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Novel method for preparing entacapone

A technology of entacapone and a compound is applied in the field of preparing catechol-O-methyltransferase inhibitor entacapone, and can solve the problems of low isomer purity, low yield, environmental hazards and the like , to achieve the effect of reducing industrial waste acid wastewater, simple operation and low cost

Inactive Publication Date: 2013-06-05
SHANGHAI AOBO PHARMTECH INC LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This route is relatively short, but there are also many defects: firstly, the starting material undergoes nitration reaction under the action of mixed acid containing nitric acid, which will produce a large amount of waste acid waste water, causing serious harm to the environment; secondly, the product entacapone E The / Z isomer ratio is not high, only about 3 / 1, and the patent does not report a method for isomer separation
Although this route can prepare relatively pure entacapone, there are also many defects: first, a large amount of mixed acid is still used during nitration, thereby producing a large amount of waste acid waste water; secondly, highly toxic dimethyl sulfate is required; In addition, the route has long steps and high cost, which is also unfavorable for industrialized production.
However, such a process not only has long steps, but also the purity of isomers is not high, and the yield is not high.
[0011] Therefore, the various defects existing in the prior art have limited the preparation of entacapone (I) on an industrial scale.

Method used

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Embodiment 1

[0040] The synthesis of embodiment one 3-methoxy group-4-hydroxyl group-5-nitrobenzaldehyde (Ⅲ)

[0041]Add 1.52 kg of vanillin (II), 8 L of acetic acid and 3.54 kg of calcium nitrate tetrahydrate into the reaction flask, and react at room temperature for 20 hours. The reaction solution was concentrated. To the residue, add 5 L of water, stir for 2 hours, filter, wash the filter cake with 2 L of water, and dry to obtain 1.65 kg of yellow solid as 3-methoxyl-4-hydroxyl-5-nitrobenzaldehyde (Ⅲ), The yield is 84%.

Embodiment 2

[0042] Embodiment two 3, the synthesis of 4-dihydroxyl-5-nitrobenzaldehyde (Ⅳ)

[0043] Add 1.65kg of compound (Ⅲ) prepared in Example 1, 3.2L of pyridine and 16L of acetonitrile into the reaction flask, control the temperature at 0-10°C, add 1.2kg of aluminum chloride in batches, raise the temperature to 50°C, and react for 10 hours . The solvent was concentrated, and the residue was poured into a mixture of 15 L of ice water and hydrochloric acid (1:1). A large amount of solids were precipitated, and the mixture was stirred for 2 hours. After suction filtration, the filter cake was washed with 2 L of water, and dried to obtain 1.38 kg of yellow solid as 3,4-dihydroxy-5-nitro-benzaldehyde (IV), with a yield of 90%.

Embodiment 3

[0044] The synthesis of embodiment three entacapone piperidine salt (Va)

[0045] Add 1.38kg of compound (Ⅳ) prepared in Example 2, 1.26kg of N,N-diethylcyanoacetamide, 704g of piperidine, 4L of ethyl acetate, and 4L of n-heptane into the reaction flask, and heat to reflux to separate water , After reacting for 10 hours, the raw material reacted completely, cooled to room temperature, stirred for 2 hours, filtered, the filter cake was washed with a small amount of ethyl acetate / n-heptane=1 / 1 solvent, and dried to obtain 2.62kg red solid as entacapone Piperidinium salt (Va), yield 89%, HPLC purity 99.0%, Z-isomer 0.1%.

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Abstract

The invention discloses a novel method for preparing entacapone (I) of which the purity is more than 99.9 percent and the Z-isomer content is 0.01 percent. The method comprises the following steps of: carrying out a nitratlon reaction between vanillin (II) and nitrate so as to generate 3-methoxy-4-hydroxy-5-nitrobenzaldehyde (III), performing a demethylation reaction on the compound (III) to generate 3,4-bihydroxy-5-nitro-benzaldehyde (IV), reacting the compound (IV) with N,N-diethylcyanoacetamide to generate entacapone salt (V) in the presence of organic base (B), and dissociating the compound (V) to generate entacapone (I) under the acid function. The route is low in cost, easy to operate and environment-friendly and is suitable for industrial production, and the product yield and purity are greatly improved.

Description

technical field [0001] The invention relates to a new method for preparing catechol-O-methyltransferase inhibitor Entacapone. The method is environmentally friendly, simple and efficient, and suitable for large-scale industrial production. Background technique [0002] Entacapone (I), the English name is Entacapone, the trade name is Kedan, 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 Orion Pharma 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 mostly occurs 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...

Claims

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Application Information

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IPC IPC(8): C07C255/41C07C253/30C07C205/44C07C201/08
Inventor 陈欢生陈宇
Owner SHANGHAI AOBO PHARMTECH INC LTD
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