Rogaratinib

The evolution of the synthesis of a benzothiophene‐2‐yl‐boronic acid ‐ a key building block for the anti‐cancer agent Rogaratinib ‐ is reported from multi‐gram scale to industrialization. The pitfalls and learnings during process development are outlined, describing the optimization of the initial research synthesis route, investigation of an alternative approach based on a palladium‐catalyzed Newman‐Kwart rearrangement and finally changing the synthetic strategy from thiophene‐construction to benzene‐ring formation. Although the initial route was utilized to deliver material on kg‐scale, the requirements for market‐supply triggered the decision to pursue a new synthetic route. Catalyst costs, high purity‐requirements, and not the least technical practicality caused the change to a synthesis with indeed higher step‐count. However, this could be mitigated by repeated application of a telescoping approach. The free boronic acid was finally selected and manufactured as a stable isolated intermediate after challenges like proto‐deboronation and trimerization to boroxine upon drying could be solved by an optimized crystallization procedure.

Advancements in cutting-edge molecular profiling techniques, such as next-generation sequencing and bioinformatic analytic tools, have allowed researchers to examine tumour biology in detail and stratify patients based on factors linked with clinical outcome and response to therapy. This manuscript highlights the most relevant prognostic and predictive biomarkers in kidney, bladder, prostate and testicular cancers with recognised impact in clinical practice. In bladder and prostate cancer, new genetic acquisitions concerning the biology of tumours have modified the therapeutic scenario and led to the approval of target directed therapies, increasing the quality of patient care. Thus, it has become of paramount importance to choose adequate molecular tests, i.e., FGFR screening for urothelial cancer and BRCA1-2 alterations for prostate cancer, to guide the treatment plan for patients. While no tissue or blood-based biomarkers are currently used in routine clinical practice for renal cell carcinoma and testicular cancers, the field is quickly expanding. In kidney tumours, gene expression signatures might be the key to identify patients who will respond better to immunotherapy or anti-angiogenic drugs. In testicular germ cell tumours, the use of microRNA has outperformed conventional serum biomarkers in the diagnosis of primary tumours, prediction of chemoresistance, follow-up monitoring, and relapse prediction.