Ayers TA et al. * Sanofi, Bridgewater, USA
Scale-Up of an Enantioselective Overman Rearrangement for an Asymmetric Synthesis of a Glycine Transporter 1 Inhibitor.
Org. Process Res. Dev. 2012;
16: 484-494
Key words
glycine transporter 1 inhibitors - Noyori asymmetric transfer hydrogenation - Overman rearrangement - [3,3]-sigmatropic rearrangement - trichloroacetimidate
Significance
The target glycine transporter 1 (GlyT1) inhibitor was of interest for the treatment of schizophrenia and acute manic disorders. Key steps in the synthesis were (1) a Noyori asymmetric transfer hydrogenation (B → D), and (2) an Overman rearrangement by which allylic alcohol D was converted into the allylic amide F. This is the first example of a multikilogram scale-up of an Overman rearrangement.
Comment
The eight-step synthesis depicted proceeded in 20% overall yield and delivered 24.2 kg of API. The initial isolated material was an undesired polymorph, but simply suspending the solid in water and heating to 55 °C for two hours resulted in smooth conversion into the desired polymorph.
