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| Product Name: | BIBW2992 DiMaleate | | Synonyms: | BIBW2992 DiMaleate;BIBW2992-MA2;Afatinib (diMaleate);Afatinib (diMaleate), BIBW2992;2-ButenaMide, N-[4-[(3-chloro-4-fluorophenyl)aMino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(diMethylaMino)-, (2E)-, (2Z)-2-butenedioate (1:2);(2E)-N-(4-[(3-chloro-4-fluorophenyl)aMino]-7-{[(3S);Afatinib double Maleate;Afatinib (BIBW2992) Dimaleate | | CAS: | 850140-73-7 | | MF: | C28H29ClFN5O7 | | MW: | 602.02 | | EINECS: | 810-416-1 | | Product Categories: | Inhibitors;tyrosine kinase receptor inhibitor | | Mol File: | 850140-73-7.mol |
| BIBW2992 DiMaleate Chemical Properties |
| Melting point | >237oC (dec.) | | storage temp. | Refrigerator | | solubility | DMSO (Slightly), Methanol (Slightly) | | form | Solid | | color | White to Pale Yellow |
| 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.
| | Description | Afatinib 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. | | Uses | Afatinib Dimaleate is a salt of Afatinib {BIBW 2992), an aminocrotonylamino-substituted quinazoline derivative used for treating cancer and diseases of the respiratory tract, lungs, gastrointestinal tract, bile duct, and gallbladder. An anilino-quinazoline that irreversibly inhibits EGFR and HER2 kinase activity. | | Definition | ChEBI: 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. | | Synthesis | Nitroquinazolinone (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. |
| BIBW2992 DiMaleate Preparation Products And Raw materials |
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