4- Amino substituted quinazolines

Denny and co-workers used their 4-thiomethyl substituted quinazolines to generate 4-amino substituted quinazolines as potential antitumor therapeutics. Treatment of 6-methyl-4-(methylthio)-6//-pyrrolo[2,3-g]quinazoline with 4-bromoaniline under thermal conditions gave the desired 4-substituted quinazoline in 85% yield. 

Preparation of Amino-Substituted Quinazoline (45) and Cleavage from the Resin to Obtain the 2-Unsubstituted 4-Arylaminoquinazoline (46) (Fig. 8)30... 

In the remaining quinazolines investigated, there were no substituent interferences. Benzo[/]quinazoline-l(2//)-one (254) afforded an excellent yield (96%) of 3-aminobenzo[/]quinazoline-l(2H)-one (255). Benzo[/]-quinazoline-3(4H)-one (256) provided l-aminobenzo[ / ]quinazoIine-3(4H)-one (257) in 70% yield (Scheme 85). Finally, two amino-substituted quinazolines, 247 and 3-aminobenzo[/]quinazoline, gave 248 in yields of 93 and 65%, respectively, in the Chichibabin reaction. 

The 2-methylthio-3-substituted quinazolin-4(3H)-one 3 was obtained by dissolving 4 in 2% alcoholic sodium hydroxide solution and methylating with dimethylsulfate whilst stirring at room temperature (yield 88%, m.p 124-126 C). The IR spectrum of 3 showed the disappearance of the amino (NH) and thioxo (CS) stretching signals of the starting materials. It showed a peak for carbonyl (CO) stretching at 1680 cm The NMR spectriun of com-... 

The same microwave procedure has also been used with guanidine derivatives 833 to give 2-amino-4-substituted quinazolines 834 <2005BML2145, 2005T3533>. 

Synthesis of pyrido[ 1,2-bJquinazolines through formation of the azole ring from properly substituted quinazoline precursors is also known (61AP556). Thus, the cyclodehydrobromination of the 2-(4-bromo-butyl)quinazolin-4-one (445) with alkali was claimed to give only the linearly annulated 1,2,3,4-tetrahydropyrido[ 1,2-6]quinazolin-4-ones (446) (61AP556). Oxidation of the 3-amino-2-(butyn-l-yl)quinazolin-4-ones (447) with lead tetraacetate led to intramolecular addition of the produced /V-nitrene intermediate to the triple bond to give 449 [86JC S(P 1) 1215]. 

Quinazolines are of great interest in the pharmaceutical industry as protein tyrosine kinase inhibitors. Dener et al 8 described a synthesis starting from 2-methoxybenzaldehyde, Wang, or Rink resins. With the aldehyde resin reductive aminations were undertaken to yield polymer-bound secondary amines (Fig. 7). The latter were subjected to 2,4-dichloro-6,7-dimethoxyquinazoline to give the 4-amino-substituted derivatives. These were then allowed to react with primary or secondary amines at 135-140° in the presence of DBU in DMA. As a result of a detailed scope and limitation study, Dener et al,28 note that some bifunctional amines, such as piperazine, give to some extent dimeric derivatives. 

In the reaction of tetraisopropylthiuram disulfide (TITD) with the dianioii obtained by double lithiation of 3-amino-2-ethylquinazolin-4(3//)-one with lithium diisopropylamide, deamination takes place to afford 2-substituted quinazolin-4(377)-one 22. °... 

Substituted 5,6,7,8-tetrahydroquinazolines are dehydrogenated to 2-substituted quinazolines by heating with palladium on charcoal in Decalin or without a solvent. The reduction in Decalin takes place in good yield when the substituent at the 2-position is amino and in lower yield where it is aliphatic or aromatic. " ... 

Various biological activities were found in the following derivatives 2,4-bis(dialkylaminoalkyl)quinazolines (curare mimetics), l-((o-dimethyl-aminoalkyl)-3-substituted quinazoline-2,4-diones (inhibition of gastric secretions), 4-alkoxycarbonylmethylthioquinazolines (radioactivity protecting agents), and 2-amino-6-hydroxymethyl(or formyl)quinazolin-4-ones (xanthine oxidase inhibitors). ... 

Fusion of 4-hydroxyquinazoIine with phosphorus pentasulfide yields 4-mercaptoquinazoline and, similarly, substituted 2,4-dimercapto-quinazolines have been obtained from the corresponding dihydroxy compounds. The greater reactivity of the 4-mercapto as compared with the 2-mercapto group has permitted the preparation of 4-amino-2-mercaptoquinazolines (see 7a). 

Kinetic studies have been carried out on the displacement reactions of various chloroazanaphthalenes with ethoxide ions and piperi-dine. - 2-Chloroquinoxaline is even more reactive than 2-chloro-quinazoline, thus demonstrating the powerfully electrophilic nature of the -carbon atoms in the quinoxaline nucleus. The ease of displacement of a-chlorine in the quinoxaline series is of preparative value thus, 2-alkoxy-, 2-amino-, - 2-raethylamino-, 2-dimethyl-amino-,2-benzylamino-, 2-mercapto-quinoxalines are all readily prepared from 2-chloroquinoxaline. The anions derived from substituted acetonitriles have also been used to displace chloride ion from 2-chloroquinoxaline, ... 

CN/CC replacements were also observed when the pyrimidine ring is part of a bicyclic system. Reaction of quinazoline with active methylene compounds, containing the cyano group (malonitrile, ethyl cyanoacetate, phenylacetonitrile) gave 2-amino-3-R-quinoline (R = CN, C02Et, Ph) (72CPB1544) (Scheme 12). The reaction has to be carried out in the absence of a base. When base is used, no ring transformation was observed only dimer formation and SnH substitution at C-4 was found. 

Fluoro atom of 2-amino-8,9-difluoro-5-methyl-6,7-dihydro-5//-pyr-ido[3,2,l-y]quinazoline-l,3-dione was replaced by 3-substituted pyrrolidines in the presence of NEt3 in DMSO at 110°C for 18h (01MIP23). 

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