A recent development for the efficient and environmentally friendly synthesis of aliphatic amines is the transitionmetal-catalyzed redox-neutral coupling of an alcohol and an amine, generally referred to as a "borrowing hydrogen" reaction. In this work, we describe the first kilogram-scale application of this technology in the synthesis of PF-03463275, a GlyT1 inhibitor developed for the treatment of schizophrenia. Using (Cp*IrCl 2 ) 2 the reaction has been optimized to achieve catalyst loadings lower than 0.05 mol % iridium (S/C g 2000) while retaining reasonable reaction times (<24 h). Water and a tertiary amine are essential for high catalytic activity, resulting in dramatically increased reaction rates compared to existing literature protocols. Methods for iridium removal are also described.
A practical synthesis of SGLT2 inhibitor candidate ertugliflozin (1) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxabicyclo[3.2.1]octane motif is prepared from commercially available 2,3,4,6-tetra-O-benzyl-D-glucose, with nucleophilic hydroxymethylation of a 5-ketogluconamide intermediate as a key step. The aglycone moiety is introduced via aryl anion addition to a methylpiperazine amide. High chemical purity of the API is assured through isolation of the crystalline penultimate intermediate, tetraacetate 39. A cocrystalline complex of the amorphous solid 1 with L-pyroglutamic acid has been prepared in order to improve the physical properties for manufacture and to ensure robust API quality.
Two routes for the synthesis of cis-N-protected-3-methylamino-4-methylpiperidine (3) were examined: a route hinging on the
electrochemical oxidation of carbamate 1 to install a ketone at
the 3 position of the piperidine followed by reductive amination
(disconnection A), and a route involving the hydrogenation of
an appropriately functionalized pyridine (disconnection B).
While both routes to the desired compound were ultimately
successful, the pyridine hydrogenation approach proved to be
more amenable to kilogram-scale preparations due to the
crystallinity and purity of intermediates in that route.
Synthesis
of (S)-5-fluoro-3-methylisobenzofuran-1(3H)-one (6), a key intermediate to lorlatinib,
is described. A few synthetic methodologies, that is, boron reduction,
enzymatic reduction, asymmetric hydrogenation, and asymmetric transfer
hydrogenation, were evaluated for the chiral reduction of the substituted
acetophenone intermediate (8). A manufacturing process,
on the basis of the asymmetric transfer hydrogenation, was developed.
This process was successfully scaled up to prepare 400 kg of 6.
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