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Preparation method for removing methyl impurities from istradefylline

A technology for istradefylline and demethylation, which is applied in the field of synthesis of istradefylline demethylation impurities, can solve problems such as shortages, and achieve the effects of high impurity purity, high efficiency, and high yield

Active Publication Date: 2021-08-13
江苏华阳制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The purpose of the present invention is to provide a method for preparing istradefylline demethylated impurities with simple preparation process, high yield and high product purity, so as to provide qualified impurities for the quality control of istradefylline raw materials and preparations Reference substance, solve the problem of impurity shortage in the market, and improve the quality monitoring level of istradefylline

Method used

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  • Preparation method for removing methyl impurities from istradefylline
  • Preparation method for removing methyl impurities from istradefylline
  • Preparation method for removing methyl impurities from istradefylline

Examples

Experimental program
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Effect test

Embodiment 1

[0044] Preparation of 8-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-1,3-diethyl-7-methylpurine-2,6-dione, the compound of formula I method, including the following steps:

[0045] Heat 10g istradefylline, 30g hydrobromic acid aqueous solution (mass fraction 48%), and 2mL water to 120°C (±5°C), the system is dissolved, and the reaction is monitored by TLC (developer: V (petroleum ether) / V (Ethyl acetate) = 1 / 8, Rf (Itraphylline) = 0.8, Rf (I) = 0.6), react for 3~4h and cool down to 0°C~10°C, stir and crystallize, filter, and use for filter cake After rinsing with an appropriate amount of water, blow air at 50°C (±2°C) and dry to constant weight to obtain 7.6g of the crude product of formula I;

[0046] Take 7.6g of the crude product of the above formula I, 22mL of N'N-dimethylformamide, stir and heat up to 85°C~90°C, add 12mL of water dropwise, after dropping, cool down to 20°C~30°C, stir and crystallize for 12h, filter, The filter cake was rinsed with an appropriate amount of water...

Embodiment 2

[0057]8-[(E)-2-(3-Hydroxy-4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methylpurine-2,6-dione (Formula II ) and 8-[(E)-2-(3-methoxy-4-hydroxyphenyl)vinyl]-1,3-diethyl-7-methylpurine-2,6-dione (formula III) Preparation method:

[0058] Take 4g (11.2mmol) of the compound of formula I, 25mL of dichloromethane (DCM), 2.2g of potassium carbonate (16.1mmol), add 2.38g of iodomethane (16.8mmol), and react at 25~30°C for 12~13h. Monitor the reaction by TLC (developing solvent: V (dichloromethane) / V (methanol) = 15 / 1, Rf (I) = 0.4~0.5, Rf (II) = 0.7, Rf (III) = 0.6), the reaction is over After filtering, the filtrate was concentrated under reduced pressure and the solvent was evaporated (concentration conditions: water bath temperature 30°C, pressure -0.1MPa) to obtain 3.9g concentrate;

[0059] Take 3 g of the above-mentioned concentrate, add 18 mL of methanol for ultrasonic dissolution, filter out a little insoluble matter, and separate according to the liquid phase separation method in ...

Embodiment 3

[0061] The preparation method of formula II and formula III compound, comprises the following steps:

[0062] Add 12g (33.6mmol) of the compound of formula I, 78mL N,N-dimethylformamide (DMF), 6.7g potassium carbonate (48.4mmol), and add 7.15g iodomethane (50.4mmol) in three batches. React at 30°C for 4.5~5h, during which the reaction can be monitored by TLC (developer: V (dichloromethane) / V (methanol)=15 / 1, Rf(I)=0.4~0.5, Rf(II)=0.7, Rf(III)=0.6), after the reaction, concentrated under reduced pressure to remove the solvent (concentration conditions: water bath temperature 55°C, pressure -0.1MPa), and obtained 25.1g of yellow oil;

[0063] Add 250mL tetrahydrofuran to the above oil, stir and heat up to 50~55°C, continue to stir for 0.5h, then concentrate the filtrate under reduced pressure (concentration conditions: water bath 45°C, pressure -0.1MPa) to obtain 14.1g of concentrate;

[0064] Take 5g of the above-mentioned concentrate, add 30mL of methanol for ultrasonic disso...

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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation and purification method for removing methyl impurities from istradefylline. Istradefylline is used as a raw material to prepare three high-purity demethylated impurity compounds I, II and III, the method is simple in process, easy to operate, simple in purification and high in yield, the prepared impurities are high in purity, and qualified impurity reference substances can be provided for quality control of istradefylline. The istradefylline impurity reference substance prepared by the invention can provide an important reference basis for monitoring the impurity in the research and development of an istradefylline process, improves the quality monitoring level of istradefylline, and has great significance and practical value for the development of medicinal istradefylline.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a synthesis method for demethylating impurities of istradefylline. Background technique [0002] Itradefylline (Istradefylline), the chemical name is 8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methylpurine- The structural formula of 2,6-diketone, istradefylline is: [0003] [0004] Itraphylline is a new anti-Parkinson's disease drug developed by Japan's Kyowa Hakko Kogyo Co., Ltd. It can selectively block the adenosine A2a receptor in the brain, and it can be combined with levodopa or selective D1 and D2 receptor agonists , can enhance the antiparkinsonian effect of these dopamine drugs. The drug was approved for marketing in Japan in March 2013. [0005] The type and content of impurities in the drug have a great impact on the efficacy and safety of the drug. Therefore, a comprehensive analysis of the drug impurity profile must be carried o...

Claims

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Application Information

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IPC IPC(8): C07D473/06
CPCC07D473/06
Inventor 徐进徐天阳车东汤怀松
Owner 江苏华阳制药有限公司
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