Synthesis and Reactivity of Some Novel Quinazoline Derivatives

About author :
Ramesh Dhani
Dept. of Pharmaceutical Chemistry
JNTUA-OTRI, India
E-mail: dhanipharmachem@gmail.com

ABSTRACT
Quinazoline is a bicyclic compound earlier known as benzo- 1, 3-diazine. The name quinazolinone (German: Chinazolin) was proposed for its compound by Weddige, on observing that this was isomeric with the then compound cinnoline and quinaoxaline. The numbering of the quinazoline ring system which is currently used was suggested by Paal and Busch. The other less commonly used names for this system are ’phenmiazine’ and 5,6-benzopyrimidine. However, the name ’Quinazoline’ is now universally accepted. The oxo-deravative is suffixed by one, that is Quinazolinone.
Key words: Chinazolin, Quinaxaline, 2-cynoquinazoline 4(3H) one, Quinazoline.
INTRODUCTION
Medicinal chemistry is concerned mainly with the organic, analytical and biological aspects of this process, but its people must interact productively with those in the other disciplines. It occupies a strategic position at the interface of chemistry and biology. There is considerable overlap with other disciplines for e.g. Medicinal chemistry and pharmacology both are concerned with mode of action and SAR of drugs. However, this kind of overlap facilities productive interactions in research. Quinazoline is a bicyclic compound earlier known as benzo- 1, 3-diazine was prepared in the laboratory by Gabriel in 1903 although one of its derivative was known much earlier. The name quinazolinone (German: Chinazolin) was proposed for its compound by Weddige, on observing that this was isomeric  with the then compound cinnoline and quinaoxaline . The numbering of the quinazoline ring system which is currently used was suggested by Paal and Busch. The other less commonly used names for this system are phenmiazine.
MATERIALS AND METHOD:
Methods of synthesis of the Quinazoline nucleus :
Quinazoline in 1905 Riedel obtained a patent describing a synthesis of quinazoline from o-nitrobenzaldehyde through reaction with formamide to the o-nitrobenzylidene-diformamide. Reduction of this with zinc and dilute acetic acid gave quinozoline in good yield. Later improvements in Riedel’s original procedure to obtain up to 65% overall yield have been reported. This is the best method of obtaining quinazoline.
It suffers only from the difficulty of obtaining o-nitrobenzaldehyde and especially substituted o-nitrobenzaldehydes. It has been applied to substitute quinozolines, for the preparation of 6,7-dimethoxy quinazoline through the intermediate 6-nitroveratradehyde. The usual synthesis of quinazolines make use of an o-disubstituted benzene structure  from which the quinozoline skeleton is completed by adding C-2 and N-3 in various ways. Substitutes could either be in the pyrimidine ring or the benzene ring or in both ring.
DERIVATIVES:
These quinazolines are obtained in high yields by heating o-acyl (and formyl) amides in a sealed tube with saturated alcoholic ammonia for a few hours.
These quinazolines are obtained in high yields by heating o-acyl (and formyl) amides in a sealed tube with saturated alcoholic ammonia for a few hours.
2 and 4-alkyquinazolines are readily prepared from o-acylaminobenzaldehyde or phenyl ketones. They show the typical reactions of alkyl groups placed ortho or para to a heterocyclic nitorgen atom. 2-methyl and 2,4-dimethylquinazoline undergo the mannich reactions. Further, sodium hypobromide add to methyl group in the four position in preference to one in the two positions.
A variant of this general synthesis, which avoids the use of sealed tubes and results in improved yields. Ammonia is passed through a fusion of the o-ketoanilides or o-acylaminoketone with ammonium or sodium acetate at 165-175^oC.Condensation of o-aminoaceto or benzophenone with oxalyl chloride gives di-anilides which on ring closure to give 2,2 biquinazolines.
2-Quinazolines :
Heating o-aminoacetophenone and an excess of urea at 190^o for 20 min gives a 60% yield of 4-methyl-2-quinazolone, o-aminobenzaldehyde similarly gives 2-quinazoline. Benzolyeneurea can be readily prepared by melting together anthranilic acid and urea or by the action of a aqueous cyanic acid on anthranilic acid.
4-Quinazolines:
The most common synthesis of 4-quinazolones is a reaction, which was first described by V. Niementowski in 1985. When anthranilic acid is heated in a open container with excess formamide at 120^oC, water is expelled and a nearly quantitative conversion to 4-quinazolone is achieved. It has been carried out with a variety of substituted anthranilic acids corresponding 2-substituted 4-quinazolones. As a rule a higher temperature or longer reaction time is required for substituted anthranilic acids.  It has been adapted to many aliphatic amides to give alkyl substituents in the 2 position. A higher temperature is required, and the yields generally decrease as the molecular weight of the amide is increased. Yield with benzamide are extremely low, but Sherril and co-worker have obtained a 50% yields of 2-phenyl-4-quinazolone by replacing benzamide with thiobenzamide or ethylimidobenzoate.
A method of wide applicability for preparation of 4-quinazolones involves the direct synthesis and isolation of the desired N-acylanthranilamide.  When heated above their melting points, these lose water with formation of the quinazoline ring. Formylanthranilamide easily yields 4-quinazolone. 
4-Quinazolone with substituents in any position can be obtained by heating 5-chloro-N-acetyl anthranilanilide at its melting point for several hours gives 6-chloro2methyl-3-phenyl-4-quinazolone.
4-keto-1, 4 dihydroquinazoline, a 4(1)-quinazolone can be obtained by heating   N-alkyl-N-acylanthranilamide at its melting point for several hours. Weddige studied these reactions with variously substituted amides. N-acylanthranilamide was converted to the quinazolone in one operation. Bogert andco-workers introduced such a variation involving acetanthranil “Acetanthranils” (3,1,4-benzoxazones) can easily be prepared by heating anthranilic acid or a substituted anthranillic with an acid anhydride.The acetanthranils react exothermally with ammonia &most amines in aqueous media to give high yields of quinazolones. 4-Quniazolones may also be made directly from the corresponding N- acylanthranilic acid by heating with ammonia or amines. Bogert and Steiner have prepared 2-methyl-3-alkyl-7 nitro-4-quinazolones from N-acyl-5-nitroanthranilic acid and a variety of amines. 4-hydroxy quinazolines react with primary amines or hydrazine to form 3-substituted 4(3H) quinzolinones. The mechanism was  shown to involve ring opening because with secondary  amines (where ring closure is not possible) N-disubstituted benzamides are formed Two methods closely allied to the above involve the heating of anthranilonitrile with an acid anhydride and the hydrolysis of an N-acylanthranilonitrile urethane and acetanilide heated for 3 hrs. with phosphorus pentoxide in toluene to give 2-methyl-4-quinazolone
RESULTS & DISCUSSIONS :
A variant of this general synthesis, which avoids the use of sealed tubes and results in improved yields. Ammonia is passed through a fusion of the o-ketoanilides or o-acylaminoketone with ammonium or sodium acetate at 165-175^oC. Condensation of o-aminoaceto or benzophenone with oxalyl chloride gives di-anilides which on ring closure to give 2, 2’biquinazolines.
CONCLUSION :
The present study of quinazolines is explained about different synthetic methods. It leads to the formation if novel synthetic derivatives. By using this methods it will produces the higher yield.