3- quinazolinone

Fluproquazone (97) contains a 2-quinazolinone nucleus and is found to be an analgetic agent useful in mild to moderate pain. One of the preparations involves reaetion of 2-isopropylamino-4-methyl-4 -fluoro-benzophenone (96) with potassium cyanate in hot acetic acid [27],... 

The 2-aminoquinazolines 259 were prepared in two independent ways. The 2-quinazolinone 258 was transformed to 2-aminoquinazoline 259 by treatment with phosphorus oxychloride and subsequently with sodium amide in liquid ammonia, or with phosphorus pentachloride under carefully controlled conditions [75JCS(P1)1471]. Attempts to prepare the N-substituted derivatives failed, but the reaction was successful with the unsubstituted cis cyclopentane-fused homolog [76JCS(P1)1415]. 

Attempts to convert 4(3//)-quinazolinone 118 to 4-bromoquinazoline with triphenylphosphine and iV-bromosucci-nimide were not very successful, although 2-bromo-4-phenylquinazoline 121 was formed from the 2-quinazolinone 120 in 49% yield under the same conditions <2001HCA1112>. 

Dihydro-2-quinazolinones are available from diphenylamine-2-acetic acids via isocyanate intermediates, and thus the nonsteroidal anti-inflammatory agent diclofenac 745 gave the dihydro derivative 746 in 63% yield on treatment with diphenylphosphoryl azide <2004BML357>. 

When the carbon dioxide is replaced with carbonyl sulfide, generated in situ from carbon monoxide and sulfur, 4-thioxo-2-quinazolinones 818 are produced <2000HAC428>. 

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>. 

Performing a Vilsmeier-Haack reaction on 3-benzoyloxy-2-methyl-quinazolin-4-one (184) afforded the isoxazolo[3,2- ]quinazolinone (185) [86IJC(B)709]. This ring system (187) was also synthesized by cyclocondensation of anthranilic acids or isatoic anhydrides with the isoxazolin-3-ones (186) (77AF766 83MIP1), or by condensation of methyl anthrani-late with 3-chloropropanoyl chloride followed by cyclization with hydroxylamine hydrochloride (77AF766). 

Although the yield in this synthesis of 2-quinazolinone is low, it provides a route to a 4-substituted ring system it deserves further study of its scope [3105]. 

Quinazolin-2(and 4)-one were first shown to exist as 0x0 tautomers by IR and UV spectroscopic comparisons akin to those above (52JA4834, 51JCS3318) like its pyrimidinone analogue, the quinazolinone (41) prefers that configuration to the pczra-quinonoid tautomer (57JCS4874), a conclusion upheld by the NMR study of simple analogues (69T783). 

Pyrazolopyrimidinones C NMR, 5, 308 methylation, 5, 310 synthesis, 5, 329 Pyrazolopyrimidinones, thioxo-synthesis, 5, 324 Pyrazoloquinazolines synthesis, 5, 317, 322 Pyrazolo[ 1,5-n]quinazolines synthesis, 5, 273 Pyrazolo[ 1,5-c]quinazolines synthesis, 5, 324 Pyrazolo[2,3-n]quinazolines synthesis, 3, 378 Pyrazoloquinazolinones synthesis, 5, 342 Pyrazolo[4,3-/]quinazolinones synthesis, 5, 273 Pyrazolo[4,3-g]quinazolinones synthesis, 5, 273 Pyrazolo[3,4-/]quinolines synthesis, 5, 273 Pyrazolo[4,3-/]quinolines synthesis, 5, 273 Pyrazolo[l,5-n]quinoxalines synthesis, 5, 339 Pyrazolo[3,4-6]quinoxalines synthesis, 5, 272... 

Quinazolin-4(3H)-one, 3-phenyl-reduction, 3, 75 Quinazolinones polymers, 1, 298 reactions, 3, 89 structure, 3, 66-67 synthesis, 2, 96 3, 133 thiation, 3, 89 Quinazolin-4-oties 2,3-disubstituted Grimmel synthesis, 3, 109 mass spectra, 2, 22... 

The lactam-lactim tautomerism of hydroxyquinazolines is reflected in their chemical reactivity. Thus they are chlorinated to 4-chloro-quinazolines (see Section VI,A), and both 0- and A-methylation have been observed. When a substituent is already present on a nitrogen atom, as in 3-methyl-4(3i7)quinazolinone, chlorination gives 4-chloroquinazoline with loss of the methyl group (see la). 2-... 

Methyl-4-hydroxyquinazoline reacts with organic halides, in the presence of sodium methoxide, to give 3-substituted 2-methyl-4(3i/)-quinazolinones. The 0-acetyl derivative of 4-hydroxyquinazoline has been prepared under anhydrous conditions and gives the hydroxy compound with water or with lithium aluminum hydride. The N-3 acetyl derivative, however, is more stable and gives 3-methyl-4(31/)-quinazolinone with lithium aluminum hydride. ... 

Hydroxyquinazolines react with primary amines or hydrazines to form 3-substituted 4(3//)quinazolinones (15). > The mechanism was shown to involve ring opening because with secondary amines (where ring closure is not possible) A-disubstituted benzamides are formed. Grignard reagents do not always react in the normal way with... 

Methylation of hydroxyquinazolines invariably produces a mixture of 0- and A -methylated derivatives. The A -methyl derivatives are, therefore, best prepared by unequivocal syntheses. 1-Methyl-2(1H)-quinazolinone (16) is not known. When o-aminobenzaldehyde is treated with methylisocyanate, 3-methyl-2(3i7)quinazolinone (17) is obtained. If this is heated in ethanol it dissolves and an alcoholate, presumably (18), crystallizes out, and this can be converted back to (17) by vacuum sublimation. Methylation of l-methyl-4(lH)Quinaz-... 

The ethers (40) are hydrolyzed in high yields, by boiling water (4 hr), to 4-hydroxyquinazoline 1-oxide, and their structures were deduced by methylation followed by reduction to 3-methyl-4(3H)-quinazolinone (Scheme 6). These N-1 oxides show the typical reac-... 

Dihydroquinazolines are normally stable compounds but they deteriorate on long standing. Some examples are known to oxidize to the corresponding 4(3H)quinazolinones. 3-Methyl-3,4-dihydroquin-azoline is converted to the 4-oxo compound after three recrystallizations from light petroleum. The most remarkable example is 3,4-dihydro-6-fluoro-3(p-fluorophenyl)quinazoline [(44), R = F] which oxidizes at its melting point (137°-I38°C), Other halogenated derivatives of (44) are more stable. ... 

Reduction of 3-methyl-4(3H)quinazolinone with lithium aluminum hydride is known to give 3-methyl-l,2,3,4-tetrahydroquinazoline. The most interesting tetrahydroquinazoline is Trbger s base ° since it has added to our knowledge of the stereochemistry of tri-... 

In cases where decarboxylation is anticipated, the quinazolinone could be obtained by heating ammonium o-formamidobenzoate or o-forra ami do benz amide for several hours. This ring closure could be effected more conveniently by boiling the o-formamidobenzamide with 3% aqueous sodium hydroxide for a few minutes, o-Amino-benzamides have also been converted to quinazolinones by refluxing with ethyl orthoformate alone or preferably in the presence of acetic anhydride. ... 

Acetanthranils react exothermically with amines to yield 2,3-disubstituted 4-quinazolinones °" (see 5a). 2,3-Disubstituted... 

H)quinazolinones, which are derivatives of the lactam form of 4-hydroxyquinazoline, are also readily obtained by boiling a solution of o-acylamidobenzoic acid in an inert solvent with the required... 

Substituted 2-mercapto-4(3i/)quinazolinones were prepared by condensing methyl anthranilate with isothiocyanates (see 7c). 

Several 2,3-disubstituted-4(3/f)quinazolinones were active against Plasmodium gallinaceum and showed antiinflammatory action on experimental edemas in animals. 6-(m-Amidinophenyldiazoamino)-... 

Alkyl-3-aryl-4(3If)quinazolinones affect the nervous system in a... 

Of agricultural importance is the plant-growth regulating activity of 6,8-dichloro-2-methyl-3-carboxymethyl-4(3H) quinazolinone which was as potent as 2,4-dichlorophenoxyacetic acid in the Lepidium test. 4-Hydroxy-5,6,7,8-tetrahydroquinazoline has been patented with reference to fungicidal activity. 

The anomalous behavior of quinazoline was first discovered by Albert et who made the surprising observation that 4-methyl-quinazoline 2.5) was a weaker base than quinazoline (pA 3.5). Mason then observed that the ultraviolet spectrum of the quinazoline cation was abnormal but that the spectrum of 4-methylquin-azoline was normal (see Fig. 2). These anomalies led to the suggestion that water adds covalently to the cation of quinazoline to give 12 (R = H). The occurrence and position of hydration were confirmed by a detailed study of the ultraviolet and infrared spectra of the anhydrous and hydrated hydrochlorides and by mild oxidation of the cation to 4(3 )-quinazolinone. Using the rapid-reaction technique (the continuous-flow method), the spectrum of the unstable... 

Oxadiazole was obtained through the first excited singlet state. When the reaction was carried out in the presence of a triplet sensitizer, 99 was not detected but the quinazolinone 100 was obtained (Scheme 41) [91JCS(P2)187]. Compound 99 cannot be obtained via the Dewar isomer. The author supposed the formation... 

Recently, the reaction of 3-methoxy-5-aryl-l,2,4-oxadiazoles in the presence of diphenylacetylene to give the corresponding quinazolinones has been reinvestigated and an electron transfer mechanism was proposed (99JOC7028). 

The isomerization described in Scheme 44 could not be observed when the 5-methyl derivative 108 was used. The quinazolinone 109 was obtained in high yield, probably via 110 through the cleavage of the O—N bond in the triplet state (Scheme 45) [89H(29)737 89H(29)1301 91 JCS(P2)187]. The same behavior (but in low yield) was observed with 111 (Scheme 45) (90JHC861). 

Reaction of malononitrile and quinazolinone 429 in the presence of three drops of NEts yielded pyrido[2,l-Z)]quinazolinone 430 (97MI7). 9,11-Dioxo-5,9-dihydro-l l//-pyrido[2,l-Z)]quinoline-8-carboxylates 432 were prepared in the reaction of anthranilonitrile and 2-piperidones 431 in boiling EtOH in the presence of AcOH (00JCS(P1)3686, 00PS133). 

The clinical acceptance of the dihydrochlorothiazide diuretics led to the synthesis of a quinazolinone bioisostere, fenquizone (54). The synthesis follows the usual pattern of heating... 

QUINAZOLINES AND QUINAZOLINONES Doxazosin (84) is an adrenergic postsynaptic a-1 receptor antagonist with antihypertensive... 

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