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Synthesis method of 4-aminoisoquinoline-8-methyl formate

A technology of aminoisoquinoline and isoquinolinecarboxylic acid, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of poor selectivity of nitration reaction, difficulty in large-scale production, difficulty in separation, etc., and achieves convenient operation, simple post-treatment, and good selectivity Effect

Active Publication Date: 2015-03-25
SUZHOU KANGRUN PHARMA
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Problems solved by technology

This method has the following disadvantages: (1) the selectivity of the nitration reaction is poor, and it is easy to generate the nitrated mixture of the 4-position, 5-position and 8-position, resulting in separation difficulties, and the nitration yield is only about 37%; (2) the bromination reaction mainly generates 4 -nitro-5-bromoisoquinoline, and 4-nitro-8-bromoisoquinoline is only a rare by-product, making large-scale production difficult

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  • Synthesis method of 4-aminoisoquinoline-8-methyl formate

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Embodiment 1

[0016] The synthetic method of 4-aminoisoquinoline-8-methyl carboxylate, technique is as follows:

[0017] The first step: the synthesis of methyl 8-isoquinolinecarboxylate

[0018] 5 g of palladium acetate was added to a solution of 8-bromoisoquinoline (104 g, 500 mmol) in methanol (1000 mL), and the reaction system was replaced with CO three times and reacted at 60° C. and 60 psi pressure for 8 h. After the mixture was evaporated to dryness, 500 mL of water and 1000 mL of dichloromethane were added. After the aqueous phase was separated, the organic layer was spin-dried, and the residue was washed with petroleum ether to obtain methyl 8-isoquinolinecarboxylate (90 g, 96%).

[0019] The second step: the synthesis of methyl 4-bromoisoquinoline-8-carboxylate

[0020] At 110°C, N-bromosuccinimide (57.0 g, 321 mmol) was added to a solution of methyl 8-isoquinolinecarboxylate (50 g, 267 mmol) in acetic acid (1000 mL), and the mixture was heated to reflux. After reacting for 16 h...

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Abstract

The invention provides a synthesis method of 4-aminoisoquinoline-8-methyl formate. According to the synthesis method, 8-bromoisoquinoline reacts with carbon monoxide in methanol in the presence of palladium acetate to generate 8-isoquinoline methyl formate; 8-isoquinoline methyl formate reacts with N-bromosuccinimide in acetic acid to generate 4-bromoisoqunoline-8-methyl formate; the compound reacts with tert-butyl carbamate in the presence of the palladium acetate and cesium carbonate to generate amino protected 4-t-butoxycarbonylaminoisoquinoline-8-methyl formate, and finally, the protecting group of 4-t-butoxycarbonylaminoisoquinoline-8-methyl formate is removed in a mixed solvent of hydrochloric acid and methanol to obtain 4-aminoisoquinoline-8-methyl formate. The synthesis method of 4-aminoisoquinoline-8-methyl formate is good in selectivity, high in total yield (71%), convenient to operate, simple in after-treatment and suitable for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and in particular relates to a synthesis method of methyl 4-aminoisoquinoline-8-carboxylate. Background technique [0002] 4-Aminoisoquinoline-8-carboxylic acid methyl ester is an important compound in organic synthesis and medicinal chemistry. The amino and carboxyl groups in this molecule can be used as active sites to react with many active groups to generate a series of novel organic compounds . The latest research shows that these compounds have good biological activity and have a strong effect on preventing or treating Alzheimer's disease and schizophrenia (US2013 / 0317010A1). Medicinal chemists also found that some of these molecules are also good blockers of sodium ion channels and calcium ion channels, which can be used to reduce nerve signaling pathways and thus have analgesic effects (WO2013 / 063459A1; WO2011 / 086377A1) . In recent years, linking 4-ami...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/22
CPCY02P20/55C07D217/22
Inventor 徐卫良徐炜政
Owner SUZHOU KANGRUN PHARMA
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