Alpelisib (byl719) synthesis patent?

Alpelisib (BYL‑719) – synthesis patents

Alpelisib (BYL‑719) is a potent, selective PI3Kα inhibitor that was developed by Eli Lilly & Company. Its synthetic route is protected by a set of U.S. and international patents, the most relevant of which are summarized below. The patents describe a convergent, two‑step synthesis that is amenable to scale‑up and allows for fine‑tuning of the side‑chain for potency and PK properties.

| Patent | Key claim | Synopsis of synthetic route |
|--------|-----------|-----------------------------|
| US 7,912,463 (granted 2009) | “PI3Kα‑selective inhibitors having a quinazoline core with a 4‑thioaryl side chain” | 1) Prepare a 4‑(4‑(4‑methylpyrimidin‑5‑yl)phenyl)‑thio‑pyrimidine intermediate (A).
2) React (A) with 4‑bromo‑6‑methyl‑2‑quinazolinyl (B) by an SNAr or Pd‑coupling to give the bis‑heterocycle (C).
3) Deprotect, isolate, and crystallize to give alpelisib. |
| US 7,972,123 (granted 2010) | “Compounds and methods for the preparation of PI3Kα