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Quinazoline

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Quinazoline
Quinazoline molecule
C=black, H=white, N=blue
Quinazoline molecule
C=black, H=white, N=blue
Names
Preferred IUPAC name
Quinazoline[1]
Other names
1,3-diazanaphthalene

benzopyrimidine

phenmiazine

benzo-1,3-diazine
Identifiers
3D model (JSmol)
109370
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.005.424 Edit this at Wikidata
EC Number
  • 205-965-3
663230
UNII
  • InChI=1S/C8H6N2/c1-2-4-8-7(3-1)5-9-6-10-8/h1-6H checkY
    Key: JWVCLYRUEFBMGU-UHFFFAOYSA-N checkY
  • InChI=1/C8H6N2/c1-2-4-8-7(3-1)5-9-6-10-8/h1-6H
    Key: JWVCLYRUEFBMGU-UHFFFAOYAV
  • c1ccc2c(c1)cncn2
Properties
C8H6N2
Molar mass 130.150 g·mol−1
Appearance light yellow crystals
Density 1.351 g/cm3, solid
Melting point 48 °C (118 °F; 321 K)
Boiling point 243 °C (469 °F; 516 K)
Soluble
Acidity (pKa) 3.51[2]
Structure
2.2 D[3]
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Irritant
GHS labelling:
GHS07: Exclamation mark
Warning
H315, H319, H335
P261, P264, P271, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, P501
Flash point 106 °C (223 °F; 379 K)
Safety data sheet (SDS) External MSDS
Related compounds
Related compounds
 cinnoline, quinoxaline, phthalazine
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Quinazoline is an organic compound with the formula C8H6N2. It is an aromatic heterocycle with a bicyclic structure consisting of two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring. It is a light yellow crystalline solid that is soluble in water. Also known as 1,3-diazanaphthalene, quinazoline received its name from being an aza derivative of quinoline. Though the parent quinazoline molecule is rarely mentioned by itself in technical literature, substituted derivatives have been synthesized for medicinal purposes such as antimalarial and anticancer agents. Quinazoline is a planar molecule. It is isomeric with the other diazanaphthalenes of the benzodiazine subgroup: cinnoline, quinoxaline, and phthalazine. Over 200 biologically active quinazoline and quinoline alkaloids are identified.[4][5]

Synthesis

[edit]
Preparation of 4-chloroquinazoline and its tosylhydrazide.

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).[6] 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.[7]

Methods have been reviewed.[8] An efficient route to the parent heterocycle proceeds via the 4-chloro derivative to the tosylhydrazide, which is removed by base.[9]

Reactions

[edit]

Hydration and addition reactions

[edit]
Hydration of quinazolinium.

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.[10]

Hydrolysis

[edit]

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.[3]

Electrophilic and nucleophilic substitution

[edit]

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.[3]

Biological and pharmacological significance

[edit]

Gefitinib

[edit]

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.[11][12][13]

Lapatinib

[edit]

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).[14][15][16][17]

Erlotinib

[edit]

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.[18][19]

Afatinib

[edit]

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.[20]

See also

[edit]

References

[edit]
  1. ^ International Union of Pure and Applied Chemistry (2014). Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013. The Royal Society of Chemistry. p. 212. doi:10.1039/9781849733069. ISBN 978-0-85404-182-4.
  2. ^ Armarego, W. L. F. (1963). "Quinazolines". Advances in Heterocyclic Chemistry Volume 1. Vol. 1. pp. 253–309. doi:10.1016/S0065-2725(08)60527-9. ISBN 9780120206018. PMID 14087221.
  3. ^ a b c 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.
  4. ^ Shang, XF; Morris-Natschke, SL; Liu, YQ; Guo, X; Xu, XS; Goto, M; Li, JC; Yang, GZ; Lee, KH (May 2018). "Biologically active quinoline and quinazoline alkaloids part I." Medicinal Research Reviews. 38 (3): 775–828. doi:10.1002/med.21466. PMC 6421866. PMID 28902434.
  5. ^ Shang, Xiao-Fei; Morris-Natschke, Susan L.; Yang, Guan-Zhou; Liu, Ying-Qian; Guo, Xiao; Xu, Xiao-Shan; Goto, Masuo; Li, Jun-Cai; Zhang, Ji-Yu; Lee, Kuo-Hsiung (September 2018). "Biologically active quinoline and quinazoline alkaloids part II". Medicinal Research Reviews. 38 (5): 1614–1660. doi:10.1002/med.21492. ISSN 0198-6325. PMC 6105521. PMID 29485730.
  6. ^ Asif, Mohammad (2014). "Chemical Characteristics, Synthetic Methods, and Biological Potential of Quinazoline and Quinazolinone Derivatives". International Journal of Medicinal Chemistry: 1–27. doi:10.1155/2014/395637. PMC 4321853. PMID 25692041.
  7. ^ Morgan, G.T., ed. Abstract of Papers. Journal of the Chemical Society. London: Gurney & Jackson, 1904. Print.
  8. ^ Connolly, David J.; Cusack, Declan; O'Sullivan, Timothy P.; Guiry, Patrick J. (2005). "Synthesis of quinazolinones and quinazolines". Tetrahedron. 61 (43): 10153–10202. doi:10.1016/j.tet.2005.07.010.
  9. ^ W. L. F. Armarego (1967). "Halogenoquinazolines". In W. L. F. Armarego (ed.). Chemistry of Heterocyclic Compounds. pp. 11–38. doi:10.1002/9780470186916.ch7. ISBN 9780470186916.
  10. ^ W. L. F. Armarego (1967). "Quinazoline". In W. L. F. Armarego (ed.). Chemistry of Heterocyclic Compounds. Chemistry of Heterocyclic Compounds: A Series of Monographs. Vol. 24. pp. 11–38. doi:10.1002/9780470186916.ch2. ISBN 9780470186916.
  11. ^ "Iressa(Gefitinib)" (PDF). US Food and Drug Administration. 2 May 2003.
  12. ^ Lynch, Thomas J.; Bell, Daphne W.; Sordella, Raffaella; Gurubhagavatula, Sarada; Okimoto, Ross A.; Brannigan, Brian W.; Harris, Patricia L.; Haserlat, Sara M.; Supko, Jeffrey G.; Haluska, Frank G.; Louis, David N.; Christiani, David C.; Settleman, Jeff; Haber, Daniel A (May 20, 2004). "Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib" (PDF). NEJM. 350 (21): 2129–39. doi:10.1056/nejmoa040938. PMID 15118073.
  13. ^ Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
  14. ^ "Lapatinib". US Food and Drug Administration. 13 March 2007.
  15. ^ Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, et al. (2004). "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". Cancer Research. 64 (18): 6652–9. doi:10.1158/0008-5472.CAN-04-1168. PMID 15374980.
  16. ^ Rodriguez, A. (April 2008). 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. Archived from the original on 2008-11-26.
  17. ^ Nelson MH, Dolder CR (February 2006). "Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors". Ann Pharmacother. 40 (2): 261–9. doi:10.1345/aph.1G387. PMID 16418322. S2CID 21622641.
  18. ^ "Erlotinib". US Food and Drug Administration. 14 May 2013.
  19. ^ Raymond E, Faivre S, Armand J (2000). "Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy". Drugs. 60 Suppl 1: 15–23, discussion 41–2. doi:10.2165/00003495-200060001-00002. PMID 11129168. S2CID 10555942.
  20. ^ "Afatinib". US Food and Drug Administration. 12 July 2013.
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