Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5382_Библиотеки_им_академика_М_И_Перельмана.pdf
8.2 ALIPHATIC FLUORINATION
R
R
]
R R
R
R R
8.2.1.1 Fluorohydrins
The production of uorohydrins is typically accomplished through a substitution
reaction with a sulfonate or related leaving group. The alcohol precursor can be
protected to mitigate the eect of the proton donor on uoride reactivity. In several
instances, a cyclic sulfonate is utilized for the installation of uoride, and the resulting
acyclic sulfonate is cleaved, resulting in a mixture of isomeric uorohydrin products.
Alternatively, a one-step radiouorination may be achieved using an epoxide precursor,
and this has been performed in reactions using HF as the uorinating reagent[44–50].
In an improvement of this approach, methods using [
developed separately by both the Zhuravlev (Scheme8.1a) and Doyle (Scheme8.1b)
labs[51, 52]. In more recent work, the Scott and Sanford laboratories developed a
method to prepare a putative [
18
F]FeF species from [18F]HF to open sterically hindered
epoxides (Scheme8.1c)[32].
18
F]Co(salen) uorides have been
Scheme 8.1 Radio-
N N
Co
O O
O
R′ R R
O
R R R
O
R
HFIP, TBME or tAmOH, (-)tetramisole
tBu tBu
18
[
F]HF
[18F](R,R)-(salen)CoF
MTBE, 50 °C, 20 min
18
[
F]F- 0.5M TFA eluent
Fe(acac)
, dioxane
3
120 °C, 20 min
tButBu
18
F OH
18
FOH
18
FOH
R R
uorination of
epoxides for the
synthesis of [
uorohydrins.
[a]
[b
[c]
18
F]
Chapter 08: Fluorine-18 Radiochemistry 255
This method employed iron(III) acetylacetonate as a promoter and typically displayed regioselectivity for the more substituted epoxide carbon center (Scheme8.1c).
Notably, this selectivity is complementary to that oered by the Co(salen)
catalyst systems.
8.2.1.2 Benzylic andAllylic Fluorination
Novel methods for benzylic and allylic uorinations have been developed and oer new
opportunities to quickly screen scaolds for suitability as drug molecules or imaging
agents by PET, and manganese complexes have been successful in promoting this transformation[53, 54]. For example, in a collaboration between the Hooker and Groves labs,
it was shown that benzylic C–H bonds can undergo radiouorination in the presence
of Mn(salen)OTs, [
well on a range of molecules, including those based on known small-molecule drugs.
While the benzylic position oers greater activity for C-H activation and uorination,
the resulting benzyl uorides can exhibit poor metabolic stability in some instances.
Despite this drawback, this approach permits facile scaold screening for further
development and can facilitate the expedient production of uorine-18 PET imaging
agents. Furthermore, the recent development of Ag[
development of a C-H activation of methyl quinolines to produce benzylic [
(Scheme8.2b)[31]. While this method is limited to quinolines, it demonstrates that benzylic methyl and methylene C–H bonds can be radiolabeled directly with Pd. Furthermore, this method illustrates the potential for further C-H radiouorination processes
to be developed.
Metal-catalyzed methods have also been developed to produce allylic uorides by
two separate laboratories[55–58]. In seminal work from the Gouverneur lab, a palladiumcatalyzed method was developed that employed an allylic methyl carbonate group,
which facilitated driving the radiouorination to completion. An example was provided
in the manuscript for radiouorination (Scheme8.2c), and the authors later described an
improved method using an iridium catalyst. Utilizing allylic methyl carbonates alongside
tetraethylammonium [
desired radiouorination was observed on three substrates (Scheme8.2d). The use of
iridium for allylic radiouorination has also been investigated by the Nguyen group. In
their method, an iridium catalyst and an allylic trichloroacetimidate precursor were utilized (Scheme8.2e). The uorine-19 method performed better with 3HF-TEA, which is not
currently available as the corresponding uorine-18 isotopolog. Later, the Nguyen laboratory further developed this method and described a general radiouorination of allylic
trichloroacetimidates using [
These methods provide access to benzylic and allylic [
initial development, and evaluation, but have several drawbacks. For example, some
incorporate toxic class II solvents and rare-earth heavy metal catalysts. Transition metals
like palladium and iridium are only allowed in a parenteral administration at a quantity
not exceeding 10 μg day
of PET imaging agents. Therefore, the development of methods with a metal that carries
18
F]KF, and an oxidant (Scheme8.2a)[53]. The conditions performed
18
F]F production has led to the
18
F]uorides
18
F]uoride as the uoride source with an Ir precatalyst, the
18
F]KF[59].
18
F]uorides for research use,
−1
, introducing diculty for routine production and purication
256 Handbook of Radiopharmaceuticals
a higher release amount, such as copper (340 μg day−1), and greener solvents would be
18
F
O
O
[d]
preferred.
R
O
O
H
R
N
H
OCOR
OCO2Me
CCl
NH
O
Mn(salen)OTs
18
PhIO, K[
R
acetone, 50 oC, 10 min
F]F, K2CO
3
R
R
R
Pd2dba3, PhI(OPiv)
Ag[18F], K
CH2Cl2, 145 oC. 30 min
[18F]TBAF, Pd(dba)2, PPh
MeCN
[18F]Et4NF, [Ir(cod)Cl]
DCM, 40 oC, 30 min
2.2.2
2
N
18
F
3
2
18
F
18
F
O
Scheme 8.2 Metal-
catalyzed methods
[a]
for the production
of benzylic [
rides and allylic [
uorides.
[b]
[c]
18
F]uo-
18
F]
O
3
[18F]KF, K
CSA, THF, rt, 10 min
, [Ir(cod)Cl]
2.2.2
2
18
F
O
[e]
8.3 CF3
The triuoromethyl group is an attractive moiety in drug design owing to its capability to
improve drug pharmacokinetic properties, such as metabolic stability. Reecting this, the
development of methods to install the triuoromethyl group has been the focus of many
laboratories. Notably, the triuoromethyl group represents a way to radiolabel many
drug and drug-like scaolds with the added benet of improved stability when compared
to terminal alkyl uorides, which are prone to elimination. In previous decades, a small
number of triuoromethyl groups have been generated by preparing a diuoro-bromo/
iodo methyl group and displacing the higher halide with either K[
18
F]F or H[18F]F[60–63].
These methods are dicult to implement on a variety of scaolds owing to the challenge
of forming the precursor and have seen limited use as a result. In the last 15 years, eorts
have been undertaken to generate aliphatic triuoromethyl groups,[64–66] including
triuoromethyl groups attached to a heteroatom (oxygen, sulfur or selenium)[63, 67–70],
as well as aryl triuoromethyl groups[54, 71–75].
Chapter 08: Fluorine-18 Radiochemistry 257
18
[c]
Me
[b]
Me
F
An improved strategy for the generation of aliphatic triuoromethyl groups was reported
in 2011 in work from Riss and Aigbirhio[64]. In this method, a diuoroalkene was generated, typically by treatment of a triuoromethylated substrate bearing an α–C–H bond
with n-butyllithium to eliminate HF. The resulting diuoroalkene can be converted to
the desired [
oxide (DMSO) with a small amount of H
required to complete the mechanism (Scheme8.3a). The reaction, unfortunately, also has
a competing addition-elimination process that results in the formation of the [
roalkene (i.e. the radiolabeled precursor). The scope of the reaction was limited to
activated diuoroalkenes, but one of the best substrates, 2,2-diuorovinyl-4-tosylate,
is also a potential prosthetic group since it can undergo a substitution reaction with a
nucleophile following radiouorination. The competing side reaction was a problem that
the authors addressed in a follow-up report[30]. In the improved labeling method for
this reaction (Scheme8.3b), alternative quenching reagents to water were investigated
to improve the ratio of [
donors like 2-propanol was superior to H
observed (up to 10:1 triuoromethyl:diuoroalkene). Later, this approach was adapted
to the synthesis of [
ratory[76]. In this work, lansoprazole, a Food and Drug Administration (FDA) approved
pharmaceutical, was treated with n-butyllithium to prepare a diuoroalkene precursor.
18
F]triuoromethyl group by treatment with [18F]KF˙K
O in the reaction mixture to provide the proton
2
18
F]triuoro vs. [18F]diuoroalkene. The use of organic proton
O, and improved yields and product ratios were
2
18
F]N-methyl-lansoprazole and [18F]lansoprazole by the Scott labo-
in dimethyl sulf-
2.2.2
18
F]diuo-
Scheme 8.3 Ali-
phatic [
18
F]tri-
uoromethyl
formation methods.
O O
S
F
O
F
O O
S
F
O
F
O
N
N
H
N
S
Me
O
K[18F]F, K
DMSO, 85 oC, 5 min
K[18F]F, K
DMSO, 90 oC, 5 min
K[18F]F, K
DMSO, 90 oC, 3 min
2.2.2
H2O
2.2.2
2-Propanol
2.2.2
NH4Cl
(aq)
Me
Me
F
F
Their investigations showed that a saturated solution of ammonium chlo-
18
F]lansoprazole or
ride as a proton source oered the highest yields of labeled [
N
N
H
O O
S
O O
S
F
O
F
O
F
[a]
18
F
F
18
F
O
N
S
Me
O
F
18
F
258 Handbook of Radiopharmaceuticals
[18F]N-methyl-lansoprazole over the corresponding diuoroalkenes (Scheme8.3c). Of the
K[18F]F, K
]
X = Br, Cl
R
triuoromethyl radiouorinations developed over the last 15 years, this method oers
the highest molar activity. [
18
F]N-methyl-lansoprazole has been advanced to clinical study
with this synthesis, showcasing the suitability of this approach for clinical translation to
PET imaging agents [77].
18
Several labs have also investigated novel techniques to generate [18F]triuoromethyl
groups attached to heteroatoms. In a method reported by Liang and co-workers,
a benzylic or aliphatic halide is treated with a combination of S
2-(triphenylphosphonio)diuoroacetate (PDFA), and [
18
F]KF˙K
beled product through a diuorocarbene intermediate (Scheme8.4a)[68]. In studies from
the Gouverneur lab, it was shown that silver can also be used to mediate halide abstraction for the synthesis of [
18
F]-OCF3 and [18F]-SCF3 containing arenes (Scheme8.4b)[78]. To
date, these methods carry limited utility in PET imaging as they oer low molar activity.
However, these types of products do have relevance in drug discovery, as there are biologically active compounds that contain a -SCF
or -OCF3 moiety, such as the approved
3
drug Cefazaur.
, 2,2-Diuoro-
8
to generate the radiola-
2.2.2
2.2.2
PDFA, S
AgOTf
8
2.2.2
N
Y18F
R
F F
18
F
F
F
S
N
Y X
F F
Y = S, O
Br
DMF, 70 oC, 1 min
K[18F]F, K
DCE, 20 min
18
Several laboratories have successfully developed improved methods for the production
of aromatic [
suered from low molar activity, which limits their utility in PET imaging as they are not
suitable methods to produce radioligands. However, these approaches may be utilized in
the generation of radiotracers, substrates, and trapped metabolite PET imaging agents
within applications where molar activity does not limit the ability to generate imaging
data[79]. These newly developed approaches to form aromatic triuoromethyl groups
in general start by forming [
18
F]triuoromethyl compounds. Unfortunately, these methods to date have
18
F]CuCF3 from triuoromethane, which can subsequently be
Scheme 8.4 [18F]
triuoromethyl
[a]
groups attached to
a heteroatom.
[b
Chapter 08: Fluorine-18 Radiochemistry 259
X = Br, Cl
R
F
Scheme 8.5 Aro-
matic [
18
F]tri-
uoromethylation
methodology.
treated with aryl iodides or aryl boronic acids. Based on previous studies on the triuoromethylation of aldehydes and ketones, Vugts and co-workers developed a method for
forming [
18
F]CHF3, which subsequently enabled the [18F]triuoromethylation of arenes
(Scheme8.5)[73, 74]. While this method currently oers the highest molar activity for
this transformation, it is still 3–5 times lower than typically achieved by other methods.
Y X
F F
Y = S, O
K[
DCE, 20 min
AgOTf
2.2.2
18
Y
R
F F
18
F]F, K
8.4 OTHER ALIPHATIC C–F BOND
Several other methodologies to generate aliphatic [18F]uorides of interest have been
developed since the last edition of the Handbook. Eorts have been undertaken in a collaboration between the Ritter and Vasdev-Liang groups to generate [
groups using aryl-pseudo halides[80]. In this method, a 2-uoro-1,2-diphenylethan-1-one
is treated with tetraethylammonium [
18
F]uoride generated using tetraethylammonium
bicarbonate for QMA cartridge elution, facilitating a halogen exchange.
The reaction mixture is subsequently treated with N-bromophthalimide followed by aqueous potassium hydroxide to produce the desired diuoromethyl arene
(Scheme8.6a). This reaction suers from poor molar activity as each molecule of precursor necessarily contains a uorine-19 atom that becomes a part of the reaction mechanism to give the diuoro product. Liang followed this work with an alternate method
to produce diuoromethylated arenes from benzylic bromides[81]. In this method, benzylic bromides are treated with tetraethylammonium [
trophilic uoride source Selectuor™ in the presence of Na
18
F]uoride, followed by the elec-
2S2O8
diuoromethylated arene (Scheme8.6b). This approach aorded a higher molar activity
than the earlier method but still three to vefold lower than standard techniques. Two
other late-stage labeling methodologies have also been developed. Zeng and co-workers
developed a (radio)uoroclick reaction to produce α-uoroenamides from ynamides with
18
[
F]KF with hexauoroisopropanol (HFIP) as a solvent[82]. The reaction is promoted
through a hydrogen-bonding cluster between the solvent and [
mixture. Five substrates with a range of functional groups were amenable to the reaction conditions. This included an ynamide, which was radiouorinated chemoselectively,
leaving the azide group intact (Scheme8.7a). Therefore, this chemistry may facilitate the
late-stage installation of labeled prosthetic groups, which can be conveniently installed
with an azide click reaction. The ve products were obtained in good RCY (76–97%, decay
corrected), although a long reaction time of one hour was utilized. In addition, Zeng and
co-workers showed that three of the radiolabeled products were stable in serum for two
18
F]diuoromethyl
to aord the desired
18
F]uoride in the reaction
260 Handbook of Radiopharmaceuticals
hours. Further work is required to demonstrate the use of this moiety for PET imaging in
]
R
]
Cl
F
NC
CN
vivo. In particular, the safety and toxicity of uoroenamides is not well established since
they are not commonly featured in pharmaceuticals.
F
(i) TEA[18F]F, N-bromophthalimide
MeCN, PhCl
(ii) KOH, H2O
O
18
F
R
F
Scheme 8.6
[a]
Methods for the
preparation of
18
[
F]diuoro-
methylarenes.
18
18
(i) TEA[
F]F, MeCN
R
Br F
(ii) SelectfluorTM, Na2S2O
MeCN:H2O:EtOH
8
R
F
[b
Scheme 8.7
Further new
R
SRO
K[18F]F, HFIP, 60 °C, 1 h
N
NH
2
N
N
O
N
N
OH
Fluorinaze, L-SeMet, K[18F]F
OH
H
18
O
18
N
N
OH
R
O
S
N
OO
R
F
NH
2
N
radiouorination methods.
[a]
[b
N
OH
The other method utilizes uorinase, which is the only known and well-characterized
enzyme to use uoride for substrate uorination. This enzyme selectively converts
S-adenosyl-
l-methionine (ADM) to 5′-uoro-5′-deoxyadenosine. Thompson and co-workers
investigated the radiouorination of other substrates with the aim of synthesizing
prosthetic groups for peptides[83]. The authors replaced the methionine group of ADM
with a chloride for an enzymatic transhalogenation in buered water (Scheme8.7b).
The incorporation of an acetylene at the C-2 position was also tolerated, enabling a
subsequent click reaction to incorporate arginine-glycine-aspartic acid peptide for the
production of a PET radioligand. The incorporation of uorine-18 in buered water is a
noteworthy development as the labeling of peptides is frequently hampered by incompatible organic solvents. Therefore, this method carries the potential to conveniently
radiolabel peptides and biomolecules, which would otherwise be challenging using other
strategies.
Chapter 08: Fluorine-18 Radiochemistry 261
8.5 AROMATIC FLUORINATION
[b]
18
F
R
[d]
Δ
Aryl uorides are prevalent in pharmaceuticals[84–88], and their 18F isotopologs are
important for PET imaging applications. As such, methods for synthesizing [
of great interest in the PET community[8, 16, 89, 90]. At the time of the previous edition
of the Handbook of Radiopharmaceuticals, there were limited methodologies to incorporate uorine-18 into an aromatic ring[91]. The most commonly used methods were
electrophilic aromatic substitution (SEAr) and nucleophilic aromatic substitution (SNAr).
An extensive discussion of these methods is beyond the scope of this chapter, although
comprehensive reviews are available[1–7, 9, 13–20]. In general, the last decade has seen a
shift away from traditional S
Ar, because the carrier-added method of [18F]F2 production
E
generally has limited site- and chemoselectivity, and the nal products inherently have
low molar activity due to the required carrier [
for carrier [
preference is to use nucleophilic [
19
F]F2 gas requires specialized equipment that is not widely available. The
18
F]uoride, which is readily available from small med-
19
F]F2 gas. Furthermore, the requirement
ical cyclotrons and possesses greater molar activity.
In the case of S
Ar, radiouorination of appropriately activated aromatic rings bearing
N
standard leaving groups such as nitro, halo, and trialkylammonium groups remains a commonly used strategy for preparing [
18
F]arenes (Scheme8.8a). For example, a microuidic
approach for radiouorination of nitroarene precursors was recently described[92].
Radiouorination of diaryliodonium salts is a newer alternative to S
Ar that was intro-
N
duced in the 1990s and continues to be utilized (Scheme8.8b)[93, 94].
18
F]arenes are
Scheme 8.8
Nucleophilic
syntheses of
18
[
F]arenes.
EWG
X = NMe3, NO2, Halide
X
I
R
N2BF
4
R
N
N
N
R
K[18F]F, K
DMSO, >140 °C
K[18F]F, K
DMSO, >140 °C
acid medium, 18F
2.2.2
2.2.2
18
F]F
K[
Δ
EWG
[a]
18
F
R
18
F
R
[c]
18
F
R
262 Handbook of Radiopharmaceuticals
Diaryliodonium salts are often symmetrical, but there can be selectivity limitations
[18F]Selectfluor Bis(triflate) [18F]-N-Fluorobenzenesulfonimide
in unsymmetrical substrates (vide infra)[95]. Other radiouorination methodologies
that are less commonly used due to their harsh conditions and limited scope are the
Balz-Schiemann decomposition and the Wallach reaction (Scheme8.8c and d). However,
all of the existing methodologies have certain limitations, including forcing conditions
and restricted substrate scopes, often stemming from challenging precursor syntheses
and an electronic mismatch between nucleophilic [
18
F]uoride and the aromatic ring. To
overcome these challenges, the last 10 years have seen a renaissance in uorine-18 radiochemistry research and an introduction of many new methods that are compatible with
a wide range of aromatic substrates. This section will highlight the new methodologies
developed since c. 2000, as well as some of their applications.
8.5.2.1 Electrophilic Radiouorination
Electrophilic radiouorination with [18F]F2 is not commonly used for the reasons outlined
previously and suers from low molar activity products and harsh reaction conditions.
However, there are groups who currently research electrophilic radiouorination and
continue to explore improvements. Eorts to develop higher-molar-activity electrophilic methods, such as the use of a uoromethane MeF electrical discharge chamber,
have occurred in recent years with some success[96, 97]. However, these approaches are
generally not technically routine or trivial and have consequently not seen widespread
usage. To overcome harsh uorinating conditions, a number of reports have investigated
converting reactive [
18
[
F]-N -uorobenzenesulfonimide (NFSI) (Figure8.2)[98–100]. These reagents are milder
and easier to handle in production laboratories but, again, suer from the requirement of
18
an [
F]F2 source in their production.
18
F]F2 into new F+ reagents, such as [18F]Selectuor bis(triate) and
8.5.2.2 New Approaches to SNAr
Since 2000, methods have been developed that have broadened the scope of nucleophilic aromatic substitution radiouorination methods. For example, the mechanism
of aromatic substitution of aromatic trimethylammonium salts has been studied, and
it has been shown that the formation of [
tion of the radiouorinated arene[101]. Furthermore, halogen exchange of aryluorides
18
F]uoromethane competes with the produc-
OTf
2
N
N
18
F
Cl
O O O O
S
S
N
18
F
Figure 8.2 Electro-
philic radiouorination reagents.
Chapter 08: Fluorine-18 Radiochemistry 263
]
18
F
]
]
]
]
(Ph)
2
R
Scheme 8.9
Further nucleo-
philic syntheses of
18
[
F]arenes.
with [18F]uoride continues to be utilized[102, 103], although this is rarer due to molar
activity limitations stemming from the inability to separate [
uct (Scheme8.9a). Improving the S
Ar of precursors with halide leaving groups has also
N
19
F]precursor from [18F]prod-
been investigated using pyridine derivatives (Scheme8.9b)[104] and oxidative strategies
(Scheme8.9c)[105]. Radiouorination of anilines via conversion to N-arylsydnones was
also recently reported, and density functional theory (DFT) calculations predict that this
operates via a typical addition-elimination S
Ar mechanism (Scheme8.9d)[106]. Triaryl-
N
sulfonium salts can also be used to achieve radiouorination via aromatic substitution
(Scheme8.9e)[107]. p-Electron-withdrawing groups provide the highest yields, while
m-substituted and electron-rich substrates give trace products. Notably, this methodology has successfully been used to synthesize PET radiotracers[108, 109].
18
[
EWG
R
R
X = Cl, Br
F
N
X
DMSO, 30 min mincroreactor
I[O]
solvent, 120–160 °C, 10 min
solvent, Δ
18
K[
K[18F]F, K
F]F
F]F, K
2.2.2
,
2.2.2
, K2CO
EWG
[a
R
[b
18
N
F
18
3
R
F
[c
O
O
N
N
Et
R
R
S
[18F]F
NHCO3, DMSO, 150 °C
4
5–20 min
[18F]F K
base
2.2.2
R
18
F
[d
18
F
[e
Another approach to overcome the scope limitations of traditional S
prosthetic groups that can be radiolabeled by S
Ar and then attached to a larger mole-
N
Ar is to design
N
cule (Figure8.3)[110–113]. While this allows biologically active molecules (e.g. peptides)
to be radiolabeled, it requires multiple steps post-[
18
F]uoride introduction, which can
lead to low yields and reproducibility issues[22]. However, this method has been applied
to the synthesis of many PET radiotracers and is routinely employed to introduce a
18
[
F]uorine into a molecule of interest[114, 115]. Methods for the synthesis of prosthetic
groups are discussed later.
264 Handbook of Radiopharmaceuticals