The Experts below are selected from a list of 510 Experts worldwide ranked by ideXlab platform
Bhubaneswar Mandal - One of the best experts on this subject based on the ideXlab platform.
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synthesis of o benzyl hydroxamates employing the Sulfonate Esters of n hydroxybenzotriazole
ChemInform, 2014Co-Authors: Nani Babu Palakurthy, Sonali Paikaray, Susmitnarayan Chaudhury, Dharm Dev, Bhubaneswar MandalAbstract:This method can also be used for the functionalization of sterically hindered amino acids and dipeptides without any significant racemization.
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Synthesis of O-benzyl hydroxamates employing the Sulfonate Esters of N-hydroxybenzotriazole
RSC Advances, 2014Co-Authors: Nani Babu Palakurthy, Sonali Paikaray, Susmitnarayan Chaudhury, Bhubaneswar MandalAbstract:The direct conversion of various carboxylic acids, that include sterically hindered amino acids and di-peptides, to O-benzyl hydroxamates is demonstrated using Sulfonate Esters of benzotriazoles under ambient and milder conditions without significant racemization. This simple and efficient protocol is extended to the synthesis of O-benzyl hydroxamates, using in situ generated solid supported TsOBt to facilitate the recovery and re-usability of HOBt and to render the isolation of the products easier. Such in situ generation and further application of a coupling reagent is novel and industrially important.
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sulfonamide synthesis via oxyma o Sulfonates compatibility to acid sensitive groups and solid phase peptide synthesis
European Journal of Organic Chemistry, 2013Co-Authors: Nani Babu Palakurthy, Dharm Dev, Shubhasmin Rana, Krishna Chaitanya Nadimpally, Bhubaneswar MandalAbstract:A milder and more efficient procedure for the synthesis of sulfonamides by activating sulfonic acid groups as the corresponding Sulfonate Esters of ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma) is reported. This method is greener than all other existing protocols for the purpose. Other important advantages lie in (a) its applicability to less nucleophilic anilines under ambient and milder conditions and (b) its compatibility with solid phase peptide synthesis and acid-labile groups such as trityl (Trt) and tBu, which empowers the solid phase synthesis of sulfonamides of various peptides. To illustrate this, the syntheses of three sulfonamide derivatives of the peptide GAILG-NH2, which is relevant in the context of drug design against type 2 diabetes, are demonstrated by using Fmoc-based solid-phase peptide synthesis (SPPS).
Andrew Teasdale - One of the best experts on this subject based on the ideXlab platform.
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a detailed study of Sulfonate ester formation and solvolysis reaction rates and application toward establishing Sulfonate ester control in pharmaceutical manufacturing processes
Organic Process Research & Development, 2010Co-Authors: Andrew Teasdale, Stephen C Eyley, Karine Jacq, Karen Taylorworth, Andrew M Lipczynski, Wilfried Hoffmann, Van D Reif, Edward J Delaney, David P. Elder, K L FacchineAbstract:Sulfonate Esters of lower alcohols possess the capacity to react with DNA and cause mutagenic events, which in turn may be cancer inducing. Consequently, the control of residues of such substances in products that may be ingested by man (in food or pharmaceuticals) is of importance to both pharmaceutical producers and to regulatory agencies. Given that a detailed study of Sulfonate ester reaction dynamics (mechanism, rates, and equilibria) has not been published to date, a detailed kinetic and mechanistic study was undertaken and is reported herein as a follow-up to our earlier communication in this journal. The study definitively demonstrates that Sulfonate Esters cannot form even at trace level if any acid present is neutralized with even the slightest excess of base. A key conclusion from this work is that the high level of regulatory concern over the potential presence of Sulfonate Esters in API Sulfonate salts is largely unwarranted and that Sulfonate salts should not be shunned by innovator pharmace...
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mechanism and processing parameters affecting the formation of methyl methaneSulfonate from methanol and methanesulfonic acid an illustrative example for Sulfonate ester impurity formation
Organic Process Research & Development, 2009Co-Authors: Andrew Teasdale, Stephen C Eyley, Karine Jacq, Karen Taylorworth, Andrew M Lipczynski, Van D Reif, Ed Delaney, K L Facchine, David P. Elder, Simon GolecAbstract:Sulfonate salts offer useful modification of physicochemical properties of active pharmaceutical ingredients (APIs) containing basic groups, but there are regulatory concerns over the presence of Sulfonate Esters as potential genotoxic impurities (PGIs). Whilst Sulfonate Esters could theoretically result from interaction between sulfonic acids and alcohols, literature on their formation is sparse. GC−MS analysis of reactions of methanesulfonic acid (MSA) and isotopically labeled methanol (18O-label) confirm methanol C−O bond cleavage in the formation of the methyl methaneSulfonate (MMS), consistent with reversal of well-established mechanisms for solvolysis of Sulfonate Esters. Studies of reaction profiles quantify methyl methaneSulfonate formation under a range of conditions relevant to API processing. Maximum conversion to MMS in reaction mixtures was 0.35%, determined by analytical methods developed specifically for reaction mixture analysis. Sulfonate ester formation is dramatically reduced at lower t...
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control and analysis of alkyl and benzyl halides and other related reactive organohalides as potential genotoxic impurities in active pharmaceutical ingredients apis
Journal of Pharmaceutical and Biomedical Analysis, 2008Co-Authors: David P. Elder, Andrew M Lipczynski, Andrew TeasdaleAbstract:This paper continues the review of the relevant scientific literature associated with the control and analysis of potential genotoxic impurities (PGIs) in active pharmaceutical ingredients (APIs). The initial review [D.P. Elder, A. Teasdale, A.M. Lipczynski, J. Pharm. Biomed. Anal. 46 (2008) 1-8.] focused on the specific class of Sulfonate Esters but in this instance reference is made to the analysis of alkyl and benzyl halides and other related reactive organohalide alkylating agents. Such reactive materials are commonly employed in pharmaceutical research and development as raw materials, reagents and intermediates in the chemical synthesis of new drug substances. Consequently a great deal of attention and effort is extended by the innovative and ethical pharmaceutical industry to ensure that appropriate and practicable control strategies are established during drug development to ensure residues of such agents, as potential impurities in new drug substances, are either eliminated or minimized to such an extent so as to not present a significant safety risk to volunteers and patients in clinical trials and beyond. The reliable trace analysis of such reactive organohalides is central to such control strategies and invariably involves a state-of-the-art combination of high-resolution separation science techniques coupled to sensitive and selective modes of detection. This article reports on the most recent developments in the regulatory environment, overall strategies for the control of alkylating agents and the latest developments in analysis culminating in a literature review of analytical approaches. The literature is sub-categorized by separation technique (gas chromatography (GC), high-performance liquid chromatography (HPLC), thin layer chromatography (TLC) and capillary zone electrophoresis (CZE)) and further tabulated by API type and impurity with brief method details and references. As part of this exercise, a selection of relevant pharmacopoeial monographs was also reviewed. The continued reliance on relatively non-specific and insensitive TLC methodologies in several monographs was noteworthy.
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control and analysis of alkyl Esters of alkyl and aryl sulfonic acids in novel active pharmaceutical ingredients apis
Journal of Pharmaceutical and Biomedical Analysis, 2008Co-Authors: David P. Elder, Andrew Teasdale, Andrew M LipczynskiAbstract:Abstract This article reviews current regulatory guidelines and relevant scientific literature pertaining to the control and analysis of potential genotoxic impurities (PGIs) in new active pharmaceutical ingredients (APIs) with specific reference to a certain sub-class of PGIs, namely alkyl Esters of alkyl and aryl sulfonic acids. Sulfonic acids are very important in pharmaceutical R&D employed both as counter-ions in the formation of acid-addition salts and also as reagents and catalysts in the synthesis of new drug substances. The article reviews the evolution of analytical methodology from early studies in the mid 1970s through development of direct injection GC and HPLC methods to liquid–liquid/solid phase extraction and headspace based techniques coupled to HPLC and GC methodologies employing UV and MS detection to new derivatisation-based techniques. The paper also reflects on the significant challenges in developing robust analytical methodology capable of the trace determination of Sulfonate Esters, the challenges in transferring methodology from R&D to QC labs and on the cost of inappropriate limits for genotox impurities. In so doing, the authors seek to inform the debate that the control of genotoxic impurities should be driven primarily by safety and risk/benefit considerations rather than by state-of-the-art analytical and process chemistry capabilities that drive controls to levels ‘as low as practicable’ regardless of the risk/safety requirements.
Andrew M Lipczynski - One of the best experts on this subject based on the ideXlab platform.
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a detailed study of Sulfonate ester formation and solvolysis reaction rates and application toward establishing Sulfonate ester control in pharmaceutical manufacturing processes
Organic Process Research & Development, 2010Co-Authors: Andrew Teasdale, Stephen C Eyley, Karine Jacq, Karen Taylorworth, Andrew M Lipczynski, Wilfried Hoffmann, Van D Reif, Edward J Delaney, David P. Elder, K L FacchineAbstract:Sulfonate Esters of lower alcohols possess the capacity to react with DNA and cause mutagenic events, which in turn may be cancer inducing. Consequently, the control of residues of such substances in products that may be ingested by man (in food or pharmaceuticals) is of importance to both pharmaceutical producers and to regulatory agencies. Given that a detailed study of Sulfonate ester reaction dynamics (mechanism, rates, and equilibria) has not been published to date, a detailed kinetic and mechanistic study was undertaken and is reported herein as a follow-up to our earlier communication in this journal. The study definitively demonstrates that Sulfonate Esters cannot form even at trace level if any acid present is neutralized with even the slightest excess of base. A key conclusion from this work is that the high level of regulatory concern over the potential presence of Sulfonate Esters in API Sulfonate salts is largely unwarranted and that Sulfonate salts should not be shunned by innovator pharmace...
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mechanism and processing parameters affecting the formation of methyl methaneSulfonate from methanol and methanesulfonic acid an illustrative example for Sulfonate ester impurity formation
Organic Process Research & Development, 2009Co-Authors: Andrew Teasdale, Stephen C Eyley, Karine Jacq, Karen Taylorworth, Andrew M Lipczynski, Van D Reif, Ed Delaney, K L Facchine, David P. Elder, Simon GolecAbstract:Sulfonate salts offer useful modification of physicochemical properties of active pharmaceutical ingredients (APIs) containing basic groups, but there are regulatory concerns over the presence of Sulfonate Esters as potential genotoxic impurities (PGIs). Whilst Sulfonate Esters could theoretically result from interaction between sulfonic acids and alcohols, literature on their formation is sparse. GC−MS analysis of reactions of methanesulfonic acid (MSA) and isotopically labeled methanol (18O-label) confirm methanol C−O bond cleavage in the formation of the methyl methaneSulfonate (MMS), consistent with reversal of well-established mechanisms for solvolysis of Sulfonate Esters. Studies of reaction profiles quantify methyl methaneSulfonate formation under a range of conditions relevant to API processing. Maximum conversion to MMS in reaction mixtures was 0.35%, determined by analytical methods developed specifically for reaction mixture analysis. Sulfonate ester formation is dramatically reduced at lower t...
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control and analysis of alkyl and benzyl halides and other related reactive organohalides as potential genotoxic impurities in active pharmaceutical ingredients apis
Journal of Pharmaceutical and Biomedical Analysis, 2008Co-Authors: David P. Elder, Andrew M Lipczynski, Andrew TeasdaleAbstract:This paper continues the review of the relevant scientific literature associated with the control and analysis of potential genotoxic impurities (PGIs) in active pharmaceutical ingredients (APIs). The initial review [D.P. Elder, A. Teasdale, A.M. Lipczynski, J. Pharm. Biomed. Anal. 46 (2008) 1-8.] focused on the specific class of Sulfonate Esters but in this instance reference is made to the analysis of alkyl and benzyl halides and other related reactive organohalide alkylating agents. Such reactive materials are commonly employed in pharmaceutical research and development as raw materials, reagents and intermediates in the chemical synthesis of new drug substances. Consequently a great deal of attention and effort is extended by the innovative and ethical pharmaceutical industry to ensure that appropriate and practicable control strategies are established during drug development to ensure residues of such agents, as potential impurities in new drug substances, are either eliminated or minimized to such an extent so as to not present a significant safety risk to volunteers and patients in clinical trials and beyond. The reliable trace analysis of such reactive organohalides is central to such control strategies and invariably involves a state-of-the-art combination of high-resolution separation science techniques coupled to sensitive and selective modes of detection. This article reports on the most recent developments in the regulatory environment, overall strategies for the control of alkylating agents and the latest developments in analysis culminating in a literature review of analytical approaches. The literature is sub-categorized by separation technique (gas chromatography (GC), high-performance liquid chromatography (HPLC), thin layer chromatography (TLC) and capillary zone electrophoresis (CZE)) and further tabulated by API type and impurity with brief method details and references. As part of this exercise, a selection of relevant pharmacopoeial monographs was also reviewed. The continued reliance on relatively non-specific and insensitive TLC methodologies in several monographs was noteworthy.
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control and analysis of alkyl Esters of alkyl and aryl sulfonic acids in novel active pharmaceutical ingredients apis
Journal of Pharmaceutical and Biomedical Analysis, 2008Co-Authors: David P. Elder, Andrew Teasdale, Andrew M LipczynskiAbstract:Abstract This article reviews current regulatory guidelines and relevant scientific literature pertaining to the control and analysis of potential genotoxic impurities (PGIs) in new active pharmaceutical ingredients (APIs) with specific reference to a certain sub-class of PGIs, namely alkyl Esters of alkyl and aryl sulfonic acids. Sulfonic acids are very important in pharmaceutical R&D employed both as counter-ions in the formation of acid-addition salts and also as reagents and catalysts in the synthesis of new drug substances. The article reviews the evolution of analytical methodology from early studies in the mid 1970s through development of direct injection GC and HPLC methods to liquid–liquid/solid phase extraction and headspace based techniques coupled to HPLC and GC methodologies employing UV and MS detection to new derivatisation-based techniques. The paper also reflects on the significant challenges in developing robust analytical methodology capable of the trace determination of Sulfonate Esters, the challenges in transferring methodology from R&D to QC labs and on the cost of inappropriate limits for genotox impurities. In so doing, the authors seek to inform the debate that the control of genotoxic impurities should be driven primarily by safety and risk/benefit considerations rather than by state-of-the-art analytical and process chemistry capabilities that drive controls to levels ‘as low as practicable’ regardless of the risk/safety requirements.
David P. Elder - One of the best experts on this subject based on the ideXlab platform.
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a detailed study of Sulfonate ester formation and solvolysis reaction rates and application toward establishing Sulfonate ester control in pharmaceutical manufacturing processes
Organic Process Research & Development, 2010Co-Authors: Andrew Teasdale, Stephen C Eyley, Karine Jacq, Karen Taylorworth, Andrew M Lipczynski, Wilfried Hoffmann, Van D Reif, Edward J Delaney, David P. Elder, K L FacchineAbstract:Sulfonate Esters of lower alcohols possess the capacity to react with DNA and cause mutagenic events, which in turn may be cancer inducing. Consequently, the control of residues of such substances in products that may be ingested by man (in food or pharmaceuticals) is of importance to both pharmaceutical producers and to regulatory agencies. Given that a detailed study of Sulfonate ester reaction dynamics (mechanism, rates, and equilibria) has not been published to date, a detailed kinetic and mechanistic study was undertaken and is reported herein as a follow-up to our earlier communication in this journal. The study definitively demonstrates that Sulfonate Esters cannot form even at trace level if any acid present is neutralized with even the slightest excess of base. A key conclusion from this work is that the high level of regulatory concern over the potential presence of Sulfonate Esters in API Sulfonate salts is largely unwarranted and that Sulfonate salts should not be shunned by innovator pharmace...
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mechanism and processing parameters affecting the formation of methyl methaneSulfonate from methanol and methanesulfonic acid an illustrative example for Sulfonate ester impurity formation
Organic Process Research & Development, 2009Co-Authors: Andrew Teasdale, Stephen C Eyley, Karine Jacq, Karen Taylorworth, Andrew M Lipczynski, Van D Reif, Ed Delaney, K L Facchine, David P. Elder, Simon GolecAbstract:Sulfonate salts offer useful modification of physicochemical properties of active pharmaceutical ingredients (APIs) containing basic groups, but there are regulatory concerns over the presence of Sulfonate Esters as potential genotoxic impurities (PGIs). Whilst Sulfonate Esters could theoretically result from interaction between sulfonic acids and alcohols, literature on their formation is sparse. GC−MS analysis of reactions of methanesulfonic acid (MSA) and isotopically labeled methanol (18O-label) confirm methanol C−O bond cleavage in the formation of the methyl methaneSulfonate (MMS), consistent with reversal of well-established mechanisms for solvolysis of Sulfonate Esters. Studies of reaction profiles quantify methyl methaneSulfonate formation under a range of conditions relevant to API processing. Maximum conversion to MMS in reaction mixtures was 0.35%, determined by analytical methods developed specifically for reaction mixture analysis. Sulfonate ester formation is dramatically reduced at lower t...
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control and analysis of alkyl and benzyl halides and other related reactive organohalides as potential genotoxic impurities in active pharmaceutical ingredients apis
Journal of Pharmaceutical and Biomedical Analysis, 2008Co-Authors: David P. Elder, Andrew M Lipczynski, Andrew TeasdaleAbstract:This paper continues the review of the relevant scientific literature associated with the control and analysis of potential genotoxic impurities (PGIs) in active pharmaceutical ingredients (APIs). The initial review [D.P. Elder, A. Teasdale, A.M. Lipczynski, J. Pharm. Biomed. Anal. 46 (2008) 1-8.] focused on the specific class of Sulfonate Esters but in this instance reference is made to the analysis of alkyl and benzyl halides and other related reactive organohalide alkylating agents. Such reactive materials are commonly employed in pharmaceutical research and development as raw materials, reagents and intermediates in the chemical synthesis of new drug substances. Consequently a great deal of attention and effort is extended by the innovative and ethical pharmaceutical industry to ensure that appropriate and practicable control strategies are established during drug development to ensure residues of such agents, as potential impurities in new drug substances, are either eliminated or minimized to such an extent so as to not present a significant safety risk to volunteers and patients in clinical trials and beyond. The reliable trace analysis of such reactive organohalides is central to such control strategies and invariably involves a state-of-the-art combination of high-resolution separation science techniques coupled to sensitive and selective modes of detection. This article reports on the most recent developments in the regulatory environment, overall strategies for the control of alkylating agents and the latest developments in analysis culminating in a literature review of analytical approaches. The literature is sub-categorized by separation technique (gas chromatography (GC), high-performance liquid chromatography (HPLC), thin layer chromatography (TLC) and capillary zone electrophoresis (CZE)) and further tabulated by API type and impurity with brief method details and references. As part of this exercise, a selection of relevant pharmacopoeial monographs was also reviewed. The continued reliance on relatively non-specific and insensitive TLC methodologies in several monographs was noteworthy.
-
control and analysis of alkyl Esters of alkyl and aryl sulfonic acids in novel active pharmaceutical ingredients apis
Journal of Pharmaceutical and Biomedical Analysis, 2008Co-Authors: David P. Elder, Andrew Teasdale, Andrew M LipczynskiAbstract:Abstract This article reviews current regulatory guidelines and relevant scientific literature pertaining to the control and analysis of potential genotoxic impurities (PGIs) in new active pharmaceutical ingredients (APIs) with specific reference to a certain sub-class of PGIs, namely alkyl Esters of alkyl and aryl sulfonic acids. Sulfonic acids are very important in pharmaceutical R&D employed both as counter-ions in the formation of acid-addition salts and also as reagents and catalysts in the synthesis of new drug substances. The article reviews the evolution of analytical methodology from early studies in the mid 1970s through development of direct injection GC and HPLC methods to liquid–liquid/solid phase extraction and headspace based techniques coupled to HPLC and GC methodologies employing UV and MS detection to new derivatisation-based techniques. The paper also reflects on the significant challenges in developing robust analytical methodology capable of the trace determination of Sulfonate Esters, the challenges in transferring methodology from R&D to QC labs and on the cost of inappropriate limits for genotox impurities. In so doing, the authors seek to inform the debate that the control of genotoxic impurities should be driven primarily by safety and risk/benefit considerations rather than by state-of-the-art analytical and process chemistry capabilities that drive controls to levels ‘as low as practicable’ regardless of the risk/safety requirements.
Nani Babu Palakurthy - One of the best experts on this subject based on the ideXlab platform.
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synthesis of o benzyl hydroxamates employing the Sulfonate Esters of n hydroxybenzotriazole
ChemInform, 2014Co-Authors: Nani Babu Palakurthy, Sonali Paikaray, Susmitnarayan Chaudhury, Dharm Dev, Bhubaneswar MandalAbstract:This method can also be used for the functionalization of sterically hindered amino acids and dipeptides without any significant racemization.
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Synthesis of O-benzyl hydroxamates employing the Sulfonate Esters of N-hydroxybenzotriazole
RSC Advances, 2014Co-Authors: Nani Babu Palakurthy, Sonali Paikaray, Susmitnarayan Chaudhury, Bhubaneswar MandalAbstract:The direct conversion of various carboxylic acids, that include sterically hindered amino acids and di-peptides, to O-benzyl hydroxamates is demonstrated using Sulfonate Esters of benzotriazoles under ambient and milder conditions without significant racemization. This simple and efficient protocol is extended to the synthesis of O-benzyl hydroxamates, using in situ generated solid supported TsOBt to facilitate the recovery and re-usability of HOBt and to render the isolation of the products easier. Such in situ generation and further application of a coupling reagent is novel and industrially important.
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sulfonamide synthesis via oxyma o Sulfonates compatibility to acid sensitive groups and solid phase peptide synthesis
European Journal of Organic Chemistry, 2013Co-Authors: Nani Babu Palakurthy, Dharm Dev, Shubhasmin Rana, Krishna Chaitanya Nadimpally, Bhubaneswar MandalAbstract:A milder and more efficient procedure for the synthesis of sulfonamides by activating sulfonic acid groups as the corresponding Sulfonate Esters of ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma) is reported. This method is greener than all other existing protocols for the purpose. Other important advantages lie in (a) its applicability to less nucleophilic anilines under ambient and milder conditions and (b) its compatibility with solid phase peptide synthesis and acid-labile groups such as trityl (Trt) and tBu, which empowers the solid phase synthesis of sulfonamides of various peptides. To illustrate this, the syntheses of three sulfonamide derivatives of the peptide GAILG-NH2, which is relevant in the context of drug design against type 2 diabetes, are demonstrated by using Fmoc-based solid-phase peptide synthesis (SPPS).
