Stereoselective Metal-Free Reduction of Chiral Imines in Batch and Flow Mode: A Convenient Strategy for the Synthesis of Chiral Active Pharmaceutical Ingredients

Detalhes bibliográficos
Autor(a) principal: Burke, Anthony J
Data de Publicação: 2016
Outros Autores: Benaglia, Maurizio, Porta, Ricardo, Fernandes, Silvia, Brenna, Davide
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10174/22350
https://doi.org/10.1002/ejoc.201601268
Resumo: he convenient, metal-free reduction of imines that contain an inexpensive and removable chiral auxiliary allowed for the synthesis of the immediate precursors of chiral active pharmaceutical ingredients (APIs). This protocol was carried out under batch and flow conditions to give the correspoding prod- ucts in high yields with almost complete stereocontrol. In the presence of trichlorosilane, an inexpensive and nontoxic reduc- ing agent, and an achiral Lewis base such as N,N-dimethyl- Introduction The pharmaceutical industry is gradually progressing towards enantiopure formulations. Most newly introduced drugs are chiral, and it is expected that approximately 95 % of pharma- ceutical drugs will be chiral by 2020. [1] In this context, chiral amines are considered a class of paramount importance, be- cause they are found in a plethora of compounds such as those of pharmaceutical interest as well as those developed for agro- chemicals, fragrances, and fine chemicals. [2] The reduction of the C=N group is one of the most widely used approaches to synthesize chiral amines, and over the last ten years, successful catalytic enantioselective methods based on both metal-pro- moted [3] and organocatalyzed [4] strategies have been devel- oped. When an industrial synthesis of a chiral pharmaceutical prod- uct must be planned, however, issues such as the chemical effi- ciency and robustness of the procedure, its general applicabil- ity, and economic considerations become crucially important. For these reasons, the applications of many chiral catalytic sys- tems are often not feasible, and the use of inexpensive and readily available chiral auxiliaries becomes an attractive and economic alternative. This also holds true for the synthesis of [a] Dipartimento di Chimica, Università degli Studi di Milano, via Golgi 19, 20133 Milano, Italy E-mail: maurizio.benaglia@unimi.it http://users2.unimi.it/Benagliagroup [b] Istituto di Scienze e Tecnologie Molecolari ISTM-CNR, Via Golgi 19, 20133 Milano, Italy [c] Department of Chemistry and Chemistry Center of Évora, University of Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal Supporting information and ORCID(s) from the author(s) for this article are available on the WWW under http://dx.doi.org/10.1002/ejoc.201601268. Eur. J. Org. Chem. 2017, 39–44 © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim39 formamide, the formal syntheses of Rivastgmine, calcimimetic NPS R-568, and a Rho kinases inhibitor were successfully accom- plished. For the first time, both the diastereoselective imine re- duction and the auxiliary removal were efficiently performed in a micro- or mesoreactor under continuous-flow conditions, which paved the way towards the development of a practical process for the syntheses of industrially relevant, biologically active, enantiopure N-alkylamines
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spelling Stereoselective Metal-Free Reduction of Chiral Imines in Batch and Flow Mode: A Convenient Strategy for the Synthesis of Chiral Active Pharmaceutical IngredientsFlow ChemistryHydrosilylationhe convenient, metal-free reduction of imines that contain an inexpensive and removable chiral auxiliary allowed for the synthesis of the immediate precursors of chiral active pharmaceutical ingredients (APIs). This protocol was carried out under batch and flow conditions to give the correspoding prod- ucts in high yields with almost complete stereocontrol. In the presence of trichlorosilane, an inexpensive and nontoxic reduc- ing agent, and an achiral Lewis base such as N,N-dimethyl- Introduction The pharmaceutical industry is gradually progressing towards enantiopure formulations. Most newly introduced drugs are chiral, and it is expected that approximately 95 % of pharma- ceutical drugs will be chiral by 2020. [1] In this context, chiral amines are considered a class of paramount importance, be- cause they are found in a plethora of compounds such as those of pharmaceutical interest as well as those developed for agro- chemicals, fragrances, and fine chemicals. [2] The reduction of the C=N group is one of the most widely used approaches to synthesize chiral amines, and over the last ten years, successful catalytic enantioselective methods based on both metal-pro- moted [3] and organocatalyzed [4] strategies have been devel- oped. When an industrial synthesis of a chiral pharmaceutical prod- uct must be planned, however, issues such as the chemical effi- ciency and robustness of the procedure, its general applicabil- ity, and economic considerations become crucially important. For these reasons, the applications of many chiral catalytic sys- tems are often not feasible, and the use of inexpensive and readily available chiral auxiliaries becomes an attractive and economic alternative. This also holds true for the synthesis of [a] Dipartimento di Chimica, Università degli Studi di Milano, via Golgi 19, 20133 Milano, Italy E-mail: maurizio.benaglia@unimi.it http://users2.unimi.it/Benagliagroup [b] Istituto di Scienze e Tecnologie Molecolari ISTM-CNR, Via Golgi 19, 20133 Milano, Italy [c] Department of Chemistry and Chemistry Center of Évora, University of Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal Supporting information and ORCID(s) from the author(s) for this article are available on the WWW under http://dx.doi.org/10.1002/ejoc.201601268. Eur. J. Org. Chem. 2017, 39–44 © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim39 formamide, the formal syntheses of Rivastgmine, calcimimetic NPS R-568, and a Rho kinases inhibitor were successfully accom- plished. For the first time, both the diastereoselective imine re- duction and the auxiliary removal were efficiently performed in a micro- or mesoreactor under continuous-flow conditions, which paved the way towards the development of a practical process for the syntheses of industrially relevant, biologically active, enantiopure N-alkylaminesWiley VCH2018-02-19T16:14:52Z2018-02-192016-11-26T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10174/22350https://doi.org/10.1002/ejoc.201601268http://hdl.handle.net/10174/22350eng39-44Eur. Journal Organic Chemistryajb@uevora.ptndndndndStereoselective Metal-Free Reduction of Chiral Imines in Batch and Flow Mode: A Convenient Strategy for the Synthesis of Chiral Active Pharmaceutical Ingredients307http://onlinelibrary.wiley.com/doi/10.1002/ejoc.201601268/epdfBurke, Anthony JBenaglia, MaurizioPorta, RicardoFernandes, SilviaBrenna, Davideinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-01-03T19:13:41Zoai:dspace.uevora.pt:10174/22350Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T01:13:27.896955Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Stereoselective Metal-Free Reduction of Chiral Imines in Batch and Flow Mode: A Convenient Strategy for the Synthesis of Chiral Active Pharmaceutical Ingredients
title Stereoselective Metal-Free Reduction of Chiral Imines in Batch and Flow Mode: A Convenient Strategy for the Synthesis of Chiral Active Pharmaceutical Ingredients
spellingShingle Stereoselective Metal-Free Reduction of Chiral Imines in Batch and Flow Mode: A Convenient Strategy for the Synthesis of Chiral Active Pharmaceutical Ingredients
Burke, Anthony J
Flow Chemistry
Hydrosilylation
title_short Stereoselective Metal-Free Reduction of Chiral Imines in Batch and Flow Mode: A Convenient Strategy for the Synthesis of Chiral Active Pharmaceutical Ingredients
title_full Stereoselective Metal-Free Reduction of Chiral Imines in Batch and Flow Mode: A Convenient Strategy for the Synthesis of Chiral Active Pharmaceutical Ingredients
title_fullStr Stereoselective Metal-Free Reduction of Chiral Imines in Batch and Flow Mode: A Convenient Strategy for the Synthesis of Chiral Active Pharmaceutical Ingredients
title_full_unstemmed Stereoselective Metal-Free Reduction of Chiral Imines in Batch and Flow Mode: A Convenient Strategy for the Synthesis of Chiral Active Pharmaceutical Ingredients
title_sort Stereoselective Metal-Free Reduction of Chiral Imines in Batch and Flow Mode: A Convenient Strategy for the Synthesis of Chiral Active Pharmaceutical Ingredients
author Burke, Anthony J
author_facet Burke, Anthony J
Benaglia, Maurizio
Porta, Ricardo
Fernandes, Silvia
Brenna, Davide
author_role author
author2 Benaglia, Maurizio
Porta, Ricardo
Fernandes, Silvia
Brenna, Davide
author2_role author
author
author
author
dc.contributor.author.fl_str_mv Burke, Anthony J
Benaglia, Maurizio
Porta, Ricardo
Fernandes, Silvia
Brenna, Davide
dc.subject.por.fl_str_mv Flow Chemistry
Hydrosilylation
topic Flow Chemistry
Hydrosilylation
description he convenient, metal-free reduction of imines that contain an inexpensive and removable chiral auxiliary allowed for the synthesis of the immediate precursors of chiral active pharmaceutical ingredients (APIs). This protocol was carried out under batch and flow conditions to give the correspoding prod- ucts in high yields with almost complete stereocontrol. In the presence of trichlorosilane, an inexpensive and nontoxic reduc- ing agent, and an achiral Lewis base such as N,N-dimethyl- Introduction The pharmaceutical industry is gradually progressing towards enantiopure formulations. Most newly introduced drugs are chiral, and it is expected that approximately 95 % of pharma- ceutical drugs will be chiral by 2020. [1] In this context, chiral amines are considered a class of paramount importance, be- cause they are found in a plethora of compounds such as those of pharmaceutical interest as well as those developed for agro- chemicals, fragrances, and fine chemicals. [2] The reduction of the C=N group is one of the most widely used approaches to synthesize chiral amines, and over the last ten years, successful catalytic enantioselective methods based on both metal-pro- moted [3] and organocatalyzed [4] strategies have been devel- oped. When an industrial synthesis of a chiral pharmaceutical prod- uct must be planned, however, issues such as the chemical effi- ciency and robustness of the procedure, its general applicabil- ity, and economic considerations become crucially important. For these reasons, the applications of many chiral catalytic sys- tems are often not feasible, and the use of inexpensive and readily available chiral auxiliaries becomes an attractive and economic alternative. This also holds true for the synthesis of [a] Dipartimento di Chimica, Università degli Studi di Milano, via Golgi 19, 20133 Milano, Italy E-mail: maurizio.benaglia@unimi.it http://users2.unimi.it/Benagliagroup [b] Istituto di Scienze e Tecnologie Molecolari ISTM-CNR, Via Golgi 19, 20133 Milano, Italy [c] Department of Chemistry and Chemistry Center of Évora, University of Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal Supporting information and ORCID(s) from the author(s) for this article are available on the WWW under http://dx.doi.org/10.1002/ejoc.201601268. Eur. J. Org. Chem. 2017, 39–44 © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim39 formamide, the formal syntheses of Rivastgmine, calcimimetic NPS R-568, and a Rho kinases inhibitor were successfully accom- plished. For the first time, both the diastereoselective imine re- duction and the auxiliary removal were efficiently performed in a micro- or mesoreactor under continuous-flow conditions, which paved the way towards the development of a practical process for the syntheses of industrially relevant, biologically active, enantiopure N-alkylamines
publishDate 2016
dc.date.none.fl_str_mv 2016-11-26T00:00:00Z
2018-02-19T16:14:52Z
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https://doi.org/10.1002/ejoc.201601268
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url http://hdl.handle.net/10174/22350
https://doi.org/10.1002/ejoc.201601268
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language eng
dc.relation.none.fl_str_mv 39-44
Eur. Journal Organic Chemistry
ajb@uevora.pt
nd
nd
nd
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Stereoselective Metal-Free Reduction of Chiral Imines in Batch and Flow Mode: A Convenient Strategy for the Synthesis of Chiral Active Pharmaceutical Ingredients
307
http://onlinelibrary.wiley.com/doi/10.1002/ejoc.201601268/epdf
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