The synthesis of [18F]pitavastatin as a tracer for hOATP using the Suzuki coupling

Article abstract of DOI:10.1039/c4ob01953a

Fluorine-18 labeled radiotracers, such as [¹⁸F]fluorodeoxyglucose, can be used as practical diagnostic agents in positron emission tomography (PET). Furthermore, the properties of pharmaceuticals can be enhanced significantly by the introduction of fluorine groups into their original structures, and significant progress has been made during the last three decades towards the development of practical procedures for the introduction of fluorine. The replacement of the fluorine atoms present in pharmaceuticals with radioactive ¹⁸F atoms is a rational approach for designing novel PET tracers. As a fluorine-containing pharmaceutical agent, pitavastatin has attracted considerable interest from researchers working in the life sciences because it can act as an antihyperlipidemic agent as well as a substrate for hepatic organic anion transporting polypeptides (hOATP). With this in mind, it was envisaged that [¹⁸F]pitavastatin would be used as an excellent imaging agent for hOATP, which prompted us to investigate the synthesis of this agent. Herein, we report a practical method for the synthesis of [¹⁸F]pitavastatin by the Suzuki coupling reaction of p-iodofluorobenzene and a quinoline boronate derivative, with the desired product being formed in a radiochemical yield of 12 ± 3% (decay corrected from [¹⁸F]fluoride ions, n = 3). This journal is

Full text of DOI:10.1039/c4ob01953a

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18
The synthesis of [ F]pitavastatin as a tracer for
hOATP using the Suzuki coupling†
Cite this: DOI: 10.1039/c4ob01953a
a
a,b
a,c
a
Yusuke Yagi,‡ Hiroyuki Kimura,*‡ Kenji Arimitsu, Masahiro Ono,
d
d
e
d,f
Kazuya Maeda, Hiroyuki Kusuhara, Tetsuya Kajimoto, Yuichi Sugiyama and
a
Hideo Saji*
18
Fluorine-18 labeled radiotracers, such as [ F]fluorodeoxyglucose, can be used as practical diagnostic
agents in positron emission tomography (PET). Furthermore, the properties of pharmaceuticals can be
enhanced significantly by the introduction of fluorine groups into their original structures, and significant
progress has been made during the last three decades towards the development of practical procedures
for the introduction of fluorine. The replacement of the fluorine atoms present in pharmaceuticals with
1
8
radioactive F atoms is a rational approach for designing novel PET tracers. As a fluorine-containing
pharmaceutical agent, pitavastatin has attracted considerable interest from researchers working in the life
sciences because it can act as an antihyperlipidemic agent as well as a substrate for hepatic organic anion
18
transporting polypeptides (hOATP). With this in mind, it was envisaged that [ F]pitavastatin would be used
Received 15th September 2014,
Accepted 12th November 2014
as an excellent imaging agent for hOATP, which prompted us to investigate the synthesis of this agent.
18
Herein, we report a practical method for the synthesis of [ F]pitavastatin by the Suzuki coupling reaction
DOI: 10.1039/c4ob01953a
of p-iodofluorobenzene and a quinoline boronate derivative, with the desired product being formed in a
18
www.rsc.org/obc
radiochemical yield of 12 ± 3% (decay corrected from [ F]fluoride ions, n = 3).
1
8
18
1b,c
18
18
[
F]florbetapir ([ F]AV-45),
[ F]flutemetamol ([ F]-
Introduction
1
d
18
18
1e
GE-067) and [ F]florbetaben ([ F]BAY94-9172), because
1
8
Positron emission tomography (PET) is an imaging technique
F has a much longer half-life (109.7 min) than most of the
that is mainly used for the diagnosis of diseases such as other positron emitting radionuclides commonly incorporated
1
1
13
cancer and Alzheimer’s disease, although this technique can into pharmaceutical agents, such as C (20 min), N (10 min)
1
5
18
also be used for the evaluation of innovative therapies and and O (2 min). The incorporation of F can also be much
1
drugs. A large number of radiotracers have been developed to easier to achieve than the incorporation of other positron emit-
1
8
18
18
1a
124
date using F, such as [ F]fluorodeoxyglucose ([ F]FDG),
ting radionuclides with longer half-lives such as I (4.2 days)
8
9
and Zr (78.4 h). Furthermore, a number of fluorine-contain-
ing pharmaceuticals have been developed during the course of
the last three decades for use in clinical applications, where
the fluorine groups were introduced to impart the appropriate
a
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical
Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku,
Kyoto 606-8501, Japan. E-mail: hsaji@pharm.kyoto-u.ac.jp; Fax: +81-75-753-4568;
Tel: +81-75-753-4556
physicochemical, drug metabolism and pharmacokinetic
DMPK) properties to the active agents. These agents could
therefore be used as potential PET tracers by the replacement
of their F atoms with radioactive F atoms without changing
any of the chemical or biological properties of the parent
pharmaceutical. In fact, several F-containing pharmaceuti-
cals have already been synthesized via the replacement of their
F atoms with F atoms, including [ F]flumazenil,
xeloda and [ F]spiperone, which have all been used as
tracers in PET imaging experiments.
2
(
b
Radioisotope Research Center of Kyoto University, Yoshida Konoe-cho, Sakyo-ku,
Kyoto 606-8501, Japan. E-mail: hkimura@pharm.kyoto-u.ac.jp
1
9
18
c
School of Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Koshien
Kyubancho, Nishinomiya, Hyogo 663-8179, Japan
d
18
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical
Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
e
Research Organization of Science and Technology, Research Center for Drug
1
9
18
18
3a,b 18
[ F]-
Discovery and Pharmaceutical Development Sciences, Ritsumeikan University, 1-1-1,
Noji-higashi, Kusatsu, Shiga 525-8577, Japan
3
c
18
3d
f
Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Research Cluster for
Innovation, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama,
Several DMPK studies have recently been reported pertain-
ing to the use of PET imaging methods and tracers to develop
a deeper understanding of hepatic organic anion transporting
polypeptides (hOATP), which play an important role in the
Kanagawa 230-0045, Japan
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob01953a
These authors contributed equally to this work.
‡
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procedures and generally affords low yields of the desired
product (approximately 10%) because fluoride ions are only
7
weakly nucleophilic. Based on these limitations, there is an
urgent need for the development of a new method for the syn-
1
8
thesis of F labeled compounds. An alternative and reliable
1
8
approach to the synthesis of F labeled compounds, which is
referred to as the assembling approach, has recently been
8
described. According to this approach, the pre-labeled unit
can be connected to another intermediate through synthesis
to provide facile access to the radiolabeled pharmaceutical
agent. Herein, we report a novel method for the synthesis of
1
8
Fig. 1 Structure of [ F]pitavastatin.
1
8
9
18
[
F]pitavastatin via the Suzuki coupling reaction of p-[ F]-
fluoroiodobenzene with a boronate ester derivative of quino-
line in the presence of a palladium catalyst.
metabolism of drugs in the liver, and several candidate tracers
were synthesized. Unfortunately, no tracers have been
4
reported to date with potential clinical applications. The major
difficulty associated with the development of tracers for hOATP
is achieving selectivity for OATP1B1, which makes a significant
Results and discussion
4
contribution to hepatic uptake in humans, over OATP1B3.
1
8
Fortunately, however, the fluorine containing antilipidemic Any potential new route for the synthesis of [ F]pitavastatin
5
18
agent pitavastatin is a selective substrate of OATP1B1 with a would need to introduce the F atom during the latter stages
1
8
hepatic uptake clearance of less than 50% hepatic blood flow. of the process because of the short half-life of F (109.7 min).
It was therefore envisaged that [ F]pitavastatin (Fig. 1) could For this reason, it was not possible to apply a previously
be used as a novel PET tracer of hOATP, and this prompted us reported route for the synthesis of [ F]pitavastatin because
to design a strategy for the synthesis of this compound.
1
8
1
0
18
1
8
this method would have required the introduction of
F
Fluorine atoms have traditionally been incorporated into during the early stages of the synthesis (Scheme 1). The
aromatic rings through electrophilic substitution reactions decision was therefore taken to establish a novel synthetic
1
8
18
using fluorine gas. However, radiofluorination reactions using route to [ F]pitavastatin, where the F atom would be incor-
1
8
[
F]F gas typically afford fluorinated products with low levels porated at the latter stages of the synthesis.
2
It was envisaged that the required F atom could be intro-
2
because the [ F]F used in these experiments is generally con- duced via a Suzuki coupling reaction between p-[ F]fluoro-
taminated with non-radioactive F as a carrier gas. Further- iodobenzene ([ F]1) and boronate 2 in the presence of a
more, the introduction of F atoms through nucleophilic palladium catalyst (Scheme 2). Compound [ F]1 was prepared
aromatic substitution reactions using fluoride ions (e.g., the by the nucleophilic aromatic substitution reaction of 4-iodo-
−
1
18
of specific radioactivity (generally less than 0.40 GBq µmol
)
1
8
18
6
18
2
1
8
18
1
8
Balz–Schiemann reaction) requires challenging experimental phenyldiphenylsulfonium triflate with a [ F]fluoride ion.
10
Scheme 1 Previously reported synthetic route of pitavastatin.
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Retrosynthetic analysis of boronate 2 revealed that this
material could be synthesized from aldehyde 4, which could
undergo
a Horner–Wadsworth–Emmons reaction in the
1
0a
forward sense with phosphonate 3 to give boronate 2.
Alde-
hyde 4 could itself be generated from 2-aminobenzonitrile (5)
through a series of transformations involving quinoline for-
mation with an appropriately functionalized β-keto ester.
1
1
The Friedlander reaction of 2-aminobenzonitrile (5) with
β-keto ester 6 was performed in the presence of tin(IV) chloride
to give aminoquinoline 7 in good yield (Scheme 3). The amino
group of compound 7 was converted to the corresponding di-
azonium salt, which was subjected to a Sandmeyer reaction
with copper(I) bromide to give aryl bromide 8. Subsequent
reduction of the methyl ester group in 8 with diisobutylalumi-
nium hydride (DIBAL) gave alcohol 8a, which was oxidized
with Dess–Martin periodinane (DMP) to give aldehyde 4.
1
2
The treatment of aldehyde 4 with phosphonate 3 yielded
the desired (E)-alkene 9 in an excellent yield (Scheme 4).
Unfortunately, the ester group in 9 underwent an undesired
hydrolysis reaction during the removal of the tert-butyldi-
methylsilyl group with tetrabutylammonium fluoride (TBAF).
To avoid the undesired hydrolysis of the methyl ester, alkene 9
was treated with diluted hydrofluoric acid in MeCN to afford
β-hydroxy ester 10 in 89% yield. Stereoselective reduction of
the carbonyl group with diethylmethoxyborane and sodium
borohydride gave the desired diol 11 as a single diastereomer.
The subsequent reaction of diol 11 with bis(pinacolato)-
diboron (12) in the presence of a palladium catalyst gave boro-
nate 2, which was the precursor to the Suzuki coupling, in
18
Scheme 2 Retrosynthesis of [ F]pitavastatin.
26% yield.
The Suzuki coupling of 1 with 2 was investigated under a
variety of different reaction conditions to determine the best
catalyst for the transformation (Table 1). When the reaction
3 4 2 3
was performed in the presence of Pd(PPh ) and Na CO in
dimethylsulfoxide (DMSO) at 90 °C, only a trace amount of the
desired product 13 was obtained (Table 1, entry 1). Similar
poor results were also obtained when PdCl
2 2 2
(dppf)CH Cl or
Pd(PPh ) Cl was used as the catalyst (Table 1, entries 2
3
2
2
2 3
and 3). In contrast, the use of Pd(OAc) in the presence of PPh
gave a slightly better yield of the desired product (Table 1,
Scheme 3 Synthesis of the aldehyde 4.
Scheme 4 Synthesis of boronate 2.
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a
Table 1 Suzuki coupling reaction of boronate 2 with 1
heated under microwave irradiation at 120 °C in the presence
of Kryptofix2.2.2 to give the desired product with a radio-
chemical yield (RCY) of 56 ± 3% (Scheme 6).
1
8
The Suzuki coupling reaction of [ F]1 with boronate 2 was
investigated under a variety of different conditions to identify
the optimum conditions for the transformation (Table 2). Con-
1
8
sidering the relatively short half-life of F, the heating time
was limited to 10 min. Moreover, the reaction was performed
in a tightly sealed tube, which was heated on a heating block
at 100 °C to avoid the spread of the radioisotope in the sur-
rounding area. Unfortunately, the optimum reaction con-
ditions developed above for the Suzuki reaction of unlabeled 1
Conditions
b
2 3 2 3
(i.e., DMSO, Pd (dba) and Na CO ) were not suitable for the
Temp. Time Yield
synthesis of the radioactive compound. Changing the solvent
from DMSO to N,N-dimethylformamide (DMF) or MeCN had
very little impact on the outcome of the reaction, with the
product being obtained in a low yield (Table 2, entries 2 and
Entry Catalyst
Solvent (°C)
(h)
(%)
1
2
3
4
5
Pd(PPh
PdCl (dppf)CH
Pd(PPh
Pd(OAc)
Pd(PPh
CH Cl
Pd (dba)
3
)
4
DMSO 90
DMSO 90
DMSO 90
DMSO 90
DMSO 90
9
9
9
9
9
<10
<10
<10
29
2
2 2
Cl
3
)
2
2
Cl
/PPh
/PdCl
2
3
2 3 2 3
3). Pleasingly, the use of Cs CO instead of Na CO led to an
3
)
4
2
(dppf)
50
increase in the yield of the product (Table 2, entries 4–6). It is
2
2
1
8
noteworthy that the methyl ester in [ F]13 underwent a spon-
6
2
3
DMSO 90
9
63
taneous hydrolysis reaction following the coupling reaction or
during the work-up procedure to yield [ F]pitavastatin when
a
b
2
: 0.08 mmol, solvent: 1.0 mL. Yield was determined from LC-MS.
18
Cs CO was used as the base. In practice, the optimum con-
2
3
ditions for the coupling reaction were determined to be
Pd (dba) and Cs CO in MeCN at 100 °C for 10 min (Table 2,
entry 4). Pleasingly, the use of a combination of Pd(PPh
3 4
) and
2
3
2
3
PdCl (dppf)CH Cl or Pd (dba) alone yielded the coupling
2
2
2
2
3
1
8
entry 9). The conditions gave [ F]pitavastatin in a chemical
yield of 63 ± 2% and a RCY of 28 ± 3% following purification
by RP-HPLC.
product in 50 and 63% yields, respectively. These results there-
fore demonstrated that we had successfully established a novel
route for the synthesis of pitavastatin, which could be used for
1
8
1
8
As a result, [ F]pitavastatin was obtained in a radiochemi-
the synthesis of [ F]pitavastatin (Scheme 5).
1
8
cal yield of 12 ± 3% (decay corrected from [ F]fluoride ions)
(Scheme 7). The identity of the radiotracer was confirmed by
RP-HPLC following its co-injection with the non-radiolabeled
reference compound (Fig. 2).
With our newly developed route in hand, we proceeded to
1
8
investigate the synthesis of [ F]1 so that it could be used to
1
8
complete the synthesis of the target molecule, [ F]pitavasta-
1
8
tin. Compound [ F]1 was synthesized according to the
1
3
Lehmann method. Namely, a mixture of 4-iodophenyldi-
1
8
2 3
phenylsulfonium triflate, [ F]KF and K CO in MeCN was
Conclusion
In summary, we developed a novel route for the synthesis of
pitavastatin using a Suzuki coupling reaction as the key step to
1
8
allow for the late stage incorporation of F. Using this route,
1
8
we successfully synthesized [ F]pitavastatin in good yield by
1
8
the Suzuki coupling of boronate 2 with p-[ F]fluoroiodo-
benzene under microwave heating conditions in the presence
of Pd (dba) and Cs CO . This Suzuki coupling strategy rep-
2
3
2
3
18
resents a useful method for the indirect F labeling of pharma-
ceuticals that could be applied to the synthesis of other PET
tracers. The in vivo evaluation of [ F]pitavastatin using PET is
currently underway in our laboratory, and the results of these
experiments will be published elsewhere in due course.
Scheme 5 Synthesis of pitavastatin.
1
8
Experimental
Chemistry
18
General methods. All of the reagents and solvents used in
the current study were purchased from Wako Pure Chemical
Scheme 6 Synthesis of
triflate.
[ F]1 from 4-iodophenyldiphenylsulfonium
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1
8
18
a
Table 2 Synthesis of [ F]pitavastatin by the Suzuki coupling of boronate 2 with [ F]1
Conditions
b
c
Entry
Base
Solvent
Temp. (°C)
MW
Yield (%)
1
2
3
4
5
6
7
8
9
Na
Na
Na
2
2
2
CO
CO
CO
3
3
3
DMSO
MeCN
DMF
DMSO
MeCN
DMF
MeCN
MeCN
MeCN
100
100
100
100
100
100
80
−
−
−
−
−
−
−
−
+
<5
13 ± 1
26 ± 9
20 ± 2
56 ± 7 (18 ± 4)
69 ± 1 (<10)
51 ± 6
51 ± 3
63 ± 2 (28 ± 3)
Cs
Cs
Cs
Cs
Cs
Cs
2
CO
CO
CO
CO
CO
CO
3
d
2
2
2
2
2
3
3
3
3
3
d
120
100
d
a
18
b
c
18
Catalyst: 1.0 mg, base: 4.0 mg, solvent: 100 µL, [ F]1: 370–740 kBq, 2: 2.0 mg. MW power: 50 W, reaction time: 1 min. Total yield of [ F]13
1
8
d
18
and [ F]pitavastatin determined by radio-HPLC. Data are the mean ± S.D. (n = 3). Isolated yield of [ F]pitavastatin (radiochemical yield). All
reactions were carried out in a sealed reaction vessel on an aluminum block heater.
18
Scheme 7 Synthesis of [ F]pitavastatin.
Industries (Tokyo, Japan), Nacalai Tesque (Kyoto, Japan), plet), number of protons and coupling constant (J). LRMS and
Merck (Darmstadt, Germany) and Sigma Aldrich (St. Louis, HRMS analyses were conducted on JEOL JMS-SX 102A QQ and
MO, USA), and used without purification. Optical rotations JEOL JMS-GC-mate mass spectrometer systems, respectively.
were measured on an AUTOPOL IV system (Rudolph Research Purifications by column chromatography were conducted over
1
Analytical, Hackettstown, NJ, USA). H NMR spectra were silica gel 60N (mesh size 63–210 µm; Kanto Chemical Co., Inc.,
recorded on a JEOL ECA-500 spectrometer (JEOL, Tokyo, Tokyo, Japan). Thin-layer chromatography (TLC) was per-
Japan) and the peaks were referenced relative to the residual formed using Merck silica gel F-254 aluminum plates, which
CHCl signal. Chemical shifts have been reported in parts per were visualized under UV light (254 nm). High performance
3
million (ppm) using the residual solvent peak as an internal liquid chromatography (HPLC) purifications and analyses were
1
standard. The H NMR spectra have been tabulated as follows: performed on a Shimadzu system (LC-10AT pump with an
chemical shift, multiplicity (br = broad, s = singlet, d = SPD-10A UV detector operating at 220 and 254 nm, Shimadzu
doublet, t = triplet, quint = quintet, sept = septet, m = multi- Corporation, Kyoto, Japan) equipped with Cosmosil 5C18-ARII
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18
Fig. 2 Analytical RP-HPLC chromatograms of [ F]pitavastatin co-injected with non-radiolabeled pitavastatin. The UV spectra were recorded at
54 nm. The peak at 12.385 min corresponds to the lactone derived from the intramolecular cyclization of pitavastatin.
2
columns (10 × 250 mm and 4.6 × 150 mm, respectively; brine and dried over MgSO . The solvent was then removed
4
Nacalai Tesque Inc., Kyoto, Japan) and a radioisotope detector. under reduced pressure to give a residue, which was purified
Experiments were conducted under microwave heating con- by column chromatography over silica gel eluting with a 20 : 1
ditions in a resonant-type microwave reactor, which was deve- (v/v) mixture of n-hexane and EtOAc to give bromide 8 as an
1
4
loped by SAIDA Inc. (Shizuoka, Japan).
Methyl (4-amino-2-cyclopropylquinolin-3-yl)carboxylate
orange solid (20.9 g, 58.0%).
1
3
H NMR (500 MHz, CDCl ) δ: 8.11 (d, J = 8.3 Hz, 1H), 7.90
(7). β-Keto ester 6 (16.6 g, 140 mmol) and tin(IV) chloride (d, J = 8.3 Hz, 1H), 7.68 (t, J = 8.3 Hz, 1H), 7.52 (t, J = 8.3 Hz,
(
73.3 g, 281 mmol) were slowly added to a solution of 2-amino- 1H), 4.05 (s, 3H), 2.06 (tt, J = 8.0, 4.6 Hz, 1H), 1.24 (qd, J = 4.6,
1
3
benzonitrile (5) (20.0 g, 140 mmol) in toluene (280 mL) under 2.9 Hz, 2H), 0.94 (dq, J = 8.0, 2.9 Hz, 2H); C NMR (125 MHz,
an argon atmosphere at 15 °C, and the resulting mixture was CDCl ): δ 167.8, 158.7, 150.8, 130.8, 130.7, 130.4, 129.2, 127.0,
3
heated at reflux for 3 h. The reaction was then cooled to room 126.9, 125.1, 53.0, 15.8, 10.7 (2C); MS (EI) m/z: 307 (M + 2, 66),
+
temperature and diluted with a saturated aqueous solution of 305 (M , 68), 277 (100), 262 (39), 246 (91), 226 (19), 167 (90);
+
Na SO before being cooled to 0 °C. The resulting precipitate HRMS calcd for C H BrNO (M ): 305.00509, found
2
4
14 12
2
was crushed into smaller pieces and filtered, and the filtrate 305.00583.
was extracted with EtOAc. The organic layer was washed with (4-Bromo-2-cyclopropylquinolin-3-yl)carbaldehyde (4). A 1.0 M
brine and dried over MgSO4 before being concentrated solution of DIBAL in n-hexane (20.8 mL, 20.8 mmol) was
in vacuo to give aminoquinoline 7 as a purple solid (28.5 g, added to a solution of bromide 8 (3.19 g, 10.4 mmol) in
8
3.9%).
toluene (20.0 mL) under an argon atmosphere at 0 °C, and the
1
H NMR (500 MHz, CDCl ) δ: 7.79 (d, J = 8.3 Hz, 1H), 7.68 resulting mixture was stirred for 1 h at room temperature. The
3
(d, J = 8.3 Hz, 1H), 7.59 (t, J = 8.3 Hz, 1H), 7.31 (t, J = 8.3 Hz, reaction was then cooled to 0 °C and quenched by the addition
1
1
H), 6.64 (br, 2H), 3.95 (s, 3H), 2.62 (tt, J = 8.0, 4.9 Hz, 1H), of a 5% solution of H
2
SO
4
. The resulting mixture was extracted
1
3
.24 (qd, J = 4.9, 2.6 Hz, 2H), 0.94 (dq, J = 8.0, 2.6 Hz, 2H);
C
with EtOAc, and the organic layer was washed with brine and
NMR (125 MHz, CDCl ): δ 170.0, 161.9, 152.3, 147.7, 130.8, dried over MgSO . The solvent was then removed under
3
4
1
29.2, 124.4, 120.4, 116.6, 103.5, 51.7, 17.2, 9.4 (2C); MS (EI) reduced pressure to give alcohol 8a as a brown solid (2.30 g).
+
1
m/z: 242 (M , 100), 214 (98), 209 (76), 183 (86), 171 (30),
H NMR (500 MHz, CDCl ) δ: 8.10 (d, J = 8.2 Hz, 1H), 7.89
3
+
1
2
54 (28); HRMS calcd for C H N O (M ): 242.1055, found (d, J = 8.2 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.5 Hz,
14 14 2 2
42.1060.
Methyl (4-bromo-2-cyclopropylquinolin-3-yl)carboxylate (8). 1.29 (qd, J = 4.2, 3.1 Hz, 2H), 1.06 (dq, J = 8.2, 3.1 Hz, 2H);
Copper(I) bromide (29.5 g, 206 mmol) and tert-butyl nitrite NMR (125 MHz, CDCl ) δ: 162.1, 147.8, 136.2, 131.6, 130.0,
1H), 5.23 (s, 2H), 2.53 (tt, J = 8.0, 4.2 Hz, 1H), 2.27 (br, 1H),
1
3
C
3
(
18.2 g, 176 mmol) were slowly added to a solution of amino- 129.0, 127.3, 126.7, 126.3, 62.4, 14.2, 11.5 (2C); MS (EI) m/z:
+
quinoline 7 (28.5 g, 117 mmol) in MeCN (280 mL) under an 279 (M + 2, 87), 277 (M , 89), 260 (100), 248 (24), 179 (37), 167
argon atmosphere at 15 °C, and the resulting mixture was (49); HRMS calcd for C H BrNO (M ): 277.0102, found
+
1
3
12
stirred at 40 °C for 2.5 h. The mixture was then cooled to room 277.0096.
temperature and stirred overnight. The reaction mixture was Dess–Martin periodinane (1.68 g, 3.95 mmol) was added to
diluted with a saturated aqueous solution of Na SO , and the a solution of alcohol 8a (1.00 g, 3.60 mmol) in CH Cl
2
2
4
2
resulting precipitate was removed by filtration. The filtrate was (20.0 mL) under an argon atmosphere at 0 °C, and the result-
extracted with EtOAc, and the organic layer was washed with ing mixture was stirred for 3 h at room temperature. The reac-
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tion was then quenched by the addition of a saturated and dried over MgSO
4
. The solvent was removed under
aqueous solution of NaHCO , and the resulting mixture was reduced pressure to give a residue, which was purified by
3
extracted with EtOAc. The organic layer was washed sequen- column chromatography over silica gel eluting with a 2 : 1 (v/v)
tially with a saturated aqueous solution of Na
2 2 3
S O and brine mixture of n-hexane and EtOAc to give β-hydroxy ester 10 as a
and dried over MgSO . The solvent was then removed under yellow solid (280 mg, 89.1%).
4
1
reduced pressure to give a residue, which was purified by
column chromatography over silica gel eluting with a 10 : 1 (d, J = 16.6 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.68 (t, J = 8.3 Hz,
v/v) mixture of n-hexane and EtOAc to give aldehyde 4 as a col- 1H), 7.53 (t, J = 8.3 Hz, 1H), 6.71 (d, J = 16.6 Hz, 1H), 4.65 (br,
orless solid (830 mg, 83.6% in 2 steps). 1H), 3.74 (s, 3H), 3.53 (br, 1H), 3.05 (dd, J = 17.1, 7.4 Hz, 1H),
) δ: 10.7 (s, 1H), 8.25 (d, J = 8.2 3.00 (dd, J = 17.1, 4.4 Hz, 1H), 2.65 (d, J = 6.6 Hz, 2H), 2.28 (tt,
Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.76 (t, J = 8.2 Hz, 1H), 7.56 (t, J = 8.0, 4.6 Hz, 1H), 1.35 (dq, J = 4.6, 3.1 Hz, 2H), 1.05 (dq, J =
3
H NMR (500 MHz, CDCl ) δ: 8.15 (d, J = 8.3 Hz, 1H), 7.93
(
1
H NMR (500 MHz, CDCl
3
1
3
J = 8.2 Hz, 1H), 3.02 (tt, J = 8.2, 4.2 Hz, 1H), 1.24 (qd, J = 4.2, 8.0, 3.1 Hz, 2H); C NMR (125 MHz, CDCl
3
3
): δ 198.6, 172.2,
.1 Hz, 2H), 0.94 (dq, J = 8.2, 3.1 Hz, 2H); C NMR (125 MHz, 160.1, 147.5, 141.0, 134.8, 134.4, 130.6, 129.5, 129.0, 127.0
CDCl ) δ: 194.0, 162.1, 149.0, 140.8, 132.5, 129.2, 127.2, 127.0, (2C), 125.8, 64.5, 51.5, 46.4, 40.6, 16.5, 11.0 (2C); MS (EI) m/z:
1
3
3
+
1
(
26.8, 125.5, 14.2, 11.5 (2C); MS (EI) m/z: 277 (M + 2, 8.6), 275 419 (M + 2, 0.1), 417 (M , 0.1), 315 (22), 236 (100), 102 (3.0), 74
M , 8.6), 247 (100), 196 (1.3), 168 (2.8); HRMS calcd for (3.0); HRMS calcd for C20
+
+
H
20BrNO
4
(M ): 417.0575, found
+
20
D
C H BrNO (M ): 274.9945, found 274.9939.
417.0583; [α] : −7.727 (c 0.99, MeOH).
1
3
10
Methyl
(3R,6E)-7-(4-bromo-2-cyclopropylquinolin-3-yl)-3-
Methyl
(3R,5S,6E)-7-(4-bromo-2-cyclopropylquinolin-3-yl)-
(tert-butyldimethyl-silyloxy)-5-oxohept-6-enoate (9). A solution 3,5-dihydroxyhept-6-enoate (11). A 1.0 M solution of diethyl-
of phosphonate 3 (7.00 g, 18.3 mmol) in THF (48.0 mL) was methoxyborane in THF (10.8 mL, 10.8 mmol) was added to a
added to a suspension of sodium hydride (0.730 g, 18.2 mmol, solution of β-hydroxy ester 10 (4.03 g, 9.63 mmol) in THF
6
0% dispersion in mineral oil) in THF (12.5 mL) under an (30.0 mL) and MeOH (6.00 mL) at −78 °C, and the resulting
argon atmosphere at 0 °C, and the resulting mixture was mixture was stirred for 20 min at −78 °C. Sodium borohydride
stirred for 1 h at 0 °C. A solution of aldehyde 4 (4.81 g, (452 mg, 10.7 mmol) was then added to the reaction mixture
1
7.4 mmol) in THF (75.0 mL) was then added to the reaction at −78 °C, and the resulting mixture was stirred for 1 h at
at 0 °C, and the resulting mixture was stirred overnight at −78 °C. The reaction was then quenched by the addition of a
room temperature. The reaction was then quenched by the solution of AcOH (5.70 mL) in EtOAc (27.0 mL), and the result-
addition of a saturated aqueous solution of NH
resulting mixture was extracted with EtOAc. The organic layer mixture was poured into a saturated aqueous solution of
was washed with brine and dried over Na SO . The solvent was NaHCO , and the resulting mixture was extracted with EtOAc.
4
Cl, and the ing mixture was stirred for 3 h at room temperature. The
2
4
3
removed under reduced pressure to give a residue, which was The organic layer was washed with brine and dried over
purified by column chromatography over silica gel eluting with MgSO before being concentrated under reduced pressure. The
4
a 5 : 1 (v/v) mixture of n-hexane and EtOAc to give alkene 9 as a resulting residue was purified by column chromatography over
yellow oil (8.57 g, 92.5%).
silica gel eluting with a 1 : 1 (v/v) mixture of n-hexane and
1
H NMR (500 MHz, CDCl ) δ: 8.16 (d, J = 8.3 Hz, 1H), 7.91 EtOAc to give diol 11 as a yellow solid (2.93 g, 72.0%).
3
1
(d, J = 16.3 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.68 (t, J = 8.3 Hz,
3
H NMR (500 MHz, CDCl ) δ: 8.13 (d, J = 8.0 Hz, 1H), 7.88
1
1
1
1
3
3
1
H), 7.53 (t, J = 8.3 Hz, 1H), 6.71 (d, J = 16.3 Hz, 1H), 4.76 (m, (d, J = 8.2 Hz, 1H), 7.63 (t, J = 8.2 Hz, 1H), 7.49 (t, J = 8.2 Hz,
H), 3.70 (s, 3H), 3.06 (dd, J = 15.8, 6.9 Hz, 1H), 2.97 (dd, J = 1H), 6.87 (dd, J = 16.0, 1.1 Hz, 1H), 6.09 (dd, J = 16.0, 5.7 Hz,
5.8, 5.7 Hz, 1H), 2.65 (dd, J = 14.7, 5.7 Hz, 1H), 2.59 (dd, J = 1H), 4.73 (br, 1H), 4.42 (br, 1H), 3.81 (s, 1H), 3.73 (s, 3H), 3.63
4.7, 6.3 Hz, 1H), 2.30 (tt, J = 8.0, 4.6 Hz, 1H), 1.35 (dq, J = 4.6, (s, 1H), 2.57 (dd, J = 6.8, 1.7 Hz, 2H), 2.42 (tt, J = 8.0, 4.6 Hz,
.0 Hz, 2H), 1.05 (dq, J = 8.0, 3.0 Hz, 2H), 0.85 (s, 9H), 0.10 (s, 1H), 1.91–1.80 (m, 2H), 1.29 (dd, J = 4.6, 2.6 Hz, 2H), 1.01 (dq,
1
3
13
H), 0.09 (s, 3H); C NMR (125 MHz, CDCl
3 3
): δ 197.5, 171.4, J = 8.0, 2.6 Hz, 2H); C NMR (125 MHz, CDCl ): δ 172.9, 160.9,
60.1, 147.5, 140.4, 135.0, 134.7, 130.5, 129.8, 129.1, 127.0 147.0, 140.0, 133.8, 131.8, 129.5, 127.0 (2C), 126.6, 126.5,
(
1
4
2C), 126.9, 125.9, 66.1, 51.5, 48.2, 42.5, 25.7 (3C), 17.9, 16.5, 126.2, 72.4, 68.4, 51.9, 42.4, 41.4, 16.4, 10.7 (2C); MS (EI) m/z:
+
+
1.0, −4.7, −4.9; MS (CI) m/z: 534 (M + 2, 100), 532 (M , 96), 421 (M + 2, 3.2), 419 (M , 3.3), 383 (7.5), 340 (38), 298 (45), 274
+
4
74 (50), 400 (39), 320 (32), 217 (39), 133 (41), 75 (41); HRMS (100), 220 (56); HRMS calcd for C20H22BrNO (M ): 419.0732,
+
20
D
20
D
calcd for C H BrNO Si (M ): 532.1518, found 532.1515; [α] : found 419.0729; [α] : +22.858 (c 1.00, MeOH).
2
6
34
4
+
1.685 (c 0.99, MeOH).
Methyl (3R,6E)-7-(4-bromo-2-cyclopropylquinolin-3-yl)-3- dioxabolan-2-yl)quinolin-3-yl}-3,5-dihydroxyhept-6-enoate (2).
hydroxy-5-oxohept-6-enoate (10). A 1 : 19 (v/v) solution of 48% PdCl (dppf)CH Cl (0.19 g, 0.240 mmol) was added to a
Methyl (3R,5S,6E)-7-{2-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3-
2
2
2
hydrofluoric acid in MeCN (4.00 mL) was added to a solution stirred solution of diol 11 (1.00 g, 2.40 mmol), bis(pinacolato)-
of alkene 9 (400 mg, 0.751 mmol) in MeCN (1.00 mL) at 0 °C, diboron (12) (0.790 g, 3.12 mmol) and K CO (1.00 g,
2
3
and the resulting mixture was stirred for 19 h at room tempera- 7.20 mmol) in DMSO (40.0 mL) under an argon atmosphere,
ture. The reaction was then quenched by the addition of an and the resulting mixture was stirred for 4 h at 70 °C. Silica gel
aqueous solution of NaHCO
3
, and the resulting mixture was was then added to the reaction, and the resulting mixture was
extracted with EtOAc. The organic layer was washed with brine filtered through Celite. The filtrate was extracted with EtOAc
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and the organic layer was washed sequentially with water and and the resulting mixture was stirred for 30 min at the same
brine before being dried over Na SO . The solvent was then temperature. The reaction mixture was then concentrated
2
4
concentrated under reduced pressure to give a residue, which under reduced pressure to give pitavastatin (sodium salt) as a
was subjected to azeotropic dehydration with MeCN and puri- colorless oil (3 mg, quant.).
1
fied by HPLC (Shimadzu system equipped with a Cosmosil
H NMR (500 MHz, DMSO-d ) δ: 7.83 (d, J = 8.3 Hz, 1H),
6
5
C18-ARII 10 × 250 mm column, MeCN–water = 50/50, flow 7.60 (t, J = 8.3 Hz, 1H), 7.36–7.23 (m, 6H), 6.48 (d, J = 16.0 Hz,
−
1
rate = 5.0 mL min ) to afford a brown oil. Powderization of 1H), 5.80 (br, 1H), 5.57 (dd, J = 16.0, 5.5 Hz, 1H), 4.93 (br, 1H),
the resulting oil with a 1 : 1 (v/v) mixture of diisopropyl ether 4.13 (m, 1H), 3.65 (br, 1H), 3.40 (m, 4H), 2.08 (d, J = 12.0 Hz,
and n-heptane gave boronate 2 as a pale yellow solid (0.290 g, 1H), 1.95 (dd, J = 15.5, 8.6 Hz, 1H), 1.40 (dt, J = 14.3, 7.8 Hz,
1
3
2
5.9%).
1H), 1.20–1.00 (m, 5H); C NMR (125 MHz, DMSO-d
6
) δ:
1
H NMR (500 MHz, CDCl ) δ: 7.91 (d, J = 9.2 Hz, 1H), 7.89 178.5, 161.6, 160.6, 144.8, 142.2, 133.1 (2C), 132.0 (dd, JF
=
3
(d, J = 9.2 Hz, 1H), 7.56 (t, J = 9.2 Hz, 1H), 7.40 (t, J = 9.2 Hz, 37.4, 8.0 Hz) (2C), 129.6, 128.8, 128.3, 125.7, 125.6 (2C), 123.1,
1
1
3
8
2
δ
H), 7.19 (dd, J = 16.0, 1.4 Hz, 1H), 6.03 (dd, J = 16.0, 5.4 Hz, 115.2 (dd, J
H), 4.66 (br, 1H), 4.38 (br, 1H), 3.75 (br, 1H), 3.73 (s, 3H), 10.7 (2C); MS (FAB+) m/z: 444 (M ); HRMS (FAB+) calcd for
F
= 21.0, 9.3 Hz) (2C), 68.9, 65.6, 44.2, 40.0, 15.3,
+
2
0
.32 (br, 1H), 2.56 (d, J = 3.4 Hz, 1H), 2.54 (s, 1H), 2.28 (tt, J =
C
25
H
4 D
26FNO : 422.1768, found 422.1762; [α] : +22.265 (c 0.22,
.0, 4.6 Hz, 1H), 1.87–1.78 (m, 2H), 1.46 (s, 12H), 1.25–1.20 (m, MeCN/H
H), 0.98 (dd, J = 8.0, 3.1 Hz, 2H); C NMR (125 MHz, CDCl3):
2
O).
1
3
172.9, 159.6, 146.3, 138.2, 135.6, 129.2, 128.9 (2C),
Radiochemistry
18
1
2
3
C
28.4, 127.2 (2C), 125.4, 84.7 (2C), 72.4, 68.5, 51.9, 42.7, 41.3,
+
5.3 (2C), 25.2 (2C), 15.4, 9.5, 9.3; MS (EI) m/z: 467 (M , 6.8), [ F]Fluoride was produced by cyclotron (CYPRIS HM-18, Sumi-
1
8
18
46 (100), 322 (80), 220 (92), 206 (57); HRMS calcd for tomo Heavy Industries, Tokyo, Japan) via an O (p,n) F reac-
+
20
26
H
34BNO
6
(M ): 467.2479, found 467.2481; [α]
D
: +22.932 tion and passed through a Sep-Pak Light QMA cartridge
(Waters Corporation, Milford, MA, USA) as an aqueous solu-
(
c 1.00, MeOH).
1
8
Methyl (3R,5S,6E)-7-{2-cyclopropyl-4-(4-fluorophenyl)quino- tion in O-enriched water. The cartridge was dried under a
1
8
3 4 2
lin-3-yl}-3,5-dihydroxyhept-6-enoate (13). Pd(PPh ) (9.10 mg, stream of N and the F activity was eluted with 1.00 mL of a
0
0
0
.00789 mmol) and PdCl (dppf)CH Cl
.00789 mmol) were added to a solution of 2 (37.0 mg, fix2.2.2 and 1.70 mg of K
.0788 mmol), 4-fluoroiodobenzene (26.2 mg, 0.118 mmol), and water). The solvent was removed by azeotropic dehydration
(6.20 mg, Kryptofix2.2.2 (Merck)/K CO solution (9.50 mg of Krypto-
2
2
2
2
3
2
CO
3
in a 96 : 4 (v/v) mixture of MeCN
and Na CO (25.0 mg, 0.236 mmol) in DMSO (40.0 mL) under with MeCN (1.00 mL) at 120 °C under a stream of argon gas
2
3
an argon atmosphere, and the resulting mixture was stirred for over 10 min.
h at 90 °C. The mixture was then cooled to room tempera- Synthesis of p-[ F]fluoroiodobenzene ([ F]1) from 4-iodo-
ture, poured into water and extracted with EtOAc. The organic phenyldiphenyl-sulfonium triflate. A solution of 4-iodophenyl-
layer was washed with brine and dried over Na SO before diphenylsulfonium triflate (2.00 mg) in MeCN (150 µL) was
1
8
18
9
2
4
1
8
being concentrated under reduced pressure. The resulting added to a reaction vessel containing the F activity (1.10–1.50
residue was subjected to azeotropic dehydration with MeCN GBq), and the reaction mixture was heated for 1 min
and purified by HPLC (Shimadzu system with a Cosmosil under microwave irradiation (50.0 W). The resulting
5
C18-ARII 10 × 250 mm column, MeCN–water = 70/30, flow mixture was cooled for 1 min and then passed through a Sep-
−
1
rate = 5.0 mL min ) to give methyl ester 13 as an amorphous Pak Light C18 column (Waters) and washed with water
solid (3.00 mg, 8.80% (isolated yield)). (10 mL). A stream of N gas was passed over the column for 10
2
1
18
18
3
H NMR (500 MHz, CDCl ) δ: 7.95 (d, J = 8.3 Hz, 1H), 7.59 s, and p-[ F]fluoroiodobenzene ([ F]1) was eluted with MeCN
1
8
(
(
(
t, J = 8.3 Hz, 1H), 7.35–7.28 (m, 2H), 7.24–7.13 (m, 4H), 6.63 (500 µL). The eluent containing [ F]1 was purified by HPLC
dd, J = 16.0, 1.4 Hz, 1H), 5.58 (dd, J = 16.0, 6.3 Hz, 1H), 4.40 analysis (RCY 56.2 ± 3.1% decay corrected, data are the mean ±
m, J = 2.6 Hz, 1H), 4.15–4.10 (m, 1H), 3.60 (br, 1H), 3.73 (s, SD (n = 3)).
1
8
3
H), 3.10 (br, 1H), 2.50–2.36 (m, 3H), 1.50 (ddd, J = 9.2, 4.0, 1.1
Synthesis of [ F]pitavastatin using the Suzuki coupling reac-
1
3
18
18
Hz, 1H), 1.37–1.30 (m, 3H), 0.98 (dd, J = 8.0, 2.3 Hz, 2H);
C
tion with [ F]1. A solution of [ F]1 in MeCN (37.0–74.0 MBq,
(dba)
60.7, 146.8, 144.2, 139.7, 133.5, 131.8 (dd, J = 28.8, 7.8 Hz) (1.00 mg) and Cs CO (4.00 mg) in MeCN (100 µL), and the
NMR (125 MHz, CDCl
1
3
): δ 172.9, 162.2 (d, J
F
= 246.5 Hz), 161.2, 100 µL) was added to a solution of 2 (2.0 mg), Pd
2
3
F
2
3
(
2C), 129.3, 128.9, 126.1, 126.0, 125.8, 125.4, 115.3 (dd, J
F
=
resulting mixture was heated to 100 °C under microwave
2
1.6, 3.3 Hz) (2C), 72.4, 68.0, 51.9, 42.3, 41.2, 15.9, 10.3, 10.2; irradiation (50.0 W) for 1 min. The mixture was then passed
+
MS (EI) m/z: 435 (M , 5.2), 314 (56), 280 (100), 274 (70), 220 through a COSMONICE(R) Filter (S) (0.45 µm, 4 mm) and puri-
+
(14); HRMS calcd for C26
H
26FNO
4
(M ): 435.1846, found fied by preparative HPLC [Cosmosil 5C18-ARII 10 × 250 mm
2
0
4
35.1849; [α]
(
D
: +35.707 (c 0.68, MeOH).
column, MeOH/20 mM phosphate buffer (pH 2.5) = 70/30,
3R,5S,6E)-7-[2-Cyclopropyl-4-{4-fluorophenyl}quinolin-3-yl]- flow rate 5.0 mL min− ] to give a solution of pure [ F]pitavas-
1
18
1
8
3
,5-dihydroxyhept-6-enoic acid (pitavastatin). A 1.0
M
tatin (Rt = 8.53 min, 12.1 ± 3.0% RCY from [ F]fluoride ions,
aqueous solution of NaOH (1 mL) was added to a solution of data are the mean ± SD (n = 3), specific activity was >10.0 GBq
3 (3 mg, 6.9 µmol) in methanol (1 mL) at room temperature, µmol− ).
1
1
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4
(a) T. Takashima, H. Nagata, T. Nakae, Y. Cui, Y. Wada,
S. Kitamura, H. Doi, M. Suzuki, K. Maeda, H. Kusuhara,
Y. Sugiyama and Y. Watanabe, J. Pharmacol. Exp. Ther.,
2010, 335, 314; (b) T. Takashima, Y. Hashizume,
Y. Katayama, M. Murai, Y. Wada, K. Maeda, Y. Sugiyama
and Y. Watanabe, Mol. Pharmaceutics, 2011, 8, 1789;
(c) R. Ijuin, T. Takashima, Y. Watanabe, Y. Sugiyama and
M. Suzuki, Bioorg. Med. Chem., 2012, 20, 3703–3709;
(d) J. He, Y. Yu, B. Prasad, J. Link, R. S. Miyaoka, X. Chen
and J. D. Unadkat, Mol. Pharmaceutics, 2014, 11, 2745.
(a) H. Fujino, I. Yamada, J. Kojima, M. Hirano,
H. Matsumoto and M. Yoneda, Xenobio. Metabol. Dispos.,
Acknowledgements
This work was supported in part by the New Energy and Indus-
trial Technology Development Organization (NEDO). Crude
phosphonate 3 material was provided by Nissan Chemical
Industries, Ltd, and Kowa Company, Ltd. We would also like to
thank KNC Laboratories Co., Ltd and Dr Hidekazu Imahori.
No other potential conflicts of interest relevant to this article
have been reported.
5
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