The development of Selectfluor® as a commercial electrophilic fluorinating agent
Submitting InstitutionUniversity of Manchester
Unit of AssessmentChemistry
Summary Impact TypeTechnological
Research Subject Area(s)
Chemical Sciences: Inorganic Chemistry, Organic Chemistry, Physical Chemistry (incl. Structural)
Summary of the impact
The development of the chemistry of Selectfluor® (F-TEDA-BF4)
has resulted in this Manchester-discovered reagent becoming the world's
most widely used commercial electrophilic fluorinating agent to introduce
fluorine into a range of pharmaceuticals and agrochemicals. Annual
worldwide production is ca. 25 tonnes and sales estimated to be US$7.5m.
Selectfluor is used in the synthesis of fluticasone, a fluorinated
corticosteroid which is the active ingredient in GSK's Advair ($3.6bn
sales in 2010) used in the treatment of asthma and chronic obstructive
pulmonary disease symptoms; top 25 selling drugs Flixonase, Flixotide,
Flonase, Flovent HFA and Advair Diskus which had total sales of over $17bn
The research was carried out in the UoA between 1993-2004. The key
Manchester researchers were:
Professor R. E. Banks (professor 1993-1994, emeritus professor 1994-2004)
Dr N. J. Lawrence (lecturer 1993-1997, senior lecturer 1997-2000)
Dr M. Besheesh (PhD student 1993-1994, PDRA 1994-2001)
Dr I. Sharif (PDRA, 1993-1994)
A.L. Popplewell (PhD student, 1994-1997)
In particular work was undertaken to show the effectiveness, range of
applications and utility of Selectfluor® as an electrophilic fluorinating
agent, an oxidising agent and as a fluorine-transfer reagent. The key
steps in demonstrating these classes of reactivity were
- Use as a fluorinating agent for 1,3-diketones and keto-amides,
demonstration that fluorination with Selectfluor® occurs more rapidly
for compounds which exist in their enolic form, and that Selectfluor®
was as effective as DesMarteau's reagent, but more advantageous, because
of its lower cost and less hazardous nature.
- Demonstration of the use of Selectfluor® as an oxidising agent for
alcohols via acid fluorides and how this may be used to effect
- Establishing that Selectfluor® can be used under a fluorine-transfer
protocol to prepare other fluorinating agents of the N-F class, which
has subsequently led to asymmetric fluorinating agents and [18-F]
variants for PET work.
- Detailing the properties of Selectfluor® compared with other N-F
reagents, how modification of counter-ions impacts on solubility and
protocols for fluorination of a wide range of substrates, including how
to activate otherwise unreactive substrates.
Some of the limitations of the reagent, due to fluorodemethylation
side-reactions, and hence how to protect against this eventuality.
References to the research
All of the papers appear in peer-reviewed international journals,
including two of the foremost Royal Society of Chemistry journals, and the
specialist journal for fluorine chemists, the Journal of Fluorine
Chemistry. Citations are from Google Scholar.
 N-Halogeno compounds. Part 18.
1-Alkyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane salts: user-friendly
site-selective electrophilic fluorinating agents of the N-fluoroammonium
class, R. E. Banks, M. K. Besheesh, S. N. Mohialdin-Khaffaf, I. Sharif, J.
Chem. Soc., Perkin 1, 1996, 2069-2076 (doi: 10.1039/P19960002069)
- 96 citations
 Efficient electrophilic fluorination of 03b2-dicarbonyl compounds
with the selectfluor reagent F-TEDA-BF4
bis(tetrafluoroborate)}, R.E. Banks, N. J. Lawrence, A. L. Popplewell, J.
Chem. Soc., Chem. Commun., 1994, 343-344. (doi: 10.1039/C39940000343)
- 66 citations
 Oxidation of benzylic alcohols and benzaldehydes with the Selectfluor
bis(tetrafluoroborate)}, R.E. Banks, N. J. Lawrence, A. L. Popplewell,
Synlett. 1994, 831-832 (doi: 10.1055/s-1994-23021)
— 26 citations
 Remote functionalization of (-)-menthol—synthesis of
4a,5,6,7,8,8a-hexahydro-4H-benzo[1,3]oxazine derivatives with the
SelectfluorTM reagent F-TEDA-BF4, R.E. Banks, N. J.
Lawrence, M. K. Besheesh, A. L. Popplewell, R.G. Pritchard, Chem. Commun.,
1996, 1629-1630. (doi: 10.1039/CC9960001629)
 N-Halogeno compounds. Part 20. Vicarious electrophilic
fluorodemethylation of 1,3,5-trimethoxybenzene and 2,4,6-trimethoxytoluene
bis(tetrafluoroborate) (Selectfluor™ reagent F-TEDA-BF4), R. E.
Banks, M. K. Besheesh, R. W. Gorski, N. J. Lawrence, A. J. Taylor, J.
Fluorine Chem., 1999 , 96, 129-133. (doi: 10.1016/S0022-1139(99)00064-0)
 N-Halogeno compounds. Part 14. "Transfer fluorination" of
quinuclidine using F-TEDA-BF4 (SelectfluorTM
reagent): laboratory synthesis of N-fluoroquinuclidinium salts not
requiring the use of elemental fluorine, M. Abdul-Ghani, R. E. Banks, M.
K. Besheesh, I. Sharif, R. G. Syvret, J. Fluorine Chem., 1995, 73,
255-257. (doi: 10.1016/0022-1139(94)03225-O)
Details of the impact
Fluorine is one of the most reactive elements in the periodic table, yet
its compounds are some of the most useful, this is exemplified in
agrochemicals and pharmaceuticals where more than 1/5th of
compounds on the market are fluorine containing, including 30% of the
top-thirty best sellers. [O'Hagan, J. Fluorine Chem. 2010, 131,
The presence of a fluorine atom can confer advantageous potency,
selectivity and/or metabolic stability attributes to prospective drug
candidate molecules. This desirability is tempered by the harsh and
hazardous nature of conventional fluorinating agents; many different
electrophilic fluorinating agents have been investigated, but most are
insufficiently reactive, too hazardous or too expensive for large-scale
applications. Selectfluor® was developed at Manchester, and between 1993
and 2004 was demonstrated to fluorinate complex molecules, to the point
where it has now been adopted as the method of choice in industry for the
synthesis of a wide range of products, including being the preferred
fluorinating reagent in medicinal chemistry drug discovery projects within
Pfizer "SelectFluor® is a milder, safer and more easily
handled alternative to DAST (diethylaminosulfur trifluoride) and, as
such, it is a preferred fluorinating reagent in medicinal chemistry drug
discovery projects within Pfizer" (Senior Director, Worldwide
Medicinal Chemistry — Oncology, Pfizer) [A], and used to prepare one of
the most prescribed billion-dollar fluorosteroid products in the modern
pharmaceutical industry. "Prior to Selectfluor®'s discovery and
development, only a very few companies would dare face the challenges of
producing fluorinated steroids because of the necessity to obtain and
handle perchlorylfluoride, the only reagent available at the time to
provide electrophilic fluorination.
[Previously] perchlorylfluoride used in the production of
fluorosteroids had resulted in the fatalities of 2 production workers,
and as a result, the industry refused to consider commercial production
using the reagent. With the development of Selectfluor® chemistry,
this stable, safe, and readily handled white solid made it possible for
any company wishing to introduce electrophilic fluorination to do so.
Selectfluor® was a game-changing innovation for commercial
production of fluorinated steroids" (Research Fellow, Arkema —
formerly at Air Products) [B].
Pathways to impact
Selectfluor® was developed in Manchester by Professor R. Eric Banks in
collaboration with, and funded by, Air Products Inc. Following its
development the research carried out in Manchester determined and
exemplified the reactivity and conditions of use for Selectfluor® which
has subsequently led to it becoming the world's most widely adopted
electrophilic fluorinating agent to date.
Our publications of Selectfluor®'s reactivity and protocols for its use
were published between 1994 and 1999, shortly afterwards patents
describing the application of Selectfluor® started to appear. In total
from 1993 to 2012, there have been 134 patents published which cite
Selectfluor® (SciFinder search 07.01.2013), that cover a wide range of
multinational companies, countries and scientific areas.
As the chemistry and applications of Selectfluor® were developed and the
industrial relevance of this compound became obvious Selectfluor®
production was developed over a 5 year period onto a commercial scale. It
is now produced on a multi-tonne quantity in America, China and other
countries, with estimated annual production and sales figures of ca. 25
tonnes and $7.5m (USD) per annum [C].
`Selectfluor®'s widespread availability at commercial volumes
and its acceptance by both academic and industrial chemists changed the
way researchers and process development chemists in pharmaceutical and
agricultural industries think about fluorination. Selectfluor® became
the first tool of choice for any process requiring electrophilic
fluorination and even today it remains the most popular reagent used'
(Research Fellow, Arkema — formerly at Air Products) [B].
This has impacted on some of the largest pharmaceutical companies, for
example: Bayer for the application and processes for the preparation of
halogen-substituted compounds, for controlling animal pests, especially
arthropods, arachnids and nematodes; Pfizer for the synthesis of fluorine-
containing morpholine compounds as therapeutic mineralocorticoid receptor
antagonists to control hypertension, congestive heart failure and chronic
kidney disease; Glaxo Group Ltd for Napththyrdin-2(1H) based compounds of
use as antibacterials, for example in the treatment of tuberculosis;
AstraZeneca AB for the synthesis of compounds used as selective/potent
GSK3 (glycogen synthase kinase 3) inhibitors of relevance to treatment in
chronic and acute neurodegenerative diseases, Alzhimer's disease,
Schizophrenia and bipolar disorders, diabetes, inflammatory diseases and
The area in which the chemistry of Selectfluor® has had the most
significant impact is as the electrophilic fluorinating agent of choice
for the generation of fluorine-substituted corticosteroids used as
anti-inflammatory drugs [D,E]. It is estimated that ca. 80 % of the
currently produced fluorinated steroids, critical for the improvement in
quality of many people's lives, are produced using Selectfluor® and this
is backed up by the patent literature [O'Hagan, J. Fluorine Chem. 2010, 131,
Fluticasone propionate (from flumethasone or flumetasone) is the active
ingredient in a very wide range of pharmaceutical products for the
treatment of asthma and chronic obstructive pulmonary disease symptoms.
This fluorinated ingredient was first developed and patented in the early
1960's, based on small scale routes involving the use of anhydrous
HF/Pb(OAc)4, SF4 or ClO3F (perchloryl
fluoride) to introduce fluorine, all of which are hazardous and difficult
to handle. Since the development of Selectfluor®'s chemistry companies,
such as Hovione, Taro and Farmabios, have patented Selectfluor®-based
methods as their preferred routes, including (but not limited to) EP
1207166 (2002), WO 02/100878 (2002) [F], US 7098328 (2006) [G], and US
7718793 (2010) [H]. These described (and cite) methods based on references
,  and R. E. Banks et al J. Fluorine Chem. 1998, 87, 1-17, as the
preferred method for the generation of this, and other corticosteroid
This fluorinated steroid produced in this way is sold-on and formulated
into a number of products which sell under tradenames such as Flixonase,
Flixotide, Flonase, Flovent HFA and Advair Diskus. The latter two GSK
products are in the top 25 selling drugs. Data from: www.drugs.com/top200.html
(accessed 8.1.2013) or from the IMS Institute for Healthcare Informatics
(which covers US sales alone) shows that these pharmaceuticals for the
years 2009-2012 had total sales of over $17bn, corresponding to ca. 75
million units for Advair Diskus alone. The reach of this
Selectfluor-prepared fluorine-containing drug is truly international and
benefits many millions of users per annum.
Sources to corroborate the impact
A) Corroboration of Selectfluor® impact. Letter from Senior Director,
B) Corroboration of commercial impact of Selectfluor®. Letter from
Research Fellow at Arkema.
C) An email discourse with scientist who was at Air Products when
Selectfluor® was commercialised.
D) C. G. Pozzoli, F. La Loggia, F. Malanga, Farmabios SpA, Synthesis of
Fluoro-corticosteroids, La Chimica, L'Industria, 2013, 124 - 128.
E) Dabbling with Fluorine, C&E News, 90(9), 27th February 2012 pp.
F) Villax, Z. Mendes, WO 02/100878,, June
11, 2002, Preparation of flumethasone and its 17- carbonyl androsten
analogue, assigned to Hovione Limited.
G) S. Chernyak, M. Zarbov, D. Gutman, US7098328,
August 29 2006, Method for the Preparation of 6α-fluoro corticosteroids,
assigned to Taro Pharmaceutical Industries.
H) S. Chernyak, M. Zarbov, D. Gutman, US7718793,
May 18, 2010, Method for the Preparation of 6-α fluoro corticosteroids,
assigned to Taro Pharmaceutical Industries