Radiosynthesis of [5-[11C]methanesulfonyl-2-((S)-2,2,2- trifluoro-1-methyl-ethoxy)-phenyl]-[5-(tetrahydro-pyran-4-yl)-1, 3-dihydro-isoindol-2-yl]-methanone ([11C]RO5013853), a novel PET tracer for the glycine transporter type i (GlyT1)

Article abstract of DOI:10.1002/jlcr.1911

The glycine transporter type 1 (GlyT1) has emerged as a key novel target for the treatment of schizophrenia. We have recently discovered and developed [¹¹C]RO5013853 as a novel positron emission tomography tracer for GlyT1 for which a reliable five-step synthetic route was established. The incorporation of the radioisotope was achieved in the final step through methylation of a sodium sulfinate precursor, itself easily accessible upon reduction of the corresponding sulfonyl-chloride analog. [¹¹C] RO5013853 was prepared with high specific activity (>49 GBq/μmol) and high radiochemical purity (100%). A validation study of [¹¹C]RO5013853 in animal imaging studies is in progress. Copyright

Full text of DOI:10.1002/jlcr.1911

Research Article
Received 10 February 2011,
Revised 2 May 2011,
Accepted 1 June 2011
Published online 11 August 2011 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1911
Radiosynthesis of [5-[11C]methanesulfonyl-2-
((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-
[5-(tetrahydro-pyran-4-yl)-1,3-dihydro-isoindol-
2-yl]-methanone ([11C]RO5013853), a novel
PET tracer for the glycine transporter
type I (GlyT1)
a
a
a
a
*
Emmanuel Pinard, Serge Burner, Philipp Cueni, Thomas Hartung,
Roger D. Norcross,a Philipp Schmid,a Pius Waldmeier,a Guy Zielinski,a
Hayden T. Ravert,b Daniel P. Holt,b and Robert F. Dannalsb
The glycine transporter type 1 (GlyT1) has emerged as a key novel target for the treatment of schizophrenia. We have recently
discovered and developed [11C]RO5013853 as a novel positron emission tomography tracer for GlyT1 for which a reliable
five-step synthetic route was established. The incorporation of the radioisotope was achieved in the final step through
methylation of a sodium sulfinate precursor, itself easily accessible upon reduction of the corresponding sulfonyl-chloride
analog. [11C]RO5013853 was prepared with high specific activity (>49GBq/mmol) and high radiochemical purity (100%). A
validation study of [11C]RO5013853 in animal imaging studies is in progress.
Keywords: [11C]RO5013853; carbon-11; PET; GlyT1; glycine; transporter; radiolabeling
schizophrenia. Several of these have entered clinical trial
Introduction
stage.5 In 2009, Roche disclosed positive phase II results with
The glycine transporter type 1 (GlyT1) is a selective transporter of
RG1678 in schizophrenic patients, effectively providing for the
the neurotransmitter glycine. It belongs to the Na+/ClÀ-depen-
first time a proof-of-concept for glycine reuptake inhibition as a
therapeutic approach.6,7
dent neurotransmitter transporter superfamily and its distribu-
tion in the central nervous system (CNS) overlaps the
A positron emission tomography (PET) ligand for GlyT1 is an
important imaging tool that may serve to improve the under-
expression pattern of the N-methyl-D-aspartate (NMDA) recep-
tors for which glycine is an obligatory co-agonist.1,2 GlyT1 pro-
standing of the pathology of schizophrenia as well as to facilitate
vides tight regulation of the extracellular glycine concentration
the development of therapeutic candidates for this target. We
at this receptor. Inhibition of glycine reuptake via selective block-
have recently described the identification of benzoylisoindolines
as a novel class of glycine reuptake inhibitors.8 From this series,
ade of GlyT1 leads to an increase in local glycine concentration
and potentiation of the NMDA receptor synaptic activity.3 Com-
[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-
pelling evidence suggests that impairment in NMDA neurotrans-
[5-(tetrahydro-pyran-4-yl)-1,3-dihydro-isoindol-2-yl]-methanone
mission is involved in the pathophysiology of schizophrenia.4
(RO5013853, Figure 1) was found to exhibit properties that sup-
This hypothesis originated from the observation that selective
ported its further evaluation as a potential PET ligand candidate:
NMDA-R blockers are able to reproduce, in healthy subjects,
the positive, negative, and cognitive symptoms of schizophrenia.
Thus, normalization of NMDA receptor neurotransmission by
high target affinity for human GlyT1 (hGlyT1 EC50: 14nM), high
increasing the availability of glycine at its modulatory site on
aF. Hoffmann-La Roche Ltd., Pharmaceutical Division, CH-4070 Basel, Switzerland
the receptor may provide a novel therapeutic intervention to this
severe CNS disorder for which there is a strong need to identify bThe Johns Hopkins University School of Medicine, Department of Radiology, Divi-
sion of Nuclear Medicine, 600 North Wolfe Street, Baltimore, MD 21287-0816, USA
more efficacious and safer agents than the currently marketed
dopaminergic-based drugs. As a result, considerable effort has
been focused, over the last decade, on the discovery and
92/8.64, CH-4070 Basel, Switzerland.
development of selective glycine reuptake inhibitors for E-mail: emmanuel.pinard@roche.com
*Correspondence to: Dr. Emmanuel Pinard, F. Hoffmann-La Roche Ltd., Building
J. Label Compd. Radiopharm 2011, 54 702–707
Copyright © 2011 John Wiley & Sons, Ltd.

E. Pinard et al.
sulfide. This approach suffers nevertheless from several limita-
tions and drawbacks: (1) the thiol is often not very stable and
is prone to dimerization to form the corresponding disulfide;
(2) the radioisotope is not incorporated in the last step of the
synthesis; and (3) the final oxidation step is often incomplete
and leads to a mixture of sulfone and sulfoxides. Recently, an
alternative approach was introduced by Perrio et al.,11 in which
the starting thiol is first oxidized with N-sulfonyloxaziridine to a
lithium sulfinate intermediate, which is then, in the final step,
S-methylated with [11C]methyl iodide at 150ꢀC in a THF/H2O sol-
vent mixture. This method, which allows the introduction of the
methyl group in the final step, still suffers however from the uti-
lization of a potentially unstable thiol as a starting material. To
circumvent this issue, we proposed to prepare the intermediate
sulfinate by reduction of a sulfonyl-chloride. This reaction is well
described and can be performed under very mild condition in
the presence of sodium sulfite.
Thus, the synthesis of RO5013853 (Figure 2) was started with
commercially available 2-fluorobenzoic acid (1), which, upon
treatment at 100ꢀC with the sodium salt of (S)-1,1,1-trifluoro-
propan-2-ol12, provided 2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-
benzoic acid (2) with excellent yield. Coupling of (2) with
5-(tetrahydro-pyran-4-yl)-2,3-dihydro-1H-isoindole13 using 2-(1H-
benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate
(TBTU) as an acid activating agent afforded amide (3). Friedel-
CF3
O
O
N
SO2CH3
O
RO5013853
Figure 1. Chemical structure of [5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-
ethoxy)-phenyl]-[5-(tetrahydro-pyran-4-yl)-1,3-dihydro-isoindol-2-yl]-methanone
(RO5013853).
target selectivity (≫100-fold selectivity for human GlyT1 versus
GlyT2 and versus a CEREP panel of 92 receptors), moderate
lipophilicity (clogP: 2.91), good brain penetration (rat brain/
plasma: 0.6), and the possibility for radiolabeling employing
readily available PET chemistry synthons such as [11C]methyl
iodide (vide infra).
We report herein on the development of a suitable synthetic
route to [11C]RO5013853, an essential prerequisite for its evalua-
tion as a GlyT1 PET radiotracer.
Results and discussion
The strategy we followed was to label the methyl-sulfone substi- Crafts chlorosulfonylation of (3) proceeded in a fully regioselec-
tuent of RO5013853 with 11C. The methyl-sulfone moiety has tive manner at the most activated aromatic position to provide
already been reported by several groups as a useful position the desired sulfonyl-chloride intermediate (4). Reduction of
for the labeling of PET ligands.9,10 In these published studies, (4) proceeded uneventfully in the presence of sodium sulfite at
the labeling strategy typically involves the methylation of a thiol 40ꢀC. After basification with sodium bicarbonate and purification
group followed by the double oxidation of the resulting methyl on a reverse-phase column, the sulfinate sodium salt (5) was
O
O
CF3
N
5-(Tetrahydro-pyran-4-yl)-2,3-
(S)-1,1,1-Trifluoro-propan-2-ol
CF3
O
O
F
dihydro-1H-isoindole
O
HO
HO
TBTU, DIPEA, DMF
RT, 24 h
NaH, dioxane
140 h, reflux
O
93%
82%
3
2
1
O
O
CF3
CF3
O
O
CH3I
sodium sulfite
H2O, EtOH
40°C, 1 h
then NaHCO3
N
Chlorosulfonic acid
N
DMF
RT, 30 min
SO2Cl
SO2Na
1,2-dichloroethane
55°C, 30 min
O
O
51%
48%
76%
4
5
CF3
O
O
N
SO2CH3
O
RO5013853
Figure 2. Chemical synthesis of RO5013853.
J. Label Compd. Radiopharm 2011, 54 702–707
Copyright © 2011 John Wiley & Sons, Ltd.
www.jlcr.org

E. Pinard et al.
isolated with 48% yield as a pure and stable white solid. The approximately 7% (calculated at end of synthesis, not corrected
reaction of (5) in solution with one equivalent of methyl iodide for decay). The average time of synthesis was 33min (from
in dimethylformamide (DMF) provided RO5013853 in excellent end-of-bombardment to radiotracer product in vial). The average
yield (76%). The reaction was rapid: the full conversion of sulfi- specific radioactivity was 49.3Æ29.6GBq/mmol (13342Æ7998
nate (5) was reached in less than 30min at room temperature. mCi/mmol) calculated at end of synthesis. Analytical HPLC
Moreover, under these reaction conditions, the formation of (Figure 5) demonstrated the product to be radiochemically
the corresponding sulfinic methylester resulting from the com- pure (100%). [11C]RO5013853 co-eluted with an authentic non-
peting O-alkylation was not detected, making the purification radioactive standard of the product. The radiotracer was ster-
of RO5013853 very straightforward.
ile and free from pyrogens (<5EU/mL) by standard analytical
The methylation reaction conditions established for sulfi- tests.
nate precursor (5) were then applied to the preparation of
[11C]RO5013853. [11C]RO5013853 was synthesized remotely
using a captive solvent system by reaction of [11C]methyl iodide
Conclusions
with the nor-methyl precursor (5) in DMF (Figure 3). After the
reaction, the product was purified by semi-preparative HPLC. We have established a reliable and convenient synthesis of [11C]
Figure 4 shows a typical semi-preparative chromatogram. [11C] RO5013853, a PET ligand of GlyT1. The incorporation of the
RO5013853 was collected in water, concentrated on a reverse- radioisotope was achieved in the final step through radiomethyl-
phase SPE, eluted through a sterile filter into a sterile vial with ation with [11C]methyl iodide of a sodium sulfinate precursor,
absolute ethanol, and then diluted with sterile saline. A typical itself easily accessible by reduction of the corresponding
synthesis produced 4.13Æ1.46GBq (111.7Æ39.6mCi; n=95) sulfonyl-chloride analog. Results from the evaluation of [11C]
of final [11C]RO5013853. Based on a calculated production RO5013853 in baboon and human PET studies will be reported
of 56GBq [11C]carbon dioxide, the radiochemical yield was in due course.
CF3
O
O
CF3
O
O
11CH3I
DMF
N
N
SO211CH3
SO2Na
O
O
11C]RO5013853
5
[
Figure 3. Radiosynthesis of [11C]RO5013853.
1.000.000
900.000
800.000
700.000
600.000
500.000
400.000
300.000
200.000
Precursor
1.38
1.5
[
11C]RO5013853
100.000
0
0
0.5
1
2
2.5
3
3.5
4
4.5
5
5.5
6
6.5
7
7.5
8
8.5
9
9.5
5.500
5.000
4.500
4.000
3.500
3.000
2.500
2.000
1.500
1.000
500
[
11C]RO5013853
4.33
3.69
1.59
1.39
1.17
3.09
3
0
0
0.5
1
1.5
2
2.5
3.5
4
4.5
5
5.5
6
6.5
7
7.5
8
8.5
9
9.5
Figure 4. Semi-preparative HPLC of reaction mixture. Top panel, UV chromatogram. Bottom panel, radiochromatogram. [11C]RO5013853 elutes at approximately 8min.
www.jlcr.org
Copyright © 2011 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2011, 54 702–707

E. Pinard et al.
600
500
400
300
200
100
0
[
11C]RO5013853
Precursor
-100
-200
-300
0
0.5
1.0
1.5
2.0
2.5
3.0
3.4
11C]RO5013853
70.000
60.000
50.000
40.000
30.000
20.000
10.000
[
0
0.5
1.0
1.5
2.0
2.5
3.0
3.4
Figure 5. Analytical HPLC of final radiotracer product. Top panel is UV chromatogram. Bottom panel is radiochromatogram. [11C]RO5013853 elutes at approx. 2.1min.
Prostar 210 pump with a Prostar 410 autosampler, a Varian Prostar
325 LC detector (205nm), and a Bioscan Flow-Count module with a
diode radioactivity detector. The analytical HPLC column was a
Experimental
Chemistry
Phenomenex Luna C-18(2) 5mm, 4.6Â150mm column thermore-
All solvents and reagents were obtained from commercial
sources and were used as received. All reactions were followed
by thin layer chromatography (TLC) (TLC plates F254, Merck) or
liquid chromatography-mass spectrometry (LCMS) analysis. Pro-
gulated to a temperature of 30ꢀC, eluted with a mixture of 50:50
acetonitrile/water containing 0.2% formic acid at a flow rate of 3
mL/min. Chromatographic data were acquired and analyzed on a
Varian Galaxie chromatography data system (version 1.9.302.952).
ton NMR spectra were obtained on a Bruker 300- or 400-MHz
Radioactivity measurements were made using a Capintec CRC-15R
instrument with chemical shifts (d in ppm) reported relative to
tetramethylsilane as internal standard. NMR abbreviations are
dose calibrator.
as follows: s, singlet; d, doublet; t, triplet; q, quadruplet; quint,
quintuplet; sext, sextuplet; hept, heptuplet; m, multiplet; br, 2-((S)-2,2,2-Trifluoro-1-methyl-ethoxy)-benzoic acid (2)
broadened. Elemental analyses were performed by Solvias AG
(S)-1,1,1-Trifluoro-propan-2-ol12 (36.0g, 316mmol) was added to
(Mattenstrasse, Postfach, CH-4002 Basel, Switzerland). Column
chromatography was carried out on silica gel 60 (32–60 mesh,
60Å) or on prepacked columns (Isolute Flash Si). Mass spectra
a cooled (0 to 5ꢀC) suspension of NaH (60% dispersion in mineral
oil) (17.0g, 425mmol) in dioxane (200mL). The suspension
was stirred at room temperature for 0.5h and then cooled (0 to
were recorded on a SSQ 7000 (Finnigan-MAT) spectrometer
5ꢀC), and a solution of 2-fluoro-benzoic acid (20.0g, 143mmol)
using electron impact ionization.
in dioxane (100mL) was added. The mixture was stirred for 0.5
h at room temperature and then for 140h under reflux. The mix-
Radiochemistry
ture was poured into water (800mL), washed with methyl-t-
For radiochemical syntheses, DMF was stirred over barium oxide butylether (MTBE) (300mL), and then acidified to pH2 with
for 24h and then vacuum distilled. Carbon-11-labeled carbon hydrochloric acid; the product was extracted with MTBE. The sol-
dioxide was produced by proton bombardment of nitrogen-14 vent was evaporated in vacuo, and the residue was crystallized
from ethanol/water to provide 27.3g (82%) of the desired pro-
duct (2) as a white solid. 1H NMR (300MHz, CDCl3) d 10.3 (br,
1H), 8.15 (m, 1H), 7.56 (m, 1H), 7.22 (m, 1H), 7.07 (m, 1H), 4.86
(m, 1H), 1.62 (d, J=6.6Hz, 3H). MS (EI) m/e: 234.1 [M]+.
gas in a General Electric PETtrace 18MeV cyclotron. Carbon-11-
labeled methyl iodide ([11C]CH3I) was synthesized using a Gen-
eral Electric MeI Microlab gas phase system. A Bioscan Auto-
loopW (software version 1.0.233) captive solvent methylation
system was used to trap and react the [11C]methyl iodide with
the precursor. Semipreparative chromatography (connected in
concert with the Autoloop) was performed with a Waters 610
pump, Waters 486 UV detector (254nm), and a Bioscan Flow-
[5-(Tetrahydro-pyran-4-yl)-1,3-dihydro-isoindol-2-yl]-[2-((S)-
2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone (3)
Count module with a diode radioactivity detector. The semi- To a solution of 2 (0.9g, 3.8mmol) in DMF (9mL) under argon at
preparative HPLC column was a Waters XTerra C18 5mm, 19Â room temperature was added TBTU (1.4g, 4.2mmol), N-ethyldii-
100mm column eluted with a mixture of 40:60 acetonitrile/water sopropylamine (3.3mL, 19.2mmol), and finally 5-(tetrahydro-
containing 0.1N ammonium formate at a flow rate of 18mL/min. pyran-4-yl)-2,3-dihydro-1H-isoindole (0.8g, 3.8mmol).13 The
The analytical chromatography system consisted of a Varian mixture was stirred at room temperature overnight. The
J. Label Compd. Radiopharm 2011, 54 702–707
Copyright © 2011 John Wiley & Sons, Ltd.
www.jlcr.org

E. Pinard et al.
solvent was removed in vacuo. The residue was dissolved in The residue was purified by flash-column chromatography on
ethyl acetate. The solution was washed twice with water and silica eluting with a gradient formed from heptane and ethylace-
twice with sat. NaHCO3 solution, dried over Na2SO4, filtered, tate to provide 15mg (76%) of the desired product (RO5013853)
1
and concentrated in vacuo. The crude oil was purified by flash- as a white solid. [a]2D0 À5.96ꢀ (c=1.32, CHCl3). H NMR (300MHz,
column chromatography on silica eluting with a gradient formed CDCl3) d 8.01 (dt, J=8.7, 2.2Hz, 1H), 7.95 (d, J=2.2Hz, 1H) 7.31–
from heptane and ethylacetate to provide 1.5g (93%) of the desired 7.00 (m, 4H), 4.97 (m, 2H), 4.82 (quint., J=6.1Hz, 1H), 4.61–4.53
product (3) as a yellow oil. 1H NMR (300MHz, CDCl3) d 7.44–7.28 (m, 2H), 4.12–4.05 (m, 2H), 3.58–3.47 (m, 2H), 3.07 (s, 3H), 2.80–
(m, 2H), 7.21–6.99 (m, 5H), 4.96 (m, 2H), 4.69–4.50 (m, 3H), 2.75 (m, 1H), 1.86–1.73 (m, 4H), 1.53 (d, J=6.5Hz, 3H). MS (EI)
4.16–4.04 (m, 2H), 3.58–3.47 (m, 2H), 2.82–2.73 (m, 1H), m/e: 498.4 [M+H]+. Anal. calcd. for C24H26F3NO5S: C, 57.94; H,
1.86–1.72 (m, 4H), 1.45 (d, J=6.6Hz, 3H). MS (EI) m/e: 420.2 [M+H]+. 5.27; N, 2.82; S, 6.44; F, 11.46. Found: C, 57.77; H, 5.32; N, 2.93;
S, 6.48; F, 11.64. HPLC, analytical Chiralpack ADW column (flow
rate: 1mL/ min, pressure: 25bar, detection at 254nm) using
heptane/isopropanol (80:20) as eluant, retention time: 14.4min
ee>99%.
3-[5-(Tetrahydro-pyran-4-yl)-1,3-dihydro-isoindole-2-
carbonyl]-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-
benzenesulfonyl chloride (4)
The R-enantiomer was independently prepared, and the
retention time under the above HPLC conditions is 7.8min.
A solution 3 (0.2g, 0.47mmol) in 1,2-dichloroethane (2mL) was
added dropwise to chlorosulfonic acid (0.32mL, 4.7mmol) under
ice-bath cooling. The mixture was stirred at room temperature
for 30min and then at 55ꢀC for 30min. The mixture was cooled
in an ice bath, and water (2mL) was added dropwise. Dichloro-
methane was also added. The organic layer was separated, and
the aqueous layer was extracted twice with dichloromethane.
The combined dichloromethane extracts were dried over
Na2SO4, filtered, and concentrated in vacuo. The resulting foam
was stirred with ethylacetate. The solid was removed by filtra-
tion. The filtrate was washed twice with a saturated solution of
NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo
to provide 0.12g (51%) of the desired product (4) as a light yel-
[5-[11C]Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-
ethoxy)-phenyl]-[5-(tetrahydro-pyran-4-yl)-1,3-dihydro-
isoindol-2-yl]-methanone; [11C]RO5013853
At end of bombardment (EOB), the [11C]carbon dioxide was
released from the target into the GE MeI Microlab system, and
the [11C]methyl iodide module was started. At approximately
7min post-EOB, between 0.5 and 1mg of 5 in DMF (100 mL)
was added to the cleaned loop of the Bioscan AutoloopW sys-
tem. At approximately 10min post-EOB, [11C]methyl iodide was
released from the Microlab system in a stream of helium at a
flow rate of 20mL/min through the loop methylation system
until the radioactivity reached a plateau (approximately 2min).
Upon reaching a plateau, the reaction was kept at room tem-
perature in the loop for 4.5min. The reaction mixture was auto-
matically injected into the preparative HPLC column. [11C]
RO5013853 (retention time of approximately 8min) was col-
lected in a reservoir containing water (50mL). After collection,
the reservoir was emptied through a reverse-phase SPE (Waters
C-18 SepPak Plus) cartridge previously conditioned with absolute
ethanol (10mL) followed by water (10mL). The SPE cartridge was
then washed with sterile saline (10ml) that was sent to waste.
The output of the SPE cartridge was connected to a sterile filter
(Millipore Millex-FG,0.2mm, 25mm diameter). Absolute ethanol
(1ml) was passed through the SPE cartridge to elute the [11C]
RO5013853 into a sterile vial previously charged with sterile sal-
ine (4mL). The SPE cartridge was further washed with sterile sal-
ine (10mL) into same sterile vial. Before an aliquot was
aseptically removed for quality control, the radioactivity content
of the sterile product vial was assayed. Radiochemical purity,
chemical purity, chemical identity, and specific activity were
determined by analytical HPLC (retention time (RO5013853)=
2.12min; retention time (5)=2.86min). The final pH was approxi-
mately 5. The product was assayed by gas chromatography
(method not presented here) and determined to have consider-
ably less than 20ppm of residual acetonitrile and DMF. Pyrogen
testing using an Endosafe PTSW (Charles River Laboratories,
MA) was performed. Sterility testing was performed according
to the United States Pharmacopeia, Chapter 71.
1
low foam. H NMR (300MHz, CDCl3) d 8.13–8.06 (m, 2H), 7.32–
6.91 (m, 4H), 4.98 (m, 2H), 4.99–4.86 (m, 1H), 4.63–4.54 (m, 2H),
4.13–4.05 (m, 2H), 3.58–3.47 (m, 2H), 2.80–2.76 (m, 1H), 1.86–
1.73 (m, 4H), 1.55 (d, J=6.6Hz, 3H). MS (EI) m/e: 517.1 [M]+.
3-[5-(Tetrahydro-pyran-4-yl)-1,3-dihydro-isoindole-2-
carbonyl]-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-
benzenesulfinate sodium salt (5)
Na2SO3 (1.15g, 8.94mmol) and Na2HPO4 hydrate (1.70g, 9.60
mmol) were dissolved in water (13mL). An ethanolic solution of
4 (2.40g, 4.63mmol) was added. The reaction mixture was stirred
at 35 to 40ꢀC for 1h and then at room temperature overnight.
Speedex (1.3g) was added; the reaction mixture was filtered;
and the filtrate was concentrated in vacuo. The crude product
was treated with aqueous citric acid/NaCl solution and then
extracted with MTBE/THF (1:1). The organic solvent was evapo-
rated, and the residue was dissolved in MeOH/water (2:1) and
then treated with NaHCO3 (800mg, 9.52mmol). Speedex (1g)
was added, and the reaction mixture was filtrated and concen-
trated in vacuo. The residue was purified by chromatography
on a reverse-phase column (RP-18, water/methanol) to provide
1
1.12g (48%) of the desired product (5) as a white solid. H NMR
(300MHz, DMSO-d6) d 7.51–7.14 (m, 6H), 5.21 (m, 1H), 4.78 (m,
2H), 4.43 (m, 2H), 3.93 (m, 2H), 3.41 (m, 2H), 2.73 (m, 1H), 1.70–
1.64 (m, 4H), 1.35 (d, J=6.0Hz, 3H). MS (EI) m/e: 484.3 [M+H]+.
[5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-
phenyl]-[5-(tetrahydro-pyran-4-yl)-1,3-dihydro-isoindol-2-yl]-
methanone; RO5013853
Acknowledgements
To a solution of 5 (20mg, 0.040mmol) in DMF (0.5mL) was added
dropwise at room temperature iodomethane (5.6mg, 0.040
mmol) in solution in DMF. The mixture was stirred at room tem-
The authors would like to thank Roland Degen and Mathias
Müller for their skillful and dedicated technical assistance, and
Robert Smoot and Jack (Jay) Brown for their assistance with
perature for 30min, and the solvent was evaporated in vacuo. radiochemistry.
www.jlcr.org
Copyright © 2011 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2011, 54 702–707

E. Pinard et al.
H. Stalder, R. Wermuth, J. G. Wettstein, D. Zimmerli, J. Med. Chem.
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