 eq.), sodium persulfate (47.6 g, 0.2 mol, 1.0 eq.), and diethyl iodophenyl ester (64.4 g, 0.2 mol, 1.0 eq.) were added sequentially to a three-necked flask. The mixture was purged with nitrogen three times. Under nitrogen protection, the temperature was raised to 80 °C and maintained for 6 h. After cooling to room temperature, 250 mL of saturated sodium bicarbonate solution was added. The mixture was stirred for 20 minutes and allowed to stand to separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized from petroleum ether and dried under vacuum at 50 °C to obtain intermediate II (35.9 g, 79%).

[0071] Example 8

[0072] 1,2-Dichloroethane (250 mL), 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), sodium bromide (20.6 g, 0.2 mol, 1.0 eq.), benzoyl peroxide (48.4 g, 0.2 mol, 1.0 eq.), and diethyl iodophenyl ester (64.4 g, 0.2 mol, 1.0 eq.) were added sequentially to a three-necked flask. The mixture was purged with nitrogen three times. Under nitrogen protection, the temperature was raised to 80 °C and the reaction was maintained for 6 h. After cooling to room temperature, 250 mL of saturated sodium bicarbonate solution was added. The mixture was stirred for 20 minutes and allowed to stand to separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized from petroleum ether and dried under vacuum at 50 °C to obtain intermediate II (39 g, 86%).

[0073] Example 9

[0074] 1,2-Dichloroethane (250 mL), 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), sodium bromide (20.6 g, 0.2 mol, 1.0 eq.), elemental iodine (50.8 g, 0.2 mol, 1.0 eq.), and diethyl iodophenyl ester (64.4 g, 0.2 mol, 1.0 eq.) were added sequentially to a three-necked flask. The mixture was purged with nitrogen three times. Under nitrogen protection, the temperature was raised to 80 °C and maintained for 6 h. After cooling to room temperature, 250 mL of saturated sodium bicarbonate solution was added. The mixture was stirred for 20 minutes and allowed to stand to separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized from petroleum ether and dried under vacuum at 50 °C to obtain intermediate II (25.4 g, 56%).

[0075] Example 10

[0076] Acetonitrile (250 mL), 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), sodium bromide (20.6 g, 0.2 mol, 1.0 eq.), sodium bromate (42.8 g, 0.2 mol, 1.0 eq.), and diethyl iodophenyl ester (64.4 g, 0.2 mol, 1.0 eq.) were added sequentially to a three-necked flask. The mixture was purged with nitrogen three times, heated to 80 °C under nitrogen protection, and reacted for 6 h. After cooling to room temperature, saturated sodium bicarbonate solution (250 mL) was added, and the mixture was stirred for 20 minutes. The mixture was allowed to stand and separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized from petroleum ether and dried under vacuum at 50 °C to obtain intermediate II (34.5 g, 76%).

[0077] Example 11

[0078] Trifluoroethanol (250 mL), 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), sodium bromide (20.6 g, 0.2 mol, 1.0 eq.), sodium bromate (42.8 g, 0.2 mol, 1.0 eq.), and diethyl iodophenyl ester (64.4 g, 0.2 mol, 1.0 eq.) were added sequentially to a three-necked flask. The mixture was purged with nitrogen three times, heated to reflux at 78 °C under nitrogen protection, and reacted for 6 h. After cooling to room temperature, saturated sodium bicarbonate solution (250 mL) was added, and the mixture was stirred for 20 minutes. The mixture was allowed to stand and separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized from petroleum ether and dried under vacuum at 50 °C to obtain intermediate II (19.5 g, 43%).

[0079] Example 12

[0080] Ethyl acetate (250 mL), 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), sodium bromide (20.6 g, 0.2 mol, 1.0 eq.), sodium bromate (42.8 g, 0.2 mol, 1.0 eq.), and diethyl iodophenyl ester (64.4 g, 0.2 mol, 1.0 eq.) were added sequentially to a three-necked flask. The mixture was purged with nitrogen three times, heated to reflux at 76 °C under nitrogen protection, and reacted for 6 h. After cooling to room temperature, saturated sodium bicarbonate solution (250 mL) was added, and the mixture was stirred for 20 minutes. The mixture was allowed to stand and separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized from petroleum ether and dried under vacuum at 50 °C to obtain intermediate II (17.3 g, 38%).

[0081] Example 13

[0082] Dichloromethane (250 mL), 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), sodium bromide (20.6 g, 0.2 mol, 1.0 eq.), sodium bromate (42.8 g, 0.2 mol, 1.0 eq.), and diethyl iodophenyl ester (64.4 g, 0.2 mol, 1.0 eq.) were added sequentially to a three-necked flask. The mixture was purged with nitrogen three times. Under nitrogen protection, the mixture was heated to reflux at 40 °C and maintained at this temperature for 6 h. Thin-layer chromatography (TLC) showed no reaction. The reaction mixture (petroleum ether / ethyl acetate = 8:1) was kept at this temperature for 16 hours, cooled to room temperature, and 250 mL of saturated sodium bicarbonate solution was added. After stirring for 20 minutes, the mixture was allowed to stand and separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized from petroleum ether and dried under vacuum at 50 °C to obtain intermediate II (6.8 g, 15%).

[0083] Example 14

[0084] 1,2-Dichloroethane (250 mL), 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), sodium bromide (20.6 g, 0.2 mol, 1.0 eq.), sodium bromate (30.2 g, 0.2 mol, 1.0 eq.), and diethyl iodophenyl ester (64.4 g, 0.2 mol, 1.0 eq.) were added sequentially to a three-necked flask. The mixture was purged with nitrogen three times. Under nitrogen protection, the temperature was raised to 50 °C and the reaction was maintained for 6 h. After cooling to room temperature, 250 mL of saturated sodium bicarbonate solution was added. The mixture was stirred for 20 minutes and allowed to stand to separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized from petroleum ether and dried under vacuum at 50 °C to obtain intermediate II (18.6 g, 41%).

[0085] Example 15

[0086] 1,2-Dichloroethane (250 mL), 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), sodium bromide (10.3 g, 0.1 mol, 0.5 eq.), sodium bromate (30.2 g, 0.2 mol, 1.0 eq.), and diethyl iodophenyl ester (64.4 g, 0.2 mol, 1.0 eq.) were added sequentially to a three-necked flask. The mixture was purged with nitrogen three times. Under nitrogen protection, the temperature was raised to 80 °C and the reaction was maintained for 6 h. After cooling to room temperature, 250 mL of saturated sodium bicarbonate solution was added. The mixture was stirred for 20 minutes and allowed to stand to separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized from petroleum ether and dried under vacuum at 50 °C to obtain intermediate II (20.4 g, 45%).

[0087] Example 16

[0088] Add 250 mL of 1,2-dichloroethane, 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), sodium bromide (30.9 g, 0.3 mol, 1.5 eq.), sodium bromate (30.2 g, 0.2 mol, 1.0 eq.), and diethyl iodophenyl ester (64.4 g, 0.2 mol, 1.0 eq.) to a three-necked flask in sequence. Purge the flask three times with nitrogen. Under nitrogen protection, heat to 80 °C. The reaction was carried out at ℃ for 6 hours, then cooled to room temperature. A saturated sodium bicarbonate solution (250 mL) was added, and the mixture was stirred for 20 minutes. The mixture was allowed to stand and separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized with petroleum ether and dried under vacuum at 50℃ to obtain intermediate II (41.2 g, 90.8%).

[0089] Example 17

[0090] 1,2-Dichloroethane (250 mL), 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), sodium bromide (20.6 g, 0.2 mol, 1.0 eq.), sodium bromate (15.1 g, 0.1 mol, 0.5 eq.), and diethyl iodophenyl ester (64.4 g, 0.2 mol, 1.0 eq.) were added sequentially to a three-necked flask. The mixture was purged with nitrogen three times, heated to 80 °C under nitrogen protection, and reacted for 6 h. After cooling to room temperature, 250 mL of saturated sodium bicarbonate solution was added. The mixture was stirred for 20 minutes and allowed to stand to separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized from petroleum ether and dried under vacuum at 50 °C to obtain intermediate II (34.1 g, 75%).

[0091] Example 18

[0092] 1,2-Dichloroethane (250 mL), 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), sodium bromide (20.6 g, 0.2 mol, 1.0 eq.), sodium bromate (45.3 g, 0.3 mol, 1.5 eq.), and diethyl iodophenyl ester (64.4 g, 0.2 mol, 1.0 eq.) were added sequentially to a three-necked flask. The mixture was purged with nitrogen three times. Under nitrogen protection, the temperature was raised to 80 °C and maintained for 6 h. After cooling to room temperature, 250 mL of saturated sodium bicarbonate solution was added. The mixture was stirred for 20 minutes and allowed to stand to separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized from petroleum ether and dried under vacuum at 50 °C to obtain intermediate II (38.1 g, 84%).

[0093] Example 19

[0094] 1,2-Dichloroethane (250 mL), 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), sodium bromide (20.6 g, 0.2 mol, 1.0 eq.), sodium bromate (30.2 g, 0.2 mol, 1.0 eq.), and diethyl iodophenyl ester (32.2 g, 0.1 mol, 0.5 eq.) were added sequentially to a three-necked flask. The mixture was purged with nitrogen three times. Under nitrogen protection, the temperature was raised to 80 °C and the reaction was maintained for 6 h. After cooling to room temperature, 250 mL of saturated sodium bicarbonate solution was added. The mixture was stirred for 20 minutes and allowed to stand to separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized from petroleum ether and dried under vacuum at 50 °C to obtain intermediate II (18.2 g, 40%).

[0095] 2. Preparation of Intermediate III (3-methyl-5-phenoxyisobenzofuran-1 (3H)-one)

[0096] 1,2-Dichloroethane (250 mL), 4-bromo-2-ethylbenzoic acid I (45.8 g, 0.2 mol), sodium bromide (20.6 g, 0.2 mol, 1.0 eq.), sodium bromate (30.2 g, 0.2 mol, 1.0 eq.), and diethyl iodophenyl ester (96.6 g, 0.3 mol, 1.5 eq.) were added sequentially to a three-necked flask. The mixture was purged with nitrogen three times. Under nitrogen protection, the temperature was raised to 80 °C and maintained for 6 h. After cooling to room temperature, 250 mL of saturated sodium bicarbonate solution was added. The mixture was stirred for 20 minutes and allowed to stand to separate into layers. The aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined and washed once each with saturated sodium sulfite solution and purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid. The liquid was recrystallized from petroleum ether to obtain intermediate II (41.3 g, 91%).

[0097] Example 20

[0098] Example 21

[0099] Add the following to a three-necked flask in sequence: N,N-dimethylacetamide (100 mL), 3-methyl-5-bromoisobenzofuran-1(3H)-one II (22.7 g, 0.1 mol), phenol (12.2 g, 0.13 mol, 1.3 eq.), cuprous oxide (2.15 g, 0.015 mol, 0.15 eq.), N,N'-dimethylethylenediamine (1.76 g, 0.02 mol, 0.2 eq.), and potassium phosphate (31.8 mL). (g, 0.15mol, 1.5eq.) was heated to 110℃ and reacted for 10h. After cooling to room temperature, water was added, and the mixture was stirred for 30min. The mixture was filtered, the filter cake was washed with water, dissolved in dichloromethane, and washed once each with 1M hydrochloric acid solution and purified water. The mixture was concentrated under reduced pressure, 10mL of methanol was added, and the mixture was stirred at 5-10℃ for 30min. The mixture was filtered, the filter cake was washed with cold methanol, and dried under vacuum at 50℃ for 5h to obtain intermediate III compound (20.6g, 85.8%). MS m / z 241 [M+H] + .

[0100] Example 22

[0101] Add tert-butanol (100 mL), 3-methyl-5-bromoisobenzofuran-1(3H)-one II (22.7 g, 0.1 mol), phenol (12.2 g, 0.13 mol, 1.3 eq.), anhydrous copper acetate (1.85 g, 0.015 mol, 0.15 eq.), N,N'-dimethylethylenediamine (1.76 g, 0.02 mol, 0.2 eq.), and potassium tert-butoxide (16.8 g, 100 mL) to a three-necked flask in sequence. 0.15 mol (1.5 eq.) was heated to 85 °C and reacted for 10 h. After cooling to room temperature, water was added, and the mixture was stirred for 30 min. The mixture was filtered, the filter cake was washed with water, dissolved in dichloromethane, and washed once each with 1 M hydrochloric acid solution and purified water. The mixture was concentrated under reduced pressure, 10 mL of methanol was added, and the mixture was stirred at 5-10 °C for 30 min. The mixture was filtered, the filter cake was washed with cold methanol, and dried under vacuum at 50 °C for 5 h to obtain intermediate III compound (15.8 g, 65.8%).

[0102] Preparation of Roxadustat

[0103] Add xylene (100 mL), 3-methyl-5-bromoisobenzofuran-1(3H)-one II (22.7 g, 0.1 mol), phenol (12.2 g, 0.13 mol, 1.3 eq.), cuprous bromide (2.15 g, 0.015 mol, 0.15 eq.), L-proline (2.3 g, 0.02 mol, 0.2 eq.), and potassium carbonate (0.7 g, 0.15 eq.) to a three-necked flask in sequence. 1,5 eq.) was heated to 110 °C and reacted for 10 h. After cooling to room temperature, water was added and stirred for 30 min. The mixture was filtered, the filter cake was washed with water, dissolved in dichloromethane, washed once each with 1 M hydrochloric acid solution and purified water, concentrated under reduced pressure, 10 mL of methanol was added, and the mixture was stirred at 5-10 °C for 30 min. After filtration, the filter cake was washed with cold methanol and dried under vacuum at 50 °C for 5 h to obtain intermediate III compound (18.9 g, 78.8%).

[0104] Example 23

[0105]

[0106] ​

[0107] Preparation of intermediate IV (methyl 2-(1-chloroethyl)-4-phenoxybenzoate)

[0108] Toluene (100 mL) was added to the reactor and stirring was started. Then, 3-methyl-5-phenoxyisobenzofuran-1(3H)-one III (24 g, 0.1 mol), thionyl chloride (14.5 g, 0.14 mol), boric acid (0.3 g, 0.005 mol), dichlorotriphenylphosphine (1 g, 0.003 mol), and potassium carbonate (31.1 g, 0.225 mol) were added to the reactor. The mixture was heated to reflux for 5 h, and the solvent was concentrated to dryness under reduced pressure. Methanol (60 mL) was added dropwise at room temperature, and the mixture was heated to reflux for 3 h after the addition was complete. The solvent was concentrated to dryness under reduced pressure. DMAC was added, and the resulting DMAC solution of methyl 2-(1-chloroethyl)-4-phenoxybenzoate IV was used directly in the next step of the reaction.

[0109] Preparation of intermediate V (methyl 2-(1-(N-methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino)ethyl)-4-phenoxybenzoate) and intermediate VI (methyl 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline carboxylate)

[0110] Stirring was started, and DMAC solution of methyl 2-(1-chloroethyl)-4-phenoxybenzoate IV (approximately 130 g), methyl p-toluenesulfonylglycine (26.7 g, 0.11 mol), sodium iodide (1.5 g, 0.01 mmol), and potassium carbonate (23.5 g, 0.17 mol) were added sequentially to the reaction flask. The mixture was heated to 60 °C and reacted for 5 h. The reaction solution was cooled to room temperature to obtain a mixed solution containing the target product V. MS m / z 498 [M+H] + A methanol solution of sodium methoxide (10.8 g, 0.2 mol) was added dropwise to the above mixed solution. After the addition was complete, the mixture was heated to 40 °C and reacted for 5 h. The reaction was quenched with water (100 mL) / glacial acetic acid (50 mL) and stirred at room temperature for 1 h. The mixture was filtered, washed with water, recrystallized with acetone, and dried under vacuum at 50 °C to give product VI (20.1 g, 65% yield in three steps), HPLC: 99.5%, MS m / z 310 [M+H]. + .

[0111] Preparation of intermediate VII (N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline)carbonyl]glycine methyl ester)

[0112] 2240 mL of anhydrous dichloromethane was added to a reaction flask. Methyl 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline carboxylate VI (30.9 g, 0.1 mol), glycine methyl ester hydrochloride (15.1 g, 0.12 mol), and 679 g of PyBOP (57.2 g, 0.11 mol), along with N,N-diisopropylethylamine (32.3 g, 0.25 mol), were added under stirring. The mixture was heated to 40 °C and reacted for 6 h. After cooling to room temperature, water was added to separate the layers. The dichloromethane layer was separated and washed with dilute hydrochloric acid, saturated sodium bicarbonate solution, and water. The solvent was concentrated under reduced pressure to dryness to obtain a reddish-brown concentrate. This concentrate was recrystallized from methanol and dried under vacuum at 50 °C to obtain a pale yellow intermediate VII (35.6 g, 97%). MS m / z 367 [M+H] + .

[0113] Preparation of Roxadustat (N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline)carbonyl]glycine)

[0114] Add 190 mL of methanol to a reaction flask, and while stirring, add N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline)carbonyl]glycine methyl ester VII (36.7 g, 0.1 mol) and 199.6 g of sodium hydroxide aqueous solution (9.6 g sodium hydroxide and 190 mL water). Heat to reflux for 6 hours, cool to room temperature, add 4N HCl dropwise to adjust the pH to 2-3, stir for 1 hour, filter, wash the filter cake with pure water, recrystallize with acetone, and dry under vacuum at 50 °C to obtain pale yellow roxadustat (33.7 g, 95.7%). MS m / z 353 [M+H] + . 1 HNMR DMSO-d6,400MHz: 13.233(1H,s),12.808(1H,s),9.091(1H,t),8.287(1H,d),7.608( 1H,d),7.465-7.541(3H,m),7.261(1H,t),7.185(2H,m),4.068(2H,d),2.702(3H,s).

[0115] The various specific technical features described in the above embodiments of the present invention can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

[0116] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A method for preparing roxadustat intermediate III, comprising: Using 4-bromo-2-ethylbenzoic acid as a starting material, a self-cyclization reaction occurs in the presence of 1,2-dichloroethane and a catalyst consisting of diethyl iodophenyl ester, an inorganic salt containing bromide ions, and an oxidant to generate 5-bromo-3-methylisobenzofuran-1(3-ethylbenzoic acid). H )-ketone; The carbon-oxygen coupling reaction of 5-bromo-3-methylisobenzofuran-1(3H)-one with phenol occurs under basic conditions in the presence of a solvent, catalyst, and ligand, wherein the roxadustat intermediate III is 3-methyl-5-phenoxyisobenzofuran-1(3H)-one. H )-ketone; The molar ratio of diethyl iodophenyl ester, the inorganic salt containing bromide ions, and the oxidant is 1-3:1-3:1-3; The solvent is selected from one or more of N,N-dimethylacetamide, tert-butanol, and xylene; The catalyst is selected from one or more of anhydrous copper acetate, cuprous oxide, and cuprous bromide; The base is selected from one or more of potassium phosphate, potassium tert-butoxide, and potassium carbonate; The ligand is N,N'-dimethylethylenediamine or L-proline.

2. The method according to claim 1, characterized in that, The inorganic salt containing bromide ions is selected from at least one of potassium bromide, sodium bromide, ammonium bromide, and tetrabutylammonium bromide.

3. The method according to claim 1, characterized in that, The oxidant is selected from at least one of sodium bromate, sodium periodate, sodium persulfate, benzoyl peroxide, and elemental iodine.

4. The method according to claim 1, characterized in that, The catalyst is selected from diethyl iodophenyl ester, potassium bromide, sodium bromide, ammonium bromide and tetrabutylammonium bromide, and sodium bromate, sodium periodate, sodium persulfate, benzoyl peroxide and elemental iodine.

5. The method according to claim 4, characterized in that, The catalyst is selected from the following combinations: potassium bromide, sodium bromate and diethyl iodophthalate, sodium bromide, sodium bromate and diethyl iodophthalate, ammonium bromide, sodium bromate and diethyl iodophthalate, tetrabutylammonium bromide, sodium bromate and diethyl iodophthalate, sodium bromide, sodium periodate and diethyl iodophthalate, sodium bromide, sodium persulfate and diethyl iodophthalate, sodium bromide, benzoyl peroxide and diethyl iodophthalate, sodium bromide, elemental iodine and diethyl iodophthalate.

6. The method according to claim 1, characterized in that, The molar ratio of diethyl iodophenyl ester, bromide-containing inorganic salt, and oxidant in the catalyst is 2-3:1-3:2-3.

7. The method according to claim 1, characterized in that, The molar ratio of diethyl iodophenyl ester, bromide-containing inorganic salt, and oxidant in the catalyst is 2-3:2-3:2 or 2-3:2-3:

3.

8. The method according to claim 1, characterized in that, The molar ratio of diethyl iodophenyl ester, bromide-containing inorganic salt, and oxidant in the catalyst is 1-1.5:1:1-1.

5.

9. The method according to claim 1, characterized in that, The molar ratio of diethyl iodophenyl ester, bromide-containing inorganic salt, and oxidant in the catalyst is 1:1:1, 1.5:1:1, or 1:1:1.

5.

10. The method according to claim 1, characterized in that, The self-cyclization reaction of 4-bromo-2-ethylbenzoic acid takes place at a temperature of 50-80℃.

11. The method according to claim 1, characterized in that, The self-cyclization reaction of 4-bromo-2-ethylbenzoic acid takes place at a temperature of 75-80℃.

12. A method for preparing roxadustat, characterized in that, Roxadustat was prepared from roxadustat intermediate III, wherein roxadustat intermediate III was prepared by the method described in any one of claims 1-11.

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