Synthesis of 3-[(2S)-azetidin-2-ylmethoxy]-5-[11C]-methylpyridine, an analogue of A-85380, via a Stille coupling

Article abstract of DOI:10.1002/jlcr.569

3-[(2S)-azetidin-2-ylmethoxy]-5-[¹¹C]-methylpyridine (5d), which might be a novel ligand for nicotinic receptors, was synthesized via coupling [¹¹C]iodomethane with tert-butyl (2S)-2-({[5-(trimethylstannyl)pyridin-3-yl]oxy}methyl) azetidine-1-carboxylate (4) at 80°C for 5 min with tri-o-tolylphosphine-bound, unsaturated palladium(O), followed by deprotection using trifluoroacetic acid (TFA). The previous problem (solid-phase extraction before injection on semi-preparative LC) with automation of Stille coupling reactions has been overcome. In a typical experiment, 0.46 GBq of 5d was obtained from 5.2GBq of [¹¹C]iodomethane. The decay-corrected radiochemical yield was 39% (based on the quantity [¹¹C]iodomethane trapped). The synthesis time was 43 min from end of radionuclide production. During a production condition using 36 μAh of proton beam irradiation, a specific radioactivity of 50 GBq/ μmol of the final product was obtained in biological buffer. Copyright

Full text of DOI:10.1002/jlcr.569

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2002; 45: 423–434.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.569
Research Article
Synthesis of 3-[(2S)-azetidin-2-ylmethoxy]-5-
[11C]-methylpyridine, an analogue of A-
85380, via a Stille coupling
1
1,2
(
.
Farhad Karimi and Bengt Langstrom *
1 Institute of Chemistry, Department of Organic Chemistry, Box 531,
S-751 21 Uppsala, Sweden
2 Uppsala University PET Centre, Uppsala University, S-751 85 Uppsala,
Sweden
Summary
3-[(2S)-azetidin-2-ylmethoxy]-5-[11C]-methylpyridine (5d), which might be a
novel ligand for nicotinic receptors, was synthesized via coupling [11C]iodo-
methane with tert-butyl (2S)-2-({[5-(trimethylstannyl)pyridin-3-yl]oxy}methyl)
azetidine-1-carboxylate (4) at 808C for 5 min with tri-o-tolylphosphine-bound,
unsaturated palladium(0), followed by deprotection using trifluoroacetic acid
(TFA). The previous problem (solid-phase extraction before injection on semi-
preparative LC) with automation of Stille coupling reactions has been
overcome. In a typical experiment, 0.46 GBq of 5d was obtained from
5.2 GBq of [11C]iodomethane. The decay-corrected radiochemical yield was
39% (based on the quantity [11C]iodomethane trapped). The synthesis time was
43 min from end of radionuclide production. During a production condition
using 36 mAh of proton beam irradiation, a specific radioactivity of 50 GBq/
mmol of the final product was obtained in biological buffer. Copyright # 2002
John Wiley & Sons, Ltd.
Key Words: [11C]iodomethane; stille coupling; methylation; nicotinic receptor
ligand
*Correspondence to: B. Langstrom, Uppsala University PET Centre, Uppsala University, S-751 85
¨
Uppsala, Sweden.
Copyright # 2002 John Wiley & Sons, Ltd.
Received 24 August 2001
Revised 21 September 2001
Accepted 17 December 2001

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F. KARIMI AND B. LANGSTROM
424
Introduction
Positron emission tomography (PET) is a powerful tool for clinical
diagnosis and research1–3 and in drug development.4 Amongst these
applications there is a great interest in developing PET tracers for
imaging central nicotinic acetylcholine receptors (nAChRs) due to their
importance in several neurodegenerative diseases.5,6
[11C](ꢀ)-Nicotine has been used for PET imaging of human nAChRs,
but this radiotracer suffers from high non-specific binding, low-affinity
and blood-flow dependence.7,8 Therefore, there has been a continuous
search for suitable radioligands with high affinity and selectively.9–12
In some of the previously reported work, analogues based on A-
85380 (3-(azetidin-2-ylmethoxy)pyridine) as the lead compound were
investigated.9,12,13
A
76Br-labelled analogue, [76Br]BAP (3-(azetidin-2-
ylmethoxy)-5-[76Br]-bromopyridine),13 was also prepared in our lab.
However, there are drawbacks with the long half-life of 76Br, for
example, when repeated studies are required and the high radiation
dosimetry for 76Br. We therefore extended our studies to look at the
compound 11C- methylated in the 5-position using the Stille reaction.
[11C]-labelled MAP (3-[(2S)-azetidin-2-ylmethoxy]-5-[11C]-methylpyri-
dine) is thus an interesting analogue for further investigation for
positron emission tomography studies of nicotinic receptors. The in
vitro properties of this compound have been reported previously in
literature ([3H]cytisine Ki ¼ 0:047 ꢁ 0:002 nM).14
Results and discussion
(S)-2-Azetidinecarboxylic acid was reduced and protected with Boc-
group in one pot, according to Scheme 1. The crude product was
analysed by GC–MS to determine the purity of compound 1 and no
trace of impurity was observed. Diborane rapidly reacted with
carboxylic acid to form a triacyloxyborane intermediate as a result of
protonolysis of the B–H bonds in borane complex.15 We assumed that
the configuration of the final product was the same as (S)-2-
azetidinecarboxylic acid, since the stereocentre is not involved in any
other step. The compound 1 was synthesized previously in two steps
(3 days reaction times).16
The compound tert-butyl (2S)-2-{[(5-chloropyridin-3-yl)oxy]methyl}-
azetidine-1-carboxylate (3a) was synthesized by two different methods.
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 423–434

SYNTHESIS OF 3-[(2S)-AZETIDIN
OTs
425
X
O
X
N
OH
N
COOH
N
N
H
(2a) X = Cl
(2b) X = Br
(2c) X = CH3
Boc
Boc
N
(3a) X = Cl
(3b) X = Br
(1)
O
Y
O
SnMe3
N
X
N
Boc
N
N
(4)
(5a) X = Boc, Y = CH3
(5b) X = H, Y = CH3
(5c) X = Boc, Y = 11CH3
(5d) X = H, Y = 11CH3
Scheme 1.
In method A, a reaction between the tosylated pyridine derivative 2a
and Boc-protected azetidinemethanol (1) in the presence of anhydrous
potassium hydroxide was performed in anhydrous DMF (N, N-
dimethylformamide) at 80 ꢁ 58C. This method can be applied if the
higher yield is of interest. Method B was based on the transfer catalysis
concept using tetra-butylammonium bisulphate (QHSO4).17 This
approach can be used in large-scale synthesis since the starting material
(3,5-dichloropyridine) is commercially available. In an attempt using a
catalytic amount of QHSO4, only 13% of the desired compound was
obtained. When the amount of the QHSO4 was increased to one
equivalent compared to the azetidinemethanol (1), the yield increased to
48%. tert-Butyl (2S)-2-{[(5-bromopyridin-3-yl)oxy]methyl}azetidine-1-
carboxylate (3b) and tert-butyl (2S)-2-{[(5-methylpyridin-3-yl)oxy]-
methyl}azetidine-1-carboxylate (5a) were prepared as described in
method ‘A’ using 2b or 2c. Method ‘B’ failed in the synthesis of 3b.
Compounds 3a and 3b have been synthesized before using Mitsunobu
condition (3 days reactions time).18
5-Bromo-3-hydroxypyridine was synthesized according to the litera-
ture,19 followed by tosylation to give 2b. 5-Methylpyridin-3-yl 4-
methylbenzenesulfonate (2c) was prepared from 2b using tetramethyltin
and a catalytic amount of tetrakis(triphenylphosphine)palladium(0). An
effort to synthesise 2c from 3-picoline 1-oxide and p-toluenesulphfonyl
chloride according to literature20 gave a very poor yield.
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F. KARIMI AND B. LANGSTROM
426
The stannyl compound 4 was obtained by reaction between
trimethylstannyl lithium and the corresponding halide, 3a. The
trimethylstannyl salt was prepared from stannous chloride (1 equiva-
lent) and methyllithium (3 equivalents). Since the concentration of
methyllithium is an important parameter, using the other described
method might be of interest.18 Compound 4 was also prepared from
hexamethylditin and the corresponding halide 3b in the presence of
catalytic amount of tetrakis(triphenylphosphine)palladium(0).
Rapid coupling of iodomethane with organostannyl compounds for
incorporation of short-lived radionuclides has been reported previously
in literature.21–23 The reaction between tris(dibenzylideneacetone)palla-
dium(0) (Pd2(dba)3) and tri-o-tolylphosphine ((o-tol)3P) will generate
activated Pd(0) species [(o-tol)3P-Pd-P((o-tol)3].21 The bulkiness (cone
angle=1948) of tri-o-tolylphosphine is assumed to contribute to the
activity of the Pd(0) species formed.24 According to previous experience
we supposed that an excess of ligand [(o-tol)3P] might stabilise the
activated Pd(0) complex. This species can then undergo oxidative
addition to form Pd(II) complex followed by transmetallation, which is
the rate limiting step in Stille reactions.25,26 Due to the stepwise labelling
procedure we assumed that scrambling (i.e. interaction of other methyl
moieties) was negligible.
A polar aprotic solvent such as DMSO was used for a efficient
trapping of [11C]iodomethane. The [11C]iodomethane produced was
transferred directly to the reaction vessel using nitrogen gas as a carrier
(20 ml /min), and trapped in a solution of Pd2(dba)3 and (o-tol)3P in
DMSO (Scheme 2).
O
SnMe3
11
O
CH3
N
N
H
Boc
N
N
(4)
(5d)
11
(a) CuCl, Pd dba , CH I, (O-tol) P), DMSO
2
3
3
3
(b) TFA
Scheme 2.
The stannyl compound 4 and copper(I) chloride were then transferred
to the reaction vessel. The resulting mixture was heated at 808C for
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 423–434

SYNTHESIS OF 3-[(2S)-AZETIDIN
427
5 min, followed by deprotection. The specific radioactivity of compound
5d (using free base 5b) was on order of 5.19 ꢁ 0.56 GBq/mmol using
2.0 ꢁ 0.41 mAh proton bombardment (number of runs=4). The
determined specific radioactivity (based on a single experiment) using
higher beam (36 mAh) was in the range of 50 GBq/mmol. The low specific
radioactivity in the former case was due to the low specific radioactivity
of [11C]iodomethane produced. The decay corrected radiochemical yield
was 39% calculated from the amount of [11C] iodomethane and the
radiochemical purity determined by analytical LC was >97%. The total
synthesis time (including formulation in biological buffer) was less than
50 min from the end of radionuclide production. The identity of 5d was
determined by analytical LC, after addition of authentic reference
compound, and by LC–MS analysis.
According to the previous report22 solid-phase extraction (SPE) was
necessary before injection on a semi-preparative LC. The reported
synthetic method for the Stille coupling is more easily automated than
previous described method.22
Experimental
General
[11C]Carbon dioxide was produced at the Uppsala University PET
Centre via the 14N(p,a)11C reaction in a gas target containing nitrogen
(AGA, Nitrogen 6.0) and 0.1% oxygen (AGA. Oxygen 4.8), bombarded
with 17 MeV protons produced from the Scanditronix MC-17 cyclotron.
[11C]Carbon dioxide was converted in two steps into [11C]iodomethane
via reduction with lithium aluminium hydride followed by treatment
with hydroiodic acid.27 Liquid chromatographic analysis (LC) was
performed with a Beckman 126 gradient pump and a Beckman 166
variable wavelength UV-detector (Fullerton, CA, USA) in series with a
b+-flow detector.28 The following mobile phases were used: acetonitrile/
water (50:7) (A), 0.01 M trifluoroacetic acid (B). For analytical LC, a
Jones chromatography genesis C18, 4 mm, 250 mm ꢂ 4.6 mm ID column
was used at a flow of 1.5 ml/min. For semi-preparative LC, a Jones
chromatography genesis C18, 4 mm, 250 mm ꢂ 10 mm (i.d.), was used at a
flow of 5 ml/min. Synthia, an automated synthesis system,29 was used for
LC injection and fraction collection. Data collection and LC control
were performed with the use of a Beckman system gold chromatography
software package (USA). Radioactivity was measured in an ion chamber
Copyright # 2002 John Wiley & Sons, Ltd.
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F. KARIMI AND B. LANGSTROM
428
(Veenstra Instrumenten bv, VDC-202, Holland). For coarse estimations
of radioactivity during synthesis a portable dose-rate metre was used
(
.
(Langenas eltekniska AB, Sweden).
In the analysis of the 11C-labelled compound, reference substance was
used for comparison in all the LC runs. Identities of synthesized
1
materials were determined using both H NMR, 13C NMR, LC–MS
and GC–MS. NMR spectra were recorded on a Varian XL 300
(300 MHz) with tetramethylsilane, chloroform-d1 or acetone-d6 as
internal standards. LC–MS was performed using a Micromass VG
Quattro with electrospray ionisation. A Beckman 126 pump, a CMA
240 autosampler and a Beckman Ultrasphere ODS C18 column (5 mm,
100 mm ꢂ 4.6 mm i.d.) were used. Mass spectra were recorded
on Finnigan GCQ mass spectrometer coupled to Finnigan Q-GC using
electron impact. THF (tetrahydrofuran) was distilled under nitrogen
from sodium/benzophenone. Pyridine was purified by distillation over
calcium hydride. All chemicals were purchased from Aldrich (Sweden).
tert-Butyl (2S)-2-(hydroxymethyl)azetidine-1-carboxylate (1)
To an ice-cooled solution of (S)-2-azetidinecarboxylic acid (1.00 g,
9.9 mmol) in anhydrous THF (12 ml), borane/THF complex (1 M,
25 ml, 2.5 equiv.) was added at 08C under argon. The mixture was
refluxed for 75 min then was cooled and quenched by addition of
aqueous solution of potassium hydrogen sulphate (10%, 10 ml) and
refluxed for additional 15 min. The volatiles were removed under
reduced pressure. To the cooled reaction mixture NaOH(aq) (1 M,
20 ml), 1,4-dioxane (15 ml), water (20 ml) and di-tert-butyl dicarbonate
(2.38 g, 10.8 mmol) were added. The mixture was stirred in an ice-bath
for 30 min then at room temperature for additional 3 h. The reaction
mixture was then poured into ice-cooled saturated solution of sodium
bicarbonate at 08C. The organic layer was separated and the aqueous
layer was extracted with ethyl acetate (3 ml ꢂ 100 ml), dried (MgSO4)
and concentrated in vacuo, yielding pure 1 (1.83 g, 99%) as a colourless
oil. 1H NMR (CDCl3): d 4.44 (1H, m), 3.81 (4H, m), 2.17 (1H, m), 1.93
(1H, m), 1.46 (9H, s). 13C NMR (CDCl3): d 157.1, 80.3, 66.6, 63.6, 46.6,
28.3, 17.9. MS: m=z=188, 156.
5-chloropyridin-3-yl 4-methylbenzenesulfonate (2a)
Under an argon atmosphere, p-toluenesulphfonyl chloride (1.94 g,
10.16 mmol) was added to a solution of 5-chloro-3-hydroxypyridine
Copyright # 2002 John Wiley & Sons, Ltd.
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SYNTHESIS OF 3-[(2S)-AZETIDIN
429
(1.01 g, 7.79 mmol) in anhydrous pyridine (20 ml) at room temperature.
The resulting mixture was refluxed for 5 h. The volatiles parts were
removed in vacuo and the residue was partitioned between saturated
sodium bicarbonate and dichloromethane. The aqueous layer was
extracted with dichloromethane (3 ml ꢂ 70 ml) and washed with water
(2 ml ꢂ 50 ml). The combined organic phases were dried (MgSO4) and
evaporated under reduced pressure. The crude product was purified on
flash silica gel column chromatography. Elution with ethyl acetate/
1
pentane (20:80) yielded (2.16 g, 98%) colourless oil that solidified. H
NMR (CDCl3): d 8.47 (1H, d), 8.03 (1H, d), 7.72 (2H, d), 7.51 (1H, dd),
7.35 (2H, d), 2.45 (3H, s). 13C NMR (CDCl3): d 147.3, 141.7, 130.3,
130.2, 128.5, 21.8. MS: m=z=283, 155.
5-bromopyridin-3-yl 4-methylbenzenesulphfonate (2b)
The synthesis was performed as described for 2a except that 5-bromo-3-
hydroxypyridine was used. The reaction mixture was refluxed for 16 h.
The purified compound 2b was obtained (75%) as a colourless solid. 1H
NMR (CDCl3): d 8.55 (1H, d), 8.05 (1H, d), 7.70 (3H, m), 7.35 (2H, d),
2.45 (3H, s). 13C NMR (CDCl3): d 149.4, 142.0, 133.1, 130.1, 128.5,
21.8. MS: m=z=327, 155.
5-methylpyridin-3-yl 4-methylbenzenesulphfonate (2c)
To a DMF solution (3 ml) of 2b (300 mg, 914.2 mmol) was added
tetramethyltin (196.2 mg, 1.10 mmol) and tetrakis(triphenylphosphine)-
palladium(0) (15 mg, 13.0 mmol). The reaction mixture was heated for
17 h at 1008C. The reaction mixture was then poured into brine (100 ml)
and extracted with dichloromethane (3 ml ꢂ 50 ml). Rotary evaporation
followed by silica gel chromatography using ethyl acetate gave (239 mg,
99%) of 2c as a colourless solid. 1H NMR (CDCl3): d 8.32 (1H, br), 7.90
(1H, br), 7.68 (2H, dd), 7.31 (3H, dd), 2.45 (3H, s), 2.35 (3H, s). 13C
NMR (CDCl3): d 148.7, 145.9, 140.7, 129.9, 128.4, 21.7, 18.1. MS:
m=z=263, 155. LC–MS (ESI+), solvent (A–B), m=z 263 [M+H]+.
tert-Butyl (2S)-2-{[(5-chloropyridin-3-yl)oxy]methyl}azetidine-1-
carboxylate (3a)
Method A: A solution of Boc-protected azetidinemethanol 1 (91 mg,
486 mmol), anhydrous potassium hydroxide (58 mg, 1.03 mmol) in
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F. KARIMI AND B. LANGSTROM
430
anhydrous DMF (6 ml) was heated at 808C for 10 min under argon. To
this 2a (157.8 mg, 556 mmol) dissolved in anhydrous DMF (6 ml) was
added and the mixture was stirred for 24 h at 808C. The reaction
mixture was diluted with water and extracted with ethyl acetate
(3 ml ꢂ 50 ml). The combined organic extracts were dried (MgSO4) and
evaporated under reduced pressure. The resulting crude product was
purified by flash chromatography. Elution with ethyl acetate/pentane
1
(1:1) gave (100 mg, 69%) of the title compound. H NMR (CDCl3): d
8.25 (1H, d), 8.20 (1H, d), 7.28 (1H, dd), 4.52 (1H, m), 4.34 (1H, m),
4.13 (1H, m), 3.89 (2H, m), 2.32 (2H, m), 1.43 (9H, s). 13C NMR
(CDCl3): d 140.9, 136.2, 121.4, 79.9, 68.9, 59.9, 28.4, 18.9. MS:
m=z=298, 225.
Method B: A solution of Boc-protected azetidinemethanol 1 (100 mg,
534 mmol), 3,5-dichloropyridine (176 mg, 1.19 mmol) and tetra-buty-
lammonium bisulphate (181 mg, 534 mmol) in 50% aqueous sodium
hydroxide (6 ml) and THF (6 ml) was heated at 80 ꢁ 58C for 11 h. The
volatile fraction was removed under reduced pressure. The residue was
diluted by water (30 ml) and extracted with ethyl acetate (3 ml ꢂ 70 ml).
The pooled organic phases were washed with water, dried (MgSO4) and
evaporated in vacuo. The crude product was purified by flash
chromatography. Elution with ethyl acetate/pentane (1:1) yielded
(78 mg, 49%) of the desired pyridine derivative.
tert-Butyl (2S)-2-{[(5-bromopyridin-3-yl)oxy]methyl}azetidine-1-
carboxylate (3b)
The synthesis was performed as described for 3a (method A) except that
2b was used instead of 2a. The title compound was obtained (73%) as
1
colourless oil. H NMR (CDCl3): d 8.28 (2H, m), 7.42 (1H, dd), 4.51
(1H, m), 4.33 (1H, m), 4.13 (1H, m), 3.89 (2H, m), 2.32 (2H, m), 1.43
(9H, s). 13C NMR (CDCl3): d 156.1, 143.1, 136.6, 124.1, 79.8, 69.4, 59.9,
28.4, 18.9. MS: m=z=343, 270.
tert-Butyl (2S)-2-({[5-(trimethylstannyl)pyridin-3-yl]oxy}methyl)
azetidine-1-carboxylate (4)
Method A: A diluted solution of methyllithium (1.4 M in ether, 21.1 ml,
3 eqv., in ether 50 ml) was added dropwise to a stirred suspension of
anhydrous stannous chloride (1.87 g, 9.88 mmol) in 20 ml of ether at
Copyright # 2002 John Wiley & Sons, Ltd.
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SYNTHESIS OF 3-[(2S)-AZETIDIN
431
ꢀ108C. The reaction mixture was transferred by cannula to a solution
of 3a (0.59 g, 1.98 mmol) in anhydrous DME (ethylene glycol dimethyl
ether) (10 ml) and stirred at room temperature for 3 h. The solvent was
removed in vacuo and the residue extracted with ether (4 ml ꢂ 10 ml).
The ether was evaporated and the crude material was purified by flash
chromatography (pentane- ethyl acetate, 1:1) to give 4 (0.41 g, 49%) as a
colourless oil. 1H NMR (CDCl3): d 8.23 (2H, m), 7.33 (1H, d), 4.52 (1H,
m), 4.33 (1H, m), 4.15 (1H, m), 3.91 (2H, m), 2.32 (2H, m), 1.42 (9H, s),
0.34 (9H, m). 13C NMR(CDCl3): d 147.8, 137.6, 129.0, 79.7, 68.6, 60.1,
28.4, 19.1, ꢀ9.5. MS: m=z=428, 355. LC–MS (ESI+), solvent (A–B),
m=z 428 [M+H]+.
Method B: Hexamethylditin (190.8 mg, 582.6 mmol) and tetrakis(tri-
phenylphosphine)-palladium(0) (9 mg, 7.8 mmol) were added to a
solution of 3b (100 mg, 291.3 mmol) in degassed toluene (3 ml). The
reaction was heated for 12 h at 908C under argon atmosphere and the
solvent was evaporated under reduced pressure. The residue was
extracted with ether and purified as described in method A, to give 4
(47%).
tert-Butyl (2S)-2-{[(5-methylpyridin-3-yl)oxy]methyl}azetidine-1-
carboxylate (5a)
Method A: A solution of tris(dibenzylideneacetone)palladium(0)
(131 mg, 144 mmol), tri-o-tolylphosphine (176 mg, 577 mmol), anhydrous
potassium carbonate (78.7 mg, 577 mmol) and copper(I) chloride
(57.7 mg, 577 mmol)) in anhydrous DMF (2 ml) was stirred at room
temperature for 30 min under argon atmosphere. To this mixture was
added a solution of stannyl compound 4a (90 mg, 211 mmol) in
anhydrous DMF (2 ml) followed by methyl iodide (60 mg, 423 mmol).
This was heated at 608C for 1 h then poured into brine (30 ml) and
extracted with ethyl acetate (3 ml ꢂ 30 ml). The pooled extracts were
dried (MgSO4) and concentrated to give compound 5a (50 mg, 85%). 1H
NMR (CDCl3): d 8.18 (1H, d), 8.06 (1H, s), 7.04 (1H, s), 4.51 (1H, m),
4.31 (1H, m), 4.14 (1H, m), 3.90 (2H, t), 2.30 (5H, m), 1.42 (9H, s). 13C
NMR(CDCl3): d 156.1, 142.6, 122.1, 79.7, 68.5, 63.6, 60.1, 28.3, 19.0,
18.0. MS: m=z=278, 205.
Method B. The synthesis was performed as described for 3a (method
A) except that 2c was used instead of 2a. The title compound was
obtained (66%) as oil.
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F. KARIMI AND B. LANGSTROM
432
3-[(2s)-azetidin-2-ylmethoxy]-5-methylpyridine, salt with
trifluoroactetic acid (5b)
To a mixture of 5a (17 mg, 61.1 mmol) in anhydrous dichloromethane
(0.4 ml) at 08C TFA (1 ml) was added. After stirring for 2 h at room
temperature the volatile fraction was removed under reduced pressure.
The crude product was purified by semi-preparative LC, solvent A–B
(2%:98%) isocratic at 2% for 3 min, linear gradient to 50%:50% during
10 min then ramped up to 90%:10% over 2 min, flow 5 ml/min,
tR ¼ 10:4 min. The collected fractions were repeatedly evaporated with
HPLC-grade acetone for azeotropical removal of water to yield the title
compound 5b (16.5 mg, 92%).
1H NMR (Acetone-d6): d 8.50 (1H, br), 8.40 (1H, br), 7.97 (1H, s),
5.78 (1H, m), 5.08 (1H, m), 4.85 (3H, m), 2.95 (1H, m), 2.65 (2H, m), 2.5
(3H, s). 13C NMR(Acetone-d6): d 138.1, 130.1, 129.6, 70.1, 96.1, 56.7,
18.6. LC–MS (ESI+), solvent (A–B) m=z 179 [M+H]+. The salt 5b was
treated with aqueous NaOH (3M) and extracted with CH2Cl2. The
solvent was evaporated under reduced pressure to give the free base of
5b which was later used for determination of specific radioactivity.
3-[(2s)-azetidin-2-ylmethoxy]-5-[11C]-methylpyridine (5d)
A solution containing Pd2(dba)3 (1.1 mg, 1.2 mmol) and (o-Tol)3P
(6.7 mg, 22.2 mmol) in DMSO (350 ml) that was kept at room
temperature for 10 min was filtered (ThermoHypersil F2513-3, PTFE
syringe filter 0.45 mm) before use. [11C]Iodomethane was trapped in the
resulting yellowish solution (300 ml) and heated at 808C for 2 min. To
this was added a solution of the tin compound 4 (1 mg, 2.3 mmol) and
CuCl (1.0 mg, 10 mmol) in DMSO (50 ml). The reaction mixture was
vigorously shaken before heating at 808C for 5 min. TFA (0.45 ml) was
then added followed by heating at 808C for 7 min. The reaction mixture
was diluted by water (0.15 ml) and then separated on a semi-preparative
LC column, as described for 5b. The product was collected after
10.4 min. The organic solvent was evaporated and the residue was
dissolved in sterile phosphate buffer (pH=7.5, 5 ml). Sterile filtration of
the final product solution through a filter (Dynagard ME, 0.22 mm pore
size) into a sterile vial was performed. Radiochemical purity (>97%)
was determined by analytical LC. Analytical LC, same method as semi-
preparative LC, flow 1.5 ml/min, wavelength 254 nm, tR ¼ 5:3 min. LC–
MS (ESI+), solvent (A–B), m=z 179 [M+H]+.
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 423–434

SYNTHESIS OF 3-[(2S)-AZETIDIN
433
Acknowledgements
We thank Dr. Robert Moulder for checking the language. The Swedish
Nature Research Council is acknowledged for its support through
Grant No. K3464 (B.L.).
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