3- quinazolone reactions

Finally, some results obtained from indazoles substituted in the carbocycle are of interest, even though in these cases the reaction does not involve the heterocyclic moiety (Section 4.04.2.3.2(ii)). For example, pyrazolo[3,4-/]- (566) and pyrazolo[4,3-/]-quinolines (567) have been obtained from aminoindazoles by the Skraup synthesis (76JHC899). Diethylethoxy-methylenemalonate can also be used to give (566 R = C02Et, R = OH) (77JHC1175). Pyrazolo-[4,3-/]- and -[4,3-g]-quinazolones (568) and (569) have been obtained from the reaction of formamide with 5-amino-4-methoxycarbonyl- and 6-amino-5-carboxyindazole, respectively (81CB1624). 

The quinazoline ring also gives some anomalous quatemization reactions, which presumably reflect the influence of the unusual 3,4-bond. 3-Methyl-4-quinazolone (71 Y = O) and, more... 

The lack of structural specificity among sedative-hypnotic drugs has been alluded to before. It is perhaps not too surprising that quinazolones, too, show this activity. The prototype, methaqualone (149), is obtained in a single step from the condensation of the"anthranilamide, 148, with o-toluidine.(The reaction may well involve first formation of the bisamide cycli-zation will then give the quinazolone ring system.) Condensation... 

In a similar vein, condensation of the substituted anthranilamide 96 with trimethyl orthoformate affords directly the quinazolone 98. Reaction with phosphorus... 

Electrocyclic ring closure reactions of phenyl ketenimides 331 allow the construction of the quinazolone ring (Scheme 73). For instance, quina-zolones 332 were synthesized some years ago in 4-85% yield by heating 331 (R2 = Ph) in addition, dimerization through a [4 + 2] cycloaddition leading to 333 (30-73% yield) was observed (78S760). Compound 331 (R1 = CF3) has been employed for the preparation of the trifluoromethy-lated quinazolone 334 (71% yield) [90TL(31 )2717]. 

Incorporation of a piperazine function on the heterocyclic ring leads to a compound in which bronchodilator activity predominates. Treatment of the amino-amide (73-1) with trimethyl orthoformate provides the additional carbon atom for the formation of the quinazolone ring in (73-2). Reaction with phosphoms oxychloride in effect converts the ring to its aromatic form (73-3) by locking in the former amide as an enol chloride. Displacement of the halogen with the isobutyryl urethane (73-4) from piperazine affords piquizil (73-5) [82]. 

Condensation of anthrandic acid (77-1) with an iminoether represents another method for preparing quinazolones. The reaction with the iminoether (77-2) from 2-cyano-5-nitrofuran and ethanohc acid can be visualized as proceeding through the formation of the amidine from addition-elimination of anthranilic acid cycliza-tion then affords the observed product (77-3). This is then converted to chloride (77-4) in the usual way. Displacement of the newly introduced chlorine with diethanolamine leads to the formation of nifurquinazol (77-5) [86], one of the antibacterial nitrofmans (see Chapter 8). 

The particularly good activity against protein kinases of a-aminoquinazoline derivatives is borne out by their activity against both in vitro and in vivo models of human tumors. The examples that follow are but two of a number of compounds from this structural class that have emerged from the focus that has been devoted to this stmctural class. Nitration of the benzoate (78-1) with nitric acid affords the nitro derivative. Hydrogenation converts this to the anthrandate (78-2). In one of the standard conditions for forming quinazolones, that intermediate is then treated with ammonium formate to yield the heterocycle (78-3). Reaction of this last product with phosphorus oxychloride leads to the corresponding enol chloride (78-4). Condensation of this last intermediate with meta-iodoanUine (78-5) leads to displacement of chlorine and the consequent formation of the aminoquinazoline... 

One of the first quinazolone-based drugs, the sedative hypnotic methaqualone (83-4), gained considerable notoriety as a drug of abuse under the alias ludes after the original tradename Quaalude. The compound is prepared in a straightforward fashion by fusion of anthranilamide (83-1) with orf/zo-toluidine (83-2) [93] the reaction can be envisaged as proceeding via the di-amide (83-3). 

Condensation of an aminoketone with urea leads to the formation of a quinazolone by incorporation of carbonyl carbon and one amino group. Thus reaction of the aminobenzophenone (84-1) with urea can be rationalized by assuming the initial formation of the urea exchange intermediate (84-2). Cyclization will then give fluproquazone (84-3) [94], a nonopioid analgesic that shows NSAID-like activity in the absence of a typical acidic function. 

A quinazolone moiety also provides the nucleus for a highly simplified leukotriene antagonist (compare this compound with verlukast (29-6), discussed earlier in this chapter). Condensation of the anthranilate ester (85-1) with formamide leads to the formation of the quinazolone (85-2). Reaction of the salt from the reaction of this product with a strong base with ethyl 3-bromoacrylate leads to vinylation on nitrogen by what is probably an addition-elimination sequence the product is largely the E isomer (85-3). Saponification then affords tiacrilast (85-4) [95]. 

The use of activated anthranihc acid derivatives facUitates the preparation of the amides in those cases where the amines are either umeactive or difficult to obtain. Thus, reaction of (87-1) with phosgene gives the reactive the isatoic anhydride (89-1). Condensation of that with ortho-toluidine leads to the acylation product (89-2) formed with a simultaneous loss of carbon dioxide. This is then converted to the quinazolone (89-3) by heating with acetic anhydride. Reaction with sodium borohydride in the presence of aluminum chloride selectively reduces the double bond to yield the diuretic agent metolazone (89-4) [99]. 

Synthesis from quinazoline precursors was achieved by carrying out a Vilsmeier-Haack reaction on 3-amino-2-methyl-4-quinazolone (96) to give the intermediate diformyl derivative 97 that cyclized to 3-formylpyra-zolo[5,l-b]-quinazolin-9-one (98) [73IJC532 84IJC(B)161]. 

Methyl isatogenate and 2-phenylisatogen react with tetracyanoethyl-ene, or trichloroacetonitrile, in boiling xylene to give quinazolones (154 R = C02Me, Ph).63,72 No reaction occurs with acetonitrile, and N-benzoylanthranilic acid is formed when 2-phenylisatogen is treated with potassium cyanide (see also Section III,A,1). No mechanism has been proposed for this unusual reaction. 

Semicarbazide gives 3-aminoquinazolinedione (175).76,207 Reaction of IA with guanidine forms the diquinazolone 177207 and with cyclic ureas such as 176 tetracyclic quinazolones (178) are produced217 (Scheme 29). 

Lactim ethers and thioethers (300) furnish condensed quinazolones 301 when interacted with IA.303 Ring opening of IA s to the corresponding anthranilic acids and reaction of its potassium salts with chloroacetone yields 2-indolyl ketones 302.304 Potassium cyanide with (V-substituted IA s produces iminoindolinones 303, which were readily hydrolyzed to the corresponding isatins.305 Reaction of 303 to the spiroindoloquinazoline... 

Reaction of the enamine-ester 513 with guanidine in boiling ethanol afforded the quinazolone 517. Hydrogenation of which gave the dihydro derivative 518 (92JHC1375) (Scheme 111). 

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