Pyrido quinazoline-2-carboxylic acids

The structures of 5-ethyl-1 ]-methyl-9-oxo-5,l l-dihydro-9/7-pyrido[2,1-6]-quinazohne-8-carboxylic acid (00K669), the chromophore 4 of isopyoverdin siderophores (01T1019), and that of 5,5n,6,7,8,9-hexahydro-l l//-pyrido [2,]-6]quinazoline (99SL1383) were justified by X-ray analysis. 

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). 

Heating 6-[(2-carboxylphenyl)amino]-5-cyano-2-methylpyridine-3-carboxylate in refluxing POCI3 afforded 6-cyano-8-ethoxycarbonyl-9-methyl-ll//-pyrido[2,T3]quinazolin-ll-one, but in PPA at 135-145°C 2-methyl-3-ethoxycarbonyl-4-methyl-5-oxo-5,10-dihydrobenzo(3)-l,8-napthyridine-9-carboxylic acid formed <2004CHE510>. 

Cyclocondensation of 2-chloronicotinic acid with 2-amino-5-iodobenzoic acid and methyl 2-amino l-bromobenzoate in boiling EtOH in the presence of cone. HC1 gave the 2-iodo and 3-bromo derivatives of ll-oxo-117/-pyrido[2,l-A]-quinazoline-6-carboxylic acid <1998WO98/023616, 1998WO98/023617, 1999USP5908840, 1999USP5914327>. 

Oxidation of 6-formyl-5,7,8,9-tetrahydro-ll//-pyrido[2,l-b]quinazolin-11-one with potassium permanganate in pyridine at ambient temperature for 3 h gave 11 -oxo-5,7,8,9-tetrahydro-l 17/-pyrido[2,l-b]quinazoline-6-carboxylic acid in 24% yield (84JHC1301). 

Bromo-ll//-pyrido[2,l-b]quinazolin-ll-one and its 8-methyl and 8-isopropyl derivatives (127, R = Br, R1 = H, Me, iPr) were treated with carbon monoxide and nickel carbonyl in wet dimethylformamide in the presence of calcium hydroxyde to yield 2-carboxylic acid derivatives (127, R = COOH, R1 = H, Me, iPr). 2-Bromo-8-isopropyl-ll//-pyrido[2,l-b]-quinazolin-ll-one (127, R = Br, R1 = iPr) was reacted with copper(I) cyanide in iV-methyl-2-pyrrolidone at 180°C for 10 h, then with ferric chloride hexahydrate in diluted hydrochloric acid at 90°C for 30 min to give the 2-cyano derivative (127, R = CN, R1 = iPr) (85CP1189509). 

Cyclocondensation of cis- and trans-2-amino-4-cyclohexene-l-carboxylic acid with 2-methoxy-3,4,5,6-tetrahydropyrimidine in boiling chlorobenzene for 6 h gave ds-4a,lla-H- and trani-4a,lla-H-l,4,4a,6,7,8,9,lla-octahydro-1 l//-pyrido[2,l-6]quinazolin-l 1-ones (75 and 78) (90PHA109). 

Tetrazolyl)- and 2- and 8-carboxylic acids derivatives of 11//-pyrido[2,l-h]quinazolin-ll-one were patented for the treatment of hyperuricemia (88GEP3704203) and hyperlipidemia (89EUP312076) and as cardioprotective agents (90GEP3902639). 

Reaction of 5-bromo-l,2,3,4-tetrahydroquinoline-8-carboxylic acid with COCl2 in THF at room temperature for 16 h gave 8-bromo-6,7-dihy-dro-lH,3H,5H-pyrido[3,2,l-//J[3,lJbenzoxazine-l,3-dione in 80% yield (07WOP2007/028789). 8-Bromo-2-aryl-2,3,6,7-tetrahydro-lH,5H-pyrido [3,2,1-zy]quinazoline-l,3-diones were also prepared in the reaction of N-aryl-5-bromo-l, 2,3,4-tetrahydroquinoline-8-carboxamides and ClC02Ph in boiling 1,2-dichloroethane for 30 min. 

A 3-amino-/V-[2-chloro-4 [(3-hydroxyphenyl)methyl]aminocarbonyl benzoyl-L-alanine substituted Wang resin was /V-acylated with 2-methoxy-11-oxo-l l/7-pyrido[2,l-Z>]-quinazoline-8-carboxylic acid in A-methylpyrro-lidone in the presence of l-hydroxy-7-azabenzotriazole and diisopropylcar-bodiimide (00MIP2). The product was cleaved from the resin by treatment with 50% TFA in a mixture of CH2C12 and MeOH. 

Amides and mono substituted amides of anthranilic acid react with y- or -oxocarboxylic acids to give the pyrrolo- or pyrido[l,2-a]quinazolines 76 ( = 0,Reactions were carried out under reflux in the presence of or without - p-toluenesulfonic acid. Instead of the carboxylic acids, the esters can be applied. 

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. 

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. ... 

In 1872, Griess fused urea and 2-aminobenzoic acid and, although unaware of the nature of his product, had made quinazoline-2,4-dione. Since that time, the reaction has been frequently used for converting C-substituted 2-aminobenzoic acids to their corresponding quinazoline-2,4-diones in excellent yields, usually at 190°-200°C maintained for 1-5 hr.307,308 In addition, 2-aminopyridine-3-carboxylic acid and urea, slowly heated to 210°C, gave a good yield of pyrido[2,3-rf]pyrimidine-2,4-dione.286 Pyrido-[3,4-d]pyrimidine-2,4-dione was formed similarly (yield not given).288... 

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