Synthesis technology of cardiovascular medicine Apabetalone

A synthetic process and cardiovascular technology, applied in cardiovascular system diseases, drug combination, organic chemistry, etc., can solve the problems of inconvenient industrial production and achieve the effect of easy industrial production, high purity and high yield

Active Publication Date: 2018-12-14
HEFEI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this process uses cesium carbonate, ammonia water, and 100°C sealed pressure-resistant tubes to react, which is inconvenient for industrial production

Method used

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  • Synthesis technology of cardiovascular medicine Apabetalone
  • Synthesis technology of cardiovascular medicine Apabetalone
  • Synthesis technology of cardiovascular medicine Apabetalone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Synthesis of N-(2,4-dimethoxyphenyl 1)-2-(oximino)acetamide:

[0030] Add 120g (0.73mol) of hydroxylamine sulfate, 90g (0.54mol) of chloral hydrate, and 200g (0.62mol) of sodium sulfate decahydrate into the reaction flask, stir thoroughly, and then add 2,4-dihydrochloride dissolved in 80ml hydrochloric acid and 60ml aqueous solution 81g (0.52mol) of methoxyaniline, heated and stirred to reflux for 2h, cooled and crystallized, suction filtered and dried to obtain 98.2g of N-(2,4-dimethoxyphenyl)-2-(oximino) Acetamide, yield 82.7%.

[0031] Synthesis of 5,6-dimethoxyisatin:

[0032]Add 400 g (4.08 mol) of concentrated sulfuric acid into the reaction flask, heat to 50°C, add 90 g (0.40 mol) of N-(2,4-dimethoxyphenyl)-2-(oximino)acetamide in batches, Control the internal temperature at 60-70°C. After adding, keep warm at 80°C for 30 minutes, pour into 10 times the reaction volume of water, let stand for 3 hours, crystallize, filter, wash with water until neutral, and recr...

Embodiment 2

[0038] Synthesis of N-(2,4-dimethoxyphenyl 1)-2-(oximino)acetamide:

[0039] Add 120g (0.73mol) of hydroxylamine sulfate, 90g (0.54mol) of chloral hydrate, and 200g (0.62mol) of sodium sulfate decahydrate into the reaction flask, stir thoroughly, and then add 2,4-dihydrochloride dissolved in 80ml hydrochloric acid and 60ml aqueous solution 81g (0.52mol) of methoxyaniline, heated and stirred to reflux for 2h, cooled and crystallized, suction filtered and dried to obtain 99.1g of N-(2,4-dimethoxyphenyl)-2-(oximino) Acetamide, yield 83.5%.

[0040] Synthesis of 5,6-dimethoxyisatin:

[0041] Add 400 g (4.08 mol) of concentrated sulfuric acid into the reaction flask, heat to 50°C, add 90 g (0.40 mol) of N-(2,4-dimethoxyphenyl)-2-(oximino)acetamide in batches, Control the internal temperature at 60-70°C, after adding, keep warm at 80°C for 30 minutes, pour into 10 times the reaction volume of water, let it stand for 3 hours, crystallize, filter, wash with water until neutral, and ...

Embodiment 3

[0047] Synthesis of N-(2,4-dimethoxyphenyl 1)-2-(oximino)acetamide:

[0048] Add 120g (0.73mol) of hydroxylamine sulfate, 90g (0.54mol) of chloral hydrate, and 200g (0.62mol) of sodium sulfate decahydrate into the reaction flask, stir thoroughly, and then add 2,4-dihydrochloride dissolved in 80ml hydrochloric acid and 60ml aqueous solution 81g (0.52mol) of methoxyaniline, heated and stirred to reflux for 2h, cooled and crystallized, suction filtered and dried to obtain 99.5g of N-(2,4-dimethoxyphenyl)-2-(oximino) Acetamide, yield 83.8%.

[0049] Synthesis of 5,6-dimethoxyisatin:

[0050] Add 400 g (4.08 mol) of concentrated sulfuric acid into the reaction flask, heat to 50°C, add 90 g (0.40 mol) of N-(2,4-dimethoxyphenyl)-2-(oximino)acetamide in batches, Control the internal temperature at 60-70°C, after adding, keep warm at 80°C for 30 minutes, pour into 10 times the reaction volume of water, let it stand for 3 hours, crystallize, filter, wash with water until neutral, and ...

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Abstract

The invention discloses a synthesis technology of a cardiovascular medicine Apabetalone, and relates to the technical field of organic synthesis of medicines. The synthesis technology comprises the following steps: with 3,5-dimethoxyaniline as a raw material, firstly performing a condensation reaction on the 3,5-dimethoxyaniline, hydroxylamine sulfate and chloral hydrate to obtain N-(2,4-dimethoxyphenyl)-2-(oximido)acetamide, then performing a cyclization reaction to obtain 5,6-dimethoxy isatin under the effect of concentrated sulfuric acid, then performing an oxidation reaction on the 5,6-dimethoxy isatin and ammonia water or ammonia gas to obtain 2-amino-4,6-dimethoxybenzonitrile in the presence of divalent copper and an oxidant, finally performing a condensation reaction on the 2-amino-4,6-dimethoxybenzonitrile and 4-(2-hydroxyethoxy)-3,5-dimethylbenzaldehyde in an organic solvent under the effect of an alkaline substance to obtain the Apabetalone. Compared with the synthesis technology recorded in the existing literature, the synthesis technology provided by the invention has the advantages as follows: the raw material is cheap and easy to obtain, a reaction condition is mild,high-temperature and high-pressure conditions are not required, the posttreatment operation is simple, a synthesis route is short, and industrial production is easy.

Description

Technical field: [0001] The invention relates to the technical field of organic synthesis of medicines, in particular to a synthesis process of cardiovascular drug Apabetalone. Background technique: [0002] Epidemiological data suggest an inverse correlation between circulating levels of high-density lipoprotein cholesterol (HDL-C) and the incidence of clinically significant atherosclerosis. A 1 mg / dL increase in HDL-C serum level is associated with a 2-3% reduction in cardiovascular risk; a 1% reduction in LDL-C is associated with a 2% reduction in coronary heart disease (CHD) risk (Gordon et al. (1997) Am.J. Med. 62, 707-714). Experimental evidence further supports the protective role of HDL-C against cardiovascular disease. For example, in subjects with low HDL-C, administration of gemfibrozil increased HDL-C levels by 6%, corresponding to a 22% reduction in CHD risk (Rubins et al. (1999) N. Engl. J. Medd .341, 410-418). Observations in genetic diseases associated wi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/91A61P9/00
CPCA61P9/00C07D239/91
Inventor 陈仕云刘慧陈俊
Owner HEFEI UNIV
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