Scalable synthesis of biologically active novel ethyl 1-(4-alkyl-3-oxo-3,4-dihydro quinoxaline-2-yl)-1H-pyrazole-4-carboxylate derivatives

Abstract A one pot synthesis of ethyl 1-(1,2-dihydro-2-oxoquinoxalin-3-yl)-1H-pyrazole-4-carboxylate has been developed using the 3-hydrazineylquinoxalin-2(1H)-N-alkylation derivatizes one and ethyl 2-Formyl-3-oxopropionate and further this scaffold to afford the various novel ethyl 1-(4-Alkyl-3-oxo-3,4-dihydroquinoxalin-2-yl)-1H-pyrazole-4-carboxylate derivatives. The developed method is a novel, cost-effective, and industrially viable method. Consequently, the process described is less cumbersome due to the number of reaction stages reduced, the purity of the organic compound produced, and the substantial yield. This novel synthetic route is believed to be the shortest and most efficient of previous synthetic routes. The established route could be facilitated to prepare various key intermediates and active pharmaceutical ingredients. GRAPHICAL ABSTRACT


Introduction
Heterocyclic compounds have high medicinal values [1a-1c] because of various biological activities [2] due to their skeleton having hetero atoms like nitrogen, [3] oxygen, [4a,4b] and Sulphur. [5a,5b] Most of the marketed drugs are available with one or more heteroatoms. Similarly, the quinoxaline compounds also show diversities in therapeutic values, [6] after the main core of quinoxaline is derivatized by constructing the cyclic ring or alkylating the nitrogen. [7a-7c] As of now, most of the literature supports imidazoquinoxalinone [8a,8b] or triazoloquinoxalinone [9a-9e] compounds for various therapeutic activities. The triazoloquinoxalinone and imidazoquinoxalinone scaffolds are very well known for their biological activities, such as anti-microbial, [10,12] anti-viral, [11,12] Anticancer activity, Anti-inflammatory Activity, Anticonvulsant Activity, Antimalarial Activity, Antileishmanial Activity, HT 3 Receptor Antagonist Activity, Trypanocidal Activity, AMPA Antagonist Activity, Anti-amoebic Activity, Vascular smooth muscle cell proliferation inhibitor Activity, and Antiglaucoma Activity. [12] While our project was underway, Niu et al., have published the synthesis of 1-(4-Alkyl-3-oxo-3,4-dihydroquinoxalin-2-yl)-1H-pyrazole derivatives by electro oxidative C-H azolation of quinoxalin-2-(1H)-ones [13] Here, we report the results of our attempts to synthesize the active molecules through one pot reaction, particularly by constructing the pyrazole ring and various N-alkyl substitutions. We further present the results of studies on the biological activities of the title compounds. The primary synthetic methods that were employed for the production of the pyrazole ring included first creating the 3-hydrazineylquinoxalin-2(1H)-one (1c) [14] as the essential starting material, and then following it up with an alkylation step (Schemes 1 and 2).
There are many types of core molecules of quinoxaline compounds associated with triazole [10,14] and imidazole [8,15] with a fused ring system, but very few analogs are reported with substituted pyrazole ring structures. In view of the information presented above, an effort has been made to develop a generic approach that is generally risk-free Scheme 1. Synthetic strategies for the generation of N-Substituted pyrazole quinoxaline (previous and current). and scalable for the synthesis of new pyrazole quinoxalinones. This is being done in preparation for future biological investigations. This compelled us to create new targets of pyrazole quinoxaline with N-substitution using a variety of alkylating chemicals to investigate a reliable approach for the synthesis of pyrazole targets (3a-3s). We have established an efficient method for the scalable one-pot synthesis of pyrazole quinoxaline to make the synthetic process less laborious and risky (3).

Results and discussion
The 3-hydrazinylquinoxalin-2(1H)-one (1c) recently has been prepared [14] and further used for the preparation of pyrazole ring construction followed by N-substitution as target molecules (3a-3s) for methodological scope and biological activities screening purpose (Scheme 3, Fig. 1).
To optimize the cyclization reaction condition to produce the hydroxy pyrazole (2). The results of the screening with the different solvents prompted us to adjust the reaction conditions. The aforesaid synthetic results concluded that the solvent has a significant impact on the yield of the hydroxy pyrazole (2). We performed experiments using polar and nonpolar solvents, polar solvents resulted in higher product yield. The intermediate hydroxy pyrazole (2) compound synthesis was attempted by using various solvents, including methanol, ethanol, isopropyl alcohol, toluene, THF, DMSO, and DCM. In the presence of ethanol solvent, we observed that the hydroxy pyrazole cyclized compound (2) formed with a 90% yield in 2 h. Moreover, the protic polar solvents show the optimum conversion due to the high degree of solubility of 3-hydrazinylquinoxalin-2(1H)-one (1c). Synthetic optimization conditions of hydroxy pyrazole cyclized compound (2) using various solvents are present in Table 1.
Further, we have also screened the different dehydrating reagents to eliminate the water molecules for complete aromatization. Using various catalysts, such as sulfuric acid, p-TSA, and amberlyst-15 gives quinoxaline-2,3(1H,4H)-dione (1b) as an undesired product along with several impurities may be due to the pyrazole ring being highly unstable nature. Detailed synthetic information was present in Table 2.
Based on the above experimental observation, the polar protic and high boiling solvent is the preferred choice for the complete conversion of quinoxaline pyrazole-4-carboxylate (3) without adding any dehydrating reagent. Hence, the reaction was initiated by using ethanol and continued heating up to 24 h without adding any catalyst, without  making the choice of other polar protic solvents to avoid the trans-esterified undesired products with respective alcohols. These results suggest that the aforesaid synthetic conditions are preferable for the synthesis of pyrazole quinoxaline (3). These synthetic results were presented in the given Table 3.
For the final alkylation reaction purpose DMF solvent is used as a good choice because of the high solubility of pyrazole quinoxaline (3) starting material (Scheme 4). The inorganic bases are tried to get the optimum yield and purity. It has been found that whenever potassium carbonate is being used as a base, we have seen additional Oalkylated undesired product at a higher level than comparatively cesium carbonate. The O-alkylated undesired product (6f and 6h) was isolated by column chromatography and    Bold values indicate that the optimisation conditions is giving higher yield. characterized by 1 H-NMR and 13 C-NMR. Other compounds were prepared without making a choice of isolation of respective O-alkylated products because which is not in the scope of targeted synthesis. The results are summarized in Tables 4 and 5.

Conclusion
In this study, we describe an economically viable and less cumbersome method for the synthesis of novel pyrazole quinoxaline derivatives with sustainable yield. Preparation of hydroxy pyrazole intermediate (2) using various solvents, such as methanol, ethanol, isopropyl alcohol, toluene, THF, DMSO, and DCM. In the presence of ethanol solvent, hydroxy pyrazole compound (2) formed with a 90% yield. N-alkyl pyrazole quinoxaline and O-alkyl pyrazole quinoxaline. The developed method could be used to synthesize various pyrazole quinoxaline derivatives for pharmaceutical applications.
Note: The compounds 3c, 3e, 3f, 3g, 3h, and 3i were purified by column chromatography on 60-120 mesh silica gel by using ethyl acetate and n-Hexane as a gradient. Yield