Synthesis of Verubecestat, a BACE1 Inhibitor for the Treatment of Alzheimer’s Disease

Abstract

Verubecestat is an inhibitor of β-secretase being evaluated for the treatment of Alzheimer's disease. The first-generation route relies on an amide coupling with a functionalized aniline, the preparation of which introduces synthetic inefficiencies. The second-generation route replaces this with a copper-catalyzed C-N coupling, allowing for more direct access to the target. Other features of the new route include a diastereoselective Mannich-type addition into an Ellman sulfinyl ketimine and a late-stage guanidinylation.

Inhibition of BACE1 Facilitates Macrophage-based Immunotherapy to Suppress Malignant Growth of Glioblastoma

“…1d,e), suggesting that MK-8931 is a potent activator of macrophage phagocytosis of cancer cells. As MK-8931 was originally developed as a BACE1-speci c inhibitor for AD patients 33,41 , we then con rmed that BACE1 was expressed by the iPSC-derived macrophages but not by the iPSCs (Fig. 1f).…”

Mechanochemical synthesis of N-tert-butanesulfinyl imines under metal-free conditions

“…Increasing the reaction time from 15 to 20 minutes lead to a slight enhancement of the yield, but any further increase of the reaction time (> 20 min) led to a slight decrease in the reaction yield (Table 1, entries 9-11). Decreasing the iodine loading from 10 mol% to 2 mol% lead to a significant decrease in the conversion of benzaldehyde to the desired sulfinylimine, while increasing the catalyst loading over 10% showed no significant effect on the reaction outcome (Table 1, entries [12][13][14][15]. Addition of anhydrous sodium sulfate (1 equivalent) had no impact on the reaction outcome (Table 1, entry 16).…”

“…10 They also find applications in the total synthesis of natural products and biologically active molecules. [11][12][13] Chiral N-sulfinyl imines are the condensation products of carbonyl compounds with commercially available chiral sulfinamides such as p-toluenesulfinamide and tertbutanesulfinamide. However, such condensations typically require the utilization of excess amounts (2-5 equivalents) of metal reagents such as Ti(IV) derivatives and CuSO4 that act as Lewis acids and dehydrating agents at the same time.…”

Integration of Bromine and Cyanogen Bromide Generators for the Continuous‐Flow Synthesis of Cyclic Guanidines

“…In order to process transformations where ar eactive crystallization step is essential, for example,the guanidinylation step toward the synthesis of verubecestat, [28] the reactor set-up was modified. TheBrCN stream with the coupled Br 2 / BrCN generator was introduced into ar eaction vessel containing the substrate solution ( Figure 6), thus mimicking ac ontinuous stirred-tank reactor (CSTR) where slurries can be handled.…”

“…By applying these optimized conditions,as et of 5-membered cyclic guanidines (1a-d)a nd 2-aminobenzoxazoles (2a-g), was synthesized in excellent yields (80-94 %) from the corresponding 1,2-diaminobenzens and 2-aminophenols, respectively (Figure 4). To access the medicinally interesting cyclic 6-membered guanidine moiety, [27,28] 1,3-diamines and 2aminobenzamides were reacted with BrCN to generate cyclic…”