Process Optimization Of Synthesis Of 1,2,3-triazole Letrozole-based Derivatives

We can treat hormone dependent type of breast cancer by inhibit ing the aromatase which is the key enzyme to synthesis estrogen for the postmenopausal female. It has been confirmed by a lot of researches and experiments that letrozole can act as good aromatase inhibitors and individual types of letrozole derivatives have better effects with stronger pertinence and smaller side effects than letrozole itself. In order to increase the kinds of aromatase inhibitors, and explore more kinds of breast cancer drugs with better efficacy and smaller side effects, process optimization of synthesis of 1,2,3-triazole letrozole-based derivatives was made in this dissertation.In this dissertation the target product 1,2,3-triazole letrozole-based derivatives were synthesized with small molecules by chemical method. A proper synthesis path was found which only contains four steps and photochemical method was brought in. First of all, there was a nucleophilic substitut ion reaction between 4- fluorobenzonitrile, 4- methylbenzonitrile, and t- Bu OK under the low temperature and anhydrous and anaerobic environment which kept for two hours and then the product experienced a free radical bromination under the light of an incandescent lamp. After that the product reacted with Na N3 and then turned to the target product by the classical click chemistry. To get the pure product the traditional column chromatography was replaced by the recrystallization which is more efficient and easy to operate. The yield is much higher than the domestic similar synthesis process. In the first step, the yield can be more than 50% while the yield of the similar process is only 30%. The yield of the second step is as high as more than 60% and the yie lds of the last two steps are also more than 90%. All the yie lds of the steps are higher than the known ones.The exploration and optimization of experimental conditions and operation process were made in the dissertation. The photochemical method was brought in to protect the environment. The process was simplified and the high price reagents were replaced by cheaper ones. The most suitable time for reacts was found and a process which has the advantages of low cost, high yield, mild condition of preparation method was achieved to optimize the preparation process of letrozole derivatives and increased the yield of it.