Pyridopyrimidine and its derivatives have been studied due to a variety of chemical and biological significance. The importance of pyridopyrimidines as biologically active compounds includes their use as antibacterial [1-3], antiallergic [4], antitumor [2,3] antifolate [5], tyrosine kinase [6], antimicroibial [7], calcium channel antagonists [8], antibacterial [9-12], anti-inflammatory, analgesic [13], antihypertensive [14], antileishmanial [15], tuber-culostatic [16], anticonvulsants [17], diuretic, potassiumsparing [18], and antiaggressive activities [19]. The need to reduce the amount of toxic waste and byproduct arising from chemical processes requires increasing emphasis on the use of less toxic and environmentally compatible materials in the design of new synthetic methods. One of the most promising approaches is using water as the reaction media [20-26].

Several approaches have been developed for the synthesis of pyridopyrimidines such as: 1) the reaction of benzylidene derivatives of malononitrile with 6-amino-3, 4-dihydropyrimidine in refluxing ethanol [27,28]; 2) the reaction of 6-amino-1-thio uracil with ethyl-3-phenyl-2- cyanoacrylate in absolute ethanol and in the presence of Et₃N by heating [29,30]; 3) the three-component reaction of aldehydes, alkyl nitriles and aminopyrimidines in water and in the presence of KF-Al₂O₃ as catalyst [31]; 4)

the similar three-component reaction catalyzed by TEBAC [32] or reaction of amino-uracil with α,β-unsaturated compounds in ionic liquid at 90˚C [33]. Some of the reported methods have their merit such as: 1) multi-step synthesis with the use of expensive harmful reagents and 2) low yields. Thus, the development of efficient method for the synthesis of biologically active compounds such as pyrido[2,3-d]pyrimidines, in one-step would be highly valuable and desirable.

The utility of microwave energy in synthetic organic chemistry has been increasingly recognized in recent years. It was shown that MWI-irradiated multi-component reactions have constituted an especially attractive synthetic strategy for rapid and efficient library generation. It has some advantages such as environmentally friendly, improving the bond forming efficiency (BFE), time saving, experimental simplicity, and also in view of atom economy, multi-component reaction is preferred [34-36] and this approach was used for academic and industries research [37]. Meanwhile, there has been increasing interest in the development of new catalysts, which are cheap, and effective in aqueous media. Recently, diammonium hydrogen phosphate [(NH₄)₂HPO₄] (DAHP) in aqueous media has emerged as a very effective catalyst for various organic transformation, and our group has been developing organic synthesis in aqueous media. DAHP is very inexpensive, water soluble, non-toxic and commercially available so it can be used in the laboratory without special precautions [38]. This encouraged us to consider DAHP as an ideal catalyst for the one-pot synthesis of pyrido[2,3-d]pyrimidines.

Due to the potential interest in finding more new versatile procedures, a microwave-assisted synthesis and using DAHP as a mild catalyst in aqueous media was investigated.

In this context, we introduce an efficient one-pot threecomponent reaction of aromatic aldehydes 1, malononitrile 2, and 4(6)-aminouracil 3 and MWI for the synthesis of pyrido[2,3-d]pyrimidines using microwave irradiation (Scheme 1, method A) and also in the presence of catalytic amounts of DAHP (10 mol%) in refluxing aqueous ethanol (Scheme 1, method B)

With the aim to develop more efficient processes, reduce the number of separate reaction steps, and minimize byproducts for the synthesis of pyrido[2,3-d]pyrimidines [39,40], and in continuation of our previous work on the development of new and efficient methods for the preparation of heterocyclic compounds [41-45], a convenient, practical, inexpensive, rapid procedure for the preparation of pyrido[2,3-d]pyrimidine derivatives 4(a-h) was reported (Scheme 1, methods A, B).

To explore the scope and versatility of this method, various solvents were investigated. We used the reaction of 4-nitrobenzaldehyde (1h, 1 mmol), malononitrile (2, 1.2 mmol) and 4(6)-aminouracil (3, 1 mmol) for the preparation of compound 4h as a model and various solvents such as glacial acetic acid (HOAc), ethanol, glycol, water and N,N-dimethylformamide (DMF) as solvent

(1.0 mL) were used, also reaction was checked in solventfree conditions at 120˚C respectively. All the reactions were carried out at the maximum power of 250 W. The results are summarized in Table 1. The heating characteristics of a solvent under microwave irradiation conditions are dependent on the dielectric properties of the solvent. This fact is shown in Table 1, where the best result was achieved using DMF as solvent. So DMF was chosen as the reaction solvent. More over in order to optimize the other reaction conditions the different powers and temperatures for the same reaction were examined, so microwave irradiation at 250 W gave the highest yield and the maximum temperature reached during the reaction was 120˚C. Therefore, microwave power of 250 W was chosen as the optimum power.

Table 2 shows the results obtained in the reaction of a series of representative aldehydes 1 with malononitrile (2, 1.2 mmol) and 4(6)-aminouracil (3, 1 mmol) under microwave irradiation. In method B we have used aqueous media catalyzed by DAHP at reflux conditions for the preparation of corresponding products 4(a-h). In this manner and in order to optimize the reaction conditions the catalytic amount of DAHP was varied finding that 10 mol% of DAHP afforded the best yields. It is important to note that in the absence of DAHP the reaction times are increased, meanwhile the yields are decreased mainly. The results are summarized in Table 2. In order to optimize the reaction conditions the catalytic amount of DAHP was varied finding that 10 mol% of DAHP afforded the best yields. It is important to note that in the absence of DAHP the reaction did not take place at all. To show that DAHP is an efficient catalyst rather than a mild base, we adjusted the reaction conditions to pH 8, but we found that the reaction did not proceed.