Method preparing temozolomide in one-pot mode and refining method of temozolomide

Abstract

The invention discloses a method preparing temozolomide in a one-pot mode and further discloses a refining method of temozolomide. The refining method of temozolomide omits a rectification separation step of methyl isocyanate, and reduces the contacting times of temozolomide with the outside environment, thereby improving safety in the production process. By adjusting using quantities of a reaction substrate and a solvent, on the condition that the reaction steps are omitted, high yield of temozolomide can still be maintained. By screening various reaction conditions, the method achieves synthesis of temozolomide by one-pot boiling, and not only is production cost reduced, but also the industrialized mass production method is provided for production of temozolomide. Simultaneously, the improved refining method of temozolomide is adopted, recrystallization operation of temozolomide is effectively simplified, the recrystallization yield is remarkably improved, operation time for recrystallization is effectively shortened, and accordingly the whole production cycle is remarkably shortened.

Description

technical field [0001] The invention relates to a novel method for preparing temozolomide in one pot; the invention also relates to a refining method of temozolomide. Background technique [0002] Temozolomide (Temozolomide) chemical name 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-1,2,3,5-tetrazine-8-amide, is a Alkylating anticancer drugs, used for the treatment of adult refractory glioblastoma multiforme, is a new anticancer drug for the treatment of glioma and malignant melanoma. It was initiated by Can research ventures in the UK and developed by Schering-Plough. It was approved by the FDA on August 11, 1999 and launched in the United States. [0003] Temozolomide has the following structure: [0004] [0005] J.Med.Chem.1984, 27, 196-201 provides a classic method for synthesizing temozolomide: converting 5-amino-1H-imidazole-4-carboxamide (Aka, AIC, the same below) into Aka Diazonium salt (DIC, the same below), and then cyclization reaction with methyl isocyanate (M...

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Problems solved by technology

However, in this invention, the methyl isocyanate produced by the reaction still needs to be purified by rectification. This step inevitably increases the possibility of methyl isocyanate leaking to the external environment, and the safety of its production will inevitably decrease. ; Not only that, this method needs methyl isocyanate to be rectified and purified first, and then reacted, and the process route is still complicated, and the production cost increases thereupon. Therefore, this patented method is not suitable for large-scale production of temozolomide, and can only be used as a chemical Experimental small test

[0008] As we all know, the chemical experiment small test is the development stage of the process route, which can be used to clarify the synthetic process route, as well as obtain a yield and calculate the approximate cost. There are no special requirements, and there is no need to consider economic benefits; however, during chemical production, the amount of feed increases significantly, which is more than a thousand times that of the small test, and the original various subtle reactions are also enlarged, coupled with the limitations of industrial production conditions ( Such as uneven stirring, slow mass transfer and heat transfer rate, etc.), and other problems that are difficult to meet in small tests, make it difficult to grasp the amount of raw materials and production conditions in large-scale industrial production, which may eventually lead to a significant reduction in the yield of the final product, or even unavailable final product

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