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Roxadustat intermediate impurity compound as well as preparation method and application thereof

A technology of roxadustat and compounds, applied in the field of drug synthesis, capable of solving problems such as unreported

Pending Publication Date: 2021-12-24
JIANGSU LONG HEALTHCARE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In view of the fact that compound I' is a key intermediate in the preparation process of roxadustat, its quality research and impurity control are very important for controlling the quality of the final product roxadustat. So far, there is no related impurity for compound I' has been reported

Method used

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  • Roxadustat intermediate impurity compound as well as preparation method and application thereof
  • Roxadustat intermediate impurity compound as well as preparation method and application thereof
  • Roxadustat intermediate impurity compound as well as preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0039] The preparation of formula I compound:

[0040] Add 10.0g (II) of methyl 1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate into a 100ml reaction flask, add 20ml of methanol, and add the previously prepared potassium hydroxide aqueous solution (8.65g of potassium hydroxide was dissolved in 20ml of water), the temperature was raised to reflux, and the temperature was kept overnight, and no raw material was detected by TLC; 5.6g of hydrochloric acid was added to adjust the pH to 7-8. The reaction solution was concentrated, 30 ml of ethyl acetate was added, 15 ml of water was added to extract and separate layers, and the ethyl acetate phase was concentrated to obtain 5.8 g of crude compound I, with a yield of 84.9% and a HPLC purity of 75.2%;

[0041] Add 5.8g of crude compound I to a 100ml three-neck flask, add 10ml of tetrahydrofuran, heat to 65°C, stir to dissolve, add dropwise 20ml of n-heptane, cool down to 0°C; filter with suction and concentrate to obtain 4.1g o...

Embodiment 2

[0043] The preparation of formula I compound:

[0044] Add 10.0g (II) of methyl 1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate into a 100ml reaction flask, add 20ml of acetonitrile, and add the previously prepared barium hydroxide aqueous solution (15.6 g of barium hydroxide was dissolved in 25 ml of water), the temperature was raised to reflux, and the temperature was kept overnight, and no raw materials were detected by TLC; 3.3 g of hydrochloric acid was added to adjust the pH to 7-8. Concentrate the reaction solution, add 30ml of ethyl acetate, add 15ml of water to extract and separate layers, concentrate the ethyl acetate phase to obtain 4.8g of compound I crude product, yield 79.0%, HPLC purity: 82.1%;

[0045] Add 4.8g of crude compound I to a 100ml three-neck flask, add 10ml of ethyl acetate, heat to 65°C, stir to dissolve, add dropwise 20ml of n-heptane, cool down to 0°C; filter with suction and concentrate to obtain the purified compound I 3.5 g, 75% recover...

Embodiment 3

[0047] The preparation of formula I compound:

[0048] Add 10.0g (II) of methyl 1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate into a 100ml reaction flask, add 20ml of methanol, and add the previously prepared potassium hydroxide aqueous solution (8.5 g of potassium hydroxide was dissolved in 15 ml of water), the temperature was raised to reflux, and the temperature was kept overnight, and no raw material was detected by TLC; 5.6 g of hydrochloric acid was added to adjust the pH to 7-8. Concentrate the reaction solution, add 30ml of ethyl acetate, add 15ml of water to extract and separate layers, concentrate the ethyl acetate phase to obtain 4.5g of compound I crude product, yield 79.0%, HPLC purity: 76.5%;

[0049] Add 4.5g of crude compound I to a 100ml three-neck flask, add 10ml of tetrahydrofuran, heat to 65°C, stir to dissolve, add dropwise 20ml of methyl tert-butyl ether, cool down to 0°C; filter with suction and concentrate to obtain purified compound I Product...

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Abstract

The invention provides a roxadustat intermediate impurity compound as well as a preparation method and application thereof, and belongs to the technical field of medicine synthesis. The structure of the compound is represented by a formula I. The preparation method comprises the preparation steps: 1, taking a compound II as a raw material, dissolving the compound II in a solvent, and obtaining a crude compound I under the action of inorganic alkali; and 2, recrystallizing the obtained crude product of the compound I to obtain the purified impurity compound I. The invention also discloses an impurity reference substance for the quality research of the rosaxostat intermediate, the impurity content in the rosaxostat intermediate can be effectively and conveniently monitored, and the quality of the rosaxostat intermediate is favorably controlled.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and relates to a roxadustat intermediate impurity compound and a preparation method and application thereof. Background technique [0002] Roxadustat (Roxadustat), its chemical name is N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinolyl)carbonyl]glycine, this product can be used for the treatment of chronic anemia The trade name is Eredro; Roxadustat Capsules is the world's first small molecule hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) drug for the treatment of renal anemia; hypoxia-inducible factor The physiological role of (HIF) is not only to increase the expression of erythropoietin, but also to increase the expression of erythropoietin receptors and proteins that promote iron absorption and circulation. The role of roxadustat is to inhibit the PH enzyme by simulating one of the substrates of prolyl hydroxylase (PH), ketoglutarate, and affect the role of the...

Claims

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Application Information

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IPC IPC(8): C07D217/24
CPCC07D217/24
Inventor 陈嘉伟杨寿海杨其龙蔡汶
Owner JIANGSU LONG HEALTHCARE
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