Preparation method of roxadustat intermediate

A technology of roxadustat and an intermediate, which is applied in the fields of organic synthesis and the preparation of raw materials, and can solve the problems of low production efficiency and the like

Pending Publication Date: 2021-07-06
SHANGHAI FAMO BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The purpose of the present invention is to overcome the defects that the existing preparation method is difficult to scale up the preparation and the production efficiency is too low, and to provide a kind of preparation roxadustat intermediate 1 with easy-to-obtain raw materials, simple process, convenient operation, low cost and higher yield -method of methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] A preparation process of m-phenoxyacetophenone (compound 10 in formula III, hereinafter referred to as compound 10), is as follows:

[0033] Take a 1L three-necked flask, add DMF 300mL, potassium carbonate (62g, 0.45mol) in turn, stir, add 3-bromoacetophenone (60g, 0.3mol), phenol (31g, 0.33mol), cuprous bromide (14.3g , 0.1mol), under nitrogen protection, heated to 80-90°C for 6 hours, followed by TLC to complete the reaction, cooled to room temperature, poured the reactant into 1kg of water, stirred, added 800mL of ethyl acetate, stood still to separate the liquid, and washed the organic phase with water (500mL×3), the organic phase was concentrated and dried under reduced pressure to obtain a yellow oil, which was distilled under reduced pressure, and fractions (1mmHg) at 145-150°C were collected to obtain compound 10 (52g, 82%) as a colorless liquid.

[0034] The prepared compound 10 1 The nuclear magnetic resonance spectra of H NMR and MS (ESI) are as follows:

...

Embodiment 2

[0040] A preparation process of m-phenoxyacetophenone (compound 10 in formula III, hereinafter referred to as compound 10), is as follows:

[0041]Take a 1L three-necked flask, add toluene 600mL, potassium hydroxide (28g, 0.5mol), stir, add 3-bromoacetophenone (50g, 0.25mol), phenol (28g, 0.30mol), copper acetate (20g, 0.1 mol), nitrogen protection, reflux reaction for 10h, TLC traced the end of the reaction, cooled to room temperature, filtered off the insoluble matter, washed the organic phase (500mL×2), concentrated and dried the organic phase under reduced pressure to obtain a yellow oil, and purified by column chromatography to obtain the compound 10 (38 g, 73%).

[0042] Its spectrogram detection result is with embodiment 1.

Embodiment 3

[0044] A preparation process of methyl 2-nitro-3,3-dimethoxypropionate (compound 11 in formula III, hereinafter referred to as compound 11), specifically as follows:

[0045] Add methyl nitroacetate (60 g, 0.5 mol) and trimethyl orthoformate (70 g, 0.66 mol) into acetic anhydride (100 g), and react at 80° C. for 12 h. Concentration under reduced pressure gave a yellow oil, which was distilled under reduced pressure, and the 110-115°C fraction (1 mmHg) was collected to obtain light yellow liquid compound 11 (39 g, 84%).

[0046] The prepared compound 11 1 The nuclear magnetic resonance spectrum of H NMR is as follows:

[0047] 1 H NMR (400MHz, CDCl 3 )δ5.79-5.66(m,1H),5.10-5.17(m,1H),3.66(s,3H),3.41(s,6H).

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Abstract

The invention discloses a preparation method of a roxadustat intermediate, which comprises the following steps of: firstly, reacting methyl nitroacetate with trimethyl orthoformate to obtain a product I, and performing catalytic hydrogenation reduction to obtain a product II; then reacting the product II with m-phenoxyacetophenone to obtain a product III; carrying out a Pomeranz-Fritsch reaction on the product III, and completing intramolecular ring closing to obtain a product IV; finally, carrying out an oxidation reaction on the product IV to obtain the roxadustat intermediate 1-methyl-4-hydroxy-7-phenoxy isoquinoline-3-methyl carboxylate. According to the preparation method of the roxadustat intermediate, the raw materials are easy to obtain, and the production cost can be remarkably reduced. The whole process is simple, the whole consumed time is short, the production efficiency is high, the yield is high, the reaction condition is mild, the post-treatment is simple and convenient, and the method is suitable for large-scale preparation and has a great application prospect.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis and preparation of raw materials, and relates to a preparation method of a roxadustat intermediate, in particular to a key intermediate 1-methyl of roxadustat used for the treatment of renal anemia A new method for the preparation of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate. Background technique [0002] Roxadustat (code name FG-4592) is a drug used in the treatment of renal anemia, especially for the treatment of anemia caused by chronic kidney disease (CKD) in patients receiving dialysis, and is jointly developed by AstraZeneca and Developed by FibroGen, it was first marketed in China and Japan in 2018 and 2019, respectively, and the drug's marketing applications in Europe and the United States are under preparation. Oral drug Roxadustat Capsules is the first small molecule hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) developed in the world to treat rena...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/26
CPCC07D217/26
Inventor 唐家邓王小梅茆勇军王金刚唐家闰
Owner SHANGHAI FAMO BIOTECH CO LTD
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