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Synthetic method for temozolomide and intermediate

A technology of temozolomide and its synthesis method, which is applied in the field of high-efficiency synthesis, can solve problems such as difficult control of reaction conditions, low reaction yield, and high toxicity of MIC, and achieve the effects of low cost, simple process route, and high purity

Active Publication Date: 2014-03-12
SINOPHARM A THINK PHARMA
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Problems solved by technology

However, due to the high toxicity of MIC and the difficulty in controlling the reaction conditions, it is not easy to transport, which brings certain difficulties to production.
In WO2008038031, lithium chloride and sodium nitrite are used for ring closure, which avoids the use of toxic reagent methyl isocyanate, but the reaction yield is still not high

Method used

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  • Synthetic method for temozolomide and intermediate
  • Synthetic method for temozolomide and intermediate
  • Synthetic method for temozolomide and intermediate

Examples

Experimental program
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Embodiment 1

[0026] The preparation of embodiment 1 temozolomide

[0027] Preparation of step A intermediate 2

[0028]

[0029] In a 5 L three-neck round bottom flask equipped with a thermometer, add 5-aminoimidazole-4-carboxamide in sequence A (80g, 634.32 mmol), dichloromethane (1920 mL), triethylamine (176.82 mL, 1268.63 mmol)), stirred at 25°C for 10 minutes, lowered the temperature of the reaction system below 0°C, after 10 minutes, drop Add 4-nitrophenyl chloroformate (255.71 g, 1268.36 mmol) dissolved in 1280 mL of dichloromethane, react at below 0 °C for 4 hours, then control the temperature at 25 °C for 18 hours . The reaction solution was suction-filtered with a Buchner funnel, and the obtained filter cake was beaten and washed with 1000 mL of dichloromethane and 200 ml of water mixture for 1 hour, then suction-filtered again, the filter cake was washed with dichloromethane, and dried at room temperature to obtain a yellow solid product. Yield: 92%, melting point: ...

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Abstract

The invention discloses a modified optimized synthetic method for temozolomide and an intermediate thereof. The synthetic method is characterized in that a new oxidation ring-closing reagent is introduced for a reaction with lithium chloride and sodium nitrite in an aqueous solution, and the synthetic method helps to improve the yield of the reaction, increase the controllability on the reaction and avoid usage of methyl isocyanate with relatively high toxicity.

Description

technical field [0001] The invention relates to a high-efficiency synthesis method of an antitumor drug temozolomide. Background technique [0002] Temozolomide, whose chemical name is 3-methyl-8-aminocarbonyl-imidazo[5,1-d]-1,2,3,5-4(3H)-one, is a kind of A new drug with good curative effect; it has high bioavailability, can be taken orally, easily penetrates the blood-brain barrier, has no superimposed toxicity compared with other drugs, and has a wider anti-tumor spectrum. At present, temozolomide is a better anticancer drug for the treatment of glioma and malignant melanoma. [0003] The conventional synthesis method of temozolomide is to react 5-amino-1H-imidazole-4-carboxamide or its hydrochloride with sodium nitrite, diazotization, and then react with methyl isocyanate (MIC). Temozolomide (see J. Med. Chem., 1984, 27, 196-201 and Chem. Commun., 1994, 1687-1688). However, due to the high toxicity of MIC and the difficulty in controlling the reaction conditions, it i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D233/90
CPCC07D233/90C07D487/04
Inventor 不公告发明人
Owner SINOPHARM A THINK PHARMA
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