Dacomitinib

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Column 1
dak" oh mi' ti nib
Vizimpro
PF-00299804
Monograph
a618055
.mw-parser-output .plainlist ol,.mw-parser-output .plainlist ul{line-height:inherit;list-style:none;margin:0;padding:0}.mw-parser-output .plainlist ol li,.mw-parser-output .plainlist ul li{margin-bottom:0}
US DailyMed: Dacomitinib
By mouth
L01EB07 (WHO)
CA: ℞-only
US: ℞-only
EU: Rx-only
In general: ℞ (Prescription only)
80%
98%
CYP2D6, CYP3A4
O-desmethyl-dacomitinib
70 hrs
79% faeces, 3% urine
IUPAC name
(2E)-N-{4-[(3-Chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl}-4-(1-piperidinyl)-2-butenamide
1110813-31-4 Y
11511120
7422
DB11963
9685914
2XJX250C20
D09883as salt: D10514
CHEBI:132268
ChEMBL2105719
1C9 (PDBe, RCSB PDB)
DTXSID50149493
C24H25ClFN5O2
469.95 g·mol−1
Interactive image
SMILES
COC1=C(C=C2C(=C1)N=CN=C2NC3=CC(=C(C=C3)F)Cl)NC(=O)/C=C/CN4CCCCC4
InChI
InChI=1S/C24H25ClFN5O2/c1-33-22-14-20-17(24(28-15-27-20)29-16-7-8-19(26)18(25)12-16)13-21(22)30-23(32)6-5-11-31-9-3-2-4-10-31/h5-8,12-15H,2-4,9-11H2,1H3,(H,30,32)(H,27,28,29)/b6-5+Key:LVXJQMNHJWSHET-AATRIKPKSA-N

Dacomitinib, sold under the brand name Vizimpro, is a medication for the treatment of non-small-cell lung carcinoma (NSCLC). It is a selective and irreversible inhibitor of EGFR.

Dacomitinib has advanced to several Phase III clinical trials. In January 2014, results of the first trials were disappointing, with a failure to meet the study goals, but additional Phase III trials continued. In 2017, results of a trial comparing dacomitinib to gefitinib for NSCLC (driven by mutated EGFR) were announced.

Dacomitinib was approved for medical use in the United States in September 2018, in Japan in 2019, and in the European Union in 2019; for the treatment of non-small cell lung cancer with epidermal growth factor receptor (EGFR) gene mutation.

The commercial process for the synthesis of dacomitinib was recently reported by Pfizer. An overall yield of 58% is reported.

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Catalytic hydrogenation of [1269400-04-5] (1) gave the aniline (2), which was used without purification for the next step. The reaction of methyl 4-bromocrotonate [6000-00-6] (3) with piperidine, followed by saponification of the ester gave (E)-4-(piperidin-1-yl)but-2-enoic acid [768341-84-0] (4). The amide formation between 2 & 4 was facilitated by T3P and 2,6-lutidine in acetonitrile. A reverse quench with aqueous NaOH was performed to minimize hydrolysis of the formamidine group to give PC156701138 (5). The intermediate underwent a Dimroth rearrangement in the presence of 3-chloro-4-fluoroaniline [367-21-5] (6) completing the synthesis of dacomitinib (7). It is worth noting that the intermediate as well as dacomitinib are unstable under the high temperatures typically used for Dimroth rearrangements (refluxing in HOAc). The reaction was optimized to occur at lower temperatures. The reaction was made to occur at 30 °C in neat acetic acid using two equivalents of aniline (6) to increase the reaction rate.

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• "Dacomitinib". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 13 December 2019.

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