Preparation method of roxadustat key intermediate

An intermediate, m-phenoxyacetophenone technology, applied in the preparation of ethyl 1-methyl-7-phenoxyisoquinoline-3-carboxylate, the key intermediate field of roxadustat, can solve Expensive and other issues

Active Publication Date: 2022-02-08
TIANJIN LISHENG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The reagents used (Pd(OAc)2, DPEPhos, etc.) are expensive

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Add 2.41 g (0.01 mol) m-phenoxyacetophenone derivative 1, 0.15 g (2.5 mol%) dichloro(pentamethylcyclopentadienyl) Rhodium (III) dimer, 1.68 g (0.02 mol) of methyl propiolate, 1.64 g (0.02 mol) of sodium acetate, and 20 ml of tert-butanol were added, and the temperature was raised to reflux, and the reaction was continued for 24 h. After the TLC detection reaction was finished, the reaction solution was down to room temperature, 20 ml of water was added to the reaction solution, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride and water successively, dried over anhydrous sodium sulfate, concentrated, The obtained concentrate was recrystallized from ethyl acetate and n-hexane, and dried to obtain 2.04 g of roxadustat intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylate, with a yield of 69.7%.

Embodiment 2

[0046]Add 2.41 g (0.01 mol) m-phenoxyacetophenone derivative 1, 0.15 g (2.5 mol%) dichloro(pentamethylcyclopentadienyl) Rhodium (III) dimer, 1.68 g (0.02 mol) of methyl propiolate, 1.96 g (0.02 mol) of potassium acetate, and 20 ml of tert-butanol were added, and the temperature was raised to reflux, and the reaction was continued for 24 hours. After the TLC detection reaction was finished, the reaction solution was down to room temperature, 20 ml of water was added to the reaction solution, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride and water successively, dried over anhydrous sodium sulfate, concentrated, The obtained concentrate was recrystallized from ethyl acetate and n-hexane, and dried to obtain 2.09 g of roxadustat intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester, with a yield of 71.2%.

Embodiment 3

[0048] Add 2.41 g (0.01 mol) m-phenoxyacetophenone derivative 1, 0.15 g (2.5 mol%) dichloro(pentamethylcyclopentadienyl) Rhodium (III) dimer, 1.68 g (0.02 mol) of methyl propiolate, 3.34 g (0.02 mol) of silver acetate, and 20 ml of tert-butanol were added, and the temperature was raised to reflux, and the reaction was continued for 24 h. After the TLC detection reaction was finished, the reaction solution was down to room temperature, 20 ml of water was added to the reaction solution, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride and water successively, dried over anhydrous sodium sulfate, concentrated, The obtained concentrate was recrystallized from ethyl acetate and n-hexane, and dried to obtain 2.44 g of roxadustat intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester, with a yield of 83.2%.

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Abstract

The invention relates to a preparation method of a roxadustat key intermediate. The method is characterized in that an m-phenoxyacetophenone derivative and methyl propiolate are used as starting materials and are subjected to cyclization reaction under the catalysis of a catalyst, so that a roxadustat intermediate, namely, 1-methyl-7-phenoxyisoquinoline-3-methyl formate is synthesized. The synthesis route simplifies the introduction mode of isoquinoline C-1 methylation, and has the characteristics of simple process, convenience in operation, no need of column chromatography purification, high yield and the like.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and relates to a method for synthesizing pharmaceutical intermediates, more specifically, the key intermediate of roxadustat, i.e. ethyl 1-methyl-7-phenoxyisoquinoline-3-carboxylate Preparation. [0002] Background technique [0003] The chemical name of Roxadustat is: N -[(4-Hydroxy-1-methyl-7-phenoxy-3-isoquinoline)carbonyl]glycine, the chemical structure of Roxadustat is as follows: [0004] [0005] The core structure of roxadustat [0006] Roxadustat (Roxadustat) is a new small molecule hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) developed by FibroGen in the United States. It is clinically used to treat anemia associated with chronic kidney disease and end-stage renal disease. Roxadustat can affect HIF, increase the content of hemoglobin, increase the absorption and utilization of iron, so as to achieve the purpose of treating anemia. A...

Claims

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Application Information

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IPC IPC(8): C07D217/26
CPCC07D217/26
Inventor 石亮亮张瑜张杰霍志甲姜根华姚媛璐
Owner TIANJIN LISHENG PHARM CO LTD
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