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Preparation method of roxadustat intermediate IV

A technology for roxadustat and intermediates, which is applied in the field of preparation of roxadustat intermediate IV, can solve the problems of unsuitability for large-scale production, unfavorable industrial amplification, and high equipment requirements, and achieve improved safety factor, low cost, The effect of simple and easy-to-obtain raw materials

Inactive Publication Date: 2021-02-19
天津掌心医药科技有限公司
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

[0024] Aiming at the deficiencies of the prior art, the present invention provides a method for preparing roxadustat intermediate IV, which solves the eighth step reaction of introducing a methyl group in the patent WO2004108681, which requires the use of environmentally sensitive reagents n-butyllithium and The poisonous reagent methyl iodide is not suitable for large-scale production; patent WO2013013609 introduces the process of introducing methyl using Suzuki reaction, uses palladium catalyst and highly flammable gas trimethylborane, which is not conducive to industrial scale-up; patent WO2014014834 introduces the seventh step of methyl The reaction requires palladium-carbon-hydrogen to reduce acetate, which is a special reaction and has high requirements for equipment; although the patent CN104892509 introduces methyl in advance, the second step requires a high temperature of 173 degrees, which requires high equipment. In the fifth step, there are safety problems in using hydrogen peroxide

Method used

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  • Preparation method of roxadustat intermediate IV
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  • Preparation method of roxadustat intermediate IV

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preparation example Construction

[0052] This embodiment is a preparation method of roxadustat intermediate IV, and its preparation includes the following steps:

[0053] Step 1. Intermediate II is obtained by addition of 4-bromophthalic anhydride (compound I) and methyl Grignard reagent: Step 2. Intermediate II is first reduced by sodium borohydride, and then cyclized under acidic conditions to form Intermediate III: Step 3, intermediate III and phenol undergo aryl alkylation reaction to obtain roxadustat intermediate IV, such as figure 1 .

[0054] In addition: the present invention also proposes following subsidiary technical scheme:

[0055] In the preparation process of intermediate II, the methyl Grignard reagent used in the anhydride ring-opening reaction process is methylmagnesium bromide or methylmagnesium chloride, preferably methylmagnesium bromide;

[0056] In the preparation process of intermediate II, the reaction temperature is controlled at -10~5°C during the ring-opening reaction of the acid ...

Embodiment 1

[0064] Example 1: Preparation of intermediate II (4-bromo-2-acetylbenzoic acid), such as image 3 .

[0065] Add 4-bromophthalic anhydride I (45.4g, 200mmol) and tetrahydrofuran (180mL), 0.1eq. cuprous iodide to the three-necked flask, stir to dissolve, cool to -10~0°C and switch nitrogen gas 3 times under vacuum , under the protection of nitrogen, slowly drop methylmagnesium chloride tetrahydrofuran solution (2.0M, 110mL) into the reaction bottle, keep it warm for 2-4h after the drop, after the reaction, add 1mol / L dilute hydrochloric acid (440mL) to quench the reaction , the aqueous phase was extracted twice with ethyl acetate (180mL), the combined organic phase was washed once with saturated brine (180mL), dried over anhydrous sodium sulfate, concentrated and recrystallized with a mixed solvent of petroleum ether ethyl acetate to obtain intermediate II ( 39.5g, 81.27%).

[0066] MS m / z 244 [M+H]+ 1H-NMR (400Hz, CDCl3-d6) δ1.90 (s, 3H), 7.70-7.77 (m, 3H).

Embodiment 2

[0067] Example 2: Preparation of intermediate III [3-methyl-5-bromoisobenzofuran-1(3H)-one], such as Figure 4 .

[0068] Add 5% sodium hydroxide solution (120g) and 4-bromo-2-acetylbenzoic acid II (36.45g, 150mmol) into the three-necked flask, stir at room temperature for 1h, cool down to 0~10°C, add hydroboration in batches Sodium (6.8g), after the addition was complete, stirring was continued for 3h. After the reaction is complete, add dichloromethane, adjust the pH to 2 with 6mol / L hydrochloric acid, stir well, let it stand for layering, separate liquids, extract the aqueous phase twice with dichloromethane, combine the organic phases, and wash with 5% carbonic acid Wash with sodium hydrogen solution until neutral, wash once with purified water, and dry over anhydrous magnesium sulfate. Filtration and distillation under reduced pressure gave an oily liquid, which was recrystallized from ethyl acetate to give Intermediate III (25.88g, 76.04%).

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Abstract

The invention discloses a preparation method of a roxadustat intermediate IV. The method comprises the following steps: 1, carrying out addition reaction on 4-bromo-phthalic anhydride (compound I) anda methyl Grignard reagent to obtain an intermediate II; 2, carrying out sodium borohydridereduction on the intermediate II first, and then, carrying outcyclization under an acid condition to obtain an intermediate III; and 3, carrying out an aryl alkylation reaction on the intermediate III and phenol to obtain the roxadustat intermediate IV. According to the preparation method of the roxadustat intermediate IV, the raw materials are simple and easy to obtain, a plurality of suppliers exist in China, and the cost is low; and methyl is introduced in advance, the methyl introduction process is mild in reaction condition, hydrogenation special reaction, ultralow temperature and other dangerous unit operation reactions are avoided, and the method is more suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine production, in particular to a preparation method of roxadustat intermediate IV. Background technique [0002] The chemical name of Roxadustat is N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline)carbonyl]glycine, and its structural formula is: [0003] [0004] Roxadustat (Roxadustat) is an oral hypoxia-inducible factor (HIF) proline hydroxylase inhibitor originally developed by FibroBen in the United States and currently co-developed with AstraZeneca. It is mainly used for the treatment of chronic anemia. On December 17, 2018, the National Medical Products Administration (NMPA) approved the listing of a new class 1 drug, Roxadustat Capsules (trade name: Arizhuo). [0005] The key technical routes for preparing roxadustat mainly contain the following five methods: [0006] Method 1): The original research company disclosed the following preparation methods (WO2004108681A1, CN102718708A, CN1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/88
CPCC07D307/88
Inventor 杨明波王玉健章志明侯庆伟王二敬
Owner 天津掌心医药科技有限公司
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