New preparation method of (2E)-2-cyano-3-(3,4-dihydroxy-5-nitrobenzene)-N,N-diethyl-2-acrylamide

A technology of diethyl cyanoacetamide and acrylamide, which is applied in the preparation of carboxylic acid nitriles, chemical instruments and methods, and the preparation of organic compounds. It can solve the problems of many steps, low yields, and complicated operations, and meet the reaction conditions. Mild, high yield, short reaction time

Active Publication Date: 2011-07-13
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The method includes three steps of condensation, salt formation and

Method used

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  • New preparation method of (2E)-2-cyano-3-(3,4-dihydroxy-5-nitrobenzene)-N,N-diethyl-2-acrylamide
  • New preparation method of (2E)-2-cyano-3-(3,4-dihydroxy-5-nitrobenzene)-N,N-diethyl-2-acrylamide
  • New preparation method of (2E)-2-cyano-3-(3,4-dihydroxy-5-nitrobenzene)-N,N-diethyl-2-acrylamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Add 38.0 grams of compound (II), 34.8 grams of compound (III), 19.4 grams of piperidine, 150 milliliters of ethyl acetate, and 150 milliliters of n-heptane into a 1000 milliliter three-necked reaction flask in sequence, heat to reflux to separate water, and react for 6 hours Afterwards, the raw material reacted completely, cooled to room temperature, stirred for 2 hours, filtered, and the filter cake was washed with a small amount of ethyl acetate / n-heptane=1 / 1 solvent, dried to obtain 75.3 grams of entacapone piperidine salt (IV), Yield 93%.

[0034] HPLC purity 99.2%, Z-isomer 0.1%.

[0035] Suspend the above 75.3 grams of compound (IV) in 400 milliliters of isopropanol, add 23.2 grams of glacial acetic acid in 400 milliliters of distilled aqueous solution dropwise, keep the temperature at 40-50 ° C, after the addition is complete, continue to stir for 2 hours, cool Stir at room temperature for 1 hour, filter, the filter cake is washed successively with 100 millilite...

Embodiment 2

[0038] Add 38.0 grams of compound (II), 34.8 grams of compound (III), 19.4 grams of piperidine, 150 milliliters of isopropyl acetate, and 150 milliliters of n-hexane into a 1000 milliliter three-necked reaction flask in sequence, heat to reflux to separate water, and react for 6 hours Afterwards, the raw material reacted completely, cooled to room temperature, stirred for 2 hours, filtered, and the filter cake was washed with a small amount of isopropyl acetate / n-hexane=1 / 1 solvent, dried to obtain 72.8 grams of entacapone piperidine salt (IV), Yield 90%.

[0039] HPLC purity 98.9%, Z-isomer 0.2%.

[0040] Suspend the above 72.8 grams of compound (IV) in 400 milliliters of isopropanol, add 22.4 grams of glacial acetic acid in 400 milliliters of distilled aqueous solution dropwise to the system, keep the temperature at 40-50 ° C, after the addition, continue to stir for 2 hours, cool Stir at room temperature for 1 hour, filter, the filter cake is washed successively with 100 m...

Embodiment 3

[0043] Add 38.0 grams of compound (II), 34.8 grams of compound (III), 19.4 grams of piperidine, 100 milliliters of ethyl acetate, 100 milliliters of n-heptane, and 100 milliliters of isopropanol into a 1000 milliliter three-necked reaction flask, and heat to reflux Water was separated, and after 8 hours of reaction, the raw materials were completely reacted, cooled to room temperature, stirred for 2 hours, filtered, and the filter cake was washed with a small amount of ethyl acetate / n-heptane / isopropanol=1 / 1 / 1 solvent, dried to obtain 72.1 Keentacarbone piperidine salt (IV), yield 89%.

[0044] HPLC purity 99.0%, Z-isomer 0.1%.

[0045] Suspend the above 72.1 grams of compound (IV) in 400 milliliters of isopropanol, add 22.2 grams of glacial acetic acid in 400 milliliters of distilled aqueous solution dropwise, keep the temperature at 40-50 °C, after the addition is complete, continue to stir for 2 hours, cool Stir at room temperature for 1 hour, filter, the filter cake is wa...

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Abstract

The invention discloses a new method for preparing (2E)-2-cyano-3-(3,4-dihydroxy-5-nitrobenzene)-N,N-diethyl-2-acrylamide (I) of which purity is more than 99.9% and Z-isomer content is 0.01%. The method is as follows: 3,4-dihydroxy-5-nitrobenzaldehyde (II) performs condensation with N,N-diethylcyanoacetamide (III) in the presence of mixed solvent and alkali (B) to obtain entacapone salt (IV), and the obtained compound (IV) performs acid dissociation in proper solvent to obtain entacapone (I) with pure enantiomers. The method disclosed by the invention has high yield, environmental friend and mild reaction conditions and is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of catechol-O-methyltransferase inhibitor Entacapone (Entacapone). The method is simple and efficient, and is suitable for large-scale industrial production. Background technique [0002] Entacapone (I), the English name is Entacapone, the trade name is Ke Dan, Comtan, the chemical name is (2E)-2-cyano-3-(3,4-dihydroxy-5-nitrobenzene)- N, N-diethyl-2-acrylamide is an anti-Parkinson's disease drug developed by OrionPharma in Finland, which was first launched in the United States in 1999. Parkinson's disease (Parkinson's, PD), also known as Parkinson's paralysis, is a chronic and disabling neurological disease that occurs mostly in the elderly. Entacapone as an adjuvant to levodopa / carbidopa therapy in the treatment of Parkinson's disease. It is an effective peripheral selective COMT inhibitor, which can prolong the elimination half-life of levodopa by 33%, and increase the bioavailability by 35%, thereby ...

Claims

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Application Information

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IPC IPC(8): C07C255/41C07C253/30
Inventor 卢玉华陈欢生陈宇竺伟甘立新马大为
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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