Pyrimido 2-carboxylic acid derivatives

A final approach to pyrimido[4,5-( ]pyridazines involves construction of a pyrimidine ring from a 3-aminopyridazine -carboxylic acid derivative as described in both CHEC(1984) and CHEC-II(1996) <1984CHEC(3)329, 1996CHEC-II(7)737>. Further examples of this approach have appeared since the publication of CHEC-II(1996) <2000JCCS951, 2006JHC243> and the approach has been used to prepare peri-fused systems (Scheme 20) <1993JRM1239>. 

Heating 3-bromo-2-methyl-4//-pyrimido[2,l -a]isoquinolin-4-one (152) in 10% sodium hydroxide for 5 h afforded 2-methylimidazo[2,l-a]isoquino-line (190, R = H) and its 3-carboxylic acid derivative (190, R = COOH) in 74% and 19% yields, respectively (80KGS1656). 

Wamhoff and Hendrikx prepared pyrimido[4,5-h]azepine-6-carboxylic acid derivatives 514 and 515 from carbodiimide 513 by reacting it with 5% sodium hydroxide solution or with hydrazine and i-propylamine in boiling... 

Pyrimidines bearing amino groups adjacent to a carboxylic acid152,203,204 or carboxylic acid derivatives 1 10,205 208 have been used in the synthesis of pyrimido[5,4-r/]pyrimidines. Thus, methyl 2,5,6-triaminopyrimidine-4-carboxylate (1) on heating with benzamidine at 100 C furnishes 6,8-diamino-2-phenylpyrimido[5,4- f]pyrimidin-4-ol (2).110... 

A pyrimido[ 1,2-c]quinazoline-4-carboxylic acid derivative (FR50948) exhibits excellent antiallergic effects <88MI 825-01 >. 

Acid derivatives First, various pyrimido[4,5-b]quinoline-2-carboxylic acid derivatives were examined (Figure 5). The nearly equal activity of the acid VI and corresponding ethyl (VII) and butyl (XX) esters suggests that the acid is the active species. However, the ethyl ester is definitely advantageous for oral activity, being nearly 10 times more potent than the butyl ester or the carboxylic acid. This suggests that the lipophilic character of the ester is important for oral absorption. The carboxamide (XXI) which may not be readily hydrolyzed to the acid in vivo exhibits significantly reduced potency both intravenously and orally, and the N-ethyl carboxamide (XXII) is inactive at comparable doses. 

The (lS)-5-amino-8,9-dihydroxy-2,3-dihydro-l//-pyrimido[l,2-a]quinoline-3-carboxylic acid (8) form of pyoverdin PaA was halogenated at position 7 with a 30-fold excess of ferric chloride and bromide in acidic water at room termperature for 18 h (97TL97). Acidic hydrolysis of (15)-5-amino-8,9-dihy droxy-2,3-hy dro-1 //-pyrimido [1,2-a] quinoline- 1-carboxylic acid (8) in boiling 6 N hydrochloric acid for 48 h gave the 5,8,9-trihydroxy derivative (90MI2). Treatment of 2,3-dihydro-l//-pyrimido[l,2-a]quinoline hydrochlorides with aqueous 10% sodium hydroxide gave 4a-hydroxy-2,3,4,4a-tetrahydro-l//-pyrimido[l,2-a]quinolines (60) (69YZ759). 

Oxo-4//-pyrimido[2,l-a]isoquinoline-3-carboxylic acids and their 6,7-dihydro derivatives were prepared by the hydrolysis of ethyl 4-oxo-4H-pyrimido[2,l-a]isoquinoline-3-carboxylates (97) and their 6,7-dihydro derivatives (98) under acidic (in a boiling mixture of acetic acid and cone, hydrochloric acid) and basic conditions (in 2% sodium hydroxide solution, and in a boiling mixture of 2% sodium hydroxide and ethanol) [78USP4127720 84JAP(K)84/172472 85EUP143001]. 

Pyrimido[5.4-r/]pyrimidines 5 and 6 are readily prepared by the condensation of 5-amino-2,6-dihydroxypyrimidine-4-carboxylic acid ( orotic acid ) with formamidc or urea. Reaction of the starting pyrimidine with formamide gives pyrimido[5,4-c/]pyrimidine-2,4,8-triol (5), which can also be prepared from ethyl 5-aminoorotate in 72% yield. In this case, the 5-amino group is first converted into the (ethoxymethylene)amino derivative and then treated with ammonia.207 The corresponding tetrol 6 results from reaction of the starting pyrimidine with urea.152,203... 

The cyclization ofthe2-(4-methylpiperazinyl) derivative of1046 (R = 4-methyl-1 -piperaziny 1) afforded pyrimido[2,3-c/]pyrimidine-6-carboxylate (1047, R = 4-methyl-l-piperazinyl, R1 = Et) in 82% yield when it was heated in polyphosphoric acid at 140°C for 20 min (74GEP2341146). 

Catalytic hydrogenation of ethyl 4-oxo-4//-pyrimido[2,l-a]isoquinoline-3-carboxylate (97, R = H) in acetic acid over 10% Pd/C gave a 6,7-dihydro derivative (98, R = H) (78USP4127720). 

Nitration of ethyl l-oxo-l//-pyrimido[l,2-a]quinoline-2-carboxylate (38, R = Et) in 98% sulfuric acid with 100% nitric acid at 0°C for 15 min, then at room temperature for 90 min afforded the 5-nitro derivative (74MIP1). 

Treatment of ethyl 10-(dimethylaminomethylene)-ll-cyano-4-oxo-7,8, 9,10-tetrahydro-4//-pyrimido[l,2-b]isoquinoline-3-carboxylate (119) with 2 N hydochloric acid at 20°C for 3 h afforded tetracyclic derivative 160 (84KFZ931). 

SWP605940 80JCS(P1)227]. Earlier, products 231 and 232 were described as [l,3]diazepino[l,2-a]quinoline derivatives (73GEP2315422). When the cyclization was carried out in a mixture of polyphosphoric acid and phosphoryl chloride at 110-120°C for 2.5 h, in addition to 2-(l-oxo-lH-pyrimido[l,2-a]quinolin-2-yl)acetate (230) (42%), ethyl l-(2-quinolyl)-5-chloropyrroline-3-carboxylate (233) was also obtained in 16% yield [78JCS(P1)795]. 

Heating diethyl (l-isoquinolylamino)methylenemalonates in diphenyl ether gave ethyl 4-oxo-4//-pyrimido[2,l-a]isoquinoline-3-carboxylates (97) (78USP4127720). Cyclization of diethyl[(4-amino-l-isoquinolyl)amino] methylenemalonate in a mixture of acetic anhydride and pyridine in methylene chloride at ambient temperature afforded ethyl 7-acetylamino-4-oxo-4//-pyrimido[2,l-a]isoquinoline-3-carboxylate [84JAP(K)84/172472]. The 7-nitro derivative was prepared similarly. Cyclization of diethyl [(7-methoxy-3-methyl-l-isoquinolyl)amino]methylenemalonate in polyphos-phoric acid at 130°C for 6 h gave 10-methoxy-6-methyl-4//-pyrimido[2,l-a]isoquinolin-4-one in 29% yield [94IJC(B)795]. 

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