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Method for preparing isoquinolinone compound

A compound, selected technology, applied in the direction of organic chemistry, etc., can solve the problems of harsh reaction conditions, difficult purification, and many side reactions.

Pending Publication Date: 2021-04-20
SHANGHAI DESANO CHEM PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] 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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  • Method for preparing isoquinolinone compound
  • Method for preparing isoquinolinone compound
  • Method for preparing isoquinolinone compound

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preparation example Construction

[0129] The preparation method of the isoquinolinone compound of formula 4 structure

[0130] The present invention provides a method for preparing a compound of formula 3, specifically, the method comprises the steps of:

[0131] The compound of formula 3 is converted by active metal catalysis to obtain the compound of formula 4;

[0132]

[0133] where R 0 Is H, C1-C10 alkyl or C6-C10 aryl;

[0134] R 1 and R 2 independently C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, C6-C10 aryl-C1-C10 alkyl-, or R 1 and R 2 and the nitrogen atom connected to it together form a 3-10 membered heterocycloalkyl group, and the 3-10 membered heterocycloalkyl group contains 1-2 (preferably 1 or 2) N atoms and 0-2 ( Preferably 0, 1 or 2) are selected from O and S heteroatoms.

[0135] In another preferred embodiment, wherein R 0 is H or methyl.

[0136] In another preferred example, R1 and R2 are independently methyl or benzyl, or R1 and R2 together with the nitrogen atom connected to...

Embodiment 1

[0214]

[0215] 1) Add methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (20g, 68mmol) into acetonitrile, slowly add DBU (20.7g, 136mmol) dropwise, then add glycine (7.66g, 102mmol) , the temperature was raised to 50° C. for 6 h, the reaction was detected by TLC plate, cooled to room temperature, and filtered. Dilute the filtrate with water, adjust the pH to weak acidity, stir and crystallize, filter and dry the material to obtain 22g of (4-hydroxyl-7-phenoxyisoquinoline-3-carboxamido)acetic acid, the yield is 95.6%, and the purity determined by HPLC is 98.4%. 1 H-NMR (400MHz, CDCl 3 ): δ12.85(s,1H),8.48–8.37(m,2H),8.34(d,J=9.0Hz,1H),7.52–7.37(m,3H),7.23(d,J=7.4Hz, 1H), 7.15–7.08 (m, 2H), 4.28 (d, J=5.8Hz, 2H); MSm / z (ESI): 339 (M+1).

[0216] 2) (4-hydroxyl-7-phenoxyisoquinoline-3-carboxamido)acetic acid (2.2g, 6.5mmol) and acetic acid were mixed, then slowly added tetramethylmethanediamine (13mmol), the reaction After the system was replaced with argon, the tempera...

Embodiment 2

[0219]

[0220] 1) Add methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (20g, 68mmol) into DMSO, slowly add TEA (13.7g, 136mmol) dropwise, then add glycine (10.2g, 136mmol) , the temperature was raised to 65° C. for 6 h, the reaction was detected by TLC plate, cooled to room temperature, and filtered. Dilute the filtrate with water, adjust the pH to weak acidity, stir and crystallize, filter and dry the material to obtain 21.5 g of (4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)acetic acid, the yield is 93.5%, and the purity is determined by HPLC was 97.9%.

[0221] 2) Mix (4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)acetic acid (2.2g, 6.5mmol) and trifluoroacetic acid, slowly add tetrabenzylmethylenediamine (26mmol), argon After replacement, the temperature was raised to 100° C. for 3 h, and TLC detected that the reaction was complete, and the resulting reaction system did not need to be treated, and was directly carried out to the next step. A small amount of the ...

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Abstract

The invention provides a method for preparing an isoquinolinone compound. Specifically, the invention provides a method for preparing a compound as shown in a formula 4, and the method comprises the step of carrying out catalytic conversion on a compound as shown in a formula 3 through active metal to obtain the compound as shown in the formula 4. The method disclosed by the invention has the excellent technical effects of reasonable route, convenience, feasibility, high preparation yield and purity, suitability for industrial production and the like.

Description

technical field [0001] The present application relates to the field of medicinal chemistry, in particular to a method for preparing isoquinolinone compounds. Background technique [0002] 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: [0003] [0004] 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 erythropoietin, but also increases the expression of erythropoietin receptor and proteins that promote iron absorption and circulation. Roxadustat inhibits PH e...

Claims

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Application Information

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IPC IPC(8): C07D217/26
CPCY02P20/55
Inventor 焦宁朱占群孙国峰宋彦彬邢贺吴欣超
Owner SHANGHAI DESANO CHEM PHARMA
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