426
T. YAO AND Z. LI
(E)-4-(2-(6-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-
methylbenzenamine (1) non-radioactive ([F]AV-45)
A mixture of compound 17 (35 mg, 0.074 mmol) and 5 mL HCl in 5 mL DMSO was stirred
at RT overnight. To the mixture 20 mL 4% NaOH solution was added. The mixture was
extract by EtOAc. The combined organic layer was dried over Na2SO4. After filtration,
the filtrate was concentrated under vacuum and the residue was purified by column chro-
matography (SiO2, PE/AcOEt ¼ 1:1) to afford compound 1 (22 mg, yield: 80%). IR (neat):
1
3168, 2364, 2336, 2178, 1614, 1250, 1108 cm−1. H-NMR (CDCl3): δ 8.13 (d, J ¼ 2.0 Hz,
1H), 7.76 (dd, J ¼ 2.4 Hz, J ¼ 8.8 Hz, 1H), 7.34 (d, J ¼ 8.8 Hz, 2H), 6.92–6.75 (m, 3H),
6.59 (d, J ¼ 8.4 Hz, 2H), 4.63–4.61 (m, 1H), 4.51–4.47 (m, 3H), 3.88–3.85 (m, 2H),
3.80–3.78 (m, 1H), 3.75–3.70 (m, 5H), 2.86 (s, 3H), 1.25 (s, 1H). 13C-NMR (CDCl3):
δ 162.5, 149.0, 144.9, 135.0, 128.2, 127.6, 126.4, 120.3, 112.4, 111.2, 84.0, 82.3, 70.8, 70.7,
70.5, 70.3, 69.8, 65.1, 30.6, 29.7. HRMS (FAB) calcd for C20H25FN2O3 (MHþ): 360.1849;
found: 360.1854. The data are identical with those reported in literature.[1f]
Conclusion
In summary, TEG-substituted 4-(N-methyl-N-Boc-amino)styrylpyridine (5) which can
serve as key precursor for many monodentate and multidentate PET imaging agents has
been synthesized with cost-effective starting materials through simple reactions. Our
new method is more concise (five steps with six stages) than the reported methods. The
overall yield of the new method is 25%, which is higher than our previously published
method[4] (the overall yield is 16%). Toxic and smelly reagent (e.g., 4-methylbenzenethiol)
was excluded as well. Our new method can be applied for synthesis of TEG-substituted
4-(N-methyl-N-Boc-amino)styrylpyridine (5) in multi-gram scale. The non-radioactive
monodentate PET imaging agent ([F]AV-45) 1 has also been prepared in good yield from 5.
Our new method could be employed for mass production of AV-45 and other multidentate
imaging agents.
Funding
This work is supported by Fundamental Research Funds for the Central Universities (2016JBM069)
and National Science Foundation of China (NSFC 21302011).
References
[1] (a) Wong, D.; Rosenberg, P.; Zhou, Y.; Kumar, A.; Raymont, V.; Ravert, H.; Dannals, R.; Nandi,
A.; Brasic, J.; Ye, W.; J. Nucl. Med. 2010, 51, 913–920; (b) Kung, H.; Choi, S.; Qu, W.; Zhang, W.;
Skovronsky, D. J. Med. Chem. 2009, 53, 933–941; (c) Choi, S.; Golding, G.; Zhuang, Z.; Zhang,
W.; Lim, N.; Hefti, F.; Benedum, T.; Kilbourn, M.; Skovronsky, D.; Kung, H. J. Nucl. Med. 2009,
50, 1887–1894; (d) Zhang, W.; Kung, M.; Oya, S.; Hou, C.; Kung, H. Nucl. Med. Biol. 2007, 34,
89–97; (e) Clark, C. M.; Schneider, J. A.; Bedell, B. J.; Beach, T. G.; Bilker, W. B.; Mintun, M. A.;
Pontecorvo, M. J.; Hefti, F.; Carpenter, A. P.; Flitter, M. L.; J. Am. Med. Assoc. 2011, 305,
275–283; (f) Kung, M.-P.; Kung, H. F. WO Patent 2007/126733 A2, 2007.
[2] Zha, Z.; Choi, S. R.; Ploessl, K.; Lieberman, B. P.; Qu, W.; Hefti, F.; Mintun, M.; Skovronsky, D.;
Kung, H. F. J. Med. Chem. 2011, 54, 8085–8098.
[3] For synthesis of AV-45 from TEG-substituted 4-(N-methyl-N-Boc-amino)styrylpyridine (5),
please see: (a) Hayashi, K.; Tachibana, A.; Tazawa, S.; Mizukawa, Y.; Osaki, K.; Morimoto, Y.;
Zochi, R.; Kurahashi, M.; Aki, H.; Takahashi, K. J. Labelled Compd. Radiopharm. 2013, 56,