Synthesis of intermediates for the preparation of Active Pharmaceutical Ingredients (APIs)

Maytansinoids are ansa macrocycles extracted from shrubs of Maytenus ovatus. Their anticancer activity is known since the 1970s, but it could be possible to be exploited only recently, as conjugated to different antibody in the context of antibody drug conjugates (ADCs). This kind of approach allowed to drive the pharmacologically active compound (payload) selectively towards the target cancer cells, avoiding to exert the cytotoxicity also in healthy cells. Ansamitocin P3, isolated from fermentation of Actinosynnema pretiosum, is a useful precursor for the preparation of DM1, the payload present within ado-trastuzumab emtansine, commercially available as Kadcyla® for the treatment of metastatic breast cancer. To date, several methods for the synthesis of DM1 have been described in literature, all of them based on the reductive hydrolysis of ansamitocin P3 ester to the corresponding secondary alcohol maytansinol and its further functionalization. In the first section of this thesis it was described a new method to perform the reductive hydrolysis, using different methodologies with respect to the traditional in batch reaction. Moreover, a new, unprecedently reported method for the synthesis of the methyl disulfide derivative of DM1 (DM1-SMe) was developed, so that it was possible to achieve prepare the payload in a complete diastereoselective manner.