Alflutinib Chemical Properties

Density 

1.29±0.1 g/cm3(Predicted)

form 

Solid

pka

11?+-.0.70(Predicted)

color 

White to off-white

InChIKey

GHKOONMJXNWOIW-UHFFFAOYSA-N

SMILES

CN1C2=CC=CC=C2C(C2C=CN=C(NC3C=C(NC(=O)C=C)C(N(C)CCN(C)C)=NC=3OCC(F)(F)F)N=2)=C1

Alflutinib Usage And Synthesis

Uses

Firmonertinib (Alflutinib; Furmonertinib) is an orally active, mutant-selective, and highly brain penetrant EGFR inhibitor. Firmonertinib inhibits EGFR active mutations as well as the T790M acquired resistant mutation. Firmonertinib has the potential for the research of cancer diseases, especially advanced non-small cell lung cancer (NSCLC) with EGFR ex20ins mutation[1].

Mechanism of action

As a third-generation EGFR TKI, Alflutinib can irreversibly bind to the EGFR protein, especially to tumor cells carrying the T790M drug-resistant mutation. This specific binding helps reduce damage to normal cells while effectively inhibiting the proliferation of tumor cells.

Synthesis

Arylation of the indole prepared the chloropyridine 21.7, which was then reacted with the aniline 21.4 in the presence of excess p-toluenesulfonic acid to produce 21.8 (see Figure 7.3.2). The second SNAr reaction used the diamine 21.9, which was coprecipitated with water in DMF to give the amine 21.10 in 77% yield over a two-step reaction. Reduction of the nitro group using sodium sulfite gave the corresponding amine under metal-free and mild conditions. The crude aniline was then converted to the dihydrochloride salt 21.11, which was isolated as a solid in high purity (99.8%) and yield (94%) after slurrying in methanol and ethanol. Finally, a two-step approach was used to install the α,β-unsaturated amide, as opposed to the earlier route that used acryloyl chloride directly. The acylation reaction used the chloroacyl chloride 21.12 to give the alkyl chloride 21.13, which was isolated by filtration. Subsequently, an elimination reaction was carried out with triethylamine at reflux in acetonitrile to prepare alflutinib (21) in 93% yield and 99.2% purity.

IC 50

EGFR

References

[1] Y. Shi, et al. P2.03-028 Third Generation EGFR Inhibitor AST2818 (Alflutinib) in NSCLC Patients with EGFR T790M Mutation: A phase1/2 Multi-Center Clinical Trial.
[2] Alexander I. Spira, et al. FURVENT: Phase 3 trial of furmonertinib vs chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertion mutations (FURMO-004). Journal of Clinical Oncology. Volume 42, Number 16_suppl.