Quinazoline

:File:4-ClQuinazoline.png

The synthesis of quinazoline was first reported in 1895 by August Bischler and Lang through the decarboxylation of the 2-carboxy derivative (quinazoline-2-carboxylic acid).{{cite journal | doi = 10.1155/2014/395637 | title = Chemical Characteristics, Synthetic Methods, and Biological Potential of Quinazoline and Quinazolinone Derivatives | date = 2014 | last1 = Asif | first1 = Mohammad | journal = International Journal of Medicinal Chemistry | pages = 1–27 | doi-access = free | pmid = 25692041 | pmc = 4321853 }} In 1903, Siegmund Gabriel reported the synthesis of the parent quinazoline from o-nitrobenzylamine, which was reduced with hydrogen iodide and red phosphorus to 2-aminobenzylamine. The reduced intermediate condenses with formic acid to yield dihydroquinazoline, which was oxidized to quinazoline.Morgan, G.T., ed. Abstract of Papers. Journal of the Chemical Society. London: Gurney & Jackson, 1904. Print.

Methods have been reviewed.{{cite journal |doi=10.1016/j.tet.2005.07.010|title=Synthesis of quinazolinones and quinazolines|year=2005|last1=Connolly|first1=David J.|last2=Cusack|first2=Declan|last3=O'Sullivan|first3=Timothy P.|last4=Guiry|first4=Patrick J.|journal=Tetrahedron|volume=61|issue=43|pages=10153–10202}} An efficient route to the parent heterocycle proceeds via the 4-chloro derivative to the tosylhydrazide, which is removed by base.{{cite book |doi=10.1002/9780470186916.ch7|chapter=Halogenoquinazolines|editor=W. L. F. Armarego|author=W. L. F. Armarego|title=Chemistry of Heterocyclic Compounds|year=1967|pages=11–38|isbn=9780470186916}}

:File:QuinazolineHydration.png

Quinazoline protonates (and methylates) at N3. Protonation induces hydration. Many mildly acidic substrates add across the C=N3 bond, these include hydrogen cyanide, sodium bisulfite, and methyl ketones.{{cite book |doi=10.1002/9780470186916.ch2|chapter=Quinazoline|editor=W. L. F. Armarego|author=W. L. F. Armarego|title=Chemistry of Heterocyclic Compounds|series=Chemistry of Heterocyclic Compounds: A Series of Monographs|year=1967|volume=24 |pages=11–38|isbn=9780470186916}}

In warm solution, quinazoline hydrolyzes under acidic and alkaline conditions to 2-aminobenzaldehyde (or the products of its self-condensation) and formic acid and ammonia/ammonium.Büchel, K. H., ed. Methods of Organic Chemistry (Houben-Weyl): Additional and Supplementary Volumes to the 4th Edition. New York: Georg Thieme Verlag Stuttgart, 2001.

The pyrimidine ring resists electrophilic substitution, although the 4-position is more reactive than the 2-position. In comparison, the benzene ring is more susceptible to electrophilic substitution. The ring position order of reactivity is 8 > 6 > 5 > 7. 2- and 4-halo derivatives of quinazoline undergo displacement by nucleophiles, such as piperidine.

In May 2003, the U.S. Food and Drug Administration (FDA) approved the quinazoline gefitinib. The drug, produced by AstraZeneca, is an inhibitor of the protein kinase of epidermal growth factor receptor (EGFR). It binds to the ATP-binding site of EGFR, thus inactivating the anti-apoptotic Ras signal transduction cascade preventing further growth of cancer cells.{{cite news|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/021399lbl.pdf|title=Iressa(Gefitinib)|publisher=US Food and Drug Administration|date=2 May 2003}}{{cite journal|last1=Lynch|first1=Thomas J.|last2=Bell|first2=Daphne W.|last3=Sordella|first3=Raffaella|last4=Gurubhagavatula|first4=Sarada|last5=Okimoto|first5=Ross A.|last6=Brannigan|first6=Brian W.|last7=Harris|first7=Patricia L.|last8=Haserlat|first8=Sara M.|last9=Supko|first9=Jeffrey G.|last10=Haluska|first10=Frank G.|last11=Louis|first11=David N.|last12=Christiani|first12=David C.|last13=Settleman|first13=Jeff|last14=Haber|first14=Daniel A|title=Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib|journal=NEJM|date=May 20, 2004|volume=350|issue=21|pages=2129–39|doi=10.1056/nejmoa040938|pmid=15118073|url=http://repository.cshl.edu/22429/1/EGFR%20Mutations.pdf }}Takimoto CH, Calvo E. [http://www.cancernetwork.com/cancer-management-11/chapter03/article/10165/1402628 "Principles of Oncologic Pharmacotherapy"] in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) [http://www.cancernetwork.com/cancer-management-11/ Cancer Management: A Multidisciplinary Approach]. 11 ed. 2008.

In March 2007, GlaxoSmithKline's drug lapatinib was approved by the U.S. FDA to treat advanced-stage or metastatic breast cancer in combination with Roche's capecitabine. Lapatinib eliminates the growth of breast cancer stem cells that cause tumor growth. The binding of lapatinib to the ATP-binding site in the EGFR and human epidermal growth factor receptor 2 (HER2) protein kinase domains inhibits signal mechanism activation (through reversible, competitive inhibition).{{cite news|url=https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm129252.htm|archive-url=https://web.archive.org/web/20111124180432/http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm129252.htm|url-status=dead|archive-date=November 24, 2011|title=Lapatinib|publisher=US Food and Drug Administration|date=13 March 2007}}{{cite journal | last1 = Wood | first1 = ER | last2 = Truesdale | first2 = AT | last3 = McDonald | first3 = OB | last4 = Yuan | first4 = D | last5 = Hassell | first5 = A | last6 = Dickerson | first6 = SH | last7 = Ellis | first7 = B | last8 = Pennisi | first8 = C | last9 = Horne | first9 = E | last10 = Lackey | first10 = K | last11 = Alligood | first11 = K. J. | last12 = Rusnak | first12 = D. W. | last13 = Gilmer | first13 = T. M. | last14 = Shewchuk | first14 = L | title = A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells | journal = Cancer Research | volume = 64 | issue = 18 | pages = 6652–9 | year = 2004 | pmid = 15374980 |name-list-style=vanc | doi = 10.1158/0008-5472.CAN-04-1168 | display-authors = 8 | doi-access = free }}{{cite conference |author=Rodriguez, A. |date=April 2008 |title=New type of drug shrinks primary breast cancer tumors significantly in just six weeks; research provides leads to a new target in cancer treatment – the cancer stem cell |url=http://www.ecco-org.eu/News/Press-room/Press-release/page.aspx/439?xf_itemId=265&xf_catId=27 |url-status=dead |archive-url=https://web.archive.org/web/20081126082044/http://www.ecco-org.eu/News/Press-room/Press-release/page.aspx/439?xf_itemId=265&xf_catId=27 |archive-date=2008-11-26 }}{{cite journal |vauthors=Nelson MH, Dolder CR |title=Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors |journal=Ann Pharmacother |volume=40 |issue=2 |pages=261–9 |date=February 2006 |pmid=16418322 |doi=10.1345/aph.1G387|s2cid=21622641 }}

In May 2013, erlotinib, a drug manufactured by Astellas, was approved by the U.S. FDA to treat NSCLC patients with tumors caused by mutations of EGFR. The binding of erlotinib to the ATP-binding sites of the EGFR receptors prevents EGFR from producing phosphotyrosine residues (due to competitive inhibition), thus rendering the receptor incapable of generating signal cascades to promote cell growth.{{cite news|url=https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm352317.htm|archive-url=https://web.archive.org/web/20131126012721/http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm352317.htm|url-status=dead|archive-date=November 26, 2013|title=Erlotinib|publisher=US Food and Drug Administration|date=14 May 2013}}{{cite journal |vauthors=Raymond E, Faivre S, Armand J |title=Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy |journal=Drugs |volume=60 Suppl 1 |pages=15–23; discussion 41–2 |year= 2000|pmid=11129168 |doi=10.2165/00003495-200060001-00002|s2cid=10555942 |doi-access=free }}

In July 2013, the U.S. FDA approved afatinib, a drug developed by Boehringer Ingelheim, as an irreversible, competitive inhibitor of HER2 and EGFR kinases. While afatinib demonstrates a similar mechanism to laptinib in which it acts as an irreversible HER2 and EGFR inhibitor, afatinib has also shown activity against tyrosine kinases that have become resistant to gefinitib and erlotinib.{{cite news|url=https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm360574.htm|archive-url=https://web.archive.org/web/20130801033125/http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm360574.htm|url-status=dead|archive-date=August 1, 2013|title=Afatinib|publisher=US Food and Drug Administration|date=12 July 2013}}

File:Gefitinib structure.svg|Gefitinib for treatment of non-small-cell lung carcinoma.

File:Lapatinib.svg|Lapatinib for treatment of advanced-stage or metastatic breast cancer.

File:Erlotinib.svg|Erlotinib, an anti-tumor agent.

File:Afatinib skeletal.svg|Afatinib for treatment of cancers resistant to gefinitib and erlotinib.

• Quinazolinone
• Niementowski quinazoline synthesis

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Category:Aromatic bases

Category:Simple aromatic rings