Process for the preparation of roxadustat

Abstract

The application provides a preparation method of roxadustat, and the roxadustat (compound 1) is prepared from 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (compound 2) through condensation reaction with N,N-dimethylformamide dimethyl acetal, reduction reaction and ammonolysis reaction. The synthesis method has the advantages of short steps, low cost, safety, environmental protection, simple operation and industrialization value. The roxadustat prepared by the method has good quality, and can be used for preparing roxadustat preparations for clinical use.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of synthetic chemistry of pharmaceuticals, and in particular, the present application provides a preparation method of Roxadustat. BACKGROUND

[0002] Roxadustat (structural formula as follows), chemical name N-[(4-methyl-1-methyl-7-phenoxy-3-isoquinoline) carbonyl] glycine, is a small molecule inhibitor of inhibiting the activity of hypoxia inducible factor prolyl hydroxylase (HIF-PH) originally researched by FibroGen company, which can stabilize HIF-2 and induce the expression of EPO. It was first listed in China in December 2018.

[0003] .

[0004] The most valuable and industrialized preparation method of roxadustat is reported by the original research company FibroGen CN103435546.

[0005] .

[0006] The innovation of this route is the introduction of Claisen ester condensation to construct isoquinoline ring and the introduction of 1-methyl on the ring. The route has 9 reaction steps, the yield of each step is moderate, the reaction conditions are relatively mild, and each intermediate does not need to be separated and purified by chromatography. However, in the process of preparing compound 4 from 4-hydroxy-7-phenoxy isoquinoline-3-carboxylate methyl ester (compound 2) in the route, it is too long and complex. In order to introduce methyl at the 1 position of compound 2, 4 steps of reactions are added.

[0007] There are patents reported that compound 5 in the route is directly reduced by zinc powder to prepare compound 4, thereby reducing two steps of reactions. However, zinc powder reduction needs to use a large amount of inorganic acid, which has great environmental pressure, and the purity of the obtained intermediate is not high. However, roxadustat has poor refining effect in the finished product stage, and often needs to control the purity in the previous synthesis steps or intermediates, so as to prepare roxadustat meeting the pharmaceutical quality requirements.

[0008] In summary, at present, the preparation method of roxadustat still has the disadvantages of long reaction steps, great environmental pressure and high production cost. Therefore, the present application aims to solve the above-mentioned defects, and research and develop a roxadustat synthesis route and preparation method suitable for industrialization and having advantages of technical indicators and economic indicators. SUMMARY

[0009] The preparation method of roxadustat provided by the present application comprises the following steps:

[0010] (a) preparing compound 3 by condensation reaction and acidolysis treatment of compound 2 and N,N-dimethylformamide dimethyl acetal;

[0011] (b) preparing compound 4 from compound 3 by a reduction reaction;

[0012] (c) preparing Roxadustat from compound 4 by an aminolysis reaction with glycine;

[0013] .

[0014] In step (a), the feeding amount of N,N-dimethylformamide dimethyl acetal is 5-8 times the weight of compound 2, the reaction temperature of the condensation reaction is 100-110°C, and the acid used in the acidolysis treatment is 5-10% hydrochloric acid aqueous solution. In step (b), the reduction reaction refers to a catalytic hydrogenation reaction, the metal catalyst of the catalytic hydrogenation reaction is palladium-carbon, the strong acid catalyst of the catalytic hydrogenation reaction is sulfuric acid or perchloric acid, the reaction solvent of the catalytic hydrogenation reaction is acetic acid, the reaction temperature is 60-80°C, and the amount of each catalyst is 3-5% by weight of compound 3. In step (c), the aminolysis reaction uses a catalyst sodium methoxide.

[0015] The preparation method of Roxadustat presented by the present application is described in detail as follows:

[0016] .

[0017] In the preparation of compound 3 from compound 2 and N,N-dimethylformamide dimethyl acetal, an intermediate state of intermediate state 1 is experienced. Intermediate state 1 can easily obtain compound 3 in high yield under the acidolysis action of dilute hydrochloric acid aqueous solution. Compound 3 contains benzaldehyde structure, which can further easily undergo catalytic hydrogenation reaction to obtain high-purity compound 4, thereby introducing the required methyl at the 1-position of the isoquinoline of Roxadustat. Finally, compound 4 and glycine are catalyzed by inexpensive sodium methoxide to obtain Roxadustat.

[0018] Compared with the prior art, the preparation method of Roxadustat provided by the present application shortens the reaction steps by two steps, the reaction conditions are relatively mild, the operation is relatively simple, the production cycle is also greatly shortened, and the whole process does not use high-risk reagents. Overall, this method has advantages in technical indicators and economic indicators, and has industrial prospects. In addition, since the Roxadustat crude product prepared by the method has high purity and good quality, it can be directly used for preparation of a preparation.

[0019] The present application will be further described below by way of examples, and various substitutions or combinations made according to ordinary technical knowledge and conventional means in the art shall be included in the scope of the present application.

[0020] Example 1 Preparation of compound 3

[0021] Compound 2 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester 295 g was added into N,N-dimethylformamide dimethyl acetal 1475 g (5 times weight) and reacted at 110 °C for 8-10 hours. The excess N,N-dimethylformamide dimethyl acetal was evaporated under reduced pressure, and the residue was added into 5% dilute hydrochloric acid aqueous solution 2000 mL and stirred at room temperature for 1 hour. The mixture was filtered, and the filter cake was washed with water until neutral and dried to obtain compound 3 as a white solid 294 g, with a molar yield of 91%, HPLC content of 99.5%, and HRMS: [M+H] 324.07, [M+Na] 346.05.

[0022] Example 2 Preparation of compound 3

[0023] Compound 2 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester 295 g was added into N,N-dimethylformamide dimethyl acetal 1475 g (5 times weight) and reacted at 110 °C for 8-10 hours. The excess N,N-dimethylformamide dimethyl acetal was evaporated under reduced pressure, and the residue was added into 5% dilute hydrochloric acid aqueous solution 2000 mL and stirred at room temperature for 1 hour. The mixture was filtered, and the filter cake was washed with water until neutral and dried to obtain compound 3 as a white solid 294 g, with a molar yield of 91%, HPLC content of 99.5%, and HRMS: [M+H] 324.07, [M+Na] 346.05.

[0024] Example 3 Preparation of compound 4

[0025] Compound 3 260 g, acetic acid 1500 mL, 5% palladium on carbon 13 g (5% weight), sulfuric acid 13 g (5% weight) were sequentially added into an autoclave, hydrogen was introduced, the pressure was maintained at 0.5-0.6 MPa, and the temperature was raised to 60 °C for reaction for 8 hours. The palladium on carbon was filtered off, the filtrate was evaporated under reduced pressure, and the residue was recrystallized from methanol 1300 mL to obtain compound 4 as a white solid 236 g, with a molar yield of 95%, HPLC content of 99.8%, and HRMS: [M+H] 310.02, [M+Na] 332.09.

[0026] Example 4 Preparation of compound 4

[0027] Compound 3 260 g, acetic acid 1500 mL, 5% palladium on carbon 13 g (5% weight), sulfuric acid 13 g (5% weight) were sequentially added into an autoclave, hydrogen was introduced, the pressure was maintained at 0.5-0.6 MPa, and the temperature was raised to 60 °C for reaction for 8 hours. The palladium on carbon was filtered off, the filtrate was evaporated under reduced pressure, and the residue was recrystallized from methanol 1300 mL to obtain compound 4 as a white solid 236 g, with a molar yield of 95%, HPLC content of 99.8%, and HRMS: [M+H] 310.02, [M+Na] 332.09.

[0028] Example 5 Preparation of Compound 1 Roxadustat

[0029] Compound 4 200 g, glycine 145 g, sodium methoxide 100 g were added into methanol 2000 mL successively, and the mixture was heated to 110 °C and reacted for 8 hours. After cooling to room temperature, the mixture was filtered. The filter cake was added into water 1000 mL, stirred to dissolve, and the pH was adjusted to 5-6 with 5% hydrochloric acid aqueous solution. The mixture was stirred for 1 hour, filtered, and the filter cake was dried to obtain roxadustat 205 g, with a molar yield of 90%, HPLC content of 99.9%, and HRMS: [M+H] 353.06, [M+Na] 375.08.

[0030] Example 6 Preparation of roxadustat capsules

[0031] Roxadustat 200 g prepared according to the method of the example (prepared in a clean area), lactose monohydrate 1.0 kg, microcrystalline cellulose PH-101 100 g, polyvinylpyrrolidone K29 / 32 67 g, croscarmellose sodium 51 g, and purified water 400 g were granulated, dried, sieved, and then mixed with magnesium stearate 6 g. The mixture was filled into capsules according to the specifications of 20 mg or 50 mg to obtain roxadustat capsules.

Claims

1. A process for preparing Roxadustat, ； The process comprises the following steps: (a) mixing compound 2 and 5-8 times compound 2 weight of N,N-dimethylformamide dimethyl acetal, reacting at 100-110℃ for 8-12 hours, distilling off excess N,N-dimethylformamide dimethyl acetal, and then acid hydrolyzing with 5-10% hydrochloric acid aqueous solution to obtain compound 3, ； (b) catalytic hydrogenation of compound 3 and hydrogen in the presence of a transition metal catalyst, palladium on carbon, and a strong acid catalyst, perchloric acid or sulfuric acid, to obtain compound 4, ； (c) ammonolysis of compound 4 and glycine in the presence of sodium methoxide to obtain Roxadustat, 。 2. The method of claim 1, wherein: The reaction solvent for the catalytic hydrogenation reaction in step (b) is acetic acid.

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