György Keglevich - Academia.edu (original) (raw)
Papers by György Keglevich
Green Processing and Synthesis, Apr 1, 2014
According to literature, the synthesis of dronic acid derivatives from the corresponding carboxyl... more 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.
Beilstein Journal of Organic Chemistry
![Research paper thumbnail of Fragmentation-Related Phosphonylation of Nucleophiles Utilizing P-Alkyl 2,3-oxaphosphabicyclo[2.2.2]octene 3-oxide Precursors](https://attachments.academia-assets.com/119098244/thumbnails/1.jpg)
](Heteroatom Chemistry, 2015
New P-alkyl 2,3-oxaphosphabicyclo-[2.2.2]octene 3-oxides were synthesized by the Bayer-Villiger o... more New P-alkyl 2,3-oxaphosphabicyclo-[2.2.2]octene 3-oxides were synthesized by the Bayer-Villiger oxidation of the corresponding 7-phosphanorbornene 7-oxides and were used as precursors for reactive alkylmetaphosphonates useful in the phosphonylation of alcohols. This is the first case that the reactivity of the two regioisomers formed by O-insertion was differentiated and that the fragmentation-related phosphonylation leading to phosphonic acid-esters was achieved under microwave-assisted conditions.
Periodica Polytechnica Chemical Engineering, Jan 21, 2015
Dr Pierre Faury (Chinoin-Sanofi) conveyed their laudation. The gift of Chinoin-Sanofi comprising ... more Dr Pierre Faury (Chinoin-Sanofi) conveyed their laudation. The gift of Chinoin-Sanofi comprising equipment and instruments was acknowledged by the Dean. The celebration was followed by a poster session including the recent research results of the Department and by buffet. More detailed information about this nice session may be read in
Current Organic Synthesis, 2015
The deoxygenation of phosphine oxides was studied on two model reactions, on the reduction of 3me... more The deoxygenation of phosphine oxides was studied on two model reactions, on the reduction of 3methyl-1-phenyl-3-phospholene 1-oxide and triphenylphosphine oxide using an aralkylsilane, arylsilanes, diarylsilanes, a disiloxane, a polysiloxane and a disilane under solvent-free, thermal or microwave-assisted conditions. The deoxygenations were optimized, and the reactivity of the silanes was evaluated. User-friendly accomplishments were elaborated.
Catalysts, 2015
The solid-liquid phase C-alkylation of active methylene containing compounds with C=O or P=O func... more The solid-liquid phase C-alkylation of active methylene containing compounds with C=O or P=O functions under phase transfer catalysis or microwave conditions has been summarized in this minireview. The mono-and dialkylation of the methylene containing derivatives was investigated under microwave (MW) conditions. It was found that in many cases, there was no need to use phase transfer catalyst under MW conditions. Moreover, most of the reactions were carried out without any solvent. These results mean a serious green chemical advantage.
Letters in Drug Design & Discovery, 2013
The synthesis of Etidronate (as the disodium salt) by the reaction of acetic acid with phosphorus... more The synthesis of Etidronate (as the disodium salt) by the reaction of acetic acid with phosphorus trichloride/phosphorus acid in methanesulfonic acid was studied and optimized. We showed that it is enough to use 3.2 equivalents of the phosphorus trichloride and there is no need to apply phosphorus acid. In the two-step variation of the synthesis, the acetyl chloride was formed by the reaction of acetic acid with phosphorus trichloride, thionyl chloride or triphosgene, then the intermediate was converted to etidronate by reaction with 2.2 equivalents of phosphorus trichloride. The work-up included in all cases hydrolysis and pH adjustment.
Current Organic Chemistry, 2007
SpringerBriefs in Molecular Science, 2016
The second part focuses on the summary of typical organic chemical reactions selected, such as co... more The second part focuses on the summary of typical organic chemical reactions selected, such as coupling reactions (C-C bond formation reactions, carbon-heteroatom bond formations),
Molecules
New hydroxy-methylenebisphosphonic derivatives were prepared with different P-functions. The outc... more New hydroxy-methylenebisphosphonic derivatives were prepared with different P-functions. The outcome of the reaction of α-oxophosphonates (YC(O)P(O)(OR)2) and dialkyl phosphites or diarylphosphine oxides depended on the Y substituent of the oxo-compound, the nature of the P-reagent and the amount of the diethylamine catalyst. Starting from dimethyl α-oxoethylphosphonate, in the presence of 5% of diethylamine, the corresponding Pudovik adduct was the single product. While using 40% of the catalyst, the rearranged species with the >P(O)–O–CH–P(O)< skeleton was the exclusive component. A similar reaction of α-oxobenzylphosphonate followed the rearrangement protocol. X-ray crystallography revealed not only the spatial structures of the three products, but also an intricate pattern evolving from the interplay of slight chemical differences, solvent inclusion and disorder as well as H-bridge patterns, which invite further investigation. In vitro activity of the compounds was assesse...
Pharmaceuticals
Encouraged by the significant cytotoxic activity of simple α-aminophosphonates, a molecular libra... more Encouraged by the significant cytotoxic activity of simple α-aminophosphonates, a molecular library comprising phosphonoylmethyl- and phosphinoylmethyl-α-aminophosphonates, a tris derivative, and N-acylated species was established. The promising aminophosphonate derivatives were subjected to a comparative structure–activity analysis. We evaluated 12 new aminophosphonate derivatives on tumor cell cultures of different tissue origins (skin, lung, breast, and prostate). Several derivatives showed pronounced, even selective cytostatic effects. According to IC50 values, phosphinoylmethyl-aminophosphonate derivative 2e elicited a significant cytostatic effect on breast adenocarcinoma cells, but it was even more effective against prostatic carcinoma cells. Based on our data, these new compounds exhibited promising antitumor activity on different tumor types, and they might represent a new group of alternative chemotherapeutic agents.
Pharmaceutics
α-Aminophosphonates are organophosphorus compounds with an obvious similarity with α-amino acids.... more α-Aminophosphonates are organophosphorus compounds with an obvious similarity with α-amino acids. Owing to their biological and pharmacological characteristics, they have attracted the attention of many medicinal chemists. α-Aminophosphonates are known to exhibit antiviral, antitumor, antimicrobial, antioxidant and antibacterial activities, which can all be important in pathological dermatological conditions. However, their ADMET properties are not well studied. The aim of the current study was to provide preliminary information about the skin penetration of three preselected α-aminophosphonates when applying them as topical cream formulations in static and dynamic diffusion chambers. The results indicate that aminophosphonate 1a, without any substituent in the para position, shows the best release from the formulation and the highest absorption through the excised skin. However, based on our previous study, the in vitro pharmacological potency was higher in the case of para-substit...
The 26th International Electronic Conference on Synthetic Organic Chemistry, Nov 16, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Molecules
Forty years have passed since a real “phosphabenzene” (a phosphinine) was prepared for the first ... more Forty years have passed since a real “phosphabenzene” (a phosphinine) was prepared for the first time applying steric protection methodology with the sterically demanding 2,4,6-tri-tertiary-butylphenyl (“supermesityl”) group [...]
Molecules
The reaction of diethyl α-oxoethylphosphonate and diethyl oxobenzylphosphonate with diethyl phosp... more The reaction of diethyl α-oxoethylphosphonate and diethyl oxobenzylphosphonate with diethyl phosphite, dimethyl phosphite, and diphenylphosphine oxide affords, depending on the substrates and conditions (nature and quantity of the amine catalyst, temperature, and solvent), the Pudovik adduct and/or the corresponding >P(O)–CH–O–P(O)< product formed by rearrangement. The nature of the substituent on the central carbon atom (a methyl or phenyl group) influences the inclination for the rearrangement. The asymmetric products (either adducts or rearranged species) with different P(O)Y functions (Y = RO or Ph) exhibit interesting NMR features.
ECSOC-25
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Proceedings of The 21st International Electronic Conference on Synthetic Organic Chemistry, 2017
α-Aminophosphonates and related derivatives represent one of the most important class of organoph... more α-Aminophosphonates and related derivatives represent one of the most important class of organophosphorus compounds. The most widely applied synthetic routes towards α-aminophosphonates involve the Kabachnik-Fields condensation and the Pudovik reaction. In this paper the microwave (MW)-assisted catalyst-and mostly solvent-free syntheses of various α-aminophosphonates and α-aminophosphine oxides are discussed. Bis(aminophosphonate) derivatives were also prepared by the double Kabachnik-Fields reaction. Furthermore, the synthesis of amino-methylenebisphosphonates and amino-methylenebisphosphine oxides is also described.
Molecules, 2022
An efficient method applying acyl chlorides as reagents was developed for the acylation of the hi... more An efficient method applying acyl chlorides as reagents was developed for the acylation of the hindered hydroxy group of dialkyl α-hydroxy-benzylphosphonates. The procedure did not require any catalyst. A few acylations were also performed with the SC-enantiomer of dimethyl α-hydroxy-benzylphosphonate, and the optical purity was retained. A part of the acyloxyphosphonates was tested against eight tumor cell lines of different tissue origin at c = 50 μM concentration. The compounds elicited moderate cytostatic effect against breast, skin, prostate, colon, and lung carcinomas; a melanoma cell line; and against Kaposi’s sarcoma cell lines. Then, dose-dependent cytotoxicity was assayed, and benzoylation of the α-hydroxy group was identified as a moiety that increases anticancer cytotoxicity across all cell lines. Surprisingly, a few analogues were more toxic to multidrug resistant cancer cell lines, thus evading P-glycoprotein mediated drug extrusion.
Green Processing and Synthesis, Apr 1, 2014
According to literature, the synthesis of dronic acid derivatives from the corresponding carboxyl... more 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.
Beilstein Journal of Organic Chemistry
Heteroatom Chemistry, 2015
New P-alkyl 2,3-oxaphosphabicyclo-[2.2.2]octene 3-oxides were synthesized by the Bayer-Villiger o... more New P-alkyl 2,3-oxaphosphabicyclo-[2.2.2]octene 3-oxides were synthesized by the Bayer-Villiger oxidation of the corresponding 7-phosphanorbornene 7-oxides and were used as precursors for reactive alkylmetaphosphonates useful in the phosphonylation of alcohols. This is the first case that the reactivity of the two regioisomers formed by O-insertion was differentiated and that the fragmentation-related phosphonylation leading to phosphonic acid-esters was achieved under microwave-assisted conditions.
Periodica Polytechnica Chemical Engineering, Jan 21, 2015
Dr Pierre Faury (Chinoin-Sanofi) conveyed their laudation. The gift of Chinoin-Sanofi comprising ... more Dr Pierre Faury (Chinoin-Sanofi) conveyed their laudation. The gift of Chinoin-Sanofi comprising equipment and instruments was acknowledged by the Dean. The celebration was followed by a poster session including the recent research results of the Department and by buffet. More detailed information about this nice session may be read in
Current Organic Synthesis, 2015
The deoxygenation of phosphine oxides was studied on two model reactions, on the reduction of 3me... more The deoxygenation of phosphine oxides was studied on two model reactions, on the reduction of 3methyl-1-phenyl-3-phospholene 1-oxide and triphenylphosphine oxide using an aralkylsilane, arylsilanes, diarylsilanes, a disiloxane, a polysiloxane and a disilane under solvent-free, thermal or microwave-assisted conditions. The deoxygenations were optimized, and the reactivity of the silanes was evaluated. User-friendly accomplishments were elaborated.
Catalysts, 2015
The solid-liquid phase C-alkylation of active methylene containing compounds with C=O or P=O func... more The solid-liquid phase C-alkylation of active methylene containing compounds with C=O or P=O functions under phase transfer catalysis or microwave conditions has been summarized in this minireview. The mono-and dialkylation of the methylene containing derivatives was investigated under microwave (MW) conditions. It was found that in many cases, there was no need to use phase transfer catalyst under MW conditions. Moreover, most of the reactions were carried out without any solvent. These results mean a serious green chemical advantage.
Letters in Drug Design & Discovery, 2013
The synthesis of Etidronate (as the disodium salt) by the reaction of acetic acid with phosphorus... more The synthesis of Etidronate (as the disodium salt) by the reaction of acetic acid with phosphorus trichloride/phosphorus acid in methanesulfonic acid was studied and optimized. We showed that it is enough to use 3.2 equivalents of the phosphorus trichloride and there is no need to apply phosphorus acid. In the two-step variation of the synthesis, the acetyl chloride was formed by the reaction of acetic acid with phosphorus trichloride, thionyl chloride or triphosgene, then the intermediate was converted to etidronate by reaction with 2.2 equivalents of phosphorus trichloride. The work-up included in all cases hydrolysis and pH adjustment.
Current Organic Chemistry, 2007
SpringerBriefs in Molecular Science, 2016
The second part focuses on the summary of typical organic chemical reactions selected, such as co... more The second part focuses on the summary of typical organic chemical reactions selected, such as coupling reactions (C-C bond formation reactions, carbon-heteroatom bond formations),
Molecules
New hydroxy-methylenebisphosphonic derivatives were prepared with different P-functions. The outc... more New hydroxy-methylenebisphosphonic derivatives were prepared with different P-functions. The outcome of the reaction of α-oxophosphonates (YC(O)P(O)(OR)2) and dialkyl phosphites or diarylphosphine oxides depended on the Y substituent of the oxo-compound, the nature of the P-reagent and the amount of the diethylamine catalyst. Starting from dimethyl α-oxoethylphosphonate, in the presence of 5% of diethylamine, the corresponding Pudovik adduct was the single product. While using 40% of the catalyst, the rearranged species with the >P(O)–O–CH–P(O)< skeleton was the exclusive component. A similar reaction of α-oxobenzylphosphonate followed the rearrangement protocol. X-ray crystallography revealed not only the spatial structures of the three products, but also an intricate pattern evolving from the interplay of slight chemical differences, solvent inclusion and disorder as well as H-bridge patterns, which invite further investigation. In vitro activity of the compounds was assesse...
Pharmaceuticals
Encouraged by the significant cytotoxic activity of simple α-aminophosphonates, a molecular libra... more Encouraged by the significant cytotoxic activity of simple α-aminophosphonates, a molecular library comprising phosphonoylmethyl- and phosphinoylmethyl-α-aminophosphonates, a tris derivative, and N-acylated species was established. The promising aminophosphonate derivatives were subjected to a comparative structure–activity analysis. We evaluated 12 new aminophosphonate derivatives on tumor cell cultures of different tissue origins (skin, lung, breast, and prostate). Several derivatives showed pronounced, even selective cytostatic effects. According to IC50 values, phosphinoylmethyl-aminophosphonate derivative 2e elicited a significant cytostatic effect on breast adenocarcinoma cells, but it was even more effective against prostatic carcinoma cells. Based on our data, these new compounds exhibited promising antitumor activity on different tumor types, and they might represent a new group of alternative chemotherapeutic agents.
Pharmaceutics
α-Aminophosphonates are organophosphorus compounds with an obvious similarity with α-amino acids.... more α-Aminophosphonates are organophosphorus compounds with an obvious similarity with α-amino acids. Owing to their biological and pharmacological characteristics, they have attracted the attention of many medicinal chemists. α-Aminophosphonates are known to exhibit antiviral, antitumor, antimicrobial, antioxidant and antibacterial activities, which can all be important in pathological dermatological conditions. However, their ADMET properties are not well studied. The aim of the current study was to provide preliminary information about the skin penetration of three preselected α-aminophosphonates when applying them as topical cream formulations in static and dynamic diffusion chambers. The results indicate that aminophosphonate 1a, without any substituent in the para position, shows the best release from the formulation and the highest absorption through the excised skin. However, based on our previous study, the in vitro pharmacological potency was higher in the case of para-substit...
The 26th International Electronic Conference on Synthetic Organic Chemistry, Nov 16, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Molecules
Forty years have passed since a real “phosphabenzene” (a phosphinine) was prepared for the first ... more Forty years have passed since a real “phosphabenzene” (a phosphinine) was prepared for the first time applying steric protection methodology with the sterically demanding 2,4,6-tri-tertiary-butylphenyl (“supermesityl”) group [...]
Molecules
The reaction of diethyl α-oxoethylphosphonate and diethyl oxobenzylphosphonate with diethyl phosp... more The reaction of diethyl α-oxoethylphosphonate and diethyl oxobenzylphosphonate with diethyl phosphite, dimethyl phosphite, and diphenylphosphine oxide affords, depending on the substrates and conditions (nature and quantity of the amine catalyst, temperature, and solvent), the Pudovik adduct and/or the corresponding >P(O)–CH–O–P(O)< product formed by rearrangement. The nature of the substituent on the central carbon atom (a methyl or phenyl group) influences the inclination for the rearrangement. The asymmetric products (either adducts or rearranged species) with different P(O)Y functions (Y = RO or Ph) exhibit interesting NMR features.
ECSOC-25
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Proceedings of The 21st International Electronic Conference on Synthetic Organic Chemistry, 2017
α-Aminophosphonates and related derivatives represent one of the most important class of organoph... more α-Aminophosphonates and related derivatives represent one of the most important class of organophosphorus compounds. The most widely applied synthetic routes towards α-aminophosphonates involve the Kabachnik-Fields condensation and the Pudovik reaction. In this paper the microwave (MW)-assisted catalyst-and mostly solvent-free syntheses of various α-aminophosphonates and α-aminophosphine oxides are discussed. Bis(aminophosphonate) derivatives were also prepared by the double Kabachnik-Fields reaction. Furthermore, the synthesis of amino-methylenebisphosphonates and amino-methylenebisphosphine oxides is also described.
Molecules, 2022
An efficient method applying acyl chlorides as reagents was developed for the acylation of the hi... more An efficient method applying acyl chlorides as reagents was developed for the acylation of the hindered hydroxy group of dialkyl α-hydroxy-benzylphosphonates. The procedure did not require any catalyst. A few acylations were also performed with the SC-enantiomer of dimethyl α-hydroxy-benzylphosphonate, and the optical purity was retained. A part of the acyloxyphosphonates was tested against eight tumor cell lines of different tissue origin at c = 50 μM concentration. The compounds elicited moderate cytostatic effect against breast, skin, prostate, colon, and lung carcinomas; a melanoma cell line; and against Kaposi’s sarcoma cell lines. Then, dose-dependent cytotoxicity was assayed, and benzoylation of the α-hydroxy group was identified as a moiety that increases anticancer cytotoxicity across all cell lines. Surprisingly, a few analogues were more toxic to multidrug resistant cancer cell lines, thus evading P-glycoprotein mediated drug extrusion.