A short and efficient synthesis of 3-{2-[2-(bromomethyl)thiazol-4-yl]- ethynyl}-5-fluorobenzonitrile: A precursor for PET radioligand [ 18F]SP203

Article abstract of DOI:10.1055/s-0029-1216787

An improved synthesis of 3-{2-[2-(bromomethyl)thiazol-4-yl]ethynyl}-5- fluorobenzonitrile, a precursor for PET radioligand [¹⁸F]SP203, is described, wherein a new synthon was employed for Sonogashira coupling with 3-bromo-5-fluorobenzonitrile.

Full text of DOI:10.1055/s-0029-1216787

PAPER
1979
A Short and Efficient Synthesis of 3-{2-[2-(Bromomethyl)thiazol-4-yl]-
ethynyl}-5-fluorobenzonitrile: A Precursor for PET Radioligand [18F]SP203
S
ynthesis of 3-{2-[2-(B
a
romometh
d
yl)thiazol-4-
a
t
-
5-fluo
h
r
obenzonitr
i
i
le l B. Gopinathan, Chunyang Jin, Kenneth S. Rehder*
Center for Organic and Medicinal Chemistry, RTI International, Research Triangle Park, NC 27709, USA
Fax +1(919)5418868; E-mail: krehder@rti.org
Received 8 January 2009; revised 18 February 2009
S
S
N
Abstract: An improved synthesis of 3-{2-[2-(bromomethyl)thia-
zol-4-yl]ethynyl}-5-fluorobenzonitrile, a precursor for PET radioli-
F
18F
N
gand [18F]SP203, is described, wherein a new synthon was
employed for Sonogashira coupling with 3-bromo-5-fluoroben-
zonitrile. The new five-step synthesis provided the title compound
in 56% overall yield starting from 4-bromo-2-formylthiazole.
CN
CN
1
2
F
F
Key words: PET ligand, fluorine, Sonogashira coupling, palladi-
um, bromination
S
N
Br
CN
Glutamate is the principal excitatory neurotransmitter in
the central nervous system (CNS), and regulates a variety
of neuronal activities through interacting with specific re-
ceptors.1 The metabotropic glutamate receptors (mGluRs)
are G protein coupled receptors and classified as belong-
ing to groups I, II, or III.2,3 Group I mGluRs include
mGluR1 and mGluR5 subtypes. Activation of mGluR5
stimulates phospholipase, leading to phosphoinositide hy-
drolysis and increase of intracellular Ca2+ levels.2,3 Devel-
opment of specific mGluR5 antagonists is of current
interest, which could lead to useful therapeutics for a vari-
ety of disorders.4–6 3-Fluoro-5-{2-[2-(fluoromethyl)thia-
zol-4-yl]ethynyl}benzonitrile (SP203, 1, Figure 1), a
recently synthesized mGluR5 antagonist, was found to
have exceptionally high affinity and potency in a phos-
phoinositol assay for mGluR5.6 The corresponding radio-
ligand [18F]SP203 (2) was prepared from the
bromomethyl analogue, 3-{2-[2-(bromomethyl)thiazol-4-
yl]ethynyl}-5-fluorobenzonitrile (3), and [18F]fluoride
ion. [18F]SP203 (2) was found to be effective as a positron
emission tomography (PET) radioligand in rhesus mon-
key.7 [18F]SP203 is now being studied with PET in human
subjects since it shows excellent imaging properties de-
void of issues from radiodefluorination seen in animals.8
3
F
Figure 1 Structures of SP203 (1), [18F]SP203 (2), and 3
pared in 18% overall yield from 4-bromo-2-
formylthiazole (4) using nine-step procedure
a
(Scheme 1).6 Reactions were carried out on milligram
quantities and therefore difficulties in the scale-up reac-
tions were anticipated. Of particular concern was the
large-scale preparation and purification of the unstable
stannyl intermediate 5, which was crucial for the success
of the synthesis. Therefore, two alternative synthetic ap-
proaches for 3 were investigated.
The first approach is outlined in Scheme 2. Sonogashira
coupling of 4-bromo-2-formylthiazole (4) with (trimeth-
ylsilyl)acetylene using bis(triphenylphosphine)palladi-
um(II) chloride [(Pd(PPh3)2Cl2)], CuI, and triethylamine
afforded 4-trimethylsilylethynylthiazole-2-carbaldehyde
(6) in 50% yield. When tetrakis(triphenylphosphine)pal-
ladium [Pd(PPh3)4] was used as catalyst, a 63% yield of 6
was realized. Coupling of 6 with 3-bromo-5-fluoroben-
zonitrile (7) using Pd(PPh3)4, CuI, and tetrabutylammoni-
um fluoride (TBAF) in 1,2-dimethoxyethane (DME) then
provided 3-fluoro-5-(2-formylthiazol-4-yl)benzonitrile
As part of an ongoing research program, multigram quan-
tities of 3 were required. Compound 3 was previously pre-
S
O
H
S
N
S
N
3 steps
6 steps
SnBu3
N
Br
CN
TBDMSO
Br
3
5
4
F
Scheme 1 Early synthesis of 3
SYNTHESIS 2009, No. 12, pp 1979–1982
x
x.
x
x
.
2
0
0
9
Advanced online publication: 30.04.2009
DOI: 10.1055/s-0029-1216787; Art ID: M00309SS
© Georg Thieme Verlag Stuttgart · New York

1980
M. B. Gopinathan et al.
PAPER
O
H
S
O
H
S
N
Pd(PPh3)4, CuI, TBAF
Pd(PPh3)4, CuI
Me3Si
N
H
Br
CN
Br
SiMe3
6
4
7
F
O
H
S
N
S
N
NaBH4
HO
CN
CN
9
8
F
F
Scheme 2 Attempted synthesis of 9
(8) in 37% yield. Unfortunately, subsequent sodium boro- utes, and the reaction mixture was heated for another 50
hydride reduction of 8 did not afford the expected alcohol minutes. Further optimization of the reaction conditions,
9. Instead, a product without the triple bond, as judged by including reduced TBAF, addition time (3 min), and the
1H and 13C NMR analyses, was isolated in 58% yield. It subsequent heating time (12 min) resulted in less by-prod-
appeared that sodium borohydride reduced both the triple uct formation and increased the yield of 9 to 91%. Bromi-
bond and the aldehyde group of 8.
nation of 9 was first attempted using 1.1 equivalents of
triphenylphosphine and 20 equivalents of carbon tetrabro-
mide in benzene following the reported procedure.6 Un-
fortunately, column purification of the crude product gave
only 31% yield of 3. The poor yield and use of a large ex-
cess of toxic carbon tetrabromide and benzene prompted
investigation of an alternative bromination method, which
would be applicable to the large scale reaction. Thus, pi-
lot-scale reaction of 9 with 1.1 equivalents of N-bromo-
succinimide (NBS) and 1.1 equivalents of
triphenylphosphine in dichloromethane at 0 °C afforded 3
in 87% yield. Finally, scale-up bromination of 9 using
these optimized reaction conditions furnished 3 in 74%
yield.
Alternatively, reduction of aldehyde 4 with sodium boro-
hydride in methanol at 0 °C afforded (4-bromothiazol-2-
yl)methanol (10) in 91% yield (Scheme 3).6 The alcohol
was then protected by treatment with tert-butyldimethyl-
silyl chloride (TBDMSCl) to give 4-bromo-2-(tert-bu-
tyldimethylsilyloxymethyl)thiazole (11) in 98% yield.
Sonogashira coupling of 11 with (trimethylsilyl)acetylene
using Pd(PPh3)2Cl2 and CuI at 50 °C for 18 hours provid-
ed an 80% yield of 2-(tert-butyldimethylsilyloxymethyl)-
4-[2-trimethylsilyl)ethynyl]thiazole
(12).
When
Pd(PPh3)4 was used as catalyst, the reaction was complete
in 2.5 hours and 12 was obtained in 82% yield. Subse-
quent coupling of 12 with 7 using Pd(PPh3)4, CuI, triethyl-
amine, and TBAF at 80 °C afforded 3-fluoro-5-{2-[2- In summary, significant improvements have been made to
(hydroxymethyl)thiazol-4-yl]ethynyl}benzonitrile (9) in the previously reported synthesis of 3-{2-[2-(bromometh-
55% yield. In this reaction, TBAF was slowly added to the yl)thiazol-4-yl]ethynyl}-5-fluorobenzonitrile (3) via syn-
mixture containing 12, 7, and the catalysts over 45 min- thesis of a new synthon 12 for the Sonogashira coupling
O
H
S
N
S
S
NaBH4
TBDMSCl
imidazole
N
N
HO
TBDMSO
Br
Br
Br
4
10
11
S
Pd(PPh3)4, CuI, TBAF
Pd(PPh3)4, CuI, Et3N
Me3Si
H
N
TBDMSO
Br
CN
SiMe3
12
7
F
S
S
N
N
HO
Br
NBS, Ph3P
CN
CN
9
3
F
F
Scheme 3 Synthesis of 3
Synthesis 2009, No. 12, 1979–1982 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-{2-[2-(Bromomethyl)thiazol-4-yl]ethynyl}-5-fluorobenzonitrile
1981
HRMS (ESI): m/z [M + H]+ calcd for C13H6FN2OS: 257.0185;
found: 257.0185.
reaction. The improved five-step synthesis provided the
title compound in 56% overall yield from 4-bromo-2-
formylthiazole (4). The present approach is general and
12 will be useful for preparing related ligands through
Sonogashira cross-coupling reactions with substituted
bromobenzenes.
(4-Bromothiazol-2-yl)methanol (10)
To a stirred solution of 4 (1.97 g, 10.0 mmol) in MeOH (15 mL) at
0 °C was added NaBH4 (0.39 g, 10.0 mmol) in portions over 10 min.
After stirring at 0 °C for 15 min, the reaction mixture was concen-
trated under reduced pressure. The residue was dissolved in EtOAc
(100 mL), washed with H2O (2 ꢀ 50 mL) and brine (40 mL). The or-
ganic phase was dried (Na2SO4) and concentrated under reduced
pressure to afford 10 as a colorless oil (1.76 g, 91%).
Melting points were taken on a Fisher-Johns apparatus and are un-
1
corrected. H and 13C NMR spectra were obtained on a Bruker
Avance spectrometer (300 MHz) in CDCl3 using TMS as internal
standard. 4-Bromothiazol-2-carbaldehyde was purchased from
Frontier Scientific. HRMS were performed at the University of
Michigan, Ann Arbor. MS spectra (MS) were run on a Perkin-
Elmer Sciex APR150 EX mass spectrometer outfitted with APCI
(atmospheric pressure chemical ionization) or ESI (turbospray)
sources. Flash column chromatography was done using E. Merck
silica gel 60 (230–400 mesh). Analytical TLC was carried out using
EMD silica gel 60 F254 TLC plates. Elemental analyses were done
by Atlantic Microlab Inc., Norcross, GA.
1H NMR (300 MHz, CDCl3): d = 3.76 (t, J = 6.0 Hz, 1 H), 4.94 (d,
J = 5.9 Hz, 2 H), 7.21 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 61.8, 117.0, 124.4, 173.0.
MS (ESI): m/z = 194.2 [M + H]+ (79Br), 196.2 [M + H]+ (81Br).
4-Bromo-2-(tert-butyldimethylsilyloxymethyl)thiazole (11)
To a stirred solution of 10 (1.73 g, 8.92 mmol) in anhyd CH2Cl2 (30
mL) at r.t. was added imidazole (0.67 g, 9.84 mmol) followed by
TBDMSCl (1.48 g, 9.82 mmol). After stirring at r.t. for 90 min, the
mixture was treated with aq sat. NH4Cl (10 mL) and stirred for ad-
ditional 5 min. The organic layer was separated and the aqueous lay-
er was further extracted with CH2Cl2 (2 ꢀ 20 mL). The combined
organic extracts were dried (Na2SO4) and concentrated under re-
duced pressure. Flash column chromatography of the residue on sil-
ica gel using 5 → 10% EtOAc in hexane afforded 11 as a colorless
oil (2.70 g, 98%).
1H NMR (300 MHz, CDCl3): d = 0.13 (s, 6 H), 0.95 (s, 9 H), 4.94
(s, 2 H), 7.17 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = –5.5, 18.2, 25.7, 63.0, 116.4,
124.3, 174.4.
4-Trimethylsilylethynylthiazole-2-carbaldehyde (6)
A solution of 4-bromothiazole-2-carbaldehyde (4; 0.96 g, 5.00
mmol) in Et3N (25 mL) was degassed with argon for 10 min. After-
wards, CuI (110 mg, 0.58 mmol), Pd(PPh3)4 (320 mg, 0.28 mmol),
and (trimethylsilyl)acetylene (1.06 g, 10.8 mmol) were added. The
reaction mixture was heated and stirred at 50 °C for 40 min under
argon. After cooling to r.t., the mixture was filtered through a pad
of Celite. The Celite pad was washed with Et3N (100 mL). The fil-
trate and the washings were combined and concentrated under re-
duced pressure. Flash column chromatography of the residue on
silica gel using 5 →10% EtOAc in hexane afforded 6 as a yellow
solid (0.68 g, 63%).
MS (APCI): m/z = 308.4 [M + H]+ (79Br), 310.2 [M + H]+ (81Br).
1H NMR (300 MHz, CDCl3): d = 0.29 (s, 9 H), 7.83 (d, J = 1.4 Hz,
1 H), 9.97 (d, J = 1.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = –0.4, 96.6, 96.7, 129.5, 140.4,
2-(tert-Butyldimethylsilyloxymethyl)-4-[2-(trimethylsilyl)eth-
ynyl]thiazole (12)
165.0, 183.2.
MS (APCI): m/z = 210.1 [M + H]+.
A solution of 11 (2.67 g, 8.66 mmol) in Et3N (50 mL) was degassed
with argon for 10 min. Afterwards, CuI (177 mg, 0.93 mmol),
Pd(PPh3)4 (529 mg, 0.46 mmol), and (trimethylsilyl)acetylene (1.80
g, 18.3 mmol) were added, and the reaction mixture was stirred at
50 °C for 2.5 h under argon. After cooling to r.t., the mixture was
filtered through a pad of Celite. The Celite pad was washed with
Et3N (100 mL). The filtrate and the washings were combined and
concentrated under reduced pressure. Flash column chromatogra-
phy of the residue on silica gel using 0 → 5% EtOAc in hexane af-
forded 12 as a pale-brown oil (2.44 g, 87%).
1H NMR (300 MHz, CDCl3): d = 0.12 (s, 6 H), 0.24 (s, 9 H), 0.94
(s, 9 H), 4.93 (s, 2 H), 7.42 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = –5.5, –0.3, 18.2, 25.7, 63.1, 94.4,
98.4, 123.0, 137.1, 173.1.
Anal. Calcd for C9H11NOSSi: C, 51.64; H, 5.30; N, 6.69. Found: C,
51.85; H, 5.37; N, 6.60.
3-Fluoro-5-(2-formylthiazol-4-yl)benzonitrile (8)
A solution of 6 (419 mg, 2.00 mmol) and 3-bromo-5-fluorobenzoni-
trile (7; 479 mg, 2.39 mmol) in anhyd DME (14 mL) was degassed
with argon for 10 min. Afterwards, CuI (29.4 mg, 0.15 mmol),
Pd(PPh3)4 (85.7 mg, 0.07 mmol), and Et3N (0.99 g, 9.83 mmol)
were added, and the reaction mixture was heated at 80 °C for 10 min
while argon was bubbled into the solution. TBAF (1 M solution in
THF, 2 mL, 2.00 mmol) was added to the brown solution over 35
min. After addition, the dark solution was further stirred at 80 °C for
50 min, cooled to r.t., and concentrated under reduced pressure. The
dark residue was dissolved in CH2Cl2 (50 mL), washed with H2O
(2 ꢀ 40 mL) and brine (40 mL). The organic phase was dried
(MgSO4) and concentrated under reduced pressure. Flash column
chromatography of the residue on silica gel using 5 → 30% EtOAc
in hexane afforded 8 as an off-white solid (0.19 g, 37%).
1H NMR (300 MHz, CDCl3): d = 7.40 (ddd, J = 7.8, 2.4, 1.3 Hz, 1
H), 7.53 (ddd, J = 8.7, 2.4, 1.3 Hz, 1 H), 7.68 (s, 1 H), 7.97 (d,
J = 1.2 Hz, 1 H), 10.0 (d, J = 1.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 85.2, 86.4 (d, J = 3.3 Hz), 114.5 (d,
J = 10.2 Hz), 116.6 (d, J = 3.3 Hz), 119.7 (d, J = 24.7 Hz), 123.3 (d,
J = 22.9 Hz), 125.5 (d, J = 10.0 Hz), 130.4, 131.3 (d, J = 3.5 Hz),
139.1, 161.9 (d, J = 251.9 Hz), 165.7, 183.0.
HRMS (ESI): m/z [M + H]+ calcd for C15H28NOSSi2: 326.1430;
found: 326.1419.
3-Fluoro-5-{2-[2-(hydroxymethyl)thiazol-4-yl]ethynyl}benzo-
nitrile (9)
A solution of 12 (2.28 g, 7.00 mmol) and 7 (1.68 g, 8.37 mmol) in
anhyd DME (55 mL) was degassed with argon for 10 min. After-
wards, CuI (99.0 mg, 0.52 mmol), Pd(PPh3)4 (308 mg, 0.27 mmol),
and Et3N (3.56 g, 35.2 mmol) were added, and the reaction mixture
was stirred at 80 °C for 10 min while argon was bubbled into the so-
lution. TBAF (1 M solution in THF, 14 mL, 14.0 mmol) was added
to the brown solution over 3 min. After addition, the dark solution
was further stirred at 80 °C for 12 min, cooled to r.t., and concen-
trated under reduced pressure. The dark residue was dissolved in
CH2Cl2 (250 mL), and washed with H2O (2 ꢀ 125 mL) and brine
Synthesis 2009, No. 12, 1979–1982 © Thieme Stuttgart · New York

1982
M. B. Gopinathan et al.
PAPER
(150 mL). The organic phase was dried (Na2SO4) and concentrated
under reduced pressure. Flash column chromatography of the resi-
due on silica gel using 20 → 50% EtOAc in hexane afforded 9 as a
white solid (1.65 g, 91%).
1H NMR (300 MHz, CDCl3): d = 3.35 (m, 1 H), 4.99 (d, J = 5.8 Hz,
2 H), 7.35 (ddd, J = 7.8, 2.4, 1.4 Hz, 1 H), 7.47 (ddd, J = 8.8, 2.4,
1.4 Hz, 1 H), 7.60 (s, 1 H), 7.62 (m, 1 H).
Anal. Calcd for C13H6BrFN2S: C, 48.62; H, 1.88; N, 8.72. Found:
C, 48.80; H, 1.91; N, 8.72.
Acknowledgment
This work was supported by the National Institute of Mental Health
under contract N01-MH-32005.
13C NMR (75 MHz, CDCl3): d = 62.1, 85.5 (d, J = 3.2 Hz), 86.5,
114.3 (d, J = 10.2 Hz), 116.7 (d, J = 3.2 Hz), 119.2 (d, J = 24.8 Hz),
123.1 (d, J = 23.0 Hz), 124.5, 126.1 (d, J = 10.1 Hz), 131.2 (d,
J = 3.5 Hz), 135.9, 161.9 (d, J = 251.5 Hz), 172.1.
References
(1) Ozawa, S.; Kamiya, H.; Tsuzuki, K. Prog. Neurobiol. 1998,
54, 581.
(2) Conn, P. J.; Pin, J.-P. Ann. Rev. Pharmacol. Toxicol. 1997,
37, 205.
(3) Pin, J. P.; Acher, F. Curr. Drug Targets: CNS Neurol.
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Seiders, T. J.; Chaudary, A.; Rao, S.; Varney, M. A. Bioorg.
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(5) Alagille, D.; Baldwin, R. M.; Roth, B. L.; Wroblewski, J. T.;
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(6) Siméon, F. G.; Brown, A. K.; Zoghbi, S. S.; Patterson, V.
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Brown, A. K.; Kannan, P.; Innis, R. B.; Pike, V. W.
J. Pharmacol. Exp. Ther. 2008, 327, 727.
MS (ESI): m/z = 259.5 [M + H]+.
3-{2-[2-(Bromomethyl)thiazol-4-yl]ethynyl}-5-fluorobenzoni-
trile (3)
To a stirred solution of 9 (1.55 g, 6.00 mmol) and Ph3P (1.71 g, 6.42
mmol) in anhyd CH2Cl2 (90 mL) at 0 °C was added NBS (1.16 g,
6.52 mmol), and the reaction mixture was stirred at 0 °C for 35 min.
The mixture was adsorbed on silica gel by evaporation under re-
duced pressure. Subsequent flash column chromatography on silica
gel using 5 → 15% EtOAc in hexane afforded 3 as an off-white sol-
id (1.42 g, 74%); mp 109–110 °C (Lit.6 mp 102–104 °C).
1H NMR (300 MHz, CDCl3): d = 4.73 (s, 2 H), 7.36 (ddd, J = 7.8,
2.5, 1.4 Hz, 1 H), 7.48 (ddd, J = 8.7, 2.5, 1.4 Hz, 1 H), 7.63 (m, 1
H), 7.66 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 26.0, 85.6 (d, J = 3.5 Hz), 86.2,
114.4 (d, J = 10.2 Hz), 116.7 (d, J = 3.3 Hz), 119.4 (d, J = 24.7 Hz),
123.2 (d, J = 22.8 Hz), 125.9 (d, J = 10.0 Hz), 126.2, 131.2 (d,
J = 3.5 Hz), 136.3, 161.9 (d, J = 251.7 Hz), 166.2.
(8) Brown, A. K.; Kimura, Y.; Zoghbi, S. S.; Siméon, F. G.;
Liow, J.-S.; Kreisl, W. C.; Taku, A.; Fujita, M.; Pike, V. W.;
Innis, R. B. J. Nucl. Med. 2008, 49, 2042.
MS (ESI): m/z = 321.0 [M + H]+ (79Br), 323.1 [M + H]+ (81Br).
Synthesis 2009, No. 12, 1979–1982 © Thieme Stuttgart · New York