Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Preparation method of roxadustat

A compound and selected technology, applied in organic chemistry, bulk chemical production, etc., can solve problems such as excessive three wastes, production existence, and separation difficulties

Active Publication Date: 2019-09-24
SHANGHAI PHARMA GRP QINGDAO GROWFUL PHARMA CO LTD
View PDF9 Cites 6 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] It is reported in the international patent application WO2013013609 (patentee: Zhejiang Betta Pharmaceutical Co., Ltd.) that using 4-nitrophthalonitrile as the raw material, this synthetic route will produce isomerism when synthesizing the oxazole ring solid, difficult to separate, and need to be purified by column chromatography; in the chlorination process, the method of using highly toxic phosphine oxychloride for chlorination does not meet the currently advocated "green synthesis" route (i.e. low toxicity, low pollution chemical synthesis) will be eliminated; in the methylation process, trimethylboron is selected as the methylation reagent, and the reaction reagents of this method are expensive and are not suitable for industrial production
[0005] It is reported in the international patent application WO2014014834 (patentee: FibroGen., Inc.), using methyl 4-hydroxyl-7-phenoxyisoquinoline-3-carboxylate as raw material, this synthetic route, in the second The first step will produce a variety of impurities, separation and purification are relatively difficult, and there are many three wastes, and the recycling process is more troublesome; in the third and fourth steps, special equipment-autoclaves are used, the cost of industrial production is high, and the risk is relatively high
[0006] It is reported in the patent CN104892509A (patentee: Suzhou Mingrui Pharmaceutical Technology Co., Ltd.) that tyrosine is used as a raw material. In this route, the etherification reaction easily generates amino substitutions, which brings difficulties to purification, and introduces phenolic hydroxyl groups. Sometimes hydrogen peroxide is used for oxidation, which brings safety hazards to industrial production
[0007] It is reported in the patent CN106478504A (patentee: Shanghai Xunhe Medical Technology Co., Ltd.) that 1-(3-phenoxyphenyl)ethylamine is used as the raw material. In the ring-closing step, the reaction temperature is above 190°C. Industrial production conditions are difficult to achieve, and there are safety hazards in production
[0008] 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of roxadustat
  • Preparation method of roxadustat
  • Preparation method of roxadustat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0166] Compound I-1 produces compound II-1

[0167]

[0168] Into a 100mL three-necked flask, add 30mL of water and 2.4g of sodium hydroxide, stir to dissolve, then add 30mL of methanol and 5.90mL of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (compound I-1) g, incompletely soluble. Heat to reflux for 8h, then lower to 0-10°C, add 1N hydrochloric acid to adjust pH=2-3, stir for 0.5h. After suction filtration, the filter cake was washed with 20 mL of water and 20 mL of methanol, and dried in vacuum to obtain 5.04 g of a white solid. Yield: 90%. MS(+): m / z 282.26(M+1); NMR data ( 1H NMR, TFA-d, 400MHz): δppm 9.035 (1H, s, CH), 8.838-8.861 (1H, d, J = 9.2Hz, CH), 8.153-8.182 (1H, dd, J = 2.4Hz, CH ),7.729-7.734(1H,d,J=2.0Hz,CH),7.601-7.640(2H,t,J=8Hz,CH),7.459-7.495(1H,t,J=7.2Hz,CH),7.269 -7.289 (2H,t,J=8Hz,CH).

Embodiment 2

[0169] Embodiment 2 compound II-1 generates compound III-1

[0170]

[0171] Into a 250 mL three-necked flask, add 80 mL of dichloromethane, 15.62 g of compound II-1, 12.48 g of PyBOP, 2.92 g of tert-butylamine and 7.75 g of N,N-diisopropylethylamine, stir until incompletely dissolved, and leave overnight at room temperature. Suction filtration, add 80mL of water to the filtrate, separate layers, wash the organic layer with 1N hydrochloric acid 2×40mL, wash with saturated sodium bicarbonate 2×40mL, wash with pure water 40mL, and spin dry to obtain a white solid. Add 56mL of methanol for beating, filter with suction, and vacuum-dry the filter cake to obtain 5.1g of light yellow solid, yield: 75.8%. MS(+):m / z337.38(M+1); NMR data ( 1 H NMR, CDCl 3 ,400MHz): δppm 13.593(1H,s,OH),8.423(1H,s,CH),8.355-8.377(1H,d,J=8.8Hz,CH),8.004(1H,s,NH),7.436- 7.508(3H,q,CH),7.237-7.285(2H,q,CH),7.139-7.158(2H,d,J=7.6Hz,CH),1.556(9H,s,-C(CH) 3 ).

Embodiment 3

[0172] Embodiment 3 compound III-1 generates compound IV-1

[0173]

[0174] Into a 100mL three-neck flask, add 35mL of dichloromethane and 13.36g of compound III-1, dissolve it, add 1.72g of 1,3-dibromo-5,5-dimethylhydantoin, stir and heat to reflux for 6h. Cool down to 0-10°C, filter with suction, spin dry the filtrate to obtain 3.5 g of light red solid, yield: 84.3%. MS(+):m / z 416.28(M+1); NMR data ( 1 H NMR, CDCl 3 ,400MHz): δppm13.593(1H,s,OH),8.353-8.376(1H,d,J=9.2Hz,CH),7.667(1H,s,NH),7.647-7.653(1H,d,J= 2.4Hz, CH), 7.449-7.513 (3H, q, CH), 7.287 (1H, s, CH), 7.143-7.167 (2H, q, CH), 1.549 (9H, s, -C (CH) 3 ).

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention relates to a process for the preparation of roxadustat, namely [(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)amino]acetic acid. The preparation method is low cost, simple in method and good in safety, and is suitable for industrial 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] Nordrestat is a synthetic isoquinoline derivative, hypoxia-inducible factor proline hydroxylase inhibitor (HIF-PHI) through the regulation of proline hydroxylase (PHD) on hypoxia-inducible factor (HIF) The hydroxylation of HIF inhibits the degradation of HIF protein and maintains the biological function of HIF. A variety of HIF-PHIs are currently in clinical trials, and the preliminary results are relatively satisfactory. EPO blood concentration monitoring found that after using a small amount of HIF-PHI, the EPO level was only 2-3 times normal, while the hemoglobin level increased steadily. At the same time, with the change of hemoglobin, the blood pressure d...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D217/26
CPCC07D217/26
Inventor 杨满勋谢建树陆世红夏广新刘彦君
Owner SHANGHAI PHARMA GRP QINGDAO GROWFUL PHARMA CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com