Acid Chloride Formation Research Articles

Synthesis and Antidepressant Evaluation of Heteroaromatic derivatives of Gallic Acid

Oxidative stress is a causative factor of depression and several studies have reported that gallic acid or the derivatives thereof had proven to be effective in displaying antidepressant like action in animal models. Owing to the antioxidant property of GA and the study of structural features it was hypothesized to design new small molecule antidepressant drugs based on GA containing piperazine/piperidine. The two step reaction involved the formation of acid chloride of GA and its conversion to the target compounds in presence of acetone. All the compounds were subjected to evaluation of antidepressant effect using the widely used TST and FST models in mice at dose of 40mg/kg intraperitoneally. The synthesized compounds 2b, 2c and 2e were able to reduce the immobility time in both the models as comparable to the reference compound fluoxetine (10mg/kg) while compounds 2a and 2d were not very significant in reducing the immobility of mice.

Novel Synthesis, Physicochemical Characterization of 1,3,4-Oxadiazinoindole Derivatives for the Purpose of Antidepressant Activity

The present study synthesized a series of 1,3,4-oxadiazinoindole moiety-containing compounds by combining MAOI’s hydrazide moiety and tricyclic moiety having antidepressant activity. The formation of amino acid chloride from amino acids started the synthesis. Further, they were converted into amino acid hydrazide, and then amino acid hydrazones were prepared by reaction of amino acid hydrazide with isatin. Finally, cyclization was acted on hydrazone-containing compounds in the presence of cold H2SO4. Synthesized compounds are characterized and confirmed via mass spectroscopy, 1H-nuclear magnetic resonance strategies, fourier transform infrared spectroscopy, thin layer chromatography, and melting point. The compounds were evaluated for antidepressant activity.

Palladium-catalyzed regiodivergent hydrochlorocarbonylation of alkenes for formation of acid chlorides

Novel strategy for acid chlorides formation that do not use carboxylic acids is particularly attractive in chemical synthesis but remains challenging. Herein, we reported the development of a highly effective Pd-catalyzed hydrochlorocarbonylation of alkenes with CO for the formation of alkyl acid chlorides. Chlorosilane and AcOH were found as a mild HCl source for the reaction. The reaction shows broad substrate scope and produces both branched and linear alkyl acid chlorides in good to high yields upon different ligands and solvents. Cooperating with follow-up acylation reactions, the Pd-catalyzed hydrochlorocarbonylation offers a complementary platform for the synthesis of diverse carbonyl compounds from alkenes. Mechanistic investigations suggested that the reaction proceeded though a palladium hydride pathway, and CO prompted reductive elimination of the acyl-Pd-Cl intermediate.

Synthesis and characterization of two known and one new impurities of dolutegravir: In silico evaluation of certain intermediates against SARS CoV-2 O-ribose methyltransferase (OMTase)

Besides its use against HIV infection the marketed anti-retroviral drug dolutegravir attracted attention as a potential agent against COVID-19 in multiple AI (artificial intelligence) based studies. Due to our interest in accessing the impurities of this drug we report the synthesis and characterization of three impurities of dolutegravir one of which is new. The synthesis of O-methyl ent-dolutegravir was accomplished in three-steps the first one involved the construction of fused 1,3-oxazinane ring. The cleavage of –OEt ether moiety followed by methylation afforded the target compound. The second impurity i.e. N-(2,4-difluorobenzyl)-4-methoxy-3-oxobutanamide was synthesized via a multi-step method involving sequentially the keto group protection, ester hydrolysis, acid chloride formation followed by the reaction with amine and finally keto group deprotection. The synthesis of new or dimer impurity was carried out via another multi-step method similar to the previous one starting from ethyl 4-chloro acetoacetate. The methodology involved preparation of ether derivative, keto group protection, ester hydrolysis, preparation of amide derivative via acid chloride formation in situ and then keto group deprotection for a longer duration. The last step afforded the target compound for which a plausible reaction mechanism has been proposed. All three impurities were prepared in gram scale (minimum 2 g and maximum 8 g). The in silico evaluation of three selected synthesized intermediates e.g. 7, 8 and 9 (structurally similar to dolutegravir) against SARS CoV-2 O-ribose methyltransferase (OMTase) (PDB: 3R24) indicated that compound 7 could be of interest as a possible inhibitor of this protein.

Thermodynamic and kinetic models for acid chloride formation: A computational and theoretical mechanistic study

The structural evolution pathways leading to the conversion of some α-chlorinated carboxylic acids (ClnH3-nCCOOH, n = 0, 1, 2, 3) to their respective acid chlorides by thionyl chloride are investigated via density functional theoretical (DFT) modelling. For all compounds where n = 0–3, acid chloride formation occurs via two competing pathways, consisting of three activation barriers in both cases, all of which are enthalpy-controlled and moderate (ΔGǂ < 190 kJ mol−1). Though both pathways are not limited by the same step, they are both composed of only cyclic activated complexes. Rapid intra-molecular small molecule transfer (HCl) allows one pathway to be slight more productive than the other. Whereas all acids evolve via both competing pathways, the evolution of formic acid occurs exclusively via that which involves intramolecular HCl transfer where all the constituent transition states are formed quasi-synchronously. Results for both pathways are summarized in a detail kinetic model which, of-course, is based on the thermodynamic profiles.

Stereoselective synthesis of homochiral paracyclophanylindenofuranylimidazo[3.3.3]propellanes

The reaction between N-paracyclophanyl-substituted hydrazine-carbothioamides and dicyanomethylene-1,3-indanedione (CNIND) furnished planar and central chiral substituted (epiminomethanoimino)-indenofuranyl-1,4-(1,4-dibenzenocyclohexaphane)-1,2-carboxamides as a type of paracyclophanylfuroimidazo[3.3.3]propellanes in 35–81% yields as a major product as single diastereomers, and substituted spiro[indene-2,4′-indenopyran]-3′-carbonitrile (9–12% yields) as a minor product. To prepare the homochiral paracyclophanylpropellane, oxidation of scalemic formylparacyclophane afforded the corresponding acid. Afterward, the acid chloride formation of [2.2]paracyclophane was obtained by chlorination of the corresponding acid. By repeating the previous procedure and utilizing a final HPLC purification, we succeeded in obtaining the target homochiral propellane. Various spectroscopic techniques such as mass spectrometry, 1H NMR, 13C NMR, and X-ray analysis have been used for structure determination and confirmation of the stereochemistry of the isolated products.Graphic abstract

A Practical Transferring Method from Batch to Flow Synthesis of Dipeptides via Acid Chloride Assisted by Simulation of the Reaction Rate

This paper proposes a technical approach for seamlessly setting the conditions of continuous flow synthesis from batch data. We directly detected the acid chloride formation from Fmoc-l-Phe-OH in batch using the in-line monitoring technology ReactIR and logically calculated the residence time under continuous flow conditions based on kinetic study. Assisted by this simulation method, the sequential flow operations, which consist of acid chloride formation from Fmoc-l-Phe-OH, cooling and coupling with Fmoc-l-Phe-Cl and H2N-l-Phe-OMe, were completed in approximately 1 min.

Synthesis, Characterization and Evaluation of Antimicrobial Properties of (R)-(-)-4-Phenyl-2 Oxazolidinone Based Azetidinones

Introduction: A series of (R)-(-)-4-Phenyl-2 oxazolidinone based azetidinones (4a-i) were synthesized from the reaction of (2-Oxo-4-phenyl-oxazolidin-3-yl) acetic acid with aromatic imines (3a-i) in the presence of Thionyl chloride and Triethylamine as a base. Methods: The transformation proceeds through the formation of acid chloride to ketene which finally forms the azetidinones through [2+2] cycloaddition with aromatic imines. Products obtained were screened to evaluate their antibacterial activity with respect to known bacteria like Escherichia Coli (E. Coli) and Bacillus subtilis. Results and Conclusion: In most of the cases, azetidinones were found to exhibit superior antimicrobial properties than oxazolidinones. They were found to be a good inhibitor of gram-positive and gramnegative bacteria. Enhancement of antibacterial property can be attributed to the presence of azetidinone ring and hydrophobic alkyl side chain in the scaffolds.

Atom- and Mass-economical Continuous Flow Production of 3-Chloropropionyl Chloride and its Subsequent Amidation.

3-Chloropropionyl chloride is a chemically versatile building block with applications in the field of adhesives, pharmaceuticals, herbicides and fungicides. Its current production entails problems concerning safety, prolonged reaction times and the use of excessive amounts of chlorinating reagents. We developed a continuous flow procedure for acid chloride formation from acrylic acid and a consecutive 1,4-addition of hydrogen chloride generating 3-chloropropionyl chloride, as presented in this paper. Up to 94 % conversion was reached in 25 minutes at mild temperatures and pressures. This continuous flow method offers a safer alternative and is highly efficient in terms of consumption of starting product and shorter residence time. Valorization of this building block is exemplified by the synthesis of beclamide, a compound with sedative and anticonvulsant properties. Over 80 % conversion towards this drug was achieved in 1 minute in a continuous flow setup. Further research is needed to telescope the synthesis of 3-chloropropionyl chloride and subsequent beclamide formation without intermediate purification.

Pot Economy in the Total Synthesis of Estradiol Methyl Ether by Using an Organocatalyst

AbstractEnantioselective total synthesis of estradiol methyl ether has been accomplished in a pot‐economical manner using five reaction vessels and four purifications. The key reaction is a diphenylprolinol silyl ether mediated domino Michael/aldol reaction to afford bicyclo[4.3.0]nonane derivatives, containing the A, C, and D rings of steroids, as a single isomer with excellent enantioselectivity. Six reactions such as oxidation, hydrogenation, formation of acid chloride, Friedel–Crafts reaction, deprotection, and reduction can be carried out in the last one‐pot sequence.

Pot Economy in the Total Synthesis of Estradiol Methyl Ether by Using an Organocatalyst.

Enantioselective total synthesis of estradiol methyl ether has been accomplished in a pot-economical manner using five reaction vessels and four purifications. The key reaction is a diphenylprolinol silyl ether mediated domino Michael/aldol reaction to afford bicyclo[4.3.0]nonane derivatives, containing the A, C, and D rings of steroids, as a single isomer with excellent enantioselectivity. Six reactions such as oxidation, hydrogenation, formation of acid chloride, Friedel-Crafts reaction, deprotection, and reduction can be carried out in the last one-pot sequence.

From Aryl Iodides to 1,3-Dipoles: Design and Mechanism of a Palladium Catalyzed Multicomponent Synthesis of Pyrroles.

A palladium-catalyzed multicomponent synthetic route to polysubstituted pyrroles from aryl iodides, imines, carbon monoxide, and alkynes is described. To develop this reaction, a series of mechanistic studies on the [Pd(allyl)Cl]2/P(t)Bu3 catalyzed synthesis of imidazolinium carboxylates from aryl iodides, imines, and carbon monoxide were first performed, including model reactions for each individual step in the transformation. These show that this reaction proceeds in a concurrent tandem catalytic fashion, and involves the in situ formation of acid chlorides, N-acyl iminium salts, and ultimately 1,3-dipoles, i.e., Münchnones, for subsequent cycloaddition. By employing a Pd(P(t)Bu3)2/Bu4NCl catalyst, this information was used to design the first four-component synthesis of Münchnones. Coupling the latter with 1,3-dipolar cycloaddition with electron deficient alkynes or alkenes can be used to generate diverse families of highly substituted pyrroles in good yield. This represents a modular and streamlined new approach to this class of heterocycles from readily accessible starting materials.

ChemInform Abstract: Visible‐Light‐Mediated Synthesis of Amides from Aldehydes and Amines via in situ Acid Chloride Formation.

AbstractA one‐pot photocatalysis‐based amide synthesis starting from aromatic aldehydes is described.

Visible-Light-Mediated Synthesis of Amides from Aldehydes and Amines via in Situ Acid Chloride Formation.

An efficient visible-light photocatalysis-based one-pot amide synthesis method was developed; visible-light irradiation of a mixture of an aldehyde, tert-butyl hydrogen peroxide, and N-chlorosuccinimide using a Ru(bpy)3Cl2 photocatalyst afforded an acid chloride, which subsequently reacted with amine to yield the corresponding amide. The reaction was used to synthesize moclobemide and a D3 receptor intermediate.

A Facile Preparation of α-Aryl Carboxylic Acid via One-Flow Arndt–Eistert Synthesis

An efficient, one-flow Arndt–Eistert synthesis was demonstrated. A sequence of acid chloride formation–nucleophilic acyl substitution–Wolff rearrangement–nucleophilic addition was performed in a microflow system without isolating any intermediates, which included a potentially explosive compound. The microflow system was made from simple, inexpensive, and readily available instruments and tubes. α-Aryl esters 2a and 2b were prepared in yields of 33 and 23 % (three steps) respectively.

Microwave-Assisted Functionalization of Carboxylated Multi-walled Carbon Nanotubes with Isatin Derivatives

In the present study, the microwave-assisted chemical functionalization of carboxylated multi-walled carbon nanotubes (MWNT-COOH) by Isatin derivatives has been investigated and the results were confirmed by Raman, FT-IR, hydrogen nuclear magnetic resonance spectroscopy (1HNMR), scanning electron microscopy, transmission electron microscopy (TEM), thermogravimetric analysis, and elemental analysis. The major advantage of this procedure was reducing the reaction time to the order of minutes and the amidation was completed in one step as compared with two in the conventional approach. Via this method, the acid chloride formation step was eliminated. These functionalizations have been chosen due to NH2 and NHCO active sites in MWNT-amide for future application.

A Palladium-Catalyzed Carbonylation Approach to Acid Chloride Synthesis

We describe a new approach to acid chloride synthesis via the palladium-catalyzed carbonylation of aryl iodides. The combination of sterically encumbered phosphines (P(t)Bu3) and CO coordination has been found to facilitate the rapid carbonylation of aryl iodides into acid chlorides via reductive elimination from ((t)Bu3P)(CO)Pd(COAr)Cl. The formation of acid chlorides can also be exploited to perform traditional aminocarbonylation reactions under exceptionally mild conditions (ambient temperature and pressure), and with a range of weakly nucleophilic substrates.

Comprehensive determination of the solid state stability of bethanechol chloride active pharmaceutical ingredient using combined analytical tools

The use of an integrative analytical approach allowed us to establish the intrinsic solid state stability of bethanechol chloride (BC), an active pharmaceutical ingredient used in the treatment of urinary retention. First, the crystal structure of the monoclinic form has been described using single crystal X-ray diffraction studies. Second, thermal analyses revealed that the compound degrades upon melting, with an apparent melting temperature estimated to be 231 °C. No transition from the monoclinic to the orthorhombic form has been observed, suggesting that the monoclinic form is the stable one. Third, the two-step melting–decomposition process has been elucidated by liquid chromatography and thermogravimetry coupled to mass spectrometry. The first step corresponds to the sample liquefaction, which consists of the gradual dissolution of bethanechol chloride in its liquid degradant, i.e. betamethylcholine chloride. This step is in agreement with Bawn kinetics and the activation energy of the reaction has been estimated at 35.5 kcal mol−1. The second step occurs with accelerated degradation in the melt. Elucidation of secondary decomposition pathways evidenced autocatalytic properties conferred by the formation of both isocyanic acid and methyl chloride. Finally, dynamic water vapor sorption analysis showed a substantial hygroscopicity of the drug substance. A deliquescent point has been determined at 56% relative humidity at 25 °C.

Microwave-Induced Chemical Functionalization of Carboxylated Multi-Walled Nanotubes With 2,3-diaminopyridine

In this paper, the microwave-induced chemical functionalization of carboxylated multi-walled carbon nanotubes (MWNT-COOH) by 2,3-diaminopyridine, have been investigated. The major advantage of this high-energy procedure is reducing the reaction time to the order of minutes and the number of steps in the reaction procedure compared to that of conventional functionalization processes. These functionalizations involve amidation and cycloaddition reactions, respectively. The amidation was completed in one step as compared to two in the conventional approach. The acid chloride formation step was eliminated here. The cycloaddition of MWNTs with triphenylphosphite to producing MWNT-4-azabenzimidazole was carried out in 20 minutes under microwave conditions, and the results were similar to what was achieved in 4 days using conventional methods. The interesting point is that modified MWNT can be homogeneously dispersed in DMF without sonication and the dispersed MWNT does not sediment in 1 month. The results are confirmed by FT-IR, SEM, RAMAN, TGA, DTA and elemental analysis.

Synthesis of dihydrooxazoylarylisoxazoles by conventional and under microwave conditions

The synthesis of series of 3-aryl-4-dihydrooxazolyl-5-methyl trisubstituted isoxazoles ( VI ) is reported, both under thermal and microwave conditions starting from various benzaldehydes ( I ). Benzaldehydes undergo oximation with hydroxylamine hydrosulphate to provide oximes that upon chlorination, followed by condensation with methylacetoacetate, resulted in the formation of esters. Hydrolysis of the esters to acids followed by treatment with PCl 5 , resulted in the formation of acid chlorides ( III ) that upon reaction with hydroxyamines, gave N - β -hydoxyalkyl amides ( IV ). These on further reaction with SOCl 2 , followed by cyclization with 2 N NaOH provided oxazoline substituted isoxazoles ( VI ) in good yields. The conversion acid chlorides ( III ) to isoxazoles ( VI ) was also achieved by microwave irradiation in moderate to excellent yields, with shorter reaction times compared to the conventional thermal method.