Chemistry of Quinazolinones
Quinazoline (1) is a fused bicycle compound earlier known as benzo-1 3-diazine was first prepared in the laboratory by Gabriel1 in 1903, although one of its derivatives was known much earlier2.
The name quinazoline (German : Chinazolin) was first proposed for this compound by Weddige3, on observing that this was isomeric with the compounds cinnoline (2) and quinoxaline (3). Paal and Bush4 suggested the numbering of quinazoline ring system, which is currently used. The other less commonly used names for this ring system are ‘phenmiazine’ and 5,6-benzopyrimidine. However, the name quinazoline is now universally accepted.
Of the many derivatives of quinazoline system known so far, keto-quinazolines also called as quinazolinones, are the most important compounds. Depending upon the position of the keto or oxo group, these compounds may be classified into two types: 2-(1H) quinazolinones (or) 1,2-dihydro-2-oxo quinazolines (4) and 4(3H)-quinazolines or 3,4-dihydro-oxoquinazolines (5). These systems (4&5) exhibit lactam-lactim tautomerism and undergo hydroxy group replacement reactions. 2-Cyano-4(3H)-quinazolinone was the first quinazolinone derivative to be synthesized5.
2. Brief Account of reactivity of 4(3H)-Quinazolinones:
Reactions associated with tautomeric nature of the quinazolinones are often quite complex and generally unpredictable. The recorded chemical investigation on the subject is voluminous. The amide linkages in quinazolinones should not be looked on as predominantly the keto or the enol form but as true keto-enol tautomers, showing reaction characteristic of both the forms.
Quinazolinones are always high melting crystalline solids, insoluble in water and in most organic solvents but soluble in aqueous alkali. They are generally insoluble in dilute acids but are sometimes soluble in concentrated acids. Simple 4(3H)-quinazolinones, although insoluble in dilute acids, are soluble in 6N hydrochloric acid. 4(3H)-quinazolinones form stable monohydrochlorides, chloroplatinate, chloroaurates and picrates6 and their metal salts of silver, mercury, zinc, copper, sodium and potassium7.
Stability of the ring system:
The ring system in quinazolinone is exceedingly stable in oxidation, reduction, hydrolysis reactions and other treatment designed to break the ring. There is no report of degradation of quinazolinone by simple chemical oxidation.
When a simple and 2-substituted- 4(3H)- quinazolinone is heated with an equivalent amount of phosphorous pentachloride in phosphorous oxychloride, the corresponding 4-chloroquinazoline (6) is obtained. If a methyl group is present at 3-position, prohibiting the usual tautomerism, the methyl group is lost during the chlorination8.
The position of alkylation of quinazolinones is similar to all the aromatic nitrogen heterocyclic systems in which a hydroxyl group is found ortho or para to the nitrogen position. Such compounds exist in tautomeric mixture (7), the two structures being inter-convertible by the shift of one proton and one pair of electrons. In alkaline solution the ions of such compounds exist as resonance hybrids of the two major forms differing only by the position of two pairs of electrons, as shown. Thus in alkylation of such hydroxyl derivatives of pyridine, pyrimidine and similar heterocycles, the entering group may become attached to either the nitrogen atom, thus giving for instance, an N-alkyl-pyridine or to the oxygen atom, giving an alkoxy pyridine. Alkylating agent9 and the conditions of alkylation but not the hetercyclic nucleus, were the factors determining the course of alkylation.
4(3H)-Quinazolinone on boiling with nitric acid undergoes substitution to give 6-nitro-4 (3H)-quinazolinone (8). On further nitration it has been observed that the second nitro group enters the 8-position to give 6,8-dinitro derivatives (9). 2-Substituted-4(3H)-quinazolinones were also found to behave similarly, under such conditions10-13.
2,3-Dihydro-3-methyl- 4(1H)-quinazolinone (10) could be obtained on reduction of 3-methyl-4(3H)-quinazolinone with Lithium Aluminium Hydride (LiAIH4) in benzene14.
Reactivity of the 2-methyl group :
The methyl group in 2-position of 4(3H)-quinazolinone system was found to be quite reactive since it is linked to an azomethine carbon and condenses with aldehydes to give the styryl compounds (11)15,16.
These studies, interestingly, revealed that quite a few of such quinazolinone derivatives possess a wide variety of pharmacological activities.
3. The summary of methods of preparation of 4(3H)-Quinazolinones:
Most of the methods employed for the synthesis of 4(3H)-quinazolinones make use of anthranilic acid or one of their functional derivatives as the starting materials. Based on this factor, the general methods of synthesis are:
Condensation of anthranilic acid with acid amides:
When anthranilic acid is heated in a open container with excess of formamide at 120°C, water is expelled and a nearly quantitative (90%) conversion to 4(3H)-quinazolinones (12)17 is achieved.
Condensation of acetanilides with urethanes:
A number of attempts have been made to condense a urethane derivative with aniline to give 4(3H)-quinazolinone, directly. Urethane and acetanilide, heated for 3 hours with phosphorus pentoxide in toluene, give 2-methyl-4(3H)-quinazolinone (13)18.
Condensation of N-acylanthranilic acids with primary amines:
4(3H)-Quinazolinones may also be synthesized directly from the corresponding N-acylanthranilic acid by heating with ammonia or substituted amines. Bogert and Steiner19 have prepared 2-methyl-3-alkyl-6-nitro- 4(3H)-quinazolinones (14) from N-acyl-5-nitroanthranilic acid and a variety of primary amines.
4. Biological importance of 4(3H)-Quinazolinones :
The quinazolinone skeleton is a frequently encountered heterocycle in medicinal chemistry literature with applications including antibacterial20, analgesic21, anti-inflammatory22,23, antifungal24, antimalarial25, antihypertensive26, CNS depressant27, anticonvulsant28, antihistaminic & local anaesthetic29, antiparkinsonism30, antiviral and cancer activities31. Little number of quinazolinones was reported as potent chemotherapeutic agents in the treatment of tuberculosis. For example 3-aryl-6,8-dichloro-2H-1,3-benzoxazine-2,4(3H)-diones and 3-arylquinazoline-2,4(1H,3H)-diones32 as antimycobacterial agents, quinazolinone derivatives33 as antitubercular agents.
- Gabriel, Ber., 36, (1903) 800.
- Oriefs, Ber., 2, (1869) 416.
- Weddige, J Prakt Chem., 2 , (1887) 141.
- Paal and Busch, Ber., 22, (1889) 2683.
- Griess, Ber., 2 (1869) 415.
- Soderbaum and Widman, Ber., 22, (1889) 1665.
- Korner, J Prakt Chem., 2, (1900) 165.
- Bogert and May, J Am Chem Soc., 31, (1909) 507.
- Bogert and Siel, J Am Chem Soc., 29, (1907) 517.
- Monti and Simonetti, Gazzh., 71, (1941) 654; through Chem Abstr., 37, (1943) 130.
- Magidson and Golovchinskaya, J Gen Chem USSR., 8, (1938) 1797.
- Bogert and Gieger, J Am Chem Soc., 34, (1912) 524.
- Bogert and Scatchart, J Am Chem Soc., 41, (1919) 2052.
- Misra, Science and Culture., 17, (1952) 530.
- Bogert and Clark, J Am Chem Soc., 46, (1924) 1294.
- Heilbron, Kitchen Parkes and Sutton, J Chem Soc., (1925) 2167.
- Niementowski, J Prakt Chem.., 51, (1895) 564.
- Bhattacharya, Bose and Ray, J Indian Chem Soc., 6 (1929) 279.
- Bogert and Steiner, J Am Chem Soc., 27, (1905) 1327; U S Pat., 2, 408, 633 through Chem Abstr., 41, (1947) 1251.
- Berechet Ana and Silvia Boteanu, Farmacia., 19, (1971) 683., through Chem Abstr., 78 (1973) 131903.
- B.C. Lawes and H.C. Sarborough, U.S. 3, 127, 401, through Chem Abstr., 60, (!964) 14525.
- P.N. Bhargava and G.C. Singh, J Indian Chem Soc., 38, (1961) 77.
- CH. Ravishankar, A. Devender Rao, A. Bhaskar Rao, V. Malla Reddy and P.B. Sattur, Curr Sci., 53, (1984) 1069.
- S.N. Sawhney, R.K. Tower, S.P. Singh, Omprakash and Indraprakash, Indian J Chem., 19B, (1980) 415.
- T.A. Martin, A.G. Wheller, R.F. Majewski and J.R. Corrigan, J Med Chem., 7, (1964) 812.
- J.B. Dienei, F. Dowalo, H.V. Hoeven, P. Bender and B. Love, J Med Chem., 16, (1973) 633.
- R.S. Verma, S. Bahadur and A.K. Agnihotri, Arch Pharm., 31, (1981) 97.
- M.L. Gujral, P.N. Saxena, R.P. Kohli, Indian J Med Res., 45, (1957) 201.
- V. Chandrasekhar, A. Raghurama Rao and V. Malla Reddy, Indian Drugs, 3, (1986) 24.
- P. K. Naithani, Gautam Palit, V.K. Srivastava and K. Shankar, Indian J Chem., 28B, (1989) 745.
- R.O. Dempcy and E.B. Skibo, Bioorg and Med Chem Lett., 1 (1993) 39.
- Waisser Karel, Gregor Jii, Dostal Hynek, Kunes Jioi, Kubicova Lenka, Klimesova Vera and Kaustova Jarmila, Il Farmaco, 56(10), (2001) 803.
- Kuneš Jií, Bazant Jaroslav, Pour Milan, Waisser Karel, Šlosárek Milan and Janota, Jií, Il Farmaco, 55(11-12), (2000) 725.
Dr. S.N.Meyyanathan, M.Pharm, Ph.D., is a Professor in the Department
of Pharmaceutical analysis, JSS college of pharmacy at Ooty – 643001, Tamilnadu,
India. He has sixteen years of teaching and research experience and has more than
30 publications in National and International journals. He has been nominated
as International Professional of the Year 2005 by International
Biographical centre, Cambridge, UK. His major areas of interest are Drug synthesis
and Pharmaceutical Analysis. He has supervised seventeen M.Pharm theses and is
currently supervising as co guide for many Ph.D. research scholars. Dr S.N.Meyyanathan
has presented papers in many National and International conferences. He is a life
member of member of Indian
Pharmaceutical Association and Association
of pharmaceutical Teachers of India. He is a paper reviewer for International
Journal of Pharmaceutical and biomedical analysis. His biography has been
published in Marquis
who’swho in the world and Marqius who’s who in medicine and healthcare.
He has filed one patent in the field of drug synthesis.
Contact address :
Dept.of Pharmaceutical Analysis,
J.S.S.College of Pharmacy,
P.B.20, Rocklands, Ootacamund 643 001, Tamilnadu, India.
Phone : 0423-2443393 (O)
Fax : 0423-2442937