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Preparation method of isoquinolinone compound

A compound and methylation technology, which is applied in the field of preparation of isoquinolinone compounds, can solve the problems of high equipment requirements, unfavorable industrial production, long reaction route, etc.

Active Publication Date: 2021-07-16
JIANGSU CHUANGUO PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, in the existing preparation technology of roxadustat, the reaction route often needs to be reacted under low temperature, high temperature, and airtight pressurized conditions. Many, lead to follow-up purification difficulty, make the productive rate and the purity of the synthetic roxadustat low, in addition, the existing synthetic method needs expensive catalyst, thus is unfavorable for industrialized production

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  • Preparation method of isoquinolinone compound
  • Preparation method of isoquinolinone compound
  • Preparation method of isoquinolinone compound

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preparation example Construction

[0199] The preparation method of formula 2 compound

[0200] The present invention provides a kind of preparation method of the compound of formula 2 described in the present invention, described method comprises steps:

[0201] (i) the compound of formula b is reacted with a methylating reagent to obtain the compound of formula 2;

[0202]

[0203] In a preferred example of the present invention, in the step (i), the methylation reagent includes (but not limited to): tert-butanol peroxide, acetaldehyde and peroxide mixture, or a combination thereof.

[0204] In another preferred example, the peroxide includes (but not limited to): hydrogen peroxide, tert-butyl alcohol peroxide, di-tert-butyl peroxide, or a combination thereof.

[0205] In another preferred example, the peroxide is hydrogen peroxide.

[0206] In another preferred example, in the mixture of acetaldehyde and peroxide, the molar ratio of acetaldehyde to peroxide is 1-20:1, preferably 1-15:1, More preferably...

Embodiment 1

[0298]

[0299] 4-Hydroxy-7-phenoxyisoquinoline-3-formic acid methyl ester (compound of formula 1a-1) (10g, 33.9mmol) and acetic acid (100ml) were mixed, slowly added dropwise the sulfuric acid of ferrous sulfate (68mmol) Aqueous solution (dissolve ferrous sulfate in 100ml of water, add 50ml of concentrated sulfuric acid dropwise under ice bath to obtain sulfuric acid aqueous solution of ferrous sulfate), then cool down to -25°C and add acetaldehyde (340mmol), control temperature -25°C~-15°C , add hydrogen peroxide (68mmol) dropwise, then control the temperature at -15°C to -5°C for 3h, TLC plate detection reaction is complete, add sodium thiosulfate aqueous solution to stir, add dichloromethane to extract, concentrate the organic phase to obtain 4-hydroxy- 9.5 g of methyl 1-methyl-7-phenoxyisoquinoline-3-carboxylate (compound of formula 2a-1), yield 90.7%, purity 98.1% as determined by HPLC.

[0300] 1 HNMR(400MHz,DMSO)δ12.10(s,1H),8.30(d,J=9.0Hz,1H),7.62(d,J=2.3Hz,1H),7....

Embodiment 2

[0303]

[0304]Mix 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid phenyl ester (compound of formula 1a-2) (12.1g, 33.9mmol) with 121ml of acetic acid and 121ml of tetrahydrofuran, and slowly add ferrous sulfate (68mmol) dropwise Aqueous solution of sulfuric acid (dissolve ferrous sulfate in 100ml of water, add 50ml of concentrated sulfuric acid dropwise under ice bath to obtain aqueous sulfuric acid solution of ferrous sulfate), then cool down to -25°C, control temperature -25°C~-15°C and add peroxide After the tert-butanol (135.6mmol) was dropped, the temperature was controlled at -15°C to -5°C for 3 hours, and the TLC plate detected that the reaction was complete, adding aqueous sodium thiosulfate solution and stirring, adding dichloromethane for extraction, and concentrating the organic phase to obtain 4-hydroxy- 10.8 g of methyl 1-methyl-7-phenoxyisoquinoline-3-carboxylate (compound of formula 2a-2), yield 85.9%, purity 97.8% as determined by HPLC.

[0305] 1 HNMR(4...

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Abstract

The invention relates to a preparation method of an isoquinolinone compound. Specifically, the method for preparing the compound shown in the formula 2 comprises the step that a compound shown in a formula b reacts with a methylation reagent to obtain the compound shown in the formula 2. The method provided by the invention is used for preparing the isoquinolinone compound (such as Roxadustat), and has the excellent effects of reasonable route, convenience, feasibility, high yield, high purity, suitability for industrial production and the like.

Description

technical field [0001] The application relates to the field of medicinal chemistry, in particular to a preparation method of isoquinolinone compounds. Background technique [0002] Isoquinolinone compounds have excellent effects in treating renal anemia, for example, roxadustat is a first-line drug for treating renal anemia. [0003] Roxadustat, chemical name [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, molecular formula: C 19 h 16 N 2 o 5 , molecular weight: 352.11, CAS number: 808118-40-3, chemical structural formula: [0004] [0005] Roxadustat is a disease developed by FibroGen for the treatment of renal anemia, and it was applied for marketing in China in November 2017. The drug is the world's first small-molecule hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) drug developed for the treatment of renal anemia. The physiological role of hypoxia-inducible factor (HIF) not only increases the expression of erythropoie...

Claims

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Application Information

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IPC IPC(8): C07D217/26
CPCC07D217/26Y02P20/55
Inventor 焦宁朱占群宋彦彬孙国峰邢贺吴欣超
Owner JIANGSU CHUANGUO PHARMA CO LTD
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