CEP-32496 (free base)

Agerafenib is under investigation in clinical trial NCT03052569 (Expanded Access to RXDX-105 for Cancers With RET Alterations).|Agerafenib is an orally available v-raf murine sarcoma viral oncogene homolog B1 (B-raf) serine/threonine protein kinase inhibitor with potential antineoplastic activity. Agerafenib specifically and selectively inhibits the activity of the mutated form (V600E) of B-raf kinase. This inhibits the activation of the RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) signaling pathway and may result in a decrease in the proliferation of tumor cells expressing the mutated B-raf gene. The Raf mutation BRAF V600E, in which valine is substituted for glutamic acid at residue 600, is frequently found in a variety of human tumors and results in the constitutive activation of the RAF/MEK/ERK signaling pathway that regulates cellular proliferation and survival.

To a 10 L Chemglass jacketed reactor with N2 inlet/outlet was added compound 2 (200.0 g, 637 mmol), compound 3 (177.0 g, 596 mmol) and 4-Dimethylaminopyridine (DMAP) (2.88 g) followed by 4.0 L of isopropyl acetate. The internal temperature was raised to 70°C and heated for 9 hours. The reaction remained a slurry throughout there action and HPLC showed no compound 2 remaining after heating for that period. Next, 2.0 L of heptane were added at 70°C and the reaction cooled to 20°C. The solids were stirred for lhour, filtered and the cake washed with 2.0 L of 1:1 isopropyl acetate/ heptanes. The white solids were placed in an oven with N2 bleed at 55°C under 75 mbar vacuum. The resulting solids weighed 295 g (96percent yield) of Form A0 with 99.3 percent purity by HPLC.

Molecular Weight:517.5
XLogP3:5
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:11
Rotatable Bond Count:7
Exact Mass:517.15730331
Monoisotopic Mass:517.15730331
Topological Polar Surface Area:121
Heavy Atom Count:37
Complexity:776
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes