Pyrimidine 2-carboxylic acids, fused

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>. 

Azole approach. The isoxazole ring can be regarded as analogous to the phenyl ring in the synthesis of quinazolines. One method is to react a vicinal aminocarboxamide with an activated carboxylic acid derivative to form the fused pyrimidine the isoxazole (50) is reacted in this manner (67T687). Sometimes it is advantageous to carry out this type of reaction in two steps, such as in the reaction via the 5-ethoxymethyleneamino intermediate (51) (64JOC2116). 

Fusing 8-ethyl-2-(imidazol-l-yl)-5-oxo-5,8-dihydropyrido[2,3-z/]pyrimidine-6-carboxylic acid with excess piperazine at 100 CC yields the corresponding 2-(pipcrazin-l-yl) compound.339,362... 

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... 

An additional heterocyclic ring fused to a (6 5 6) system can be constructed by a cyclocondensation reaction of an appropriately substituted tricyclic derivative with an external reagent. The NH2-CN functionality of (177) was transformed into a pyrimidine by the reaction with formamide <91H(32)895>, and cyclocondensation of the Ac-OH functionality in (178) with phenyl-hydrazine gave a pyrazole <9lH(32)90l>. A hydrazino derivative (179) was condensed with a carboxylic acid to give a 1,2,4-triazole in the reaction that involves an N-2 atom of (179) <88Ci(L)785>. 

Fused pyrimidine-2 carboxylic acids Thienopyrimidines (22,74) and pyrimidoquinoxalines (75). both of which are related to our pyrimido-[4,5-b]quinoline-2-carboxylic acid esters (XXXV and XLIII), were recently reported in the patent literature by Mead Johnson and Mitsubishi, respectively. The most potent compound in the thienopyrimidine series is XCVIII which has an oral ED50 of 3.1 mg/kg (Z3), while ethyl 7,8-di-methoxy-3,4-dihydro-4-oxopyrimido[5,6-b]quinoxaline-2-carboxylate (XCIX) appears to be about equipotent (25) with our compound XXXV. 

A well-known purine is the central nervous stimulant (CNS) caffeine (9.134), which is found in coffee and chocolate. Its synthesis (Scheme 9.77) illustrates the technique of forming the fused imidazole ring of purines. It was noted in Chapter 4 that diaminobenzenes reacted with carboxylic acids or esters to form benzimidazoles this process is known as the Phillips synthesis. It is this reaction that is used to fuse imidazoles to pyrimidines. Here, the process is known as the Traube purine synthesis. The initially formed purine is tri-methylated with methyl chloride and base to form caffeine (9.134). Note that under these conditions it is the 7-nitrogen that is methylated. 

Many ring-fused imidazole derivatives have been synthesized by various methods. Domino Michael addition retro-ene reaction of 2-alkoxyiminoimidazolidines and acetylene carboxylates provided a synthesis of 2,3-dihydroimidazo[l,2-a]pyrimidin-5-(l//)-ones <05T5303>. A single step synthesis of 3,5-dialkyl-9-nitroimidazo[l,2-c]quinazolin-2(3//)-ones from simple carbonyl compounds, primary amines or amino acid methyl esters and 2-azido-5-nitrobenzonitrile has been published <05TL5778>. Diels-Alder reaction of azadienes and benzimidazole-4,7-diones afforded imidazo[4,5-g ]quinoline-4,9-dione derivatives <05EJ01903>. Reaction between isocyanides and dialkyl acetylenedicarboxylates in the presence of 4,5-diphenyl-l,3-dihydro-2//-imidazol-2-one provided a one-pot synthesis of 5//-imidazo[2,l-ft][l,3]oxazine derivatives <05T2645>. Microwave irradiation was employed in the synthesis of 1-ary 1-3-acetyl-1,4,5,6-... 

These systems uniformly have at least one pyrimidine ring, and they are readily formed from aminodiazines, incorporating the amidine moiety, with bifunctional electrophiles serving as three-carbon fragments. In this way, most frequently, 0x0 derivatives are obtained. Alkoxymethyl-enemalonates and 2-benzoylamino-3-dimethylaminopropenoate convert the amines into 4-oxo isomers via, sometimes isolable, intermediates 2-oxo and/or 4-oxo isomers may be formed with acetylenecarboxylic or acrylic acid derivatives or with ethyl acetoacetate. The decisive factors for the regiochemistry have not yet been fully explored. The base-induced rearrangement of ethyl 2-diazanyl-5-oxo-2,5-dihydroisoxazole-4-carboxylates is also a powerful approach to the bicyclic systems. It gives 3-ethoxycarbonyl-2-hydroxy-4-oxo derivatives which present a versatile substitution pattern for further functionalization. A further important aspect of the synthetic methods discussed above is their wide applicability for preparation of the benzo-fused derivatives. 

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