Synthesis of 11C labelled methyl esters: transesterification of enol esters versus BF3 catalysed esterification—a comparative study

ARTICLE IN PRESS

Radiation Physics and Chemistry 75 (2006) 48–52 www.elsevier.com/locate/radphyschem

Synthesis of 11C labelled methyl esters: transesterification of enol esters versus BF3 catalysed esterification—a comparative study Uwe Ackermanna,, Paul Blancb, Cheryl L. Falzonb, William Issab, Jonathan Whiteb, Henri J. Tochon-Danguya, John I. Sachinidisa, Andrew M. Scotta a

Centre for PET, Austin Health, Austin Campus, Studley Road, Heidelberg, VIC 3084, Australia b Department of Chemistry, The University of Melbourne, Parkville, VIC 3010, Australia Received 14 April 2005; accepted 16 May 2005

Abstract C-11 labelled methyl esters have been synthesized via the transesterification of enol esters in the presence of C-11 methanol and 1,3 dichlorodibutylstannoxane as catalyst. This method leaves functional groups intact and allows access to a wider variety of C-11 labelled methyl esters compared to the BF3 catalysed ester formation, which uses carboxylic acids and C-11 methanol as starting materials. r 2005 Elsevier Ltd. All rights reserved. Keywords: Radiolabelling; Carbon-11; Methyl esters

1. Introduction The radiolabelling of carboxylic acids via a nucleophilic substitution mechanism using [11C]methyl iodide or [11C]methyl triflate usually requires the use of protecting groups in order to prevent labelling at multiple sites of the precursor molecule. The removal of protecting groups after the labelling step is a time consuming process, thus reducing the specific activity of the final product. We (Ackermann et al., 2004) have recently reported on the use of BF3 etherate as both solvent and catalyst for the esterification of carboxylic Corresponding author. Tel.: +61 3 9496 5790; fax: +61 3 9496 5892. E-mail address: [email protected] (U. Ackermann).

acids with [11C]CH3OH as a direct way of producing C-11 labelled esters (Fig. 1). Our study has shown that this strategy is an attractive alternative to the use of [11C]methyl iodide or [11C]methyl triflate but, due to the high temperatures necessary to promote this reaction, some functional groups such as methyl ethers are cleaved under the reaction conditions. Specifically, o-anisic acid (3) does not yield the desired [11C] 2-methoxy methyl benzoate (4) but forms exclusively [11C]methyl salicylate (5) (Fig. 2). In conventional chemistry, the transesterification of ethoxy vinyl esters with alcohols in the presence of either acid (Rothman et al., 1972) or catalysts such as SmI2 (Ishii et al., 1996) or various distannoxanes (Orita et al., 1999) is a commonly employed strategy for the preparation of esters (Fig. 3).

0969-806X/$ - see front matter r 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.radphyschem.2005.05.019

ARTICLE IN PRESS U. Ackermann et al. / Radiation Physics and Chemistry 75 (2006) 48–52

O

O

BF3·OEt2

11 OH [ C]MeOH

O11CH3

1

2

49

In this publication, we report our findings and compare the results of this novel labelling strategy to the BF3 etherate catalysed formation of C-11 labelled methyl esters.

Fig. 1. BF3 etherate catalysed esterification of benzoic acid.

2. Experimental OMe

2.1. General methods

O OMe O

4

BF3·OEt 11CH

OH

O11CH3 OH

3OH

O

3

O11CH3 5 Fig. 2. Reaction of o-anisic acid under the conditions of BF3 etherate catalysis.

O catalyst

O

ROH

OR

O

+

O OEt

O

6 Fig. 3. Transesterification of ethoxy vinyl benzoate.

OH

O 6

O

Except for LiAlH4, all chemicals and solvents were purchased from Sigma-Aldrich and used without further purification. LiAlH4 (1 M in THF) was obtained in 1 mL vials from ABX advanced biochemical compounds. For column chromatography, silica gel 60 (230–400 mesh) from Merck KGaA was used. [11C]CO2 was produced by the 14N(p,a)11C nuclear reaction using a target gas that consisted of 98.03% nitrogen and 1.97% oxygen. A 10 MeV proton beam was generated using the IBA Cyclone 10/5 cyclotron at the Austin & Repatriation Medical Centre. Typical irradiation parameters were 25 mA for 20 min, which produced 7.0–8.1 GBq (260–300 mCi) of [11C]CO2. The labelling procedure including semi-preparative HPLC purification was carried out using an in-house built automated system. Semi-preparative HPLC was performed using a Shimadzu LC-10AS isocratic pump equipped with a 1 mL injection loop, a reversed phase column (Exsil C-18, 250 mm, ID 10 mm), a Shimadzu SPD-6AV UV detector (254 nm) and a Geiger–Mu¨ller tube as radiodetector.

O

O

2.2. Enol ester synthesis

H2N OEt

7

O

OMe O 9 Fig. 4. Enol [11C]CH3OH.

O esters

OEt

8

O

OEt

O

OEt

N

tested

for

O 10

OEt

transesterification

with

This reaction is irreversible due to the formation of ethyl acetate, it leaves functional groups intact (Kabouche et al., 1991) and is therefore a mild and efficient method of ester formation. Despite this, the scope of this reaction has never been investigated in PET radiochemistry. We have prepared a series of 5 aromatic ethoxy vinyl esters bearing various functional groups (Fig. 4) and investigated the transesterification of these compounds using [11C]CH3OH and dibutyl distannoxane (Okawara and Wada, 1963) as catalyst.

2.2.1. General procedure for the synthesis of enol esters To a stirred solution of ethoxyacetylene (40% in hexane, 1.125 mL, 4.5 mmol) and RuCl2 p-cymene dimer (10 mg, 0.015 mmol) in anhydrous toluene (20 mL) at 0 1C was added dropwise the desired carboxylic acid (3.0 mmol) in dry toluene (22 mL), also at 0 1C. The solution was stirred under nitrogen overnight and the brown residue was then separated on a column of silica gel (hexane/ethyl acetate, 9:1), affording the desired enol ester. (1-Ethoxy vinyl) benzoate (3): This compound was obtained in 17.3% yield as a dark brown oil. 1 H NMR (CDCl3): d: 1.37 (t, 3 H, 6.9 Hz), 3.88 (d, 1H, 3.6 Hz), 3.95 (q, 2H, 6.9 Hz), 3.96 (d, 1H, 3.6 Hz), 7.4–7.55 (m, 2H), 7.55–7.65 (m, 1H), 8.05–8.15 (m, 2H). MS: M+1: 192.9, M–(C4H7O): 121.9, M–(C4H7O2): 104.8, M–(C5H8O3): 76.8. (1-Ethoxy vinyl) 2-methoxy benzoate (9): Compound 9 was obtained in 33.6% yield as an orange brown oil. 1 H NMR (CDCl3): d: 1.38 (t, 3H, 6.0 Hz), 3.85 (d, 1H, 3.3 Hz), 3.92 (s, 3H), 3.93 (d, 1H, 3.3 Hz), 3.94

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(q, 2H, 6.0 Hz), 6.95–7.05 (m, 2H), 7.52 (dd, 1H, 7.5, 7.5 Hz), 7.94 (dd, 1H, 6.0, 6.0 Hz). HRMS: Accurate mass (ESI): calc (M+Na) 245.0790. Found 245.0787. (1-Ethoxy vinyl) nicotinate (10): This compound was obtained in 15.5% yield as yellow crystals and showed spectroscopic properties, which were identical to those reported by Akai et al. (2002). 1 H NMR (CDCl3): d: 1.37 (t, 3H, 7.0 Hz), 3.90 (d, 1H, 3.6 Hz), 3.95 (q, 2H, 10.0 Hz), 3.99 (d, 1H, 3.6 Hz), 7.43 (m, 1H), 8.36 (d, 1H, 8.1 Hz), 8.83 (m, 1H), 9.30 (m, 1H). MS: M+1: 194.0, M–(C4H7O): 123.8, M–(C4H7O2): 105.8. (1-Ethoxy vinyl) salicylate (8): This compound was obtained in 50.3% yield. HRMS: Accurate mass (ESI): calc (M+Na) 231.0633. Found 231.0630. (1-Ethoxy vinyl) 4-amino benzoate (7): Enol ester 7 was obtained in 28.5% yield. HRMS: Accurate mass (ESI): calc (M+H) 208.0974. Found 208.0971.

Standard procedure for the formation of [11C]CH3OH : CO2 was trapped in 150 ml of a 1 M solution of LiAlH4 in THF and subsequently hydrolysed by phosphoric acid, affording [11C]methanol, which was then distilled into a V-shaped reaction vial for the labelling reaction. Standard procedure for the transesterification of enol esters: The enol ester precursor (10 mg) and the 1,3dichlorotetrabutyldistannoxane (5 mg) were dissolved in DMSO (320 mL) in a V-shaped reaction vial. [11C]methanol was then bubbled through the solution at room temperature. The vial was then sealed and heated at 150 1C for 7 min. The reaction mixture was purified by semi-preparative HPLC using 70:30 water/acetonitrile as mobile phase (flow rate of 4 mL/min). The radioactive peaks corresponding to [11C]methanol and the respective [11C]methyl ester were collected. Radiochemical yields were determined by the ratio of activity measured for the [11C]methyl esters over the unreacted [11C]methanol. 11

3. Results O

O

+

O

3.1. Chemistry

(RuCl2 p-cymene)2 O

OH OEt 6

1 Fig. 5. Synthesis of ethoxy vinyl benzoate.

Following a procedure described by Kita et al. (1993), the enol esters were prepared by reacting the respective carboxylic acids with ethoxyacetylene using (RuCl2 p-cymene)2 as catalyst (Fig. 5).

Table 1 Yields of enol ester formation using the respective carboxylic acid as starting material reagents and conditions: ethoxy acetylene, (RuCl2 p-cymene)2, toluene, RT, 16 h Enol ester

% yield

O

Enol ester

% yield

O

18–22

15–20

H2N O

O OEt

6

OH

50–55

34–40

O

O

O

OEt

O

9 16–25

O

10

OMe

O

8

N

OEt

7

OEt

OEt

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The chemical yields for the enol ester synthesis of the acids tested are given in Table 1. The formation of acid anhydride is an unwanted sidereaction which occurs when the enol ester reacts with residual carboxylic acid (Fig. 6). This was kept to a minimum by slowly adding the carboxylic acid to the solution of ethoxyacetylene. Also, purification on silica gel was performed without removal of the toluene due to the presence of free carboxylic acid in the reaction mixture.

51

able to make a direct comparison to the BF3 etherate method. Decay corrected radiochemical yields are summarized in Table 2. Yields for the BF3 etherate method are given for comparison. Specific activities for all radiolabelling experiments range from 800 to 1200 mCi/mmol at the end of synthesis.

4. Discussion 3.2. Radiochemistry Transesterification (labelling) was carried out DMSO at 150 1C for 7 min in the presence [11C]MeOH and 1,3-dichlorotetrabutyldistannoxane catalyst. These conditions were chosen in order to O

O

O

O O

O + OH OEt 1

6

11

Fig. 6. Formation of benzoic anhydride.

in of as be

The transesterification of enol esters allows access to a greater number of C-11 labelled esters compared with the BF3 etherate method. For example, C-11 labelled methyl 2-methoxybenzoate (4), a compound which cannot be produced from o-anisic acid (3) with the BF3 etherate method, can be synthesized in 4–10% yield using the enol ester pathway. The ease of working with the non-corrosive 1,3-dichlorotetrabutyldistannoxane as catalyst compared to BF3 etherate is another advantage of this method. Using our reaction conditions of 150 1C, the transesterification proceeds smoothly without cleavage of functional group. Except for unreacted [11C]CH3OH and the desired C-11 methyl ester, no other radioactive

Table 2 Yields of C-11 methyl ester formation C-11 labelled ester

O

2

% yielda

% yieldb

25–30

30–33

C-11 labelled ester

O

N

10–15

O H2N O11CH3 13

O11CH3 5 4–10

O O11CH3 4

a

Enol ester pathway. BF3 etherate pathway.

b

5–10

4–6

3–8

20–25

12

5–8

O

OMe

% yieldb

O11CH3

O11CH3

OH

% yielda

0

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U. Ackermann et al. / Radiation Physics and Chemistry 75 (2006) 48–52

products were observed and further optimization of the reaction conditions should increase the labelling yield. As expected, radiochemical yields are significantly lower compared with conventional chemistry, where the methanol would typically be used as both solvent and reactant, thus giving almost complete conversion of the enol ester to the desired methyl ester. The synthesis of the enol ester precursors can be achieved in good to moderate yields following well-established procedures. Most enol esters are stable molecules which can be stored in a freezer for an extended period of time. The selection of different acetylenes as starting materials for the enol ester formation should also be investigated as this could improve transesterification yields or extend the shelf-life of the enol esters.

5. Conclusion We have demonstrated that the transesterification of enol esters is a mild and efficient labelling method for the formation of C-11 methyl esters. The reaction proceeds smoothly and leaves functional groups intact. It requires only one synthesis step compared to conventional methods, thus improving the specific activity of the final product and making automation easier.

References Ackermann, U., Tochon-Danguy, H.J., Scott, A.M., 2004. BF3 etherate catalysed formation of [11C]methyl esters: a novel

radiolabelling technique. J. Labelled Compd. Rad. 47 (8), 523–530. Akai, S., Naka, T., Fujita, T., Takebe, Y., Tsujino, T., Kita, Y., 2002. Efficient lipase-catalyzed enantioselective desymmetrization of Prochiral 2,2-Disubstituted 1,3-Propanediols and Meso 1,2-Diols using 1-Ethoxyvinyl 2-Furoate. J. Org. Chem. 67 (2), 411–419. Ishii, Y., Takeno, M., Kawasaki, Y., Muromachi, A., Nishiyama, Y., Sakaguchi, S., 1996. Acylation of alcohols and amines with vinyl acetates catalyzed by Cp2Sm(thf)2. J. Org. Chem. 61, 3088–3092. Kabouche, Z., Bruneau, C., Dixneuf, P.H., 1991. Enol esters as intermediates for the facile conversion of amino acids into amides and dipeptides. Tetrahedron Lett. 32 (39), 5359–5362. Kita, Y., Maeda, H., Omori, K., Okuno, T., Tamura, Y., 1993. Novel efficient synthesis of 1-ethoxyvinyl esters using ruthenium catalysts and their use in acylation of amines and alcohols: synthesis of hydrophilic 30 -N-acylated oxaunomycin derivatives. J. Chem. Soc. Perkin Trans. 1, 2999–3005. Okawara, R., Wada, M., 1963. Preparation and properties of dimeric tetra-alkyldistannoxane derivatives: XR2SnOSnR2OH and XR2SnOSnR2OR0 . J. Organomet. Chem. 1, 81–88. Orita, A., Sakamoto, K., Hamada, Y., Mitsutome, A., Otera, J., 1999. Mild and practical acylation of alcohols with esters or acetic anhydride under distannoxane catalysis. Tetrahedron 55, 2899–2910. Rothman, E., Hecht, S., Pfeffer, P.E., Silbert, L.S., 1972. Enol esters. XV. Synthesis of highly hindered esters via isopropenyl ester intermediates. J. Org. Chem. 37, 3551–3552.