- Trapping of muscle relaxant methocarbamol degradation product by complexation with copper(II) ion: Spectroscopic and quantum chemical studies
-
Structural properties of methocarbamol (Mcm) were extensively studied both experimentally and theoretically using FT IR, 1H NMR, UV-Vis., geometry optimization, Mulliken charge, and molecular electrostatic potential. Stability arises from hyper
- Mansour, Ahmed M.,Shehab, Ola R.
-
-
Read Online
- Bitterless guaifenesin prodrugs—design, synthesis, characterization, in vitro kinetics, and bitterness studies
-
A respected number of drugs suffer from bitter taste which results in patient incompliance. With the aim of solving the bitterness of guaifenesin, dimethyl maleate, maleate, glutarate, succinate, and dimethyl succinate prodrugs were designed and synthesized. Molecular orbital methods were utilized for the design of the ester prodrugs. The density functional theory (DFT) calculations revealed that the hydrolysis efficiency of the synthesized prodrugs is significantly sensitive to the pattern of substitution on C=C bond and distance between the nucleophile and the electrophile. The hydrolysis of the prodrugs was largely affected by the pH of the medium. The experimental t1/2 for the hydrolysis of guaifenesin dimaleate ester prodrugs in 1N HCl was the least and for guaifenesin dimethyl succinate was the highest. Functional heterologous expression of TAS2R14, a broadly tuned bitter taste receptor responding to guaifenesin, and experiments using these prodrugs revealed that, while some of the prodrugs still activated the receptor similarly or even stronger than the parent substance, succinate derivatization resulted in the complete loss of receptor responses. The predicted binding modes of guaifenesin and its prodrugs to the TAS2R14 homology model suggest that the decreased activity of the succinate derivatives may be caused by a clash with Phe247.
- Thawabteh, Amin,Lelario, Filomena,Scrano, Laura,Bufo, Sabino A.,Nowak, Stefanie,Behrens, Maik,Di Pizio, Antonella,Niv, Masha Y.,Karaman, Rafik
-
-
Read Online
- Ligand-Free Copper-Catalyzed Ullmann-Type C?O Bond Formation in Non-Innocent Deep Eutectic Solvents under Aerobic Conditions
-
An efficient and novel protocol was developed for a Cu-catalyzed Ullmann-type aryl alkyl ether synthesis by reacting various (hetero)aryl halides (Cl, Br, I) with alcohols as active components of environmentally benign choline chloride-based eutectic mixtures. Under optimized conditions, the reaction proceeded under mild conditions (80 °C) in air, in the absence of additional ligands, with a catalyst [CuI or CuII species] loading up to 5 mol% and K2CO3 as the base, providing the desired aryloxy derivatives in up to 98 % yield. The potential application of the methodology was demonstrated in the valorization of cheap, easily available, and naturally occurring polyols (e. g., glycerol) for the synthesis of some pharmacologically active aryloxypropanediols (Guaiphenesin, Mephenesin, and Chlorphenesin) on a 2 g scale in 70–96 % yield. Catalyst, base, and deep eutectic solvent could easily and successfully be recycled up to seven times with an E-factor as low as 5.76.
- Capriati, Vito,García-álvarez, Joaquín,Marinò, Manuela,Perna, Filippo M.,Quivelli, Andrea Francesca,Vitale, Paola
-
-
- Revisiting Hydroxyalkylation of Phenols with Cyclic Carbonates
-
Described is a tetrabutylammonium fluoride-mediated hydroxyalkylation reaction of phenols with cyclic carbonates. This operationally simple method enables the synthesis of a variety of aryl β-hydroxyethyl ethers in good to excellent yields with a very small amount of catalyst loading (0.1–1 mol%). Of particular note is the efficient conversion of aromatic diols and phloroglucinol to the corresponding bis- and tris-hydroxyethylated products. To further showcase the versatility of this protocol, guaifenesin was prepared with a single step by the condensation of guaiacol and glycerol carbonate. We also developed a flow ethoxylation process permitting the continuous synthesis of multiflorol. (Figure presented.).
- Kao, Shih-Chieh,Lin, Yi-Ching,Ryu, Ilhyong,Wu, Yen-Ku
-
supporting information
p. 3639 - 3644
(2019/07/10)
-
- Activity and selectivity of different base catalysts in synthesis of guaifenesin from guaiacol and glycidol of biomass origin
-
Guaiacol and glycidol can be obtained from biomass valorization. Guaiacol (2-methoxyphenol) and glycidol (2,3-epoxy-1-propanol) have been used for the efficient synthesis of guaifenesin ((RS)-3-(2-methoxyphenoxy) propane-1,2-diol). Different catalysts such as hydrotalcite (HT), calcined hydrotalcite (CHT), calcinated hydrotalcite supported on hexagonal mesoporous silica, magnesium oxide, alumina and, potassium promoted zirconium oxide were synthesized, out of which CHT was found to be the most active, selective and reusable catalyst. The catalyst characterization was done by different techniques. Both Oxide and hydroxide phases were observed on calcination of HT in air at 450?°C for 6?h. CHT possess both acidic and basic sites and basicity of CHT was the highest. Crystallite size, surface area and pore size of CHT play important role in catalytic activity and selectivity. Reaction was carried out in a batch reactor and influence of different parameters was systematically studied. The reaction mechanism involving two sites, acidic and basic, was proposed. A suitable kinetic model was developed and fitted against experimental data. A second order rate equation was derived on the basis of Langmuir–Hinshelwood–Hougen–Watson mechanism with weak adsorption of reactants, intermediates and products. Kinetics was used to predict reaction conditions to obtain guaifenesin selectively. Guaifenesin was efficiently obtained with 94.8% selectivity at guaiacol conversion of 38.2% over CHT at 80?°C after 4?h.
- Bhanawase, Shivaji L.,Yadav, Ganapati D.
-
p. 213 - 222
(2017/06/21)
-
- Glycerol as a source of designer solvents: Physicochemical properties of low melting mixtures containing glycerol ethers and ammonium salts
-
In this work we report the preparation of mixtures of several alkyl glyceryl ethers, as hydrogen bond donor compounds, with two ammonium salts, choline chloride and N,N,N-triethyl-2,3-dihydroxypropan-1-aminium chloride. The stability of the mixtures at different molar ratios and temperatures has been evaluated in order to determine the formation of low melting mixtures. Liquid and stable mixtures have been characterized and their physico-chemical properties such as density, viscosity, refractive index, conductivity and surface tension have been measured in the temperature range of 293.15 K to 343.15 K. Comparison of the mixtures prepared herein with the ones containing glycerol and choline chloride evidences the possibility of tuning the physico-chemical properties by changing the substitution pattern in the hydrogen bond donor compound or in the ammonium salt, thus broadening the scope of application of these mixtures.
- Leal-Duaso, Alejandro,Pérez, Pascual,Mayoral, José A.,Pires, Elisabet,García, José I.
-
p. 28302 - 28312
(2017/11/06)
-
- Method for synthesizing guaifenesin pharmaceutical intermediate 3-(o-methoxyphenoxy)-1,2-propylene glycol
-
A method for synthesizing a guaifenesin pharmaceutical intermediate 3-(o-methoxyphenoxy)-1,2-propylene glycol comprises the following steps: in a reaction vessel provided with a stirrer, a thermometer and a reflux condenser, adding 1.5 mol of sodium sulfite and 300 ml of a potassium chloride solution, controlling the stirring speed to be 130-160 rpm, slowly adding 1.3 mol of o-methoxyphenol, increasing the temperature of the solution to 45-50 DEG C, and maintaining for 2-3 h; adding 1.5-1.7 mol of 3-amino-1,2-propylene glycol (3), increasing the temperature of the solution to 85-90 DEG C, and maintaining a stirring state for 4-5 h; dropping the temperature of the solution to 10-15 DEG C, allowing to stand for 20-25 h, layering, then removing an aqueous layer, adding 200 ml of a sodium bromide solution into an oil layer, adding an oxalic acid, and adjusting the pH of the solution to maintain at 6-7; and cooling, then precipitating to obtain a solid, carrying out suction filtration, washing with a salt solution, washing with nitromethane, recrystallizing in propionitrile, and thus obtaining the crystal 3-(o-methoxyphenoxy)-1,2-propylene glycol, wherein the mass fraction of the potassium chloride solution in the steps is 15-20%, the mass fraction of the sodium bromide solution in the steps is 20%-25%, and the mass fraction of oxalic acid in the steps is 30-35%.
- -
-
Paragraph 0013; 0014
(2016/11/21)
-
- Chemoenzymatic Route for the Synthesis of (S)-Moprolol, a Potential β-Blocker
-
A biocatalytic route for the synthesis of a potential β-blocker, (S)-moprolol is reported here. Enantiopure synthesis of moprolol is mainly dependent on the chiral intermediate, 3-(2-methoxyphenoxy)-propane-1,2-diol. Various commercial lipases were screened for the enantioselective resolution of (RS)-3-(2-methoxyphenoxy)propane-1,2-diol to produce the desired enantiomer. Among them, Aspergillus Niger lipase (ANL) was selected on the basis of both stereo- and regioselectivity. The optimized values of various reaction parameters were determined such as enzyme (15 mg/mL), substrate concentration (10 mM), organic solvent (toluene), reaction temperature (30 °C), and time (18 h).The optimized conditions led to achieving >49% yield with high enantiomeric excess of (S)-3-(2-methoxyphenoxy)propane-1,2-diol. The lipase-mediated catalysis showed regioselective acylation with dual stereoselectivity. Further, the enantiopure intermediate was used for the synthesis of (S)-moprolol, which afforded the desired β-blocker. Chirality 28:313-318, 2016.
- Ghosh, Saptarshi,Bhaumik, Jayeeta,Banoth, Linga,Banesh, Sooram,Banerjee, Uttam Chand
-
p. 313 - 318
(2016/03/19)
-
- COMPOSITIONS AND METHODS FOR THE TREATMENT OF COUGH
-
The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for treating or preventing cough may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of acute respiratory tract infections, asthma, gout, fibromyalgia, facilitating conception, promotes secondary mucosal secretions in the respiratory system, muscle relaxant, allergy, asthma, chronic obstructive pulmonary disorders, spasms, respiratory and neurological diseases.
- -
-
Paragraph 0113
(2015/05/26)
-
- Guaifenesin derivatives promote neurite outgrowth and protect diabetic mice from neuropathy
-
In diabetic patients, an early index of peripheral neuropathy is the slowing of conduction velocity in large myelinated neurons and a lack of understanding of the basic pathogenic mechanisms hindered therapeutics development. Racemic (R/S)-guaifenesin (1) was identified as a potent enhancer of neurite outgrowth using an in vitro screen. Its R-enantiomer (R)-1 carried the most biological activity, whereas the S-enantiomer (S)-1 was inactive. Focused structural variations to (R/S)-1 was conducted to identify potentially essential groups for the neurite outgrowth activity. In vivo therapeutic studies indicated that both (R/S)-1 and (R)-1 partially prevented motor nerve conduction velocity slowing in a mouse model of type 1 diabetes. In vitro microsomal assays suggested that compounds (R)-1 and (S)-1 are not metabolized rapidly, and PAMPA assay indicated moderate permeability through the membrane. Findings revealed here could lead to the development of novel drugs for diabetic neuropathy.
- Hadimani, Mallinath B.,Purohit, Meena K.,Vanampally, Chandrashaker,Van Der Ploeg, Randy,Arballo, Victor,Morrow, Dwane,Frizzi, Katie E.,Calcutt, Nigel A.,Fernyhough, Paul,Kotra, Lakshmi P.
-
p. 5071 - 5078
(2013/07/26)
-
- COMPOSITIONS AND METHODS FOR THE TREATMENT OF COUGH
-
The invention relates to the compounds of formula (I) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I), and methods for treating or preventing cough may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of acute respiratory tract infections, asthma, gout, fibromyalgia, facilitating conception, promoies secondary mucosal secretions in the respiratory system, muscle relaxant, allergy, asthma, chronic obstructive pulmonary disorders, spasms, respiratory and neurological diseases.
- -
-
Paragraph 0093; 0094; 0099
(2013/12/03)
-
- One-pot synthesis of aryloxypropanediols from glycerol: Towards valuable chemicals from renewable sources
-
Glycerol offers an easy and green route for the synthesis of aryloxypropanediols of known pharmacological activity. Glycerol is selectively converted to aryloxypropanediols in a one-pot reaction, through in situ formed glycerol carbonate, under benign and solvent-free conditions. Catalyst and unreacted reagent can be recycled.
- Truscello, Ada M.,Gambarotti, Cristian,Lauria, Mirvana,Auricchio, Sergio,Leonardi, Gabriella,Shisodia, Suresh U.,Citterio, Attilio
-
supporting information
p. 625 - 628
(2013/03/29)
-
- Synergistic dual activation catalysis by palladium nanoparticles for epoxide ring opening with phenols
-
Synergistic dual activation catalysis has been devised for epoxide phenolysis wherein palladium nanoparticles induce electrophilic activation via coordination with the epoxide oxygen followed by nucleophilic activation through anion-π interaction with the aromatic ring of the phenol, and water (reaction medium) also renders assistance through 'epoxide-phenol' dual activation.
- Seth, Kapileswar,Roy, Sudipta Raha,Pipaliya, Bhavin V.,Chakraborti, Asit K.
-
supporting information
p. 5886 - 5888
(2013/07/25)
-
- An efficient synthesis of 1-(2-Methoxyphenoxy)-2,3-epoxypropane: Key intermediate of β-adrenoblockers
-
An efficient process for the preparation of 1-(2-methoxyphenoxy)-2,3- epoxypropane, a key intermediate for the synthesis of ranolazine is described.
- Madivada, Lokeswara Rao,Anumala, Raghupathi Reddy,Gilla, Goverdhan,Kagga, Mukkanti,Bandichhor, Rakeshwar
-
p. 1660 - 1664
(2013/02/25)
-
- Synthesis of ranolazine metabolites and their anti-myocardial ischemia activities
-
The anti-anginal drug Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, is thought to modulate the metabolism during myocardial ischemia by activating pyruvate dehydrogenase activity to promote glucose oxidation. Ranolazine and its five principal metabolites: CVT-2512, CVT-2513, CVT-2514, CVT-2738 and CVT-4786, were synthesized. The effect of Ranolazine and its metabolites on the ECG (electrocardiogram) of mice with myocardial ischemia induced by isoprenaline and their effect on alleviating the symptom of myocardial ischemia were tested and compared. The results showed that CVT-2738 and CVT-2513 could be protective against mice myocardial ischemia induced by isoprenaline. Within all the metabolites tested in this study, CVT-2738 exhibited the best potency, however, it was still less potent than Ranolazine.
- Yao, Zhangyu,Gong, Shubo,Guan, Teng,Li, Yunman,Wu, Xiaoming,Sun, Hongbin
-
experimental part
p. 1218 - 1222
(2010/06/16)
-
- Solid state properties and effective resolution procedure for guaifenesin, 3-(2-methoxyphenoxy)-1,2-propanediol
-
Racemic expectorant guaifenesin, 3-(2-methoxyphenoxy)-1,2-propanediol 2 undergoes spontaneous resolution upon crystallization. This fact is confirmed by thermal analysis (single eutectic V-shape binary melting phase diagram, adequate entropy and free energy characteristics). Racemic 2 could be effectively resolved into (S)- and (R)-2 by a preferential crystallization procedure. Single enantiomer drugs levomoprolol and levotensin were obtained by starting from enantiomeric 2 through the sulfite route.
- Bredikhina, Zemfira A.,Novikova, Victorina G.,Zakharychev, Dmitry V.,Bredikhin, Alexander A.
-
p. 3015 - 3020
(2007/10/03)
-
- LIQUID PHARMACEUTICAL FOR ORAL DELIVERY
-
A liquid pharmaceutical for oral delivery wherein at the time of use, a solid unit dosage form is added to the liquid wherein the unit dosage form is comprised of a substrate soluble in the liquid and a particulate pharmaceutically active material in a pharmaceutically effective amount. At the time of use, the unit dosage form is added to the liquid, without requiring measurement of the liquid, and the entire liquid is consumed to provide for oral delivery of the pharmaceutically effective amount of material.
- -
-
-
- N-Acyl-2-substituted-1,3-thiazolidines, a New Class of Non-narcotic Antitussive Agents: Studies Leading to the Discovery of Ethyl 2--β-oxothiazolidine-3-propanoate
-
The synthesis of a novel class of antitussive agents is described.The compounds were examined for antitussive activity in guinea pig after cough induction by electrical or chemical stimulation.Ethyl 2--β-oxothiazolidine-3-propanoate (BBR 2173, moguisteine, 7) and other structurally related compounds showed a significant level of activity, comparable to that of codeine and dextromethorphan.The compounds presented in this paper are characterized by the N-acyl-2-substituted-1,3-thiazolidine moiety, which is a novel entry in the field of antitussive agents.The serendipitous discovery of the role played by the thiazolidine moiety in the determining the antitussive effect promoted extensive investigations on these structures.This optimization process on N-acyl-2-substituted-1,3-thiazolidines led to the initial identification of 2--3--1,3-thiazolidine (18a) as an interesting lead compound.The careful study of the rapid and very complicated metabolism of 18a provided further insights for the design of newer related derivatives.The observation that the metabolic oxidation on the lateral chain's sulfur of 18a to sulfoxide maintained the antitussive properties suggested the introduction of isosteric functional groups with respect to the sulfoxide moiety.Subsequent structural modifications showed that hydrolyzable malonic residues in the 3-position of the thiazolidine ring were able to assure high antitussive activity.This optimization ultimately led to the selection of moguisteine (7) as the most effective and safest representative of the series.Moguisteine is completely devoid of unwanted side effects (such as sedation and addiction), and its activity was demonstrated also in clinical studies.
- Gandolfi, Carmelo A.,Domenico, Roberto Di,Spinelli, Silvano,Gallico, Licia,Fiocchi, Luigi,et al.
-
p. 508 - 525
(2007/10/02)
-
- Methocarbamol degradation in aqueous solution
-
The kinetics of the hydrolysis of methocarbamol to the corresponding diol guaifenesin in aqueous solution was studied. Methocarbamol was rather stable in acidic media but easily hydrolyzed in alkaline solution. The formation of an unknown compound, proved to be an isomer of methocarbamol [the 3-(2- methoxyphenoxy)-propanediol 2-carbamate] is involved. The amounts of methocarbamol and the two degradation products resulting from storage of methocarbamol in various buffer solutions over a pH range of 8.0 to 10.0 at 70-80 °C (ionic strength, 0.5 M), were followed as a function of time by a reversed-phase HPLC stability-indicating method to clarify the degradation pathway of methocarbamol in alkaline solutions. Analysis of the concentration-time profiles reveals that base-catalyzed methocarbamol hydrolysis proceeded mainly through the formation of its isomer. The observed degradation rates followed approximately pseudo-first-order kinetics at constant pH and temperature.
- Pouli,Antoniadou-Vyzas,Foscolos
-
p. 499 - 501
(2007/10/02)
-
- Crown Cation Complex Effects. 20. Syntheses and Cation Binding Properties of Carbon-Pivot Lariat Ethers
-
In an effort devise synthetic cation binders that will mimic the behavior of naturally occuring ionophores such as valinomycin, we have prepared approximately 30 macrocyclic (crown) polyethers bearing flexible side chains attached to the macro ring at carbon.In many of these "carbon-pivot" compounds, the side chain contains one or more neutral donor groups that, if in a suitable geometrical arrangement, may provide additional solvation to the macro-ring-bound cation.Although such donors often enhanced the cation binding ability, overall, the increases in stability constants were modest.The physical resemblance and concept of "roping and tying" the cation suggest the name "lariat ethers".Syntheses of these molecules and binding by them of Na+ and K+ cations are reported and conclusions drawn about the structural requirements and cation binding efficacy of these materials.
- Dishong, Dennis M.,Diamond, Craig J.,Cinoman, Michael I.,Gokel, Geoge W.
-
p. 586 - 593
(2007/10/02)
-
- Process for the production of guaiacol glycerine ether
-
Guaiacol glycerine ether is obtained in very good yield and in very high purity by reacting glycidol with o-methyoxyphenol in the presence of an alkali hydroxide, an alkali alcoholate, an alkali cyanate or an alkali thiocyanate at 80° to 150° C. An especially effective purification of the crude product can be obtained by adding hydrogen peroxide, preferably prior to cooling.
- -
-
-
- Lariat Ethers. Synthesis and Cation Binding of Macrocyclic Polyethers Possessing Axially Disposed Secondary Donor Groups
-
The synthesis and cation binding properties of a series of macrocyclic polyethers which possess ligating arms that enhance cation binding is presented.
- Gokel, George W.,Dishong, Dennis M.,Diamond, Craig J.
-
p. 1053 - 1054
(2007/10/02)
-