Several routes to bisulfite adduct 2 were explored, the most efficient of which involved vinyl Grignard addition to 2-indanone followed by ozonolysis and workup with aqueous NaHSO 3 to effect reduction and bisulfite formation in a single pot. The safety and calorimetry of this ozonolysis reaction was studied, and the safe scale-up to 3 kg of olefin is described. The utility of bisulfite adduct 2 as an aldehyde surrogate in a reductive amination reaction is 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.
A chemoenzymatic
route for the production of an intermediate to
a gamma secretase inhibitor is described. The route is robust and
was run at multikilogram scale. The process employs both a transaminase
catalyzed reductive amination of a substituted tetralone and an alcohol
dehydrogenase catalyzed reduction of an α-ketoester to generate
the two chiral centers in the molecule, with nearly perfect stereoselectivity.
The process also features simple isolation schemes, including a direct
drop isolation of the aminotetralin phosphate salt.
Development of an efficient bond-forming sequence and optimization of reaction conditions are described for the synthesis of CP-945,598-01 (1 • HCl), a CB 1 antagonist in clinical studies for the treatment of obesity. Reordering of the bond-forming sequence provided a more efficient synthesis and avoided the use of phosphorous oxychloride. A telescoped reaction sequence (4 f 9) was developed to avoid a problematic isolation. Product isolations were developed so as to provide efficient throughput by minimizing solvent volumes and avoiding slow filtrations.
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