A mild, high-yielding, and practical protocol for the direct amidation of alkyl cyanoacetates using DBU is presented. This method eliminates the need for activation of cyanoacetic acid and/or high temperatures. It has been applied to the large-scale synthesis of CP-690,550-10 (1), a compound under development for the treatment of autoimmune diseases.
A concise, convergent multikilogram synthesis of CI-1034 (1), a potent endothelin receptor antagonist, is described. A 15-step preparation from commercially available o-vanillin and benzenesulfonyl chloride employs a remarkably robust Suzuki coupling between a boronic acid and an aromatic sulfonate ester as the key synthetic step. A scalable route capable of producing multikilogram quantities of CI-1034 with no chromatographic steps is described in this contribution. Improvements to the process included using a 4-fluorobenzenesulfonate ester as a suitable substitute for the triflate group in the Suzuki reaction and the use of MgCl 2 as a substitute for TiCl 4 in a Dieckmann condensation to provide the benzothiazine dioxide core.
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 semiautomated device for solubility measurements in solution volumes as low as 1 mL was
developed for pharmaceutical applications. The device operates nonisothermally, and can measure
multiple samples simultaneously. Solubilities of model compounds such as paracetamol, mannitol,
adipic acid, and glycine were measured and showed a maximum deviation of 5 wt % compared
to literature data. Extrapolation of solubility data in the form of activity coefficients was found
in good agreement with the literature value over a wide range of temperatures for paracetamol
in 2-propanol and adipic acid in ethanol, while some deviation was observed for mannitol in
water. The use of the solubility-measuring device to perform solvent screening on multiple
solvents for early-stage pharmaceutical compounds was also examined. Results indicate that
the slope of the solubility curve with temperature can be estimated with limited data for multiple
solvents.
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