A roxadustat intermediate impurity and a method of preparing the same

Abstract

This invention provides an intermediate impurity of roxadustat and a method for preparing the impurity. The method for preparing roxadustat impurity I includes: dissolving compounds II and III in an organic solvent, and conducting a coupling reaction under a nitrogen atmosphere and a reaction temperature of 40–60°C in the presence of a base to obtain roxadustat impurity I. This preparation method features mild reaction conditions, simple operation, low time cost, high yield, and high product purity. It can efficiently obtain sufficient quantities of high-purity impurity reference standards, playing a positive role in the quality control of roxadustat intermediates and roxadustat active pharmaceutical ingredients, and has good application prospects.

Description

Technical Field

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

[0002] Roxadustat is the world's first marketed hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor for the treatment of renal anemia. Developed by FibroGen in the United States, it was first launched in China in December 2018, becoming the first oral treatment for renal anemia. The structure of roxadustat is shown below:

[0003]

[0004] Currently, there are numerous reports on the preparation methods of roxadustat. One of the main methods involves using compound A as a raw material and undergoing reactions such as chlorination ring-opening, cyclization, bromination, methylation, and hydrolysis to finally obtain the roxadustat product. The reaction process is shown below:

[0005]

[0006] In the aforementioned process study of roxadustat, the applicant discovered a novel roxadustat intermediate impurity with the structure shown in Formula I below:

[0007]

[0008] Because thionyl chloride was used as a chlorinating agent in the synthesis of compound B from compound A, sulfite was generated during post-processing. The residual trace amount of sulfite reacted with subsequent intermediate F to generate corresponding thiophenol impurities. These thiophenol impurities then underwent a thioetherification reaction with residual intermediate B to generate impurity I. Impurity I is difficult to remove in subsequent reactions and processing, affecting the quality of the roxadustat intermediate and the roxadustat active pharmaceutical ingredient. Furthermore, the thioalkyl group in impurity I is unstable and easily oxidized during subsequent reactions or prolonged storage, generating sulfonyl group compounds. Sulfonyl group compounds all exhibit SA_2 as specified in "Development of structural alerts for the in vivo micronucleus assay inrodents".

[0009] The presence of a "ster of sulphonic or phosphonic acid" structure, which may indicate genotoxicity, could affect the final quality of roxadustat products, with a daily intake of less than 1.5 μg / day. Therefore, controlling impurity I in the roxadustat intermediate compound F to reduce subsequent risks is crucial. Currently, there are no reports in the existing technology regarding potential genotoxic impurities that may be generated during the preparation of compound F. Therefore, to ensure the quality of roxadustat intermediates and the roxadustat product, it is essential to identify the reaction byproducts in this step and whether any unknown potential genotoxic impurities exist among these byproducts. Summary of the Invention

[0010] To address the shortcomings of existing technologies, this invention provides a roxadustat intermediate impurity and a method for preparing the impurity. The method for preparing roxadustat impurity I provided by this invention features mild reaction conditions, simple operation, low time cost, high yield, and high product purity. It can efficiently obtain sufficient quantities of high-purity impurity reference standards, playing a positive role in the quality control of roxadustat intermediates and roxadustat active pharmaceutical ingredients, and has good application prospects.

[0011] The present invention provides a roxadustat intermediate impurity, the structure of which is shown in Formula I below:

[0012]

[0013] R1 and R2 are each independently Me, Et, i-Pr or n-butyl.

[0014] Considering the structural instability of impurity I, it is easily oxidized during subsequent reactions or prolonged storage, generating sulfonyl group compounds with genotoxic properties. Therefore, the control limit of impurity I in roxadustat intermediate compound F needs to be controlled within 0.05%, the structure of which is shown below:

[0015]

[0016] R2 is Me, Et, i-Pr or n-butyl.

[0017] In the study of roxadustat, we need to examine the transfer and removal process of this impurity during the synthesis of roxadustat active pharmaceutical ingredient. This requires a certain amount of impurity I reference standard. However, simply enriching impurity I by liquid phase preparation has problems such as low efficiency and the generation of a large amount of waste liquid. Therefore, this invention also provides a method for preparing roxadustat intermediate impurity I.

[0018] This invention provides a method for preparing roxadustat intermediate impurity I, comprising: dissolving compounds II and III in an organic solvent, and conducting a coupling reaction under the action of a base in a nitrogen atmosphere and at a reaction temperature of 40–60°C to obtain compound I. The reaction route is shown below:

[0019]

[0020] Where X is a halogen; R1 and R2 are each independently Me, Et, i-Pr or n-butyl.

[0021] In one implementation, X is Cl or Br.

[0022] In one embodiment, the base is selected from one or more of N,N-diisopropylethylamine (DIPEA), 4-dimethylaminopyridine (DMAP), sodium carbonate, potassium carbonate, or cesium carbonate.

[0023] In one embodiment, the organic solvent is selected from one or more of toluene, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), 4-dimethylaminopyridine (DMAP), or acetonitrile.

[0024] In one embodiment, the molar ratio of compound II to compound III is 1:1 to 3.

[0025] In one embodiment, the molar ratio of the base to compound II is 4 to 10:1.

[0026] In one embodiment, the base is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, or sodium tert-butoxide.

[0027] In one embodiment, compound II is prepared by reacting compound IV and an alkali metal sulfide or its hydrate in a suitable solvent at 90–100°C with a carbonate and a catalyst to obtain compound II. The reaction route is shown below:

[0028]

[0029] Where M is an alkali metal, and R2 is defined as above.

[0030] In one embodiment, the alkali metal sulfide in the preparation method of compound II is selected from sodium sulfide or potassium sulfide, and the carbonate is selected from potassium carbonate, sodium carbonate or cesium carbonate.

[0031] In one embodiment, the catalyst used in the preparation method of compound II is a mixture of bis(pph3)2Cl2, palladium dichloride (Pd(pph3)2Cl2), and triphenylphosphine (Ph3P).

[0032] In one embodiment, the suitable solvent used in the preparation method of compound II is selected from one or more of tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, or water.

[0033] In one embodiment, the molar ratio of compound IV to alkali metal sulfide or its hydrate in the preparation method of compound II is 1:1 to 1.5; the molar ratio of compound IV to carbonate is 1:2 to 3.

[0034] In one embodiment, the molar ratio of compound IV to Pd(pph3)2Cl2 and Ph3P in the preparation method of compound II is 1:(0.05-0.1):(0.1-0.15).

[0035] Compound III can be purchased directly as a commercial product or prepared by means of existing technology (e.g., CN103435546B).

[0036] Compound IV can be purchased directly from commercial products or prepared by means of existing technologies (e.g., CN110903242B).

[0037] The beneficial effects of this invention are as follows: 1. It provides a new roxadustat intermediate impurity I, which has not been reported in any literature / patent, and the structure of impurity I has been qualitatively and quantitatively identified; 2. It provides a new preparation method for roxadustat intermediate impurity I, which has mild reaction conditions, simple operation, and high product yield and purity, and has industrialization value. Attached Figure Description

[0038] Figure 1 For the roxadustat impurity compound IA provided in this application 1 H-NMR spectrum.

[0039] Figure 2 For the roxadustat impurity compound IB provided in this application 1 H-NMR spectrum.

[0040] Figure 3 For the roxadustat impurity compound IC provided in this application 1 H-NMR spectrum. Detailed Implementation

[0041] Reference will now be made to detailed embodiments of the present invention, one or more of which are described below. Each example is provided for explanation and not for limitation of the invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the invention without departing from its scope or spirit. For example, features described or illustrated as part of one embodiment may be used in another embodiment to produce further embodiments.

[0042] Therefore, this invention is intended to cover such modifications and variations falling within the scope of the appended claims and their equivalents. Other objects, features, and aspects of the invention are disclosed in or will be apparent from the following detailed description. It will be understood by those skilled in the art that this discussion is merely a description of exemplary embodiments and is not intended to limit the broader aspects of the invention.

[0043] In this invention, numerical ranges are involved. Unless otherwise specified, the numerical ranges are considered continuous and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when multiple ranges are provided to describe a feature or characteristic, the ranges may be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are included.

[0044] The embodiments of this application will be described in detail below with reference to examples. Unless otherwise specified, the raw materials used in the following examples are all commercially available products.

[0045] Example 1: Preparation of Compound IV-A

[0046]

[0047] To a reaction flask, 20 g of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate, 200 mL of dichloromethane, and 11 g of dibromohydantoin were added sequentially. The reaction system was kept at 10–20 °C and the reaction was maintained for 4 hours. The mixture was filtered, and the filtrate was evaporated to dryness to obtain a yellow solid. 200 mL of methanol was then added, and the mixture was washed by stirring at room temperature. After filtration, the filter cake was dried to obtain 23.2 g of compound IV-A.

[0048] Example 2: Preparation of compound IV-B

[0049]

[0050] To a reaction flask, 45.72 g of 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate, 500 mL of dichloromethane, and 23.2 g of dibromohydantoin were added sequentially. The reaction system was kept at 15–20 °C for 5 hours. The mixture was filtered, the filtrate was evaporated to dryness, and then 400 mL of methanol was added. The mixture was then washed at room temperature, filtered, and the filter cake was dried to obtain 52 g of compound IV-B.

[0051] Example 3 Preparation of compound II-A

[0052]

[0053] To a reaction flask, 14 g of compound IV-A prepared in Example 1, 170 mL of 1,4-dioxane, 110 mL of water, 30 g of cesium carbonate, 11.22 g of sodium sulfide nonahydrate, 1.31 g of Pd(pph3)2Cl2, and 1.28 g of triphenylphosphine were added sequentially. After purging with nitrogen, the reaction system was heated to 95℃±5℃ and maintained at this temperature for 4 hours. The mixture was then cooled, and excess 1,4-dioxane was removed by vacuum distillation. 300 mL of water and 300 mL of ethyl acetate were added, and the mixture was separated. The filtrate was evaporated to dryness to obtain 8 g of compound II-A.

[0054] Example 4: Preparation of Compound II-B

[0055]

[0056] To a reaction flask, 41.6 g of compound IV-B prepared in Example 2, 300 mL of 1,4-dioxane, 200 mL of water, 27.6 g of potassium carbonate, 17 g of potassium sulfide, 7 g of Pd(pph3)2Cl2, and 2.6 g of triphenylphosphine were added sequentially. After purging with nitrogen, the reaction system was heated to 95℃±5℃ and maintained at this temperature for 5 hours. The mixture was then cooled, and excess 1,4-dioxane was removed by vacuum distillation. 500 mL of water and 500 mL of ethyl acetate were added, and the mixture was separated. The filtrate was evaporated to dryness to obtain 24.9 g of compound II-B.

[0057] Example 5 Preparation of compound II-B

[0058]

[0059] To a reaction flask, 41.6 g of commercially available compound IV-B, 350 mL of 1,4-dioxane, 200 mL of water, 97 g of cesium carbonate, 30 g of sodium sulfide nonahydrate, 4 g of Pd(pph3)2Cl2, and 3.9 g of triphenylphosphine were added sequentially. After purging with nitrogen, the reaction system was heated to 95℃±5℃ and maintained at this temperature for 6 hours. The mixture was then cooled, and excess 1,4-dioxane was removed by vacuum distillation. 500 mL of water and 500 mL of ethyl acetate were added, and the mixture was separated. The filtrate was evaporated to dryness to obtain 34 g of compound II-B.

[0060] Example 6 Preparation of Compound III-A

[0061]

[0062] To a reaction flask, add 100 g of 5-phenoxybenzofuranone, 300 mL of toluene, 12.5 g of boron trifluoride diethyl ether, and 24.6 g of tetrabutylammonium chloride sequentially. Stir and heat to 50 °C ± 5 °C. Slowly add 157.8 g of thionyl chloride dropwise over 30 min. Continue heating to approximately 100 °C and maintain the temperature until the reactants have reacted completely. Cool to 50–70 °C and add 30 mL of n-butanol dropwise over 10 min, stirring and maintaining the temperature for 4 h. Pour the reaction mixture into 500 mL of 15% potassium bicarbonate aqueous solution, separate the layers, concentrate the organic phase, and obtain 120 g of compound III-A.

[0063] Example 7 Preparation of Compound III-B

[0064]

[0065] To a reaction flask, add 20 g of 5-phenoxybenzofuranone, 100 mL of toluene, 2.51 g of boron trifluoride diethyl ether, and 4.91 g of tetrabutylammonium chloride sequentially. Stir and heat to 50 °C ± 5 °C. Slowly add 31 g of thionyl chloride dropwise over 30 min. Continue heating to approximately 100 °C and maintain the reaction temperature until the reactants have completely reacted. Cool to 50–70 °C and add 30 mL of n-butanol dropwise over 10 min, stirring and maintaining the temperature for 4 h. Pour the reaction mixture into 500 mL of 15% potassium bicarbonate aqueous solution, separate the layers, concentrate the organic phase, and obtain 19 g of compound III-B.

[0066] Example 8 Preparation of compound IA

[0067]

[0068] To a reaction flask, 32.7 g of compound II-A, 500 mL of acetonitrile, 28 g of compound III-A, and 52 g of DIPEA were added sequentially. Nitrogen gas was then introduced to displace the mixture, and the temperature was raised to 45 °C. The mixture was stirred for 8 hours. Excess acetonitrile and DIPEA were removed by vacuum distillation. 500 mL of dichloromethane was added, and the pH of the organic phase was adjusted to 2–3 with dilute hydrochloric acid. The mixture was separated, and the organic phase was washed twice with water. The organic phase was then desolvated to obtain 50 g of compound IA with a purity of 99.8%. Compound IA... 1 See the H-NMR spectrum. Figure 1 .

[0069] Example 9: Preparation of Compound IB

[0070]

[0071] To a reaction flask, 3.27 g of compound II-A, 20 mL of acetonitrile, 9.3 g of compound III-B, and 40 mL of DMAP were added sequentially. Nitrogen gas was then introduced to displace the mixture, and the temperature was raised to 60 °C. The mixture was stirred for 5 h. Excess acetonitrile and DMAP were removed by vacuum distillation. 50 mL of ethyl acetate was added, and the pH of the organic phase was adjusted to 2–3 with dilute hydrochloric acid. The mixture was separated, and the organic phase was washed twice with water. The organic phase was then desolvated to give 5.3 g of compound IB with a purity of 99%. The composition of compound IB... 1 See the H-NMR spectrum. Figure 2 .

[0072] Example 10 Preparation of Compound IC

[0073]

[0074] To a reaction flask, 3.69 g of compound II-B, 25 mL of acetonitrile, 9.2 g of compound III-B, 1.3 g of DIPEA, and 30 mL of DMAP were added sequentially. Nitrogen gas was then introduced to displace the mixture, and the temperature was raised to 55 °C. The mixture was stirred for 7 h. Excess acetonitrile and DMAP were removed by vacuum distillation. 50 mL of ethyl acetate was added, and the pH of the organic phase was adjusted to 2–3 with dilute hydrochloric acid. The mixture was separated, and the organic phase was washed twice with water. The organic phase was then desolvated to give 5.9 g of compound IC with a purity of 98.5%. Compound IC... 1 See the H-NMR spectrum. Figure 3 .

[0075] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0076] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A roxadustat intermediate impurity, the structure of which is shown in Formula I below: wherein R1 and R2 are each independently Me, Et, i-Pr, or n-butyl.

2. A roxadustat intermediate impurity according to claim 1, characterized in that, The impurity is present in ≤0.05% of the roxadustat intermediate compound F, the structure of which is shown below: The definition of R2 is the same as that in claim 1.

3. A method of preparing Roxadustat intermediate impurity I comprising: Compounds II and III were dissolved in an organic solvent and, under a nitrogen atmosphere and a reaction temperature of 40–60 °C, a coupling reaction occurred in the presence of a base to give roxadustat impurity I. The reaction route is shown below: Where X is a halogen; R1 and R2 are each independently Me, Et, i-Pr or n-butyl.

4. The production method according to claim 3, characterized by, X is either Cl or Br.

5. The preparation method according to claim 3, characterized in that, The alkali is selected from one or more of DIPEA, DMAP, sodium carbonate, potassium carbonate, or cesium carbonate; the organic solvent is selected from one or more of toluene, DMF, DMSO, NMP, DMAP, or acetonitrile; the molar ratio of compound II to compound III is 1:1 to 3; the molar ratio of the alkali to compound II is 4 to 10:

1.

6. The preparation method according to claim 3, characterized in that, The preparation method of compound II is as follows: using compound IV and alkali metal sulfides or their hydrates as raw materials, in the presence of carbonates and catalysts, in a suitable solvent, at 90–100 °C, compound II is obtained by reaction. The reaction route is shown below: Where M is an alkali metal, and R2 is defined as in claim 1.

7. The preparation method according to claim 6, characterized in that, The alkali metal sulfide mentioned in the preparation method of compound II is selected from sodium sulfide or potassium sulfide, and the carbonate is selected from potassium carbonate, sodium carbonate or cesium carbonate.

8. The preparation method according to claim 6, characterized in that, The catalyst used in the preparation method of compound II is a mixture of Pd(pph3)2Cl2 and Ph3P, and the molar ratio of compound IV to Pd(pph3)2Cl2 and Ph3P is 1:(0.05-0.1):(0.1-0.15).

9. The preparation method according to claim 6, characterized in that, The suitable solvent described in the preparation method of compound II is selected from one or more of tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, or water.

10. The preparation method according to claim 6, characterized in that, In the preparation method of compound II, the molar ratio of compound IV to alkali metal sulfide or its hydrate is 1:1 to 1.5; the molar ratio of compound IV to carbonate is 1:2 to 3.

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