Preparation method of istradefylline intermediate

A technology of istradefylline and intermediates, which is applied in the field of preparation of istradefylline, a drug for treating Parkinson's disease, can solve problems such as unfavorable scale-up of production, and achieve the effects of economical raw materials, convenient process operation, and high quality

Active Publication Date: 2015-01-07
南京恒道医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this method requires the use of high temperature and

Method used

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  • Preparation method of istradefylline intermediate
  • Preparation method of istradefylline intermediate
  • Preparation method of istradefylline intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Take a clean 5000ml three-neck flask, pour 485ml of 1,4-dioxane, then pour 960ml of 1mol / L NaOH aqueous solution, and then add accurately weighed (E)-1,3-diethyl-6 amino - 100g (0.258mol) of 5-(3,4-dimethoxyphenylacryloyl)aminouracil, heat in an oil bath, raise the temperature to 110°C until reflux occurs, stir mechanically for 1 hour, and avoid the three-necked flask during the reaction. Light, HPLC to monitor the progress of the reaction. After the reaction, the temperature was lowered to about 60°C, and the reaction solution was transferred to a 5L single-necked bottle for rotary evaporation under reduced pressure at 60°C, and the rotary evaporation was stopped when a large amount of yellow solid appeared in the bottle. Transfer the paste after rotary steaming to a 5L single-necked bottle cooled with ice packs and ice water, and slowly add concentrated hydrochloric acid dropwise to adjust the pH value to 2. Suction filter the acid-adjusted paste, add about 100ml of ...

Embodiment 2

[0029] Take a clean 5000ml three-neck flask, pour 970ml of 1,4-dioxane, then pour 1920ml of 1mol / L NaOH aqueous solution, and then add accurately weighed (E)-1,3-diethyl-6 amino - 100g (0.258mol) of 5-(3,4-dimethoxyphenylacryloyl)aminouracil, heat in an oil bath, raise the temperature to 115°C until reflux occurs, stir mechanically for 2 hours, and avoid the three-necked flask during the reaction. Light, HPLC to monitor the progress of the reaction. After the reaction, the temperature was lowered to about 60°C, and the reaction solution was transferred to a 5L single-necked bottle for rotary evaporation under reduced pressure at 70°C, and the rotary evaporation was stopped when a large amount of yellow solid appeared in the bottle. Transfer the paste after rotary steaming to a 5L single-necked bottle cooled with ice packs and ice water, and slowly add concentrated hydrochloric acid dropwise to adjust the pH value to 2. Suction filter the acid-adjusted paste, add about 100ml o...

Embodiment 3

[0032] Take a clean 10000ml three-neck flask, pour 1450ml of 1,4-dioxane, then pour 2880ml of 1mol / L NaOH aqueous solution, and then add accurately weighed (E)-1,3-diethyl-6 amino - 100g (0.258mol) of 5-(3,4-dimethoxyphenylacryloyl)aminouracil, heat in an oil bath, raise the temperature to 125°C until reflux occurs, stir mechanically for 4 hours, and avoid the three-necked flask during the reaction. Light, HPLC to monitor the progress of the reaction. After the reaction, the temperature was lowered to about 60°C, and the reaction solution was transferred to a 5L single-necked bottle for rotary evaporation under reduced pressure at 80°C, and the rotary evaporation was stopped when a large amount of yellow solid appeared in the bottle. Transfer the paste after rotary steaming to a 5L single-necked bottle cooled with ice packs and ice water, and slowly add concentrated hydrochloric acid dropwise to adjust the pH value to 2. The paste that has adjusted acid is suction filtered, a...

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PUM

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Abstract

The invention relates to a preparation method of an istradefylline intermediate, which comprises the following steps: by using (E)-1,3-diethyl-6-amino-5-(3,4-dimethoxyphenylacryloyl)amino-uracil (YQ-1) as a raw material and 1,4-dioxane as a solvent, heating under the alkaline condition of a NaOH water solution to perform condensation and cyclization to generate (E)-8-[2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-3,7-dihydro-1H-purinyl-2,6-dione (YQ-2), and carrying out rotary evaporation, acid regulation and vacuum filtration to obtain a YQ-2 crude product; and by using toluene as a solvent, recrystallizing the YQ-2 crude product to obtain the YQ-2 refined product. The method has the advantages of simple route, accessible raw materials and mild conditions, and is convenient to operate; the total yield is greater than 85%, and the purity is up to higher than 97%; and thus, the method is suitable for scale-up production.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to (E)-8-[2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-3,7-dihydro-1H - Purine-2,6-dione and its preparation method, the compound can be used to prepare the drug istradefylline for treating Parkinson's disease. Background technique [0002] Parkinson's disease is a progressive and incurable disease. Although there are drugs that can slow down the symptoms of the disease and slow down the course of the disease, there is still a lack of effective preventive drugs. The current treatment of this disease is mainly based on dopamine replacement therapy, the most commonly used are dopamine-mimicking drugs, including levodopa and direct or indirect dopamine receptor agonists. Although levodopa is the main drug for the treatment of Parkinson's, due to its poor tolerance and many adverse reactions, such as vomiting, involuntary movement and dyskinesia, and its curative effect is reduced after...

Claims

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Application Information

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IPC IPC(8): C07D473/06
CPCC07D473/06
Inventor 陶义华陈端腾段亚洲
Owner 南京恒道医药科技股份有限公司
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