Synthesis of [1-11C]ethyl iodide from [11C]carbon monoxide and its application in alkylation reactions

Article abstract of DOI:10.1002/jlcr.855

A method is presented for preparing [1-¹¹C]ethyl iodide from [¹¹C]carbon monoxide. The method utilizes methyl iodide and [ ¹¹C]carbon monoxide in a palladium-mediated carbonylation reaction to form a mixture of [1-¹¹C]acetic acid and [1-¹¹C]methyl acetate. The acetates are reduced to [1-¹¹C]ethanol and subsequently converted to [1-¹¹C]ethyl iodide. The synthesis time was 20 min and the decay-corrected radio-chemical yield of [1-¹¹C]ethyl iodide was 55 ± 5%. The position of the label was confirmed by ¹³C- labelling and ¹³C-NMR analysis. [1-¹¹C]Ethyl iodide was used in two model reactions, an O-alkylation and an N-alkylation. Starting with approximately 2.5 GBq of [¹¹C]carbon monoxide, the isolated decay-corrected radiochemical yields for the ester and the amine derivatives were 45 ± 0.5% and 25 ± 2%, respectively, based on [ ¹¹C]carbon monoxide. Starting with 10 GBq of [¹¹C]carbon monoxide, 0.55 GBq of the labelled ester was isolated within 40 min with a specific radioactivity of 36 GBq/μmol. Copyright

Full text of DOI:10.1002/jlcr.855

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2004; 47: 723–731.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.855
Research Article
1
1
11
Synthesis of [1- C]ethyl iodide from [ C]carbon
monoxide and its application in alkylation reactions
1
,2
2
1,2,
Jonas Eriksson , Gunnar Antoni and Bengt L a( ngstr o. m
*
1
Department of Organic Chemistry, Institute of Chemistry, Uppsala University,
P.O. Box 599, S-751 24 Uppsala, Sweden
2
Uppsala Imanet AB, P.O. Box 967, S-751 09, Uppsala, Sweden
Summary
1
1
A method is presented for preparing [1- C]ethyl iodide from [ C]carbon monoxide.
11
1
The method utilizes methyl iodide and [ C]carbon monoxide in a palladium-mediated
1
1
carbonylation reaction to form a mixture of [1- C]acetic acid and [1- C]methyl
1
11
1
acetate. The acetates are reduced to [1- C]ethanol and subsequently converted to
1
1
1
1- C]ethyl iodide. The synthesis time was 20 min and the decay-corrected radio-
[
1
1
chemical yield of [1- C]ethyl iodide was 55 Æ 5%. The position of the label was
confirmed by C-labelling and C-NMR analysis. [1- C]Ethyl iodide was used in
1
3
13
11
two model reactions, an O-alkylation and an N-alkylation. Starting with approxi-
1
mately 2.5 GBq of [ C]carbon monoxide, the isolated decay-corrected radiochemical
1
yields for the ester and the amine derivatives were 45 Æ 0.5% and 25 Æ 2%,
1
1
11
respectively, based on [ C]carbon monoxide. Starting with 10 GBq of [ C]carbon
monoxide, 0.55 GBq of the labelled ester was isolated within 40 min with a specific
radioactivity of 36 GBq/mmol. Copyright # 2004 John Wiley & Sons, Ltd.
1
Key Words: [1- C]ethyl iodide; [ C]carbon monoxide; carbonylation
1
11
Introduction
The use of positron emission tomography (PET) in medical applications and
1
in drug discovery has stimulated the development of new labelling methods
1
1
using C (b+, t1/2=20.3 min). Alkylation on nitrogen, oxygen and sulphur
nucleophiles has been an important synthetic method for the incorporation of
1
1
C into target molecules. [ C]Methyl iodide2À5 and [ C]methyl triflate have
11
11
6
7
À12
proven to be useful alkylating agents. Other labelled organohalides
11
such as
C]ethyl iodide, [ C]propyl iodide and [ C]aryl halides have also been
1
[
1
11
13
1
used in alkylation reactions although not as frequently as [ C]methyl iodide.
1
*
Correspondence to: B. L a( ngstr o. m, Department of Organic Chemistry, Institute of Chemistry, Uppsala
University, P.O. Box 599, S-751 24 Uppsala, Sweden. E-mail: Bengt.Langstrom@Uppsala.Imanet.se
Copyright # 2004 John Wiley & Sons, Ltd.
Received 22 March 2004
Revised 26 April 2004
Accepted 17 May 2004

7
24
J. ERIKSSON ET AL.
1
1- C]Ethyl iodide has previously been prepared from [ C]carbon dioxide
1
11
[
and a methyl Grignard reagent according to Scheme 1.
1
) LiAlH4
O
11
2) HI
1
1
11
CO + CH MgX
CH3 COMgX
CH3 CH2I
2
3
11
11
Scheme 1. Synthesis of [1- C ]ethyl iodide from [ C]carbon dioxide and methyl
Grignard reagent
Isotopic dilution originating from carbon dioxide in the environment is a
potential drawback of the Grignard method. Careful preparation and
handling of the Grignard reagent is required in order to maximize the specific
radioactivity, which is of importance in many PET applications.
11
In recent work, [ C]carbon monoxide has been applied in a variety of
1
4À18
palladium mediated carbonylation reactions
producing products of high
specific radioactivity. The low atmospheric concentration of carbon monoxide
1
1
compared to carbon dioxide makes it advantageous to work with [ C]carbon
monoxide when aiming for high specific radioactivity. Thus, we wanted to
11
11
investigate if [1- C]ethyl iodide could be synthesized from [ C]carbon
monoxide. Acetic acid, a viable intermediate in the synthesis of ethyl iodide, is
produced at industrial scale from methanol and carbon monoxide. This can be
1
9,20
done for example via the Monsanto process
where hydriodic acid and a
À
polycarbonyl rhodium complex [Rh(CO) I ] are used as catalysts. More
2
2
0
appropriate for our purpose was to use Pd -complexes which have been shown
to promote the carbonylation of organohalides with carbon monoxide under
mild conditions and at a low partial CO-pressure Scheme 2. 1À23
2
PPh3
1) LiAlH , THF
4
O
C
O
C
Pd (dba)
2) HI, aq.
2
3
11
11
CH I + CO + H O
11
+
11
CH3 CH2I
3
2
THF
OH
O
11
11
Scheme 2. Synthesis of [1- C ]ethyl iodide from [ C]carbon monoxide
1
1
In this report, a three-step synthesis of [1- C]ethyl iodide is described
together with the labelling of Etomidate and Lidocaine.
Results and discussion
11
The first step of the [1- C]ethyl iodide synthesis, i.e. the carbonylation
reaction, was performed in a stainless steel micro-autoclave using the
24
11
experimental set-up shown in Figure 1. [ C]Carbon dioxide was reduced
1
1
to [ C]carbon monoxide in a Zn-furnace, concentrated to a small volume and
then transferred to a micro-autoclave.
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 723–731

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[
C]ETHYL IODIDE FROM CARBON MONOXIDE
725
Figure 1. Schematic drawing of the experimental setup used in the carbonylation
reactions
A solution of tris(dibenzylideneacetone)dipalladium(0), triphenylphosphine,
methyl iodide and water in tetrahydrofuran was pumped into the micro-
autoclave at a pressure of 6000 psi. The micro-autoclave was then heated and a
1
1
11
mixture of [1- C]acetic acid and [1- C]methyl acetate was obtained. Methyl
acetate was assumed to originate from the alkylation of the acetic acid with
methyl iodide.
0
Pd (dba) was used due to good air stability compared to other Pd -
3
2
complexes and due to the ability to form complexes with PPh that activate
3
methyl iodide via oxidative addition. Six equivalents of PPh -ligands gave
3
better reproducibility than 4 equivalents. Water was added to the carbonyla-
tion reaction to cleave off the acyl group formed by migratory insertion of
1
[
1
C]carbon monoxide into the methyl palladium bond. Lower radiochemical
yield and low reproducibility was the result when no water was added. Hence,
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 723–731

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26
J. ERIKSSON ET AL.
it was preferred to have water present in the reaction. It seems to be beneficial
to have a nucleophile present in the reaction mixture rather than directly
transfer the palladium acyl-complex to the lithium aluminium hydride
solution.
Some experiments were carried out using methanol instead of water in the
carbonylation reaction. This resulted in slightly better yield but also in high
amounts of methyl iodide in the final step of the synthesis. Considering the
obvious competition between different alkyl halides in alkylation reactions
and possible purification problems, it was desired to keep the formation of
methyl iodide at the lowest possible level. Therefore we concluded that water
was preferred rather than methanol as nucleophile in the carbonylation
reaction.
Tetrahydrofuran was selected as the solvent in the carbonylation reaction
since it facilitated good reaction conditions, both for the carbonylation
reaction and the following reduction. Performing the carbonylation reaction at
a lower temperature than 1458C resulted in lower radiochemical purity and
1
1
yield of [1- C]ethyl iodide.
The reaction mixture was transferred from the micro-autoclave to a vial
1
containing lithium aluminium hydride where the [1- C]acetates were reduced
1
1
1
11
11
to [1- C]ethoxide. The conversion of [1- C]ethoxide to [1- C]ethyl iodide
was performed by treatment with hydriodic acid. A closed reaction vial was
11
used due to the volatility of [1- C]ethanol. In order to achieve good
11
11
conversion of [1- C]ethoxide to [1- C]ethyl iodide it was important to
thoroughly remove the tetrahydrofuran from the reaction mixture prior to the
addition of the hydriodic acid. To avoid a sudden increase of pressure, the vial
was cooled down to sub-zero temperature prior to the addition of the acid.
The vial was heated at 1208C for 5 min during the conversion. After the
11
reaction was completed, [1- C]ethyl iodide was transferred in a stream of
nitrogen gas through a phosphorus pentoxide drying-tower to a vial
containing dimethylformamide. The decay-corrected radiochemical yield of
1
1
[
1- C]ethyl iodide trapped in dimethylformamide was 55 Æ 5% calculated
1
1
from [ C]CO.
Of the transferred radioactivity, [1- C]ethyl iodide accounted for 80–90%
11
11
11
and the only by-product was [ C]methyl iodide. [ C]Methyl iodide was
1
1
assumed to be derived from the reduction of [ C]CO and the subsequent
2
iodination. Since an ascarite column efficiently trapped all unreduced CO
2
11
after the Zn-furnace, [ C]CO was assumed to be derived from the oxidation
2
1
of [ C]CO in the micro-autoclave. [ C]CO may be formed from [ C]CO at
1
11
11
2
II
the carbonylation conditions in the presence of Pd via the water-gas shift
2
reaction but also via the heterogeneous reaction with molecular oxygen on
5
26
the stainless steel surface of the micro-autoclave. The total amount of methyl
iodide in the trap vessel typically ranged between 0.5–1.3 mmol. Most of the
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 723–731

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[
C]ETHYL IODIDE FROM CARBON MONOXIDE
727
Table 1.
a
Substrate
Product
Initial
radioactivity
CO (GBq)
Yield
(%)
Product
amount
(nmol)
Specific
radioactivity
(GBq/mmol)
b
1
1
N
N
HO
N
O
N
*
H
H
2.5 Æ 0.5
45 Æ 0.5
31 Æ 6
8.4 Æ 1.2
O
O
7
25
22
15
15
22
36
O
O
1
0
N
H
N
H
N
N
2.2 Æ 0.1
25 Æ 2
H
*
a
Isolated decay-corrected radiochemical yield calculated from the initial amount of radioactivity used in the
1- C]ethyl iodide synthesis. When the reaction mixture was transferred from the micro-autoclave to the
11
[
evacuated 2 ml vial containing lithium aluminium hydride, the radioactivity in the vial was measured. The
radioactive residues left in the micro-autoclave were estimated to be less than 1%. Hence, the amount of
initial radioactivity, e.g. CO, could be determined.
11
b
The radioactivity of the isolated product measured 40 min after start of carbonylation reaction.
unlabelled methyl iodide was probably derived from methoxide contained in
the lithium aluminium hydride solution.
The labelled ethyl iodide was used in two model alkylation reactions, the
11
11
synthesis of (R)-[O-ethyl-1- C]Etomidate and [N-ethyl-1- C]Lidocaine. The
radiochemical yield and the specific radioactivity of the labelled compounds
are presented in Table 1. The alkylation reactions were performed according to
7,8
previously published methods. The ethylated products were separated from
the methylated by-products without difficulties using semi-preparative HPLC.
The isolated decay-corrected radiochemical yields of the ethylated products
1
1
were calculated from the initial amount of radioactivity, e.g. CO, and the
radioactivity of the semi-preparative LC purified products. The specific
1
1
radioactivity of the isolated (R)-[O-ethyl-1- C]Etomidate was determined
from concentration measurements by HPLC. The standard curve was
prepared using an unlabelled reference compound.
Conclusion
1
1- C]Ethyl iodide was produced from [ C]CO using a method which is
1
11
[
1
feasible for automation. The radiochemical yield of [1- C]ethyl iodide was
1
11
5
5 Æ 5%. Purified (R)-[O-ethyl-1- C]Etomidate was obtained within 40 min
with a decay-corrected radiochemical yield of 45% from 2.5 GBq of CO.
1
1
11
11
When starting with 10 GBq of [ C]CO, purified (R)-[O-ethyl-1- C]Etomidate
was obtained in 40 min with a specific radioactivity of 36 GBq/mmol. [N-ethyl-
1
1
1
- C]Lidocaine was synthesized with 25% isolated decay-corrected
radiochemical yield. The comparison with data published for (R)-[O-ethyl-
1
1
8
1
- C]Etomidate synthesized with the Grignard method (6.4 GBq/mmol)
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 723–731

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J. ERIKSSON ET AL.
suggests that the new method give products with improved specific radio-
activity. Work is in progress to expand this labelling methodology to include
higher organoiodides.
Experimental
General
1
1
14
11
C was prepared by the N(p,a) C nuclear reaction using 17 MeV protons
produced by a Scanditronix MC-17 Cyclotron at Uppsala Imanet AB. A
target filled with nitrogen (AGA nitrogen 6.0) containing 0.05% oxygen (AGA
11
oxygen 4.8) was used to produce the [ C]CO . The carbonylation reactions
2
2
4
were carried out using an experimental set-up described in detail elsewhere.
1
1
11
C]CO was reduced to [ C]CO by passage through a zinc furnace at 4008C,
containing Merck zinc granules 14–50 mesh. Alltech silica gel 100/120 was
11
used to trap and concentrate [ C]CO and [ C]CO. Tetrahydrofuran (THF)
[
2
11
2
was freshly distilled over sodium and benzophenone in a nitrogen atmosphere
before use. The palladium complex was generated in situ from tris(dibenzy-
lideneacetone)dipalladium and triphenylphosphine. All chemicals were pur-
1
3
chased from Aldrich and used as received. The C-NMR spectra were
recorded using a Varian 400 MHz spectrometer. Analytical LC was performed
on a Beckman system, equipped with a Beckman 126 pump, a Beckman 168
+
UV detector in series with a Bioscan b -flow count detector and a Waters
Spherisorb S5 ODS1 column (250 Â 4.6 mm). A Gilson 231 was used as auto
injector. Semi-preparative LC was performed on a similar Beckman system
equipped with a Genesis C18 120 4 m column (250 Â 10 mm). Mobile phase:
A1) 0.05M ammonium formate pH 4.5; A2) 0.02M potassium dihydrogen
phosphate pH 9.0; B1) acetonitrile; B2) acetonitrile/water 50/7; B3) methanol.
1
1- C]Ethyliodide. Tris(dibenzylideneacetone)dipalladium(0) (0.80 mg, 0.87
1
[
mmol) and triphenylphosphine (2.7 mg, 10.3 mmol, 12 equivalent) were placed
in a 0.8 ml vial equipped with a rubber septum. THF (360 ml) was added and
the resulting solution was degassed with argon. Methyl iodide (1.2 ml, 19 mmol,
2
2 equivalent) and nanopure water (1.0 ml) was added. The solution was
loaded into an injection valve loop and pumped into a 200 ml stainless steel
11
micro-autoclave containing [ C]CO. The micro-autoclave was heated for
min at 1458C. The reaction mixture was transferred to a 2 ml septum-
equipped evacuated glass vial containing lithium aluminium hydride (100 ml,
M). The vial was heated at 1208C for 2–3 min during the removal of THF
5
1
under a stream of nitrogen gas. Then the vial was cooled down to sub-zero
temperature. Hydriodic acid (1.0 ml, 57 wt% in water) was added and the vial
was heated for 5 min at 1208C. The vial was removed from the heating and
11
while it was still warm [1- C]ethyl iodide was transferred in a stream of
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 723–731

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[
C]ETHYL IODIDE FROM CARBON MONOXIDE
729
nitrogen (20 ml/min) through a drying tower (phosphorus pentoxide desiccant)
to a trapping vessel. Analytical LC was used to assess the identity and
À1
radiochemical purity. Mobile phase A1:B1 (50:50). Flow 1.0 ml min . R.t.
1
1
8
.7 min. Radiochemical yield of [1- C]ethyl iodide was 55 Æ 5% with a
11
radiochemical purity of 85 Æ 5%. [ C]Methyl iodide was the only radio-
chemical by-product. R.t. 6.7 min.
1
3
1- C)Ethyliodide. Tris(dibenzylideneacetone)dipalladium(0) (0.80 mg, 0.87
(
mmol) and triphenylphosphine (2.7 mg, 10.3 mmol, 12 equivalent) were placed
in a 0.8 ml vial equipped with a rubber septum. THF (360 ml) was added and
the resulting solution was degassed with argon. Methyl iodide (2.5 ml, 40 mmol,
2
2 equivalent) and nanopure water (1.0 ml) were added. The resulting solution
was loaded into an injection valve loop. A second injection valve loop was
1
3
filled with ( C)CO (1 ml, 1 atm., 40 mmol). The reagents were pumped with
1
1
THF into a 200 ml stainless steel micro-autoclave containing [ C]CO. The
micro-autoclave was heated for 15 min at 1408C. The reaction mixture was
transferred to a 5 ml septum-equipped evacuated glass vial containing lithium
aluminium hydride (150 ml, 1M). The vial was heated at 1208C for 2–3 min
during the removal of THF under a stream of nitrogen. Then the vial was
cooled to sub-zero temperature. Hydriodic acid (1.0 ml, 57 wt% in water) was
added and the vial was heated for 10 min at 1208C. The vial was removed from
the heating and while it was still warm the labelled ethyl iodide was transferred
in a stream of nitrogen (20 ml/min) through a drying tower (phosphorus
1
3
pentoxide desiccant) and trapped in chloroform-d (0.8 ml) at –408C. C-NMR
was used to assess the position of the C-labelling. (1- C)Ethyl iodide C-
13
13
13
1
3
13
NMR MHz (CDCl ) d: À0.79; ( C)Methyl iodide C-NMR MHz (CDCl3)
3
d: À23.3.
1
1
(
R)-[O-ethyl-1- C]Etomidate. In a 0.8 ml glass vial equipped with a rubber
septum, (R)-3-(1-phenyl-ethyl)-3H-imidazole-4-carboxylic acid (1.2 mg,
.5 mmol) was dissolved in dichloromethane (200 ml) at room temperature.
5
Tetrabutylammonium hydroxide in methanol (4.8 ml, 1M, 4.8 mmol) was
added. The vial was gently heated and the solvent was thoroughly removed
under a stream of nitrogen gas. Dimethylformamide (300 ml) was added.
1
1
[
1- C]Ethyl iodide, prepared as described above, was transferred in a flow of
nitrogen gas (20 ml/min) to the glass vial and bubbled through the solution.
The vial was heated for 5 min at 1208C. The reaction mixture was injected onto
a semi-preparative HPLC column and (R)-[O-ethyl-1- C]Etomidate was
1
1
À1
isolated. Mobile phase A1:B2 (52:48). Flow 4 ml min . R.t 12.1 –13.5 min.
Analytical LC was used to assess the identity and radiochemical purity.
À1
Mobile phase A1:B2 (45:55). Flow 1.5 ml min . R.t. 8.4 min. Radiochemical
purity >99%.
Copyright # 2004 John Wiley & Sons, Ltd.
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7
30
N-ethyl-1- C]Lidocaine. In a 0.8 ml glass vial equipped with a rubber
septum, des-ethyl Lidocaine (ethylaminoacet-2,6-xylidide) (2.2 mg, 11 mmol)
J. ERIKSSON ET AL.
1
1
[
1
1
was dissolved in 300 ml dimethylformamide. [1- C]Ethyl iodide prepared as
described above was transferred in a flow of nitrogen gas (20 ml/min) to the
glass vial and bubbled through the des-ethyl Lidocaine solution. The vial was
heated at 1308C for 5 min.The reaction mixture was injected onto a semi-
11
preparative HPLC column and [N-ethyl-1- C]Lidocaine was isolated. Mobile
À1
phase: A2:B3 (30:70). Flow 4 ml min . R.t 10.3 – 11.9 min. Analytical LC was
used to assess the identity and radiochemical purity. Mobile phase: A1:B3
À1
(45:55). Flow 1.0 ml min . R.t 10.2 min. Radiochemical purity >99%.
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