Preparation method of istradefylline intermediate

A technology of istradefylline and intermediates, which is applied in the field of drug synthesis, can solve the problems of product loss and low purity, and achieve the effect of easy operation

Inactive Publication Date: 2019-06-14
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After evaporating to dryness, the product has not gone through the crystallization process, so the purity is not high. In order to improve the purity, the purification steps are added, and the product is lost.

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

[0028] In a clean and dry reaction flask, put 30g (0.15mol) of 1,3-diethyl-5,6-diaminouracil, 1200ml of dichloromethane, and 60g (0.59mol) of triethylamine into a complete solution. 15~20℃, slowly add 50g (0.22mol) (E)-3,4-dimethoxyphenylacryloyl chloride, TLC detects the reaction end point, after the reaction is complete, add 1500ml of 5% sodium carbonate solution to the reaction solution , stirred for 10 minutes to completely neutralize the generated hydrochloric acid, let stand to separate layers, and removed the lower organic layer; added 1200ml of purified water to the organic layer, cooled the reaction solution to 3-7°C, and stirred for 1 hour. The reaction solution was filtered, and the filter cake was (E)-1,3-diethyl-6-amino-5-(3,4-dimethoxyphenylacryloyl)aminouracil, 53.0g, off-white solid, The purity is greater than 98%, and the yield is 90.2%.

Embodiment 2

[0030] In a clean and dry reaction flask, put 30g (0.15mol) of 1,3-diethyl-5,6-diaminouracil, 900ml of dichloromethane, and 60g (0.60mol) of triethylamine into a complete solution. Cool down to 10°C to 15°C, slowly add 50g (0.22mol) (E)-3,4-dimethoxyphenylacryloyl chloride, TLC detects the end of the reaction, after the reaction is complete, add 600ml of 5% Sodium carbonate solution, stirred for 10 minutes to completely neutralize the generated hydrochloric acid, let stand to separate layers, and removed the lower organic layer; added 900ml of purified water to the organic layer, cooled the reaction solution to 0-2°C, and stirred for 1 hour. The reaction liquid was filtered, and the filter cake was (E)-1,3-diethyl-6-amino-5-(3,4-dimethoxyphenylacryloyl)aminouracil, 51.8g, light yellow solid, The purity is greater than 98%, and the yield is 88.1%.

Embodiment 3

[0032] In a clean and dry reaction flask, put 30g (0.15mol) of 1,3-diethyl-5,6-diaminouracil, 1500ml of dichloromethane, and 60g (0.60mol) of triethylamine into a complete solution. Adjust the temperature to 20-25°C, slowly add 50g (0.22mol) (E)-3,4-dimethoxyphenylacryloyl chloride, TLC to detect the end of the reaction, after the reaction is complete, add 2400ml of 5% Sodium carbonate solution, stirred for 10 minutes to completely neutralize the generated hydrochloric acid, let stand to separate layers, and removed the lower organic layer; added 1500ml of purified water to the organic layer, cooled the reaction solution to 10-12°C, and stirred for 1 hour. The reaction solution was filtered, and the filter cake was (E)-1,3-diethyl-6-amino-5-(3,4-dimethoxyphenylacryloyl)aminouracil, 50.9g, off-white solid, The purity is greater than 98%, and the yield is 86.6%.

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Abstract

The invention provides a preparation method of an istradefylline intermediate, namely (E)-1,3-diethyl-6-amino-5-(3,4-dimethoxyphenylacryloyl)aminoauracil. The preparation method is realized through the following steps: 1,3-diethyl-5,6-diaminouracil serves as a raw material, dichloromethane serves as a solvent, triethylamine serves as an acid-binding agent, (E)3,4-dimethoxyphenylacryloyl chloride is dropwise added slowly, reacting and acid washing are conducted, water is added for crystallization, and thus the (E)-1,3-diethyl-6-amino-5-(3,4-dimethoxyphenylacryloyl)aminoauracil is obtained. According to the preparation method, a product is promoted to precipitate from an organic layer, a reactant and a by-product can be separated effectively, the obtained istradefylline intermediate is highin purity, and operation is easy and convenient.

Description

Technical field: [0001] The present invention relates to the field of drug synthesis, in particular to istradefylline intermediate (E)-1,3-diethyl-6-amino-5-(3,4-dimethoxyphenylacryloyl) aminouria Pyrimidine preparation method. Background technique: [0002] The istradefylline intermediate (E)-1,3-diethyl-6-amino-5-(3,4-dimethoxyphenylacryloyl)aminouracil has the following chemical structure: [0003] [0004] Itraphylline is a selective adenosine A2a receptor antagonist developed by Japan Kyowa Hakko Kogyo Co., Ltd., which can be used to treat Parkinson's disease. It has a novel mechanism of action and is considered to be the best drug candidate. [0005] (E)-1,3-diethyl-6-amino-5-(3,4-dimethoxyphenylacryloyl)aminouracil (abbreviated as B) is an important intermediate in the preparation of istradefylline , JP 1997040652 is produced by the acylation reaction of 1,3-diethyl-5,6-diaminouracil (referred to as A) with 3,4-dimethoxyphenylacryloyl chloride. [0006] The proc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/545
Inventor 徐豪杰王剑平李程鹏于磊窦国华石军丰宇胜
Owner SHANDONG XINHUA PHARMA CO LTD
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