The article presents a process research study of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (1), a crucial intermediate in the synthesis of baloxavir marboxil. The original four-step sequence ...exhibited various limitations, such as low yield (43%), the use of problematic solvents, a large excess of costly reagents, safety concerns, and impurity control difficulties. To address these challenges, process optimization was carried out to achieve the desired goals for large-scale industrial production. Optimization of the enamine 4b synthesis was performed, resulting in the development of an azeotropic removal method for the byproduct methanol. This improvement led to minimized ring-opening impurity 15 and a significant reduction in the consumption of the condensation reagent. Furthermore, a simplified one-pot two-step oxidation sequence was devised to streamline the process for the synthesis of compound 1. This optimization involved controlling the formation of hydrolytic impurity 16 and its downstream aldol condensation form 17. The optimized process was successfully demonstrated on a 600 g scale with a product purity of 99.9%, and the overall yield was substantially improved, rising from 43 to 66%.
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•Efficient approach to enaminoketones of 2′-carboxamidodeoxybenzoins in good yields.•Efficient approach to otherwise not readily obtainable 3-aryl-4-formylisocoumarins.•Readily ...available reagents, simple procedures, and short reaction times.•N,N-Dimethylformamide dimethyl acetal serves both as a carbon source and solvent.
The efficient synthesis of enaminoketones of 2′-carboxamidodeoxybenzoins and subsequent transformation into 1-oxo-3-aryl-1H-isochromene-4-carbaldehydes via an intermolecular cyclization under weakly acidic conditions has been demonstrated. Mild reaction conditions, a simple work-up procedure, short reaction times and high yields are the advantages of the presented method.
An efficient strategy for the synthesis of 6-unsubstituted indolo1,2-
quinazolines is described. The Pd-catalyzed reaction of
-(
-aminophenylethynyl) trifluoroacetanilides with Ar-B(OH)
afforded 2-(
...-aminophenyl)-3-arylindoles, that were converted to 12-arylindolo1,2-
quinazolines by adding dimethylformamide dimethyl acetal (DMFDMA) to the reaction mixture after extractive work-up. This reaction outcome is different from the previously reported Pd-catalyzed sequential reaction of the same substrates with Ar-I, Ar-Br and ArN
BF
, that afforded 12-arylindolo1,2-
quinazolin-6(5
)-ones. Moreover, 12-unsubstituted indolo1,2-
quinazolines can be obtained both by reacting 2-(
-aminophenyl)indoles with DMFDMA or by sequential Pd-catalyzed reaction of
-(
-aminophenylethynyl)aniline with DMFDMA.
•Knoevenagel condensation of OMPA with dimethylformamide dimethyl acetal (DMF-DMA).•The chemical modification induce a high changes on the photophysical properties of the prepared oligomer.•The ...chemical modification induce a change on the electronic properties improved by DFT computations.
The synthesized oligo 4-(methoxyphenyl) acetonitrile (OMPA) was chemically modified by Knoevenagel condensation of OMPA with dimethylformamide dimethyl acetal (DMF-DMA). The obtained oligomer is composed of short chains of poly 3-(dimethylamino)-2-(4-methoxyphenyl)acrylonitrile and denoted OMFA. Experimental measurements: ultraviolet-visible (UV-vis), steady-state and time-resolved photoluminescence spectroscopies, infrared spectroscopy, and thermogravimetric analysis (TGA), were combined with theoretical calculations, based on density functional theory (DFT) methodologies, to highlight the effect of the grafting of the dimethyl-amine group on the photo-physical and electronic properties of the as-synthesized oligomer. Thus, a redshift of the absorption and photoluminescence spectra is observed upon the chemical grafting of the functional group. Added to that, a decrease of the optical bandgap (Egopt) and the energy gap EH-L=EHOMO-ELUMO occurs upon the chemical modification. DFT computations show that the chemical insertion of the dimethyl-amine group into the monomer and the oligomer induces a drastic change on their frontier orbitals HOMO and LUMO.
Herein we report an ultrasound‐assisted zinc‐catalyzed solvent‐free process for the synthesis of enaminoketoesters from 1,3 dicarbonyl compounds, N, N‐Dimethylformamide dimethyl acetal (DMFDMA) and ...various amines with good to excellent yields. This methodology is very much applicable for primary aliphatic, aromatic and secondary alicyclic amines bearing different functional groups. The present work offers the following merits such as inexpensive reagents, one‐pot reaction, eco‐friendly and tolerance to different functional groups with short reaction time.
We have developed a highly efficient inexpensive method for the synthesis of enaminoketoesters using Zinc dust under solvent‐free conditions via sonication. The current methodology is very effective with the DMFDMA, 1,3 dicarbonyl compounds and various amines. The present work offers eco‐friendly, high yield and one pot reaction.
Two new series of 1,5-diaryl pyrazoles (5a, 5b, 7a, 7b and 10) and 1,5-diaryl pyrazoline (12a and 12b) were prepared as both Cyclooxygenase-2 and 15-lipoxygenase inhibitors. Carrageenan-induced rat ...paw edema, ulcer index and anti-COX-1/COX-2 and 15-LOX inhibition assays were also included. Cyclization of different pyrazoles was discussed using 2D NMR such as HSQC, HMBC and NOSEY determinations. Compound 5a is more effective with ED50 = 0.98 and 3.98 μM against COX-2 and 15-lipoxygenase respectively, than the references celecoxib (1.54 μM) and meclofenamate sodium (5.64 μM).
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•New thiazolo-celecoxib analogues were designed and synthesized.•Thiazolo-celecoxib drug hybrid showed higher COX-2/15-LOX inhibition properties.•Designed compounds were evaluated as anti-inflammatory activity using Carrageenan-induced rat paw edema and proved activity.•Ulcer liability index of compounds was determined and they showed higher safety profiles.•Most of the compounds were effective as anti-inflammatory and more selective towards COX-2/15-LOX.
The multicomponent reaction of 5-aminopyrazole derivatives with cyclic 1,3-dicarbonyl compounds and dimethylformamide dimethylacetal (DMFDMA) in DMF at 150 °C under controlled microwave heating ...afforded regioselectively 8,9-dihydropyrazolo1,5-aquinazolin-6(7H)-ones 6 rather than the corresponding dihydropyrazolo5,1-bquinazolin-8(5H)-ones 4.
A series of 3,4-dihydro-9-arylacridin-1(2
)-ones was synthesized and enaminone function was introduced at the C-2 position using DMFDMA catalyst which in turn successfully converted into pyrazole, ...isoxazol, 1-phenyl-1
-pyrazole by treating it with reagents such as hydrazine, hydroxylamine and phenylhydrazine. These newly synthesized compounds were evaluated for their antibacterial activity against a series of Gram-Positive bacteria including Staphylococcus
, Bacillus
, Staphylococcus
MLS16 and Gram-Negative bacteria including Klebsiella
, Escherichia
and Pseudomonas
and also against fungal strains including Candida
, Candida
, Candida
, Candida
, Aspergillus
and Issatchenkia
. The compounds
and
exhibited considerable antifungal activity (MIC value 0.007 and 0.006 μM) against Candida
and Aspergillus
respectively. The compound
showed excellent antibacterial activity towards Escherichia
(MIC = 0.003 μM) and the compound
found to show prominent DPPH radical scavenging activity with EC
value 16.85±1.5μg mL
A series of 3-substituted-4-arylquinoline derivatives were synthesized using 3-acetyl-4-arylquinoline. The acetyl function of 3-acetyl-4-arylquinoline was successfully converted into its ...corresponding enaminone using DMFDMA as a reagent which in turn successfully converted into pyrazole, isoxazole, pyrimidine, phenyl aminoprop-2-en-1-one, pyridin-2-yl-amino-prop-2-en-1-one, 2-methylpyridine-3-carboxylate by treating with reagents such as hydrazine, hydroxylamine, guanidine hydrochloride, aniline, 2-amino pyridine, ethyl acetoacetate, respectively, under solvent-free microwave irradiation as well as under the conventional thermal heating processes. All the synthesized compounds were found to be obtained in better yields under the microwave irradiation over the conventional process.
Graphical abstract
One-pot synthesis of three enaminones, (E)-1-(4-chlorophenyl)-3-morpholinoprop-2-en-1-one 1, (E)-1-(4-chlorophenyl)-3-(4-methylpiperazin-1-yl)prop-2-en-1-one 2, and ...(E)-1-(4-chlorophenyl)-3-(pyrrolidin-1-yl)prop-2-en-1-one 3 were achieved. The synthetic protocol via three components reaction of p-chloroacetophenone with DMFDMA (N,N-dimethylformamid-dimethylacetal) and the corresponding secondary amines (morpholine/N-methylpiperazine/pyrrolidine) in dioxane under heating for 2.5–4 h at 102 °C yielded the requisite enaminones. This protocol has the advantage of no separation of intermediate, no need for column purification with quantitative yield for the target compounds. The chemical features of the β-enaminones 1–3 were assigned by NMR. β-Enaminones 1, and 2 were assigned by single crystal X-ray diffraction technique. The intermolecular interactions in the crystal structures were analyzed quantitatively using Hirshfeld analysis. The Cl…H and O…H hydrogen bonds are common in both compounds while the C-H…π and N…H contacts are more significant in 2 than 1. DFT studies were investigated to show the electronic and spectroscopic properties (NMR and UV-Vis) of the studied systems.
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