Practical Asymmetric Fluorination Approach to the Scalable Synthesis of New Fluoroaminothiazine BACE Inhibitors

Abstract

Here we report an optimized protocol for the asymmetric introduction of a fluorine atom into a quaternary center facilitated by d-proline, Selectfluor®, and trifluoroethanol. The synthesis proceeds over four steps starting from a chiral amino alcohol precursor and provides the desired enantiomer with no erosion of chiral purity and good diastereoselectivity. The process optimization allowed diastereoselective preparation of the key intermediate on a multigram scale.

The Evolution of High-Throughput Experimentation in Pharmaceutical Development and Perspectives on the Future

“…Fluoroalcohols 26a and 26b were originally prepared via an oxidation/fluorination/reduction sequence (Scheme ). , One-pot formation of aldehyde pyrrolidine imine, followed by treatment with Select-Fluor, afforded fluoroaldehydes 29a and 29b . Reduction with NaBH 4 provided a 7:1 mixture of amino alcohol diastereomers ( 26a / 26b ), delivering 5% isolated yield of the desired diastereomer 26b .…”

“…Reduction with NaBH 4 provided a 7:1 mixture of amino alcohol diastereomers ( 26a / 26b ), delivering 5% isolated yield of the desired diastereomer 26b . All attempts at direct fluorination of the enamine derived from aldehyde 28 favored formation of the undesired diastereoisomer …”

“…Under most conditions tested, slow conversion and significant amounts of side products were observed; fortunately, promising results were seen with 0.3 equiv of amines 31a , 31c , 31d , and 31e . Further screening showed that stoichiometric quantities of the chiral agent afforded the best results, with 31e being optimal …”

“…After 2 h, 98% conversion was achieved, and no isomerization was observed under the reaction conditions. It was confirmed that lowering the reaction temperature to 0 °C during the addition of NaBH 4 afforded better results than running the chemistry at room temperature …”

Synthesis, Optimization, and Large-Scale Preparation of the Low-Dose Central Nervous System-Penetrant BACE1 Inhibitor LY3202626 via a [3 + 2] Nitrone Cycloaddition

“…The discovery route to 3 (Scheme ) leveraged knowledge that was gained from synthetic efforts toward 1 and 2 . , The route to prepare 3 began with lithium–iodide exchange in 4-bromo-1-fluoro-2-iodobenzene ( 4 ) using n -BuLi followed by condensation with Weinreb amide 5 (available in six steps from allylamine) at −78 °C to afford ketone 6 in 45% yield after silica gel purification. The reaction suffered from debromination through the use of n -BuLi, resulting in the low yield.…”