Current Organic Synthesis - Current Issue

The origin, synthesis, characterization and docking studies of (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R,1E,4E)-3-hydroxy-5-phenylpenta-1,4-dien-1-yl)cyclopentyl)-N-ethylhept-5-enamide, an impurity generated in the preparation of an anti-glaucoma agent-Bimatoprost has been described.

This impurity was controlled by employing 30% Pd/C, and the impurity level was brought to the permissible level, i.e., 0.03% (ICH guidelines) in the final drug preparation of Bimatoprost.

Finally, induced-fit docking calculations were performed to theoretically evaluate the binding efficiencies of these inhibitors in the crystal structure of Prostaglandin F synthase (PGFS).

There are negligible differences in RMSD and docking scores between the two ligands, which amount to only 0.18 Å and 0.313 kcal/mol, respectively. These findings strongly indicate that both ligands are likely to exhibit similar biological functions and efficiencies.

The protection of the hydroxyl group as formamides is a crucial initial step in pharmaceutical synthesis.

In this study, we investigated the O-formylation of alcohols using dimethylformamide (DMF) in a mixture with a new magnetic nanocomposite Fe3O4@Chitosan/POCl2-x.

The results demonstrate that this core-shell heterogeneous nanocomposite facilitates the formation of alkylformate, yielding products with high efficiency ranging from 79% to 96% within a remarkably short reaction time of 1 to 12 hours at room temperature, depending on the substrate structure. Significantly, the presence of this nanocomposite exhibits remarkable selectivity, favoring the formylation of less hindered benzylic and aliphatic primary alcohols. However, bulkier alcohols and phenols exhibit lower reactivity under these conditions and thiols do not react. The simplicity of the work-up procedure, combined with the magnetic recyclability, makes it reusable and environmentally friendly.

This study highlights the efficacy of this novel magnetic nanocomposite in facilitating formylation reactions, emphasizing its potential for application in pharmaceutical synthesis and bio compounds. This is due to its attributes of non-toxic nature, stability, and significant advantages over conventional methodologies.

The development of efficient and sustainable catalytic methodologies has garnered considerable attention in contemporary organic synthesis.

Herein, we present a novel approach employing the Cu@DPP-SPION catalyst for the synthesis of ethyl 4-(aryl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives. This versatile catalytic system incorporates copper nanoparticles supported on 4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)benzoic acid-functionalized superparamagnetic iron oxide nanoparticles (SPIONs). The catalyst was meticulously characterized through scanning electron microscopy (SEM), transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier-transform infrared spectroscopy (FTIR), energy dispersive spectroscopy (EDS), and inductively coupled plasma (ICP) analysis. The catalytic process, exemplified by the synthesis of heterocyclic compounds, demonstrated high isolated yields, attesting to the robust performance of the catalyst.

Furthermore, the reusability of the catalyst was validated through five consecutive reactions without a notable decrease in yield, while structural stability was confirmed by SEM analysis. The methodology combines green reaction conditions, room temperature operation, and facile magnetic catalyst separation, underscoring its potential for sustainable synthesis.

This work highlights the promise of the Cu@DPP-SPION catalyst as an innovative tool in heterogeneous catalysis and its role in advancing efficient and environmentally conscious synthetic methodologies.

Timolol maleate is clinically used for the treatment of hypertension, angina pectoris, tachycardia, and glaucoma.

The aim of this study was to enhance the safe use of timolol maleate and investigate a synthesis method for 3-S-timolol, a newly identified impurity in timolol API (Active Pharmaceutical Ingredients).

(S)-3-(tert-butylamino)propane-1,2-diol (1) was used as a raw material. 3-S-timolol maleate (7) was synthesized through a five-step reaction. Overall yield was 57.7%, with a purity of 98%.

The structure of the target compound was confirmed via analysis of its ¹H nuclear magnetic resonance, ¹³C nuclear magnetic resonance, and high-resolution mass spectrometry spectra.

The synthesis method was straightforward and yielded a high-purity product suitable for use as a reference in the analysis and identification of timolol maleate-related substances.

Despite the well-known antibacterial activity of cephalosporins, their analogous spirocyclic derivatives have not been adequately evaluated. Thus, this work aimed to prepare a series of novel 3-spirocephalosporins and evaluate their antibacterial activity.

Novel 3-spirocephalosporins were prepared through a one-pot thioalkylation of chloromethyl cephalosporin GCLE with a range of 1,2,4-triazolidine-3-thiones, followed by intramolecular Michael addition to the generated dihydrothiazine ring. The reaction was performed at room temperature under basic conditions (K2CO3, acetone, H2O). The antibacterial activities of the synthesized compounds were evaluated against a panel of Gram-positive and Gram-negative bacteria.

Most targets were obtained in moderate yield, and their structures were confirmed by ¹H and ¹³C NMR spectral techniques. All the tested compounds exhibited antibacterial activity against methicillin-resistant S. aureus.

Seven novel thiazolidine-bearing 3-spirocephalosporins were prepared, and most of them were potent against Gram-positive bacteria. Likely, the replacement of 1,2,4-triazolidine-3-thiones with other heterocycles containing bidentate nucleophiles in advantageous positions could lead to different biologically active spirocephalosporins.

New benzazacamalexin-related analogues are synthesized in an easily accessible one-pot approach. The method is based on the reaction of indoles with in situ formed electrophilic N-alkoxycarbonylbenzimidazolium reagents. For the first time, their application for N-alkylation of the indole nitrogen atom is announced toward novel tris-heterocyclic hybrids. The structure of newly obtained products was spectrally characterized by 1D and 2D-NMR, FTIR and HRMS spectral data. The current scientific research is based on the application of a convenient and efficient route for the preparation of various benzimidazoles. This approach is both straightforward and economical, utilizing readily accessible and affordable reagents leading to target compounds.

The synthesis of novel benzimidazole-indole molecular hybrids as benzazacamalexin related analogues.

A suitable in situ method has been successfully applied, using an α-amidoalkylation reaction of indoles with N,N-diacyliminium reagents derived from benzimidazoles and alkyl chloroformates.

The reactions led to the obtaining of ten novel compounds (5a-e, 6a-e), including bromine and iodine-containing benzo-analogues on a gram-scale scope and yields ranging from 82% to 99%. For the first time the synthesis of indole tris-heterocycles (7a, b) through the reaction of N-alkylation of the indole nitrogen atom is announced giving another potential synthetic application of the N,N-dialkoxycarbonyl-5,6-dimethylbenzimidazolium adducts.

The structure of the newly synthesized products is spectrally analysed and proved.

Quinazoline holds significant importance in pharmaceutical chemistry, which is included in a range of drugs, clinical contenders, and bioactive compounds. N-containing heterocyclic compounds of quinazoline have a wide and distinct range of biopharmaceutical activities.

A series of newly synthesized heterocyclic compounds, namely, N-(4-substituted benzylidene)-2-(2-aminothiazol-4-yl)-6-methylquinazolin-3(4H)-amines (3a’-3e’) and N-(4-substituted benzylidene)-2-(2-aminooxazol-4-yl)-6-methylquinazolin-3(4H)-amines (3a-3e), were synthesized starting from 6-methylquinazolin-3(4H)-amine and 4-substituted benzaldehyde and their antibacterial and antifungal properties were evaluated. Moreover, they were compared with the well-known drugs Imipenem (as an antibacterial agent) and Miconazole (as an antifungal).

Compound 3c' exhibited higher potential activity compared to newly synthesized other compounds and standard drugs when tested against the microorganism.

The structure of substances was determined through elemental analysis (C.H.N.) and various spectroscopic technique (¹H NMR, ¹³C NMR, IR, and GCMS).

It is well established that 4H-pyran derivatives hold a significant position in synthetic organic chemistry due to their diverse biological and pharmacological properties. This work aims to introduce a novel synthetic pathway for highly functionalized 4H-pyran derivatives, achieved through a 1,4-Michael addition followed by a cascade cyclization. This reaction is catalyzed by LiOH·H2O under ultrasonic irradiation in water, offering an efficient and environmentally friendly approach.

In this study, lithium hydroxide monohydrate (LiOH·H2O) was used as the catalyst. To explore environmentally friendly methods, two novel approaches utilizing pure water were investigated (Method 1 and Method 2). The first method involves the use of alkylidene reagents malononitrile and ethyl acetoacetate in an aqueous medium. The second method features a multi-component cyclocondensation of aromatic aldehydes, malononitrile, and ethyl acetoacetate, activated by ultrasound waves and conducted in pure water. The impact of various substituents on the formation of 4H-pyrans, including both electron-poor and electron-rich aromatic aldehydes, was also evaluated.

Most products were obtained in high yield and as very pure crystals with distinct colors. Generally, aromatic aldehydes with electron-withdrawing groups (Cl) exhibited greater reactivity than those with electron-donating groups (OMe). This trend is clearly demonstrated when comparing entries 3 and 4 with entries 5 and 6 in Tables.

Compared to other procedures, this method is simple, fast, eco-compatible since it uses water as a solvent. In addition, the products are obtained in good yields in the pure state after simple recrystallization without the need for other purification techniques, such as column chromatography. These factors make this novel approach highly attractive for the synthesis of 4H-pyrans.

An efficient procedure was reported for the synthesis of novel hybrid dithiazoles 7 and thiazoles 15, in good yields, by applying hydrazonyl chlorides 4 with thiocarbohydrazone derivatives 3 and 12.

The thiazole derivatives were evaluated for their antimicrobial and antioxidant activities.

According to the results, thiazoles revealed marked potency as antimicrobial and antioxidant agents. Thus, 7a's DPPH radical scavenging activity was excellent (38.19±0.33 and 14.37±0.4) at concentrations of 2.0 and 1.0 mg/mL, respectively. In addition, compound 3 exhibited activity against all bacterial strains tested, as evidenced by inhibition zones measuring that ranged from 8.5±0.43 mm for E. faecalis to 16.5±0.43 mm for S. mutans.

The MIC results showed that compound 3 was effective against E. coli, S. aureus, E. faecalis, P. aeruginosa, and S. mutans at concentrations of 1.0, 1.0, 2.0, 1.0, and 1.0 mg/mL, respectively. Furthermore, molecular docking has shown lower binding energy with different types of interactions at the active sites of Dihydropteroate synthase, Sortase A, LasR, and penicillin-binding protein pockets, indicating that these compounds could inhibit the enzyme and cause promising antimicrobial effects.