Quinazolinone carboxylic acids

Carboxylic acids can also be used as a source of the C-4 atom, and the reaction of a diphenylurea derivative 835 with carboxylic acids in polyphosphoric acid (PPA), followed by treatment of the intermediates 836 with sodium borohydride has been used as a source of 3,4-dihydro-2-quinazolinones 837 <2006H(68)1443>. 

Numerous solid-phase preparations of quinazolinones have been reported. The main synthetic strategies used are summarized in Figure 15.16. Quinazolin-2,4-diones can be prepared from anthranilic acid derived ureas or from N-(alkoxycarbonyl)-anthranilamides. These reactions have been performed on insoluble supports either in such a way that the cyclized product remains linked to the support, or such that it is simultaneously cleaved from the support upon ring formation. Quinazolin-4-ones can be prepared by cyclocondensation of anthranilamides with aldehydes, orthoesters [342], or other carboxylic acid derivatives [343]. The selection of examples listed in Table 15.29 illustrates the variety of substitution patterns accessible by means of these cyclizations. 

Egyptian researchers - treated the 2-styryl-4-quinazolinones 132 with maleic anhydride and iV-phenylmaleimide and obtained the Diels-Alder adducts 133. The latter were hydrolyzed with alcoholic sodium hydroxide to the pyrido[l,2-a]quinazoline-l,2-dicarboxylic acids 134 (R = H). The di-carboxylic acids 134 (R = H) and their diesters (R = Et) were also obtained in the reaction of the 2-styryl-4-quinazolinones 132 with maleic acid or diethyl maleate. 

Formyltetrahydropyrido[2,1 -i>]quinazolinone (362) was oxidized to the 6-carboxylic acid 363 with potassium permanganate in pyridine at ambient temperature. ... 

Carboxamides of the tricyclic compounds 244 (n = 1, R = CONH2) and 389 (w = 1, R = CONH2) were obtained from the appropriate esters or from carboxylic acids with ammonia, via mixed anhydrides. N-Substi-tuted carboxamides of the pyrido[l,2-fl]quinazolinones 211 (R = CONHR ) were prepared directly from the corresponding acids with amines in the presence of diphenylphosphoryl azide and triethylamine in dimethyl-formamide at — S C " or were obtained from esters with amines. ... 

The carboxylic acids 432 were prepared from the bromopyrido[2,l-i>]-quinazolinones 431 by the modified Cassar method, with carbon monoxide in 5% aqueous dimethylformamide under 40 psi pressure, or by the use of an equimolar amount of nickel carbonyl in the presence of calcium hydrox-... 

Oxo-l l//-pyrido[2,l-6]quinazoline-8-carboxylic acid was decarboxy-lated to the pyrido[2,l-6]quinazolinone 286. " Ethyl tetrahydro-11-oxo-1 l//-pyrido[2,l-6]quinazoline-6-carboxylate (438) was hydrolyzed and de-carboxylated at 170-180°C to give the tetrahydropyrido[2,l-6]-quinazolinone 203. ... 

A still unresolved problem is the structure of the often used adducts from phosphorus trihalides and carboxylic acid amides, which might be described by the formulae (8) or (9). With the aid of in situ generated adducts of acid amides and PX3 amidines, isonitriles, quinazolinones, alkyl chlorides, aminomethylenediphosphonic acids, carbamoyl halides, triformylaminomethane, 1,3,4-oxadia-zoles, sulfides (from sulfoxides), nitriles (from primary nitro compounds)" and bromoqui-nolines (from methoxyquinolines)" have been prepared. 

Elimination of lorazepam occurs by metabolism within the hver and renal excretion of the metabolites. Glucuronidation to form lorazepam-glucuronide is the major pathway for metabolism. Minor metabolites include a hydroxylated derivative, a quinazolinone derivative and a quinazoline carboxylic acid. Seventy... 

Cul-catalyzed coupling of amidine hydrochloride salts 172 with 2-halobenzoic acid and subsequent condensative cychzation worked well to provide 2-substituted quinazolinones 173 at room temperature (Scheme 60) [102, 103]. The ortho-substituent effect directed by the carboxylic acid group should be the reason of... 

Cobb et al.30 constructed 4-amino-2-carboxy-6-chloroquinazolin-4-one on a solid support using the 2-carboxylic ester linkage as the resin point of attachment. The quinazolinone (43) was converted to the resin-bound 4-chloroquinazoline (44) with SOCl2. The chloro group was then displaced even with anilines under acid-catalyzed conditions at room temperature. Finally, the resin-bound quinazoline-2-carboxylic ester (45) was cleaved from the resin and decarboxylated with TMSCl/Nal (Fig. 8) (yield 69%, purity 95%). 

From the reaction with dimethyl fumarate, the 1 1 cycloadduct 471 was also isolated. On oxidation with 2,3,5,6-dichlorodicyanobenzoquinone in boiling dioxane, dihydropyrrolo[l,2-fl]quinazoline-l-carboxylate (473) afforded the pyrrolo(l,2-a]quinazoline-l-carboxylate 474. The latter product also resulted when the acid 475 was treated with an excess of ethyl propiolate and acetic anhydride in boiling xylene. The reaction of the thiazo[3,2-c]quinazoline 469 with dimethyl acetylenedicarboxylate in boiling toluene led to the pyrimido[l,2-a]quinazolinone 472. 

---