1 Convenient synthesis of some methyl-N-[ 2-( 6-oxo-3p-tolyl-5 , 6-dihydro-4 H-pyridazin-1-yl )-acetamide ] alkanoates

An efficient one-pot synthesis of methyl-N-[2-(6-oxo-3-p-tolyl-5,6-dihydro-4Hpyridazin-1-yl)-acetamide]alkanoates 5a-j and dipeptides 8a-f was successfully realized starting from amino acid esters 4 and azides 3, 7, respectively. The hydrazide 6a was further reacted with selected aldehydes to give the corresponding hydrazones 9a-c.


Results and Discussion:
The synthesis of new amino acid derivatives coupled with biologically active heterocyclic moieties such as triazole quinazoline 26 and quinoline 27 attracted our attention.In this work we studied 6-p-tolyl-4,5-dihydro-2H-pyridazin-3-one (1) as biologically active heterocyclic moiety.The hydrazide 2 could be prepared by regioselective N alkylation for 1 with ethylbromoactetate which subsequently hydrazinolyzed via hydrazine hydrate (Scheme 1).The procedures of those steps were already established in literature [28][29][30] .
The acyl azide route is one of the first developed for peptide coupling by Curtius 31 .The synthesis of the target amino acid derivatives 5a-j were efficiently formed via azide coupling method, 26,27,[32][33][34] which was reported to minimize the degree of racemization in Various N-acylheteroarylhydrazones (NAH) have been synthesized and were found to possess very interesting biological activities 33,35 .The Glycyl hydrazide 6a was condensed with aldehydes and 2-acetyl furan to exhibit the hydrazone 9a-c (Scheme 2).

Scheme 2
The structure assignment of the N-substituted amino acid esters 5a-j; acyl hydrazide 6; the N-substituted dipeptides 8a-f and acyl hydrazones 9a-c is based on 1 H NMR spectral and physicochemical analysis, Figure 2.
The 1 H NMR spectra clearly confirm the regioselective N-alkylation for all isolated products.Thus, the 1 H NMR spectrum of 5a gave a singlet signal at 4.51 ppm typically associated with NCH 2. Furthermore, a multilplet, a triblet, and two singlet signals at 3.49-3.46,2.51, 3.55 and 6.63 ppm associated with two CH 2 , OMe and NH groups, respectively.Also, the 1 H NMR spectra of all compounds showed two triplets at 2.64 and 3.01 ppm associated with the two CH 2 groups of the pyridazine skeleton.

Figure 1 .
Figure 1.Biological active pyridazinones In this paper, we describe the development of a new series of dihydro-2H-pyridazin-3one derivatives, whose chemical modifications include N-terminal coupled amino acid and dipeptide derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs).
amino acid coupling.The in situ generated azide 3 solution in ethyl acetate reacted with amino acid methyl ester hydrochloride 4 in the presence of triethyl amine to afford methyl-N-[2-(6-oxo-3-p-tolyl-5,6-dihydro-4H-pyridazin-1-yl)-acetamide]alkanoates 5a-j in good yield.Further development of azide coupling was obtained by the synthesis of N-substituted dipeptide derivatives 8a-f.Thus, boiling the amino acid ester derivatives 5a,b (β-Ala, Gly) with hydrazine hydrate gave acyl hydrazide 6a,b (Scheme1).Nitrosation of acyl hydrazide 6a,b finally gave the acyl azide 7a,b by treatment with NaNO 2 and HCl mixture.The in situ generated azides solution 7a,b in ethyl acetate reacted with amino acid methyl esters hydrochloride 4 in the presence of triethyl amine produced dipeptide derivatives 8a-f in good yield, scheme 2.