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BIBW2992 DiMaleate

Basic information Description Mechanism of Action Safety Related Supplier
BIBW2992 DiMaleate Basic information
Safety Information
  • HS Code 29339900
BIBW2992 DiMaleate Usage And Synthesis
  • Description

    Afatinib dimaleate (Tovok; BIBW2992; Gilotrif) is a salt form of Afatinib. Afatinib is a second-generation, orally administered, irreversible inhibitor of the ErbB family of tyrosine kinases.

  • Mechanism of Action

    Afatinib downregulates ErbB signalling by covalently binding to the kinase domains of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER) 2 and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation; it also inhibits transphosphorylation of HER3. Afatinib is approved as monotherapy for the treatment of EGFR tyrosine kinase inhibitor (TKI)-naïve adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutations in the EU, and for the first-line treatment of patients with metastatic NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test in the US.

  • DescriptionAfatinib dimaleate was approved by the U.S. Food and Drug Administration (FDA) in 2013 for the treatment of non-small cell lung cancer (NSCLC). Specifically, it was approved for patients presenting with metastatic NSCLC tumors which contain epidermal growth factor receptor (EGFR) exon deletions or exon 21 mutations. Afatinib dimaleate is a covalent inhibitor of ErbB tyrosine kinases (tyk), which downregulates ErbB signaling by irreversible binding of EGFR tyk binding sites. While no manufacturing route has been disclosed to date, the most scalable published route likely derives from two Boehringer Ingelheim patents.
  • DefinitionChEBI: A maleate salt obtained by combining afatinib with two molar equivalents of maleic acid. Used for the first-line treatment of patients with metastatic non-small cell lung cancer.
  • Chemical SynthesisNitroquinazolinone (6), which is commercially available, was first chlorinated with phosphorous oxychloride (POCl3) followed by treatment with commercial 3-chloro-4-fluoroaniline (7) to afford SNAr adduct 8 in 90% yield over two steps. Sulfonylation to afford 9 (86%) and subsequent displacement with (S)-tetrahydrofuran- 3-ol gave 10 in 90% yield. Raney–Nickel reduction of the nitro group delivered 11 in 97% yield, which set the stage for the final side-chain functionalization. 2-(Diethoxyphosphoryl) acetic acid and N,N0-carbonyldiimidazole (CDI) were pre-mixed and added to aniline 11 to afford 12 in 70% isolated yield. Next, a Horner–Wadsworth–Emmons homologation gave the (E)-olefin 13 in quantitative yield, followed by maleate salt formation (92%) to deliver the final API. The final five steps of this synthesis have been successfully demonstrated on multi-kilogram scale.

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