Quinazoline preparation

Developments have also been seen in the synthesis of fused quinazolines. Preparation of the linear 3tf-(p-chlorophenyl)perhydropyrrolo[2,l-b]quinazolin-l-one (40a) and the angular 3a-(p-chlorophenyl)perhydropyrrolo[2,1 -njquinazolin- i -one (40b) from 3-(p-chlorobenzoyl)propanoic acid and cis-2-aminocyclohexylmethanamine has been achieved, and these tricyclics and have... 

Fig. 3 Examples of quinazolines prepared by tandem aza-Wittig/electrocyclization, heterocyclization, three-component reaction...

Little is known quantitatively about substituent effects in the nitration of derivatives of azanaphthalenes. In preparative experiments 4-hydroxy-quinoline, -cinnoline, and -quinazoline give the 6- and 8-nitro compounds, but with nitric acid alone 4-hydroxyquinoline and 2,4-di-hydroxyquinoline react at With nitric acid, 4-hydroxycinnoline... 

The preparation of quinazoline-2(and 4)-thiones follows those of the corresponding pyrimidines (67HC(24-1)270) but there is at least one special primary synthesis for quinazoline-4(3H)-thiones, illustrated by the reaction of o-aminobenzonitrile with thioacetic acid at 110 °C to give 2-methylquinazoline-4(3H)-thione in 90% yield (53JA675). 

Another quinazoline, prazosin (1040), is now a widely used antihypertensive drug, acting by vasodilation (77MI21300, B-81MI21301) its preparation is outlined in the patent literature (72NEP7206067). 

Some tricyclic systems have been prepared by intramolecular cyclization from A-aryl-pyrazoles carrying substituents both in the pyrazole ring at C-5 and in the phenyl ring at the o-position. Thus pyrazolo[l,5-n]quinazolines (563) (69JHC947) and pyrazolo[l,5-n]-[l,4]benzodiazepines (564) (77JHC1163, 77JHC1171) can be prepared from suitable precursors. 

A series of quinazolines analogous in constitution with the angostura alkaloids has been prepared by Bogert and collaborators,... 

Quinazoline (1,3-diazanaphthalene) was prepared by Gabriel in 1903 although the first derivative tvas synthesized by Griess 34 years earlier. The name was proposed by Widdege. Other names such as phenmiazine, benzo-l,3-diazine, and 5,6-benzopyrimidine have occasionally been used. The numbering suggested by Paal and Busch (1) is still in use. ... 

Quinazoline 3-oxides were first prepared by Awers and von Meyen-burg in 1891 by the dehydration of o-acylamino benzophenone oximes with acetic acid-acetic anhydride and were assigned the in-dazole structure (33). This was then modified by Bischler to the... 

Unsubstituted quinazoline 3-oxide was prepared in an attempt to react quinazoline with hydroxylamine. This reaction gave a product of variable composition, but when an acetone solution was heated in a sealed tube it gave quinazoline 3-oxide. The oxide is more conveniently prepared, in excellent yield, from o-aminobenzaldehyde oxime and ethyl orthoformate. This method appears to be of general use and has been used for the preparation of 4-methylquinazoline... 

Catalytic reduction of quinazolines unsubstituted in position 4 using palladium-charcoal, palladium on calcium carbonate, Raney nickel, or Adam s platinum has been used for preparing 3,4-dihydro-... 

Further reduction of 3,4-dihydroquinazoline to l,2,3,Jt-tetTahydro-quinazoline is more difficult, but it can be accomplished with sodium amalgam or by catalytic reduction with palladium-charcoal. 1,2,3,4-Tetrahydroquinazolines have also been prepared by condensing o-aminobenzylamines with various aldehydes and with formaldehyde or methylenediamines (see 3b). 

Decarboxylation of a-(4-quinazolinyl) acetic esters in alkaline solution is useful for the preparation of less readily accessible 4-alkyl quinazolines (see 4c). This method is limited to derivatives where... 

Aminoquinazolines have been the subject of considerable investigation and a large number of derivatives have been prepared as potential antimalarials. The secondary and tertiary amino compounds can be prepared from the corresponding chloroquinazolines and the required primary or secondary amines. The reaction depends on the reactivity of the halogen atom, e.g, the 4-chloro atom reacts more readily than the 2-chloro atom in quinazolines and also on the basic strength of the amine used (see 6a). The reaction is... 

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). 

Of greater versatility is an extension of Albert and Royer s acridine synthesis. The first successful use of this in the quinazoline series was for the removal of the chlorine atom in 2-chloro-4-phenylquin-azoline, although it had been used previously to prepare 8-nitro-6-methoxyquinazoline in very poor yield. The 4-chloroquinazoline is converted to its 4-(A -toluene-p-sulfonylhydrazino) quinazoline hydrochloride derivative which is decomposed with alkali in aqueous ethylene glycol at lOO C (Scheme 13). The yields are high (60-70%) when R is Me, Cl, OMe but low when R is NO2, and in the latter case it is preferable to use dilute sodium carbonate as the base. This reaction is unsatisfactory if the unsubstituted pyrimidine ring is unstable towards alkali, as in 1,3,8-triazanaphthalene where the pyrimi-... 

Reduction of quinazoline oxides to quinazolines, catalytically (Raney nickel, palladium on charcoal) or with iron and ferrous sulfate in 85% alcohol can be extended to the preparation of benz-substituted quinazolines. ... 

Many quinazolines possessing a wide variety of biological activities are known. The antimalarial activity of febrifugine spurred the preparation and testing of a number of quinazolines, and several... 

Amino- and hydrazino-quinazolines exhibited antibacterial ac-tivity and a patent claim on the in vitro action of 2,4-diamino-quinazolines was rnade. The preparation of thiopegan derivatives as potential antimalarials and antibacterials deserves mention. Complete inhibition of influenza virus in vitro but not in vivo was shown by. 6,8-dichloro-2,4-dihydroxyquinazoline and other cyclic ureas. Activity against trachoma virus was also displayed by several 2-trichloromethylquinazolines. ... 

Quinazoline hydroxamic acids (26) can be prepared by acylation of an o-aminobenzohydroxamic acid (25). An alternative procedure... 

Morley and Simpson prepared quaternary salts from 4-phenoxy-quinazoline and 6- and 7-nitro-derivatives of 4-anilino- and 4-acet-amido-quinazohne. 6-Nitro-4-aminoquinazoline, however, could not be quatemized under the fairly mild conditions used by the... 

Fry et al. prepared quaternary salts from 4-methyl- and 4-methyl-thio-quinazoline and found that the same cyanine dyes were obtained by suitable reactions of either salt. An unambiguous synthesis of the 4-methylthio salt (69) from l-methylquinazoline-4-thione (70) proved that both of the salts carried groups on N-1. 

Quaternary salt formation in 4-quinazoline 3-oxide and its 4-amino and 4-methyl derivatives has been studied by Adachi. These N-oxides, prepared by reaction of the simple quinazoline with hydroxylamine, react with ethyl iodide at N-1, although only in the case of the 4-amino derivative could the ethiodide be purified. The salts are degraded by alkali yielding derivatives of ethylaniline [Eq. (4)]. 

A-Substituted 11-oxo-l l//-pyrido[2,l-6]quinazoline-6-carboxamides were prepared from 11-oxo-l l//-pyrido[2,l-6]quinazoline-6-carboxylic acids and amines in the presence of (/-Pr)2EtN and benzotriazol-l-yloxytris(dimethy-lamino)phosphonium hexafluorophosphate in CH2CI2 (98MIP1, 98MIP2, 99USP5908840, 99USP5914327). 

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, ... 

Tetrahydro-l//,5//-pyrido[3,2,l-//]quinazoline-l,3-diones were prepared by the cyclization of l-tert-butoxycarbonyl-l,2,3,4-tetrahydroqui-noline-8-carboxamide on the action of 60% aqueous NaOH solution in THF at 50 °C (01M128). 

Phenyl-5,6-dihydro-l//,7//-pyrido[3,2,l-//]quinazoline-7-one and 1,7-dione 179 (X = H2 and O) were prepared from tetrahydroquinolines 206 and 207 with A-(ethoxycarbonyl)thiobenzamide and PhCOCl, respectively (98EJM763). 

The original objective of the synthetic work was the preparation of basic derivatives of the 3,1,4-benzoxadiazepine system (2) for animal testing. The basic ring system had been reported previously in the literature as the dehydration products of 2-acylaminobenzophenone oximes (1). Repetition of the work quickly cast doubt on the earlier structural assignment. Both the chemistry of the products and their spectral data suggested that the products were in fact quinazoline-3-oxides (3). ... 

Triazinoindole 146 was obtained (74T3997) in a mixture with quinoline 148 on thermolysis or of 3-(alkylthio)-6,7-dihydro[l,2,4]triazino[l,6-c]quinazolin-5-ium-l-olate 144 acid hydrolysis. The reaction presumably took place via the decomposition of 144 to a ketone and 142, which then cyclized. Compound 144 was prepared by the condensation of 142 with aldehydes, ketones, or their equivalents. Reaction of 142 with 3-amino propanol gave 143, which cyclized to 145 and then to 147 with base [80ACH(104)107] (Scheme 32). 

The key intermediate 2-thioxo-3-phenylquinazohn-4(3H)-one was prepared by adding carbon disulfide and sodium hydroxide solution simultaneously to a vigorously stirred solution of aniline 7 in dimethylsulfoxide over 30 min stirring was then continued for an additional 30 min. Dimethylsulfate was added to the reaction mixture whilst stirring at 5-10°C after which it was stirred for another 2 h and then poured into ice water to obtain a soHd dithiocarbamic acid methylester 6. The compoimd 6 and methylanthranilate 5 when refluxed in ethanol for 18 h yielded the desired 2-thioxo-3-substituted quinazolin-4(3H)-one 4. The product obtained was cycUc and not an open chain thiourea 5a. It was confirmed by its value, high melting point, and its... 

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