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Method for preparing isoquinoline compounds

A technology of compounds and mixtures, used in organic chemistry, drug combinations, extracellular fluid diseases, etc.

Active Publication Date: 2013-12-11
FIBROGEN (CHINA) MEDICAL TECHNOLOGY DEVELOPMENT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, only the halogen and cyano substituents at the 1-position of the isoquinoline are provided

Method used

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  • Method for preparing isoquinoline compounds
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  • Method for preparing isoquinoline compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0578] Preparation of 2-(4-hydroxy-1-methyl-5-phenoxyisoquinoline-3-carboxamido)acetic acid

[0579] a) Preparation of methyl 1-((dimethylamino)methyl)-4-hydroxy-5-phenoxyisoquinoline-3-carboxylate (1b)

[0580]

[0581] A round bottom flask equipped with a thermocouple and condenser can be charged with 1a and acetic acid (approximately 7 molar equivalents ± 5%). The suspension of 1a in acetic acid can be vigorously stirred with a magnetic stirrer (note: for larger scale processing, overhead stirring should be performed). A slight excess of bis-dimethylaminomethane (approximately 1.25 molar equivalents) can then be slowly added to this mixture [Remark: The reaction is slightly exothermic, a temperature rise of 15-20°C can be observed]. After the addition is complete, the mixture can be heated to 55±5° C. for at least 8 h. The reaction can then be evaluated by HPLC. If the amount of 1a is greater than 0.5%, the reaction can be stirred for an additional 2 hours at 55±5°C a...

Embodiment 2

[0595] Preparation of 2-(4-hydroxy-1-methyl-6-phenoxyisoquinoline-3-carboxamido)acetic acid

[0596] a) Preparation of methyl 1-((dimethylamino)methyl)-4-hydroxy-6-phenoxyisoquinoline-3-carboxylate (2b)

[0597]

[0598] A round bottom flask equipped with a thermocouple and condenser can be charged with 2a and acetic acid (approximately 7 molar equivalents ± 5%). The suspension of 2a in acetic acid can be vigorously stirred with a magnetic stirrer (remark: for larger scale workup, overhead stirring should be used). A slight excess of bis-dimethylaminomethane (approximately 1.25 molar equivalents) can then be slowly added to the mixture [Remark: The reaction is slightly exothermic, a temperature rise of 15-20°C can be observed]. After the addition is complete, the mixture can be heated to 55±5° C. for at least 8 h. The reaction can then be evaluated by HPLC. If the amount of 2a is greater than 0.5%, the reaction can be stirred at 55±5°C for 2 hours and re-evaluated by HPL...

Embodiment 3

[0612] Preparation of 2-(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamido)acetic acid

[0613] a) Preparation of 5-phenoxybenzofuranone

[0614]

[0615] DMF (68Kg) was charged to the reactor and stirring was started. The reactor was then charged with phenol (51 Kg), acetylacetone (8 Kg), 5-bromobenzofuranone (85 Kg), copper bromide (9 Kg) and potassium carbonate (77 Kg). The mixture was heated above 85°C and held until the reaction was complete, then cooled. Add water. The solid was filtered and washed with water. The solid was dissolved in dichloromethane and washed with aqueous HCl and then water. The solvent was removed under pressure, and methanol was added. The mixture was stirred and filtered. The solid was washed with methanol and dried in the oven to yield 5-phenoxybenzofuranone (yield: 72%, HPLC: 99.6%).

[0616] b) Preparation of methyl 2-chloromethyl-4-phenoxybenzoate

[0617]

[0618]Toluene (24Kg) was charged to the reactor and stirring was st...

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Abstract

The invention relates to a method for preparing isoquinoline compounds and intermediate compounds obtained thereby. Such compounds can be used for preparing compounds and compositions which can reduce the activity of HIF hydroxylase enzyme, thereby improving the stability and / or activity of hypoxia inducible factors (HIF).

Description

technical field [0001] The present invention relates to a process for the preparation of isoquinoline compounds and intermediate compounds obtained therefrom. Background technique [0002] Isoquinoline compounds are known to be effective in the treatment and prevention of conditions and disorders associated with HIF, including anemia and tissue damage caused by ischemia and / or hypoxia (see e.g. Robinson et al. (2008) Gastroenterology 134(1): 145 -155; Rosenberger et al. (2008) Nephrol Dial Transplant 23(11):3472-3478). Specifically, the compounds and methods disclosed herein can be used as or for the preparation of isoquinoline compounds that inhibit the activity of HIF hydroxylase, thereby improving the stability and / or activity of hypoxia-inducible factor (HIF), which can be used For the treatment and prevention of conditions and disorders associated with HIF. [0003] To date, many synthetic routes for the preparation of substituted isoquinoline compounds have been publ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/26A61P7/06A61P39/00
CPCC07D217/26A61P39/00A61P7/06
Inventor 迈克尔·道格拉斯·汤普森朴贞玟迈克尔·P·阿伦德
Owner FIBROGEN (CHINA) MEDICAL TECHNOLOGY DEVELOPMENT CO LTD
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