Fluoroalkylation reactions in aqueous media: a review

green chemistry, PROCESS, SYNTHESIS, Uncategorized Comments Off

Mar 062018

Fluoroalkylation reactions in aqueous media: a review

Green Chem., 2018, Advance Article
DOI: 10.1039/C8GC00078F, Tutorial Review

Hai-Xia Song, Qiu-Yan Han, Cheng-Long Zhao, Cheng-Pan Zhang
Recent advances in aqueous fluoroalkylation using various fluoroalkylation reagents are summarized in this review.

Fluoroalkylation reactions in aqueous media: a review

Hai-Xia Song,^a Qiu-Yan Han,^a Cheng-Long Zhao^a and Cheng-Pan Zhang*^a

Author affiliations

* Corresponding authors

^a School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 205 Luoshi Road, 430070, Wuhan, China
E-mail: zhangchengpan1982@hotmail.com, cpzhang@whut.edu.cn

Abstract

This review highlights the progress of aqueous fluoroalkylation over the past few decades. Fluorine-containing functionalities are important design elements in new pharmaceuticals, agrochemicals, and functional materials, due to their unique effects on the physical, chemical, and/or biological properties of a molecule. Because the environmental concerns are receiving increasing attention in organic synthesis, the development of methods for the mild, environment-friendly, and efficient incorporation of fluorinated or fluoroalkylated groups into the target molecules is of broad interest. At the early stage, most of the fluoroalkylation reactions and their variants were thought in principle to be hydrophobic. Recently, the environment-benign fluoroalkylation reactions by taming nucleophilic, radical, or electrophilic fluoroalkylation reagents in water or in the presence of water have been explored, building a new prospect for green chemistry. The use of significant catalytic systems and/or the newly developed reagents is the key to the success of these reactions. Water is used as a (co)solvent and/or a reactant in aqueous fluoroalkylation, including trifluoromethylation, difluoromethylation, monofluoromethylation, trifluoroethylation, perfluoroalkylation, trifluoromethylthiolation, and other conversions, under environment-friendly conditions. Although great accomplishments have been achieved, they are just the tip of the iceberg with a wide scope for improvement. This review will draw great attention and inspire more contributions in the development of new aqueous fluoroalkylation reactions

Conclusion

In conclusion, aqueous fluoroalkylation including trifluoromethylation, difluoromethylation, monofluoromethylation, trifluoroethylation, perfluoroalkylation, trifluoromethylthiolation, and difluoromethylthiolation are summarized in this review.

The successful assembly of nucleophilic, radical, and/or electrophilic fluoroalkylation reagents and water in fluoroalkylation reactions opens a new prospect for green chemistry. The valid catalytic systems and the newly developed reagents contribute greatly for the success of the aqueous fluoroalkylation. As a provisional conclusion, the shelf-stable electrophic and radical fluoroalkylation reagents such as “+CF3”, “+CF2H”, “ +CH2CF3”, RfnSO2M (M = Na, 1/2Zn, Cl), RfnX (X = I, Br), and “+ SCF3” reagents are basically compatible with water or aqueous media, which enable a variety of aqueous fluoroalkylation reactions under mild conditions. In the case of nucleophilic fluoroalkylation reagents that are moisture-sensitive (e.g., “−CF3” and “− SCF3” sources), the choice of an appreciate transition-metal partner to stabilize the fluorinated anions is crucial to promote the reaction.

By coupling with the right transition metals, these sensitive fluoroalkylation reagents or intermediates would have sufficient lifetimes to finish the target conversions. Water is abundant and environmentally benign, and it has advantages such as high dielectric constant, large cohesive energy density, and strong hydrogen bonding interaction, which desirably influence the efficiency and selectivity of chemical reactions. In this reviw, water works as a (co)solvent and/or a reactant to facilitate the fluoroalkylation by increasing the dissolving of the reaction participants, providing a proton donor, or behaving as a O-nucleophile.

The fluoroalkylation reactions performed in aqueous media are mild, easily controlled, and environmental friendly, which fit well the principles of green chemistry. Although breakthroughs have been made, siginificant improvement is still neccessary for a wide range of fluoroalkylation reactions. A tough question is whether the direct trifluoromethoxylation can be performed in aqueous conditions, despite the reaction of excess AgOCF3 with α-diazo esters surviving in CH3CN in the presence of residue moisture or a trace amount of D2O (Scheme 120).155 The ionic [Me4N][SCF3] and [Me4N][SeCF3] salts, and their variants containing free − SCF3 or − SeCF3 anions, also encounter similar problems, even through trace of water proved to be essential for the functionalization of α-diazo carbonyls.156,157 The sensitive −XCF3 (X = O, S, Se) anions tend to undergo α-fluorine elimination to generate fluoride ( − F) and carbonic difluoride (CXF2), and the presence of water is generally believed to accelerate this transformation, leading to rapid decomposition of these reagents.

We hope that this review will attract more interests and contributions in the development of aqueous fluoroalkylation with these extraordinary reagents. Aqueous fluoroalkylation methods have changed the way to synthesize fluorinated molecules in terms of the biological and physicochemical properties. Since the aspects of green chemistry have drawn much attention from society, the pursuit of more efficient and milder reaction conditions for greener fluoroalkylation in aqueous media will never be terminated. We hope that this review will serve as a guide to understand and as an appeal to engage in the field of green fluorine chemistry.

To meet the principles of green chemistry, the development of new fluoroalkylation reagents and efficient catalytic systems will be continuously vital for the mild and environment-benign fluoroalkylation. It is anticipated that a growing number of green fluoroalkylation methodologies in aqueous media will arise in the near future.

Sulfurative self-condensation of ketones and elemental sulfur: a three-component access to thiophenes catalyzed by aniline acid-base conjugate pairs

green chemistry, organic chemistry, PROCESS, spectroscopy, SYNTHESIS Comments Off

Dec 282017

Sulfurative self-condensation of ketones and elemental sulfur: a three-component access to thiophenes catalyzed by aniline acid-base conjugate pairs

Green Chem., 2018, Advance Article
DOI: 10.1039/C7GC03437G, Communication

Thanh Binh Nguyen, Pascal Retailleau
An aniline/acid-catalyzed method for constructing thiophenes 2 from inexpensive ketones 1 and elemental sulfur is reported.

Sulfurative self-condensation of ketones and elemental sulfur: a three-component access to thiophenes catalyzed by aniline acid–base conjugate pairs

Thanh Binh Nguyen*^a and Pascal Retailleau^a

Author affiliations

* Corresponding authors

^a Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, 1, av de la Terrasse, 91198 Gif-sur-Yvette, France
E-mail: nguyen@icsn.cnrs-gif.fr

Abstract

A sulfurative self-condensation method for constructing thiophenes 2 by a reaction between ketones 1 and elemental sulfur is reported. This reaction, which is catalyzed by anilines and their salts with strong acids, starts from readily available and inexpensive materials, and releases only water as a by-product.

2,4-Di-p-tolylthiophene (2b)2

2 M. Arisawa, T. Ichikawa, and M. Yamaguchi, Chem. Commun. 2015, 51, 8821

Eluent heptane:toluene 9:1. 190 mg, 72%.

1 H NMR (300 MHz, CDCl3) δ 7.60-7.54 (m, 5H), 7.34 (s, 1H), 7.27-7.23 (m, 4H), 2.42 (s, 6H).

13C NMR (75 MHz, CDCl3) δ 145.3, 143.3, 137.8, 137.2, 133.5, 131.9, 129.9, 129.8, 126.5, 126.0, 122.1, 118.9, 21.5, 21.5.

Binh Thanh Nguyen

CV Binh Nguyen

CNRS Research Associate CR1 ( ORCID , ResearchGate )

ICSN-CNRS Bât. 27

1, avenue de la Terrasse

91190 Gif-sur-Yvette France

thanh-binh.nguyen_at_cnrs.fr

+33 1 69 82 45 49

Education and work experience2015: Habilitation to Direct Research (HDR)

2011 – present: CNRS research associate at ICSN – Paris-Saclay University

2009 – 2011: Post-doctoral Fellow at ICSN (Dr. Françoise Guéritte and Dr. Qian Wang)

2003 – 2006: Ph.D. student at the UCO2M Organic Synthesis Laboratory (University of Maine, Le Mans, France, Dr. Gilles Dujardin, Dr. Arnaud Martel, Professor Robert Dhal)

Research Interests

Green chemistry (Atom, step and redox economic transformation), green synthetic tools: O2, S8, photochemistry, iron catalyst

Elemental sulfur as a synthetic tool (building block, oxidant, reductant, catalyst)

Iron-sulfur catalysts

Heterocycle synthesis

Scientific Communications

47 publications

Selected recent publications ( complete list )

[1] Adv. Synth. Catal. 2017 , 359 , 1106.

[2] Asian J. Org. Chem. 2017 , 6 , 477.

[3] Org. Lett. 2016 , 18 , 2177.

[4] Org. Process Res. Dev. 2016 , 20 , 319.

[5] Angew. Chem. Int. Ed. 2014 , 53 , 13808.

[6] J. Am. Chem. Soc. 2013 , 135 , 118.

///////////

Design and evolution of the BMS process greenness scorecard

green chemistry Comments Off

Oct 312017

Design and evolution of the BMS process greenness scorecard

Green Chem., 2017, 19,5163-5171
DOI: 10.1039/C7GC02190A, Paper

David K. Leahy, Eric M. Simmons, Victor Hung, Jason T. Sweeney, William F. Fleming, Melanie Miller
A process greenness scorecard has been developed that provides a comprehensive assessment of greenness aspects not encompassed by mass-based metrics, including environmental, health and safety impacts, in order to facilitate the design of greener, more benign and inherently safer processes.
The content of this RSS Feed (c) The Royal Society of Chemistry

Melanie Miller

Executive Director, Pharmaceutical Development at Bristol Myers Squibb

Head of API Operations, Pharmaceutical Development

Bristol Myers Squibb

New Brunswick, New Jersey

Leads manufacturing operations to deliver small molecule active pharmaceutical ingredients for investigational medicines. Scope includes all R&D API manufacturing operations within a global external and internal manufacturing network supporting delivery of small molecules, antibody-drug conjugates, peptides and oligonucleotides.

Design and evolution of the BMS process greenness scorecard

David K. Leahy,*^a Eric M. Simmons,*^a Victor Hung,^b Jason T. Sweeney,^c William F. Fleming^d and Melanie Miller^b

*Corresponding authors

^aChemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, USA
E-mail:eric.simmons@bms.com

^bAPI Operations, Bristol-Myers Squibb, New Brunswick, USA

^cDrug Product Science and Technology, Bristol-Myers Squibb, New Brunswick, USA

^dEnvironmental Health Safety and Sustainability, Bristol-Myers Squibb, East Syracuse, USA

Jason Sweeney

Associate Director at Bristol-Myers Squibb

Abstract

An accurate and comprehensive assessment of the environmental, health and safety impacts of a chemical process is critical to the design and implementation of greener, more benign and inherently safer processes. Over the past 15 years at BMS, we have developed a Process Greenness Scorecard to capture and analyse a number of metrics and attributes for each step in the synthetic sequence used to produce an API. This manuscript describes the design and evolution of the scoring methodology and implementation of the resulting scorecard, from an initial Excel-based tool to the current web-based format.

David K. Leahy

https://www.linkedin.com/in/davidkleahy/

Associate Director, Process Chemistry

Company NameTakeda

Dates EmployedJul 2017 – Present

Employment Duration4 mos

LocationCambridge, MA
Principal Scientist

Company NameBristol-Myers Squibb

Dates Employed2013 – 2017

Employment Duration4 yrs

LocationGreater New York City Area

• Project leader for two high priority small molecule oncology programs, delivering preclinical supplies for five separate analogues (three separate chemotypes) at an external CMO at least one month prior to candidate nomination. Developed a new chemical route for the most complex analogue to overcome poor efficiency (key fragment improved from 1.4% yield in 8 steps to 33% yield in 5 steps).
• Chemistry lead for a highly accelerated oncology program, responsible for the late-phase development and external execution of three complex regulatory starting materials. Invented a new synthetic route to circumvent a key scale-up liability, while removing numerous bottlenecks.
• Project leader for a biologics/small molecule conjugate PET tracer. Developed bio-orthogonal chemistry to prepare and purify the cold PET tracer analogue needed for IND toxicology studies. Key thought leader in developing new CMC strategies utilized by subsequent PET tracer teams.
• CMC leader for diabetes and fibrosis assets. Led cross-functional CMC team and Exploratory Development team through a very complex tautomer challenge. Strategically laid out and executed plans demonstrating that the tautomers posed no risk to patient safety and effectively communicated this to the FDA. Guided team to achieve key program milestone of First in Human.
• Co-invented a novel, non-chromatographic approach to purification of macro-cyclic peptides.
• Co-chair of the ACS Green Chemistry Institute Pharmaceutical Roundtable, responsible for implementation of strategic priorities and management of a $375k budget.
• Team lead for BMS corporate sustainability 2015 and 2020 goals to integrate sustainability throughout development and commercialization.
• Supervision of Ph.D. level direct reports. Committed to the professional development of project teams and direct reports, helping refine their skills, obtain promotions, and identify new roles that meet their career aspirations and passion.

Introduction

“The ability to meet the needs of the present without compromising the ability of future generations to meet their needs” The definition of sustainable development from the United Nations World Commission on Environment and Development has indeed resonated with corporate leaders across the globe.1 This is evident by the wealth of public-facing sustainability goals that Fortune 500 companies have committed to over the last decade. Within the context of the pharmaceutical industry, it is green chemistry2 that provides the key to environmentally-responsible pharmaceutical manufacturing3 , and practitioners have been rewarded with enormous impacts to their triple bottom line.4

Green chemistry is more cost-effective, safer for employees, and better for the environment. Corporate sustainability has been characterized as a key driver for innovation, which is essential for a firm to succeed.5 As part of our program in green chemistry, we anticipated that a tool that could assess the ‘greenness’ of our chemical processes would spark the innovation of our scientists, by pointing out deficient areas, prompting focus on these areas, and providing quantitative evidence that their improvements had the desired impact.6

A number of mass-based metrics are available to assess the greenness of a chemical process,7,8 with E factor (kg of waste/kg of product)9 and Process Mass Intensity (PMI = kg of inputs/kg of product)10 being most widely utilized within the pharmaceutical industry.7,8,10 We firmly believe that such metrics are very important, but we also recognized that they ignore many key green chemistry principles, most importantly safety.7,11,12

While important strides have been made in the development of quantitative methods to compare the environmental impact of chemical syntheses,13 most notably though Life Cycle Assessment (LCA)14 and the FLASC tool,15 as well as the recently introduced Green Aspiration Level (GAL),7,12 metrics that assess the safety and health hazards of chemical processes and products are lacking in comparison.16,17

In this article, we describe the strategy we have taken at Bristol-Myers Squibb to expand on existing mass-based approaches to include a comprehensive assessment of the important facets of greenness not encompassed by typical process metrics, such as E factor and PMI, to develop a Process Greenness scoring methodology that is appropriate for the assessment of the chemical processes used on scale for the synthesis of smallmolecule active pharmaceutical ingredients (APIs) and intermediates.18,19

Eric Simmons

Senior Research Investigator II at Bristol-Myers Squibb

Conclusions

The BMS process greenness scorecard is an important tool for scientists to help guide decisions made during API process development. It serves as the key methodology we use to assess the environmental and safety performance of our processes to manufacture compounds in development. This greenness score provides a useful and quantitative method, complimentary to mass based metrics such as PMI and derived from the 12 principles of green chemistry. A key advantage of this assessment is that it also considers the inherent safety of a process, both from a worker exposure and process hazards perspective. These are key green chemistry considerations that are not captured when evaluating a process using mass-based metrics alone. This assessment is especially important when facing complex decisions involving tradeoffs between improved efficiency versus enhanced process safety. While this tool is currently only suitable for use in evaluating small molecules, efforts are underway to expand this methodology to assess other important therapeutic modalities, including synthetic peptides, oligonucleotides, antibody-drug conjugates, and biologics and will be reported in due course.

William Fleming

Director, Head of Safety, Global EHS&S

Bristol-Myers Squibb

Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, USA

////////////////Bristol-Myers Squibb, bms, green

ref http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C7GC02190A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

more…………..

DOI: 10.1039/C6GC02359B (Paper) Green Chem., 2017, 19, 127-139

A data-driven strategy for predicting greenness scores, rationally comparing synthetic routes and benchmarking PMI outcomes for the synthesis of molecules in the pharmaceutical industry†

Jun Li , Eric M. Simmons and Martin D. Eastgate *
Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903, USA. E-mail: martin.eastgate@bms.com

Apixaban: Our final case study is apixaban (45), an orally bioavailable inhibitor of blood coagulation factor Xa, developed for thrombotic diseases and commercialized as Eliquis (Scheme 6).¹⁷ This highly optimized process evolved through multiple rounds of development and the data reported is taken from the validation campaign, thus ready for product launch. The actual cumulative PMI for the overall process was 197, which is significantly below the lower end of the 95% confidence interval for the predicted cumulative PMI (Fig. 14). In essence, it is lower than 99.9% of the similar chemistries executed on scale at different development stages. This is the one of a few commercial assets in our current database, and while obviously efficient, this score should be viewed with the perspective that most of the data available to us in this proof of concept study is in the development phase, and thus encompasses a wide range of optimization levels. However, in order to compare more globally, more data, from more companies, and across all phases of development is needed.


	Scheme 6 Apixaban synthetic route in validation campaign.

Fig. 14 Predicted apixaban cumulative PMI with mean 366 and 95% CI between 261 and 480.

image file: c6gc02359b-f14.tif

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent