Preparation method of drug for chronic anemia

A synthetic method and compound technology, which is applied in the field of medicine and chemical industry, can solve the problems of difficult process amplification, long overall route, and low total yield, and achieve the effects of high product purity, reduced process cost, and high total yield

Active Publication Date: 2018-08-21
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Generally speaking, the overall route of these several synthetic methods of roxadustat is too long, and the total yield is low, and the introduction of methyl on the isoquinoline in the step all needs to use more expensive methylation reagents and precious metal palladium catalysts, and the cost is very high. It is difficult to scale up high technology, and it is still necessary to find a method with simple process route, low cost and suitable for industrial production

Method used

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  • Preparation method of drug for chronic anemia
  • Preparation method of drug for chronic anemia
  • Preparation method of drug for chronic anemia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046]

[0047]Add compound 1a (27.23g, 100mmol) and dichloromethane (136mL) into reaction flask A, stir and dissolve, slowly drop into thionyl chloride (17.85g, 150mmol), reflux reaction for 4-6 hours, and distill under reduced pressure to When no distillate flowed out, dichloromethane (136 mL) was added and vortexed twice, and tetrahydrofuran (136 mL) was added to dissolve for later use. Add compound formula 2a (27.99g, 120mmol), anhydrous magnesium chloride (11.43g, 120mmol) and tetrahydrofuran (120mL) into the three-necked flask B, stir well, cool to -10~0°C in an ice-salt bath, add three Ethylamine (13.15 g, 130 mmol) was stirred at an internal temperature of -10 to 0°C for 60 minutes. Then slowly drop the acid chloride solution prepared in flask A into reaction flask B, and then slowly raise the temperature to 25-30°C to react for 6-8 hours. After the reaction, cool the reaction solution to 0-5°C, and slowly add saturated chlorine Ammonium chloride quenched the react...

Embodiment 2

[0049]

[0050] Add compound 1b (28.63g, 100mmol) and dichloromethane (143mL) into reaction flask A, stir and dissolve, slowly add thionyl chloride (17.85g, 150mmol) dropwise, reflux for 4-6 hours and then rotary evaporate to no Distillate flowed out, added dichloromethane (143mL) and vortexed twice, added acetonitrile (143mL) to dissolve and set aside. Add compound formula 2b (29.67g, 120mmol), anhydrous magnesium chloride (11.43g, 120mmol) and acetonitrile (120mL) into the three-necked flask B, stir evenly, cool to -10~0°C in an ice-salt bath, and add two Isopropylethylamine (16.80 g, 130 mmol) was stirred at an internal temperature of -10 to 0°C for 60 minutes. Then slowly drop the acid chloride solution prepared in flask A into reaction flask B, and then slowly raise the temperature to 25-30°C to react for 6-8 hours. After the reaction, cool the reaction solution to 0-5°C, and slowly add saturated chlorine Quench the reaction with ammonium chloride (143mL), add water (...

Embodiment 3

[0052]

[0053] Add compound 1c (30.03g, 100mmol) and dichloromethane (150mL) into reaction flask A, stir and dissolve, slowly add thionyl chloride (17.85g, 150mmol) dropwise, reflux reaction for 4 to 6 hours, and then rotary evaporate to no Distillate flows out, add dichloromethane (150mL) and swirl twice, add dichloromethane (150mL) to dissolve and set aside. Add compound formula 2b (29.67g, 120mmol), anhydrous magnesium chloride (11.43g, 120mmol) and dichloromethane (150mL) into the three-neck flask B, stir well, and cool to -10~0℃ in an ice-salt bath, under nitrogen protection Diisopropylethylamine (16.80 g, 130 mmol) was added, and the mixture was stirred for 60 minutes at an internal temperature of -10 to 0°C. Then slowly drop the acid chloride solution prepared in flask A into reaction flask B, and then slowly raise the temperature to 25-30°C to react for 6-8 hours. After the reaction, cool the reaction solution to 0-5°C, and slowly add saturated chlorine Ammonium c...

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Abstract

The invention discloses a synthesis method for a drug Roxadustat for chronic anemia. The synthesis method comprises the following steps: hydrolyzing and acidifying a compound shown as a formula 6 under the action of alkali to obtain a key intermediate compound shown as a formula 7; carrying out condensation reaction on the compound shown as the formula 7 and carbonyl diimidazole under suitable conditions to obtain an intermediate compound shown as a formula 8, and separating or not separating the compound shown as the formula 8 from a system to directly take part in subsequent reaction; and finally, reacting the product with glycine to obtain a final product Roxadustat shown as a formula 9. The preparation method has the advantages that the route efficiency is improved, the process cost isreduced, side products are reduced and the purity of a final product is favorably improved (The formula is shown in the description), wherein R2 in the compound shown as the formula 6 represents alkyl, and includes but not limited to methyl, ethyl, isopropyl, tertiary butyl or benzyl.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a chemical synthesis method of an intermediate and a raw material medicine of roxadustat for treating chronic anemia. Background technique [0002] Roxadustat (FG-4592) is an oral small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase. The drug was developed by the American non-Brogan company, and was later licensed by Astellas and AstraZeneca. Phase III clinical trials are currently underway. It is used to treat anemia associated with chronic kidney disease and end-stage renal disease. , with great market prospects. [0003] The chemical name of roxadustat is: N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline)carbonyl]glycine, and its structural formula is as follows: [0004] [0005] PCT patent WO2004108681 reported the synthetic route of roxadustat intermediate and preparation of roxadustat, using 4-nitrophthalonitrile as the starting mate...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/26
CPCC07D217/26
Inventor 郑旭春张一平
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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