“…Diethyl 3-oxohexanedioate was obtained as a straw-coloured liquid in a yield of 66%. This compared reasonably well with the literature yields of around 80% (Oikawa et a1 1978;Schmidt & Klade 1988) and the 85% yield of dimethyl hexanedioate reported by Pfordt et al(1981). The nuclear magnetic resonance (NMR) spectrum compared well with that reported by Taylor NMR analysis: 6 = 4.3 (q, 4H, COOCH2CH3), 3.5 (s, 2H, COCH2COOCH2CH3), 2.9 (t, 2H, CH2CH2CH2COCH2), 2.7 (t, 2H, OCH2CH2), 1.3 (t, 6H, COOCH2CH3).…”
Section: Synthesis Of Diethyl 3-oxohexanedioatesupporting
The furan dicarboxylic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (5-propyl FPA) accumulates in the plasma of patients with chronic renal failure and is a major contributor to the drug binding defect of uraemic plasma. This acid has also been implicated in several other aspects of the uraemic syndrome: anaemia, irregularities of thyroid function, neurological symptoms and inhibition of active tubular secretion. The acid is not commercially available and its synthesis, starting with Meldrum's acid and methyl succinyl chloride, is described. The pKa values were measured by titration and values of 3.2 and 3.6 respectively were assigned to the carboxylic acid groups attached directly to the ring at position 3 and at position 2 (on the side-chain). The partition coefficient (log P) between hydrochloric acid and octanol was 1.2 and the distribution coefficient (log D; octanol-phosphate buffer pH 7.4) was -0.59. The pKa values and the degree of hydrophobic character of 5-propyl FPA are consistent with those of other protein-bound acids which undergo active tubular secretion by the kidney and this substance may serve as an endogenous marker for the effects of drugs and disease on this process.
“…Diethyl 3-oxohexanedioate was obtained as a straw-coloured liquid in a yield of 66%. This compared reasonably well with the literature yields of around 80% (Oikawa et a1 1978;Schmidt & Klade 1988) and the 85% yield of dimethyl hexanedioate reported by Pfordt et al(1981). The nuclear magnetic resonance (NMR) spectrum compared well with that reported by Taylor NMR analysis: 6 = 4.3 (q, 4H, COOCH2CH3), 3.5 (s, 2H, COCH2COOCH2CH3), 2.9 (t, 2H, CH2CH2CH2COCH2), 2.7 (t, 2H, OCH2CH2), 1.3 (t, 6H, COOCH2CH3).…”
Section: Synthesis Of Diethyl 3-oxohexanedioatesupporting
The furan dicarboxylic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (5-propyl FPA) accumulates in the plasma of patients with chronic renal failure and is a major contributor to the drug binding defect of uraemic plasma. This acid has also been implicated in several other aspects of the uraemic syndrome: anaemia, irregularities of thyroid function, neurological symptoms and inhibition of active tubular secretion. The acid is not commercially available and its synthesis, starting with Meldrum's acid and methyl succinyl chloride, is described. The pKa values were measured by titration and values of 3.2 and 3.6 respectively were assigned to the carboxylic acid groups attached directly to the ring at position 3 and at position 2 (on the side-chain). The partition coefficient (log P) between hydrochloric acid and octanol was 1.2 and the distribution coefficient (log D; octanol-phosphate buffer pH 7.4) was -0.59. The pKa values and the degree of hydrophobic character of 5-propyl FPA are consistent with those of other protein-bound acids which undergo active tubular secretion by the kidney and this substance may serve as an endogenous marker for the effects of drugs and disease on this process.
“…The success of every combinatorial chemistry approach is critically dependent on the availability of the necessary building blocks. In recent years, several groups have reported the use of 5-acyl Meldrum's acids (5-AMAs) 3 as key building blocks in the construction of heterocyclic combinatorial libraries by solid-phase chemistry (see Scheme ). − However, 5-AMAs are building blocks that are not commercially available, and a search of the literature revealed only a few publications describing the actual preparation of 5-AMAs 3 . − The majority of reports deal with 5-AMAs primarily as noncharacterized intermediates for the preparation of β-ketoesters and other products. − The goal of the present work was to develop protocols for the reproducible preparation of 5-AMAs 3 with high purities and good shelf stability. 1 Heterocycles Prepared by Solid-Phase Synthesis Using 5-Acyl Meldrum's Acids…”
mentioning
confidence: 99%
“…[5][6][7][8] The majority of reports deal with 5-AMAs primarily as noncharacterized intermediates for the preparation of β-ketoesters and other products. [9][10][11][12] The goal of the present work was to develop protocols for the reproducible preparation of 5-AMAs 3 with high purities and good shelf stability.…”
The preparation of novel N-Boc-alpha-amino-5-acyl Meldrum's acids is described. The synthetic inaccessibility and instability of several of these products have led to the development of a protocol that allows the synthesis of their corresponding 4-(dimethylamino)pyridine (DMAP) salts (5-AMA-DMAP's), which exhibit superior stability compared to that of the free 5-AMA. A simple and expedient ion-exchange method was developed for the quantitative removal of DMAP to liberate the synthetically useful DMAP-free form when needed.
“…There are methods to synthesize β-keto esters from esters [34-37] (Claisen condensation) and aldehydes [38,39], but these methods have main limitation in varying the substituents. Often, a number of methods such as acylation of enolates of malonates [40,41], acylation of Meldrum's acid [42-45], mixed malonate esters [46,47] and bistrimethylsilylmalonate [48,49] have a chelating effect employed to lock the enolate anion of malonate using lithium and magnesium salts [50,51]; however, these methods suffer from inconsistent yields in the case of aliphatic acylation. There are methods to synthesize β-keto esters from ketones like caboxylation of ketone enolates [52-54] using carbon dioxide and carbon monoxide sources in the presence of palladium or transition metal catalysts.…”
BackgroundPyrazolones are traditionally synthesized by the reaction of β-keto esters with hydrazine and its derivatives. There are methods to synthesize β-keto esters from esters and aldehydes, but these methods have main limitation in varying the substituents. Often, there are a number of methods such as acylation of enolates in which a chelating effect has been employed to lock the enolate anion using lithium and magnesium salts; however, these methods suffer from inconsistent yields in the case of aliphatic acylation. There are methods to synthesize β-keto esters from ketones like caboxylation of ketone enolates using carbon dioxide and carbon monoxide sources in the presence of palladium or transition metal catalysts. Currently, the most general and simple method to synthesize β-keto ester is the reaction of dimethyl or ethyl carbonate with ketone in the presence of strong bases which also requires long reaction time, use of excessive amount of reagent and inconsistent yield. These factors lead us to develop a simple method to synthesize β-keto esters by changing the base and reagent.ResultsA series of β-keto esters were synthesized from ketones and ethyl chloroformate in the presence of base which in turn are converted to pyrazolones and then subjected to cytotoxicity studies towards various cancer cell lines and antimicrobial activity studies towards various bacterial and fungal strains.ConclusionThe β-keto esters from ethyl chloroformate was successfully attempted, and the developed method is simple, fast and applicable to the ketones having the alkyl halogens, protecting groups like Boc and Cbz that were tolerated and proved to be useful in the synthesis of fused bicyclic and tricyclic pyrazolones efficiently using cyclic ketones. Since this method is successful for different ketones, it can be useful for the synthesis of pharmaceutically important pyrazolones also. The synthesized pyrazolones were subjected to antimicrobial, docking and cytotoxicity assay against ACHN (human renal cell carcinoma), Panc-1 (human pancreatic adenocarcinoma) and HCT-116 (human colon cancer) cell line, and lead molecules have been identified. Some of the compounds are found to have promising activity against different bacterial and fungal strains tested.
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