Istradefylline preparation method

A technology of istradefylline and reaction is applied in the new field of istradefylline preparation, which can solve the problems of high toxicity of methyl iodide, complicated feeding process and the like, and achieve the effects of saving organic solvent, high reaction conversion rate and reducing production amount.

Inactive Publication Date: 2019-06-25
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The disadvantage of this process is that methyl iodide is

Method used

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  • Istradefylline preparation method

Examples

Experimental program
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Effect test

Embodiment 1

[0030] In a clean and dry reaction flask, put 15.8g (0.04mol) Intermediate I, 68ml DMF, 7.8g (0.056mol) potassium carbonate, raise the temperature to 120°C, keep the reaction temperature for 30 minutes, and then add 15.6g (0.17mol) dicarbonate to it For the methyl ester, the temperature is controlled between 120°C and 140°C for 2 hours. The temperature of the reaction solution was lowered to 0-5°C, and the temperature was kept for 1 hour to crystallize. After filtration, istraphylline was obtained as light yellow needle-like crystals, 8.2 g, with a purity of 99% and a yield of 52.4%.

Embodiment 2

[0032] In a clean and dry reaction flask, put 15.8g (0.04mol) of Intermediate I, 68ml of N-methylpyrrolidone, 7.8g (0.15mol) of potassium carbonate, raise the temperature to 150°C, keep the reaction temperature for 30 minutes, and then add 5.4g ( 0.06mol) dimethyl carbonate, the temperature is controlled at 150°C for 2 hours. The temperature of the reaction liquid was lowered to 10-20°C, and the temperature was kept for 1 hour to crystallize. After filtration, itraphylline was obtained as light yellow needle-like crystals, 7.1 g, with a purity of 99% and a yield of 45.4%.

Embodiment 3

[0034] In a clean and dry reaction flask, put 15.8g (0.04mol) Intermediate I, 68ml DMF, 7.8g (0.15mol) potassium carbonate, raise the temperature to 100°C, keep the reaction temperature for 30 minutes, and then add 36.0g (0.4mol) dicarbonate to it Methyl ester, control the temperature at 100°C to react for 2 hours. The temperature of the reaction liquid was lowered to 5-10°C, and the temperature was kept for 1 hour to crystallize. After filtration, itraphylline was obtained as light yellow needle-like crystals, 7.3 g, with a purity of 99% and a yield of 46.6%.

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Abstract

The invention provides an istradefylline preparation method. 1,3-diethyl-5,6-diaminouracil used as a starting material undergoes an acylation reaction, a ring formation reaction and a methylation reaction to prepare istradefylline. The ring formation reaction and the methylation reaction are carried out simultaneously, an istradefylline intermediate (E)-1,3-diethyl-6-amino-5-(3,4-dimethoxyphenylacryloyl)aminouracil is reacted by adding a methylating agent in an alkaline environment, and the obtained solution is filtered and crystallized to obtain the istradefylline. The ring formation and themethylation are simultaneously carried out, and the methylation is immediately carried out after the completion of the ring formation to promote the forward proceeding, so the yield of the product isincreased, large amounts of organic solvents are saved, and the generation amount of an organic waste liquid is reduced; and the method has the advantages of simplicity in operation, and high reactionconversion rate, and allows the purity of the product to be higher than 99%.

Description

Technical field: [0001] The present invention relates to the field of drug synthesis, in particular to a new preparation method of istrafylline. Background technique: [0002] Itrafylline, CAS number: 155270-99-8; trade name: NOURIAST; English chemical name: 8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7- methyl-3,7-dihydro-1H-purin-2,6-dione; English name: Istradefylline, Chinese chemical name: 8-[(E)-2-(3,4-dimethoxyphenyl) vinyl ]-1,3-Diethyl-3,7-dihydro-7-methyl-1H-purine-2,6-dione; molecular formula: C 20 H 24 N 4 O 4 ; Molecular weight: 384.18. The chemical structure is as follows: [0003] [0004] Itrafylline is a selective adenosine A2a receptor antagonist developed by 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] There have been many patent applications for the preparation process of Itrafylline. The routes of JP 1997040652, US 5484920, WO940111...

Claims

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Application Information

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IPC IPC(8): C07D473/06
Inventor 吴辉李程鹏王剑平窦国华于磊石军丰宇胜
Owner SHANDONG XINHUA PHARMA CO LTD
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