3(4-fluorophenyl)chroman-4-one (KBU2046) binds to the interface of HSP90b/CDC37 interface and inhibits osteoclast (OC) mediated bone destruction. Bisphosphonates are the most widely prescribed and used medications for the treatment of osteoporosis. Three oral bisphosphonates (alendronate, risedronate, and ibandronate) are approved by the U.S. Food and Drug Administration (FDA). A heterobifunctional compound generated by conjugating alendronate (bis) and KBU2046 through a linker yields, Dual-Acting Bone-Defender (DABD) which was more effective than KBU2046 + bis or the individual components. The reported synthesis of a DABD BTE-EN1 required 11 steps and had an overall yield of 0.7%.
To enable scale up of BTE-EN1 for pre-clinical development, here we optimized the route and the process that resulted in reducing the number of synthetic steps from 11 to 8 and increased the overall yield from 0.7% to 11% (~16-fold increase).

Results/Conclusions:

To facilitate the large-scale synthesis of BTE-EN1, we undertook an optimization of the route and the process from the commercially available resorcinol and 2-(4-fluorophenyl)acetic acid.
Our synthetic approach utilized a BF3-etherate-mediated Friedel–Crafts acylation/selective O-alkylation and the cyclization to construct the core structure.
Furthermore, the final step conditions were fine-tuned to facilitate efficient amide bond formation, resulting in a remarkable yield improvement from 16% to 71%
This optimization successfully reduced the number of synthetic steps required from 11 to 8, leading to a substantial enhancement in overall yield, increasing it from the initial 0.7% to a remarkable 11%.
This represents approximately a 16-fold improvement in efficiency compared to the previous method.
In a head-to-head comparison BTE-EN1 synthesized using the more efficient route exhibited comparable inhibition of cell migration activities to BTE-EN1 synthesized by the reported method.

Prathap Reddy Mukthapuram

Appearances