A Mechanistic Study on the Formation of Dronic Acids

Dronic acid derivatives, important drugs against bone diseases, may be synthesized from the corresponding substituted acetic acid either by reaction with phosphorus trichloride in methanesulfonic acid as the solvent or by using also phosphorous acid as the P-reactant if sulfolane is applied as the medium. The energetics of the two protocols were evaluated by high-level quantum chemical calculations on the formation of fenidronic acid and benzidronic acid. The second option, involving (HO)2P‑O‑PCl2 as the nucleophile, was found to be more favorable over the first variation, comprising Cl2P‑O‑SO2Me as the real reagent, especially for the case of benzidronate.

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"Greener" Synthesis of Zoledronic Acid from Imidazol-1-yl-acetic Acid and P-Reagents Using Diethyl Carbonate as the Solvent Component

Letters in Organic Chemistry ◽

10.2174/1570178617999200730203738 ◽

2020 ◽

Vol 17 ◽

Author(s):

Alajos Grün ◽

Zsuzsanna Szalai ◽

György Keglevich

Keyword(s):

Acetic Acid ◽

Zoledronic Acid ◽

Methanesulfonic Acid ◽

Phosphorous Acid ◽

Phosphorus Trichloride ◽

Solvent Mixtures ◽

Diethyl Carbonate ◽

Green Solvent ◽

Solvent Component ◽

Greener Synthesis

Abstract: The synthesis of a third generation dronic acid, zoledronic acid by the reaction of imidazol-1-yl-acetic acid with phosphorus trichloride/phosphorous acid in diethyl carbonate (DEC) as a "green" solvent, and in DEC – methanesulfonic acid (MSA) solvent mixtures is described. The earlier not "green" and expensive MSA and sulfolane solvents may be re-placed by DEC

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The Synthesis of 3-Phenylpropidronate Applying Phosphorus Trichloride and Phosphorous Acid in Methanesulfonic Acid

Current Organic Chemistry ◽

10.2174/1385272820666160427115559 ◽

2016 ◽

Vol 20 (16) ◽

pp. 1745-1752 ◽

Cited By ~ 2

Author(s):

Alajos Grun ◽

David I. Nagy ◽

Orsolya Nemeth ◽

Zoltan Mucsi ◽

Sandor Garadnay ◽

...

Keyword(s):

Methanesulfonic Acid ◽

Phosphorous Acid ◽

Phosphorus Trichloride

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A Study on the Synthesis of Risedronic Acid: The Role of an Ionic Liquid Additive

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180626122630 ◽

2019 ◽

Vol 16 (3) ◽

pp. 238-244 ◽

Cited By ~ 2

Author(s):

Dávid Illés Nagy ◽

Alajos Grün ◽

Júlia Sinkovicz ◽

Sándor Garadnay ◽

István Greiner ◽

...

Keyword(s):

Ionic Liquid ◽

Good Yield ◽

Methanesulfonic Acid ◽

Phosphorous Acid ◽

Phosphorus Trichloride ◽

Pure Form ◽

Risedronic Acid

Background: The synthesis of high value risedronic acid is not fully resolved, as, for the time being, the best method based on the preparation from 3-pyridylcarboxylic acid by reaction with phosphorus trichloride in methanesulfonic acid gives risedronic acid in a good yield, but in an unpure form. Methods: Alternative protocols realizing the synthesis in sulfolane as the solvent and/or in the presence of suitable IL additive were developed to obtain the target dronic acid in a pure form. Results & Conclusion: Using phosphorus trichloride and phosphorous acid in two equivalents quantities together with 0.6 equivalents of [bmim][BF4] without any solvent, the method afforded the target dronic acid in a yield of 66% in a pure form.

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“Greener” synthesis of bisphosphonic/dronic acid derivatives

Green Processing and Synthesis ◽

10.1515/gps-2013-0107 ◽

2014 ◽

Vol 3 (2) ◽

pp. 111-116 ◽

Cited By ~ 6

Author(s):

Rita Kovács ◽

Alajos Grün ◽

Sándor Garadnay ◽

István Greiner ◽

György Keglevich

Keyword(s):

Zoledronic Acid ◽

Carboxylic Acids ◽

Methanesulfonic Acid ◽

Phosphorous Acid ◽

Phosphorus Trichloride ◽

Risedronic Acid ◽

Molar Ratios ◽

Wide Range ◽

Greener Synthesis

Abstract According to literature, the synthesis of dronic acid derivatives from the corresponding carboxylic acids using phosphorus trichloride and phosphorous acid as the P-reactants is controversial, due to the wide range of molar ratios and diverse conditions. In this minireview, we summarize our results on the clarification of these problems. For example, with zoledronic acid and risedronic acid, we found that, using methanesulfonic acid (MSA) as the solvent, 3.2 equivalents of phosphorus trichloride was enough. Generalizing this optimized method, etidronate, fenidronate, ibandronate and alendronate were obtained in yields of 38%–57%, which is reasonable for valuable dronates, and in most cases, with high purities. Mechanistic aspects are also discussed.

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Analgesic and Anti-Inflammatory Effects of Aucklandia lappa Root Extracts on Acetic Acid-Induced Writhing in Mice and Monosodium Iodoacetate-Induced Osteoarthritis in Rats

Plants ◽

10.3390/plants10010042 ◽

2020 ◽

Vol 10 (1) ◽

pp. 42

Author(s):

Hee-Geun Jo ◽

Geon-Yeong Lee ◽

Chae Yun Baek ◽

Ho Sueb Song ◽

Donghun Lee

Keyword(s):

Acetic Acid ◽

Weight Bearing ◽

Bone Diseases ◽

Joint Disease ◽

Root Extracts ◽

Raw264.7 Macrophages ◽

Age Related ◽

Monosodium Iodoacetate ◽

Anti Inflammatory

Osteoarthritis (OA) is an age-related joint disease and one of the most common degenerative bone diseases among elderly people. The currently used therapeutic strategies relying on nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids for OA are often associated with gastrointestinal, cardiovascular, and kidney disorders, despite being proven effective. Aucklandia lappa is a well-known traditional medicine. The root of A. lappa root has several bioactive compounds and has been in use as a natural remedy for bone diseases and other health conditions. We evaluated the A. lappa root extracts on OA progression as a natural therapeutic agent. A. lappa substantially reduced writhing numbers in mice induced with acetic acid. Monosodium iodoacetate (MIA) was injected into the rats through their knee joints of rats to induce experimental OA, which shows similar pathological characteristics to OA in human. A. lappa substantially reduced the MIA-induced weight-bearing of hind limb and reversed the cartilage erosion in MIA rats. IL-1β, a representative inflammatory mediator in OA, was also markedly decreased by A. lappa in the serum of MIA rats. In vitro, A. lappa lowered the secretion of NO and suppressed the IL-1β, COX-2, IL-6, and iNOS production in RAW264.7 macrophages activated with LPS. Based on its analgesic and anti-inflammatory effects, A. lappa could be a potential remedial agent against OA.

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Existence Results for the Conformal Dirac–Einstein System

Advanced Nonlinear Studies ◽

10.1515/ans-2020-2115 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Chiara Guidi ◽

Ali Maalaoui ◽

Vittorio Martino

Keyword(s):

Perturbation Methods ◽

Existence Of Solutions ◽

Coupled System ◽

Existence Results ◽

First Variation ◽

The First Variation

AbstractWe consider the coupled system given by the first variation of the conformal Dirac–Einstein functional. We will show existence of solutions by means of perturbation methods.

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Perborate Oxidation of Substituted 5-Oxoacids in Aqueous Acetic Acid Medium: A Kinetic and Mechanistic Study

ISRN Physical Chemistry ◽

10.1155/2014/924827 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

S. Shree Devi ◽

B. Muthukumaran ◽

P. Krishnamoorthy

Keyword(s):

Acetic Acid ◽

Acid Medium ◽

Reaction Rate ◽

Reaction Medium ◽

Activation Parameters ◽

Reaction Rates ◽

Mechanistic Study ◽

Aqueous Acetic Acid ◽

Sodium Perborate ◽

Acetic Acid Medium

Kinetics and mechanism of oxidation of substituted 5-oxoacids by sodium perborate in aqueous acetic acid medium have been studied. The reaction exhibits first order both in [perborate] and [5-oxoacid] and second order in [H+]. Variation in ionic strength has no effect on the reaction rate, while the reaction rates are enhanced on lowering the dielectric constant of the reaction medium. Electron releasing substituents in the aromatic ring accelerate the reaction rate and electron withdrawing substituents retard the reaction. The order of reactivity among the studied 5-oxoacids is p-methoxy ≫ p-methyl > p-phenyl > –H > p-chloro > p-bromo > m-nitro. The oxidation is faster than H2O2 oxidation. The formation of H2BO3+ is the reactive species of perborate in the acid medium. Activation parameters have been evaluated using Arrhenius and Eyring’s plots. A mechanism consistent with the observed kinetic data has been proposed and discussed. Based on the mechanism a suitable rate law is derived.

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Kinetics and mechanism of meso-tetraphenylporphyriniron(III) chloride (TPP) catalysed oxidation of indole by sodium perborate

Polish Journal of Chemical Technology ◽

10.2478/pjct-2013-0031 ◽

2013 ◽

Vol 15 (2) ◽

pp. 107-111 ◽

Cited By ~ 6

Author(s):

D. Kungumathilagam ◽

K. Karunakaran

Keyword(s):

Acetic Acid ◽

Catalytic Activity ◽

Reaction System ◽

Kinetic Scheme ◽

Mechanistic Study ◽

Radical Mechanism ◽

Aqueous Acetic Acid ◽

Sodium Perborate ◽

Acetic Acid Medium ◽

Catalysed Oxidation

Developing catalyst is very significant for biologically important reactions which yield products, used as drugs. Mechanistic study on meso-tetraphenylporphyriniron(III) chloride (TPP) catalysed oxidation of indole by sodium perborate in aqueous acetic acid medium have been carried out. The reaction follows a fractional order with respect to substrate and catalyst. The order with respect to oxidant was found to be one. Increase in the percentage of acetic acid and increase in the concentration of [H+] decreased the rate. The reaction fails to initiate polymerization, and a radical mechanism is ruled out. Activation and thermodynamic parameters have been computed. A suitable kinetic scheme based on these observations has been proposed. Significant catalytic activity is observed for the reaction system in the presence of TPP.

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