Elleraas, Jeff published the artcileConformational Studies and Atropisomerism Kinetics of the ALK Clinical Candidate Lorlatinib (PF-06463922) and Desmethyl Congeners, Recommanded Product: (R)-Methyl 2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorobenzoate, the publication is Angewandte Chemie, International Edition (2016), 55(11), 3590-3595, database is CAplus and MEDLINE.
Lorlatinib (PF-06463922) is an ALK/ROS1 inhibitor and is in clin. trials for the treatment of ALK pos. or ROS1 pos. NSCLC (i.e. specific subsets of NSCLC). One of the laboratory objectives for this mol. indicated that it would be desirable to advance a mol. which was CNS penetrant in order to treat brain metastases. From this perspective, a macrocyclic template was attractive for a number of reasons. In particular, this template reduces the number of rotatable bonds, provides the potential to shield polar surface area and reinforces binding through a restricted conformation. All of these features led to better permeability for the mols. of interest and thus increased the chance for better blood brain barrier penetration. With a CNS penetrant mol., kinase selectivity is a key consideration particularly with regard to proteins such as TrkB, which are believed to influence cognitive function. Removal of the chiral benzylic Me substituent from lorlatinib was perceived as not only a means to simplify synthetic complexity, but also as a strategy to further truncate the mol. of interest. Examination of the NMR of the desmethyl analogs revealed that the compound existed as a mixture of atropisomers, which proved separable by chiral SFC. The individual atropisomers were evaluated through a series of in vitro assays, and shown to have a favorable selectivity profile when compared to lorlatinib. The challenge to develop such a mol. lies in the rate at which the atropisomers interchange dictated by the energy barrier required to do this. Here, we describe the synthesis of the desmethyl macrocycles, conformational studies on the atropisomers, and the kinetics of the interconversion. In addition, the corresponding conformational studies on lorlatinib are reported providing a hypothesis for why a single diastereomer is observed when the chiral benzylic Me group is introduced.
Angewandte Chemie, International Edition published new progress about 1454848-00-0. 1454848-00-0 belongs to pyridine-derivatives, auxiliary class Aromatic Fluorinated Building Blocks, name is (R)-Methyl 2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorobenzoate, and the molecular formula is C15H14BrFN2O3, Recommanded Product: (R)-Methyl 2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorobenzoate.
Referemce:
https://en.wikipedia.org/wiki/Pyridine,
Pyridine | C5H5N – PubChem