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An improved process for the preparation of 2-amino-N-tert-butyl-2-cyanoamide hydrochlorie.

Bożenna Cichy ,  Krzysztof Gabarski ,  Łukasz S. Kaczmarek ,  Monika Kosińska ,  Grzegorz Lipner ,  Marta Łaszcz ,  Wojciech Łuniewski 

Pharmaceutical Research Institute (IF), Rydygiera 8, Warszawa 01-793, Poland


Non commercially available 2-amino-N-tert-butyl-2-cyanoamide hydrochloride is the one of the two reagents used in the synthesis of 5-amino-N-tert-butyl-1-methylcarbamoyl imidazole-4-carboxamide. This compound is a key starting material in the straightforward synthesis of temozolomide, an oral alkylating agent which can be used for the treatment of an aggressive brain tumor or some forms of skin cancer [Figure 1].

Figure 1

Known from the literature two-step synthesis of 2-amino-N-tert-butyl-2-cyanoamide hydrochloride is based on a reaction of (diphenylmethylene)-aminoacetonitrile with tert-butyl isocyanate in the presence of potassium tert-butoxide and THF as a solvent followed by purification of the product and further acid hydrolysis which removes diphenylmethylene protecting group from the nitrogen. Unfortunately there are many drawbacks for using procedure described above, like non environmental friendly solvents. This process is also time and energy consuming. Furthermore the yield and purity of such obtained product are not satisfying.

Our invention provides an improved route for the preparation of 2-amino-N-tert-butyl-2-cyanoamide hydrochloride with high yield (72-80%) and very high purity (>99.5%, HPLC). Instead of a solution of the base, solid potassium tert-butoxide is used in the reaction with tert-butyl isocyanate in dichloromethane as a solvent. Moreover further hydrolysis in the presence of hydrogen chloride is carried out without the purification of the intermediate and both reactions with tert-butyl isocyanate and hydrolysis are done in the same solvent. Simultaneously the idea of the presented innovation is also to simplify technological operations by reducing the amount of toxic solvents, wastes, time and energy which is crucial for multi-scale synthesis.


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Submitted: 2012-03-25 22:34
Revised:   2012-04-02 09:31