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A kind of preparation method of Nordrestat

A methylation and compound technology, which is applied in the preparation of [amino]acetic acid and the field of Nordrestat, can solve the problems of expensive reagent protection and deprotection steps, and achieve low requirements for reaction equipment, easy availability of raw materials, and product purity high effect

Active Publication Date: 2021-06-22
SHANGHAI PHARMA GRP QINGDAO GROWFUL PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although several methods for the preparation of Nordrestat have been reported in the prior art, most of them have one or more disadvantages, such as involving the use of special equipment, expensive reagents and a large number of protection and deprotection steps

Method used

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  • A kind of preparation method of Nordrestat
  • A kind of preparation method of Nordrestat
  • A kind of preparation method of Nordrestat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Compound I generates Compound II

[0038]

[0039]Into a 100mL three-necked flask, add 60mL of methanol and 2.95g of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (compound I), lower the stirring temperature to 0-10°C, add 1,3-di Bromo-5,5-dimethylhydantoin 1.57g, slightly exothermic. Heat to reflux for 6h, then lower to 0-10°C, filter with suction, rinse the filter cake with 20mL of methanol, and dry in vacuo to obtain 3.0g of light yellow solid, yield: 81%.

[0040] NMR data ( 1 H NMR, CDCl 3 ,400MHz): δppm 11.793(1H,s,OH),8.398-8.420(1H,d,J=8.8Hz,CH),7.683(1H,s,CH),7.558-7.560(1H,m,CH), 7.532-7.555(1H,m,CH),7.466-7.504(2H,m,CH),7.286-7.312(1H,m,CH),7.160-7.181(2H,d,J=8.4Hz,CH),4.093 (3H,s,CH 3 ).

[0041] Compound II generates Compound III

[0042]

[0043] Under the protection of nitrogen, in a 20L three-necked flask, add 6.6L of ethylene glycol methyl ether, 367g of compound II, 176g of methyl boric acid, 766g of tripotassium phosphate, 1326g of...

Embodiment 2

[0054] Compound I generates Compound II

[0055]

[0056] Into a 100mL three-necked flask, add 60mL of methanol and 2.95g of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (compound I), lower the stirring temperature to 0-10°C, add 1,3-di Chloro-5,5-dimethylhydantoin 1.1g, slightly exothermic. Heat to reflux for 6h, then lower to 0-10°C, filter with suction, rinse the filter cake with 20mL of methanol, and dry in vacuo to obtain 2.8g of off-white solid, yield: 85%.

[0057] NMR data ( 1 H NMR, CDCl 3 ,400MHz): δppm 11.667(1H,s,OH),8.299-8.322(1H,d,J=9.2Hz,CH),7.744-7.751(1H,d,J=2.8Hz,CH),7.558-7.593( 1H, m, CH), 7.462-7.501 (2H, m, CH), 7.277-7.314 (2H, m, CH), 7.157-7.177 (2H, d, J=8.0Hz, CH), 4.090 (3H, s ,CH 3 ).

[0058] Compound II generates Compound III

[0059]

[0060] Under nitrogen protection, into a 250mL three-necked flask, add DMF 30mL, compound II 3.3g, add sodium iodide 0.3g, methyl boric acid 1.76g, K 2 CO 3 4.1g, 15g of purified water and...

Embodiment 3

[0071] Compound I generates Compound II

[0072]

[0073] Into a 100mL three-neck flask, add 60mL of dichloromethane and 2.95g of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (compound I), lower the stirring temperature to 0-10°C, add N-iodo Substituting succinimide 2.7g, slightly exothermic. Heat to reflux for 7 hours, then lower to 0-10°C, filter with suction, rinse the filter cake with 20 mL of dichloromethane, spin dry, and perform column chromatography (ethyl acetate:petroleum ether=1:10) to obtain 2.0 g of a white solid, Yield 47.5%.

[0074] NMR data ( 1 H NMR, CDCl 3 ,400MHz): δppm 11.772(1H,s,OH),8.347-8.369(1H,d,J=8.8Hz,CH),7.560-7.566(1H,d,J=2.4Hz,CH),7.471-7.524( 3H, m, CH), 7.285-7.296 (1H, m, CH), 7.163-7.185 (2H, m, CH), 4.089 (3H, s, CH 3 ).

[0075] Compound II generates Compound III

[0076]

[0077] Under nitrogen protection, into a 250mL three-necked flask, add DMF 30mL, compound II 4.21g, methyl boric acid 1.76g, K 2 CO 3 4.1g, 15g of...

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Abstract

The invention relates to a preparation method of nordrestat, namely [(4-hydroxyl-1-methyl-7-phenoxyisoquinoline-3-formyl)amino]acetic acid. The preparation method is low in cost, simple in method and good in safety, and is suitable for industrialized production.

Description

technical field [0001] The present invention relates to the field of organic chemistry and medicinal chemistry, specifically, the present invention relates to a kind of Nordrestat, namely [(4-hydroxyl-1-methyl-7-phenoxyisoquinoline-3-formyl) The preparation method of amino] acetic acid. Background technique [0002] As a synthetic isoquinoline derivative, hypoxia-inducible factor proline hydroxylase inhibitor (HIF-PHI) regulates the hydroxylation of hypoxia-inducible factor (HIF) by proline hydroxylase (PHD) , Inhibit the degradation of HIF protein and maintain the biological function of HIF. [0003] Nordrestat (Roxadustat, V), namely [(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl)amino]acetic acid, code-named FG-4592, is produced by the American phenanthrene A small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase, developed by FibroGen and licensed to Astellas and AstraZeneca. As a first-in-class new oral drug, Nordrestat is currently in Pha...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/26
CPCC07D217/26Y02P20/55
Inventor 杨满勋刘文丽魏宪明王勇宋悦凯
Owner SHANGHAI PHARMA GRP QINGDAO GROWFUL PHARMA CO LTD