Synthesis of TEG-Substituted 4-(N-Methyl-N-Boc-amino)styrylpyridine as Key Precursor for Monodentate and Multidentate Imaging Agents for A β Plaques

Article abstract of DOI:10.1080/00397911.2015.1104356

Triethylene glycol (TEG)-substituted 4-(N-methyl-N-Boc-amino)styrylpyridine, which can serve as key precursor for many monodentate and multidentate imaging agents for Aβ plaques in the human brain, has been readily synthesized with cheap starting materials. Our new method could be employed for mass production of monodentate imaging agent AV-45 and other multidentate imaging agents.

Full text of DOI:10.1080/00397911.2015.1104356

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis of TEG-Substituted 4-(N-Methyl-N-
Boc-amino)styrylpyridine as Key Precursor for
Monodentate and Multidentate Imaging Agents
for Aβ Plaques
Zhi Li, Bo Liu, Wubiao Duan & Lin Zhu
To cite this article: Zhi Li, Bo Liu, Wubiao Duan & Lin Zhu (2015) Synthesis of TEG-Substituted
4-(N-Methyl-N-Boc-amino)styrylpyridine as Key Precursor for Monodentate and Multidentate
Imaging Agents for Aβ Plaques, Synthetic Communications, 45:23, 2740-2747
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Date: 19 December 2015, At: 07:57

Synthetic Communications1, 45: 2740–2747, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1104356
SYNTHESIS OF TEG-SUBSTITUTED 4-(N-METHYL-N-
BOC-AMINO)STYRYLPYRIDINE AS KEY PRECURSOR
FOR MONODENTATE AND MULTIDENTATE IMAGING
AGENTS FOR Ab PLAQUES
Zhi Li,1 Bo Liu,1 Wubiao Duan,1 and Lin Zhu2
1Department of Chemistry, School of Science, Beijing Jiaotong University,
Beijing, China
2Department of Radioactive Pharmaceutical Chemistry, College of
Chemistry, Beijing Normal University, Beijing, China
GRAPHICAL ABSTRACT
Abstract Triethylene glycol (TEG)-substituted 4-(N-methyl-N-Boc-amino)styrylpyridine,
which can serve as key precursor for many monodentate and multidentate imaging agents
for Ab plaques in the human brain, has been readily synthesized with cheap starting
materials. Our new method could be employed for mass production of monodentate
imaging agent AV-45 and other multidentate imaging agents.
Keywords AV-105; AV-45; PET imaging agent
INTRODUCTION
Imaging Ab plaques in the brain is a potentially useful tool for studying the
pathophysiology of neurodegenerative diseases (e.g., cerebral amyloid angiopathy
and Alzheimer disease) associated with the formation of b-amyloid.[1] As shown in
Fig. 1, [18F] 1 (AV-45) is a useful monodentate positron emission tomography
(PET) agent for targeting Ab plaques in the human brain.[2] The phase III clinical
trial for 1 was completed[2e] in 2011 and this Ab-plaque-targeting imaging agent
got approval from US Food and Drug Administration in 2012.
Received August 22, 2015.
Address correspondence to Zhi Li, Department of Chemistry, School of Science, Beijing Jiaotong
University, 3# Shangyuan Cun Road, Beijing 100044, China. E-mail: zhili@bjtu.edu.cn
2740

SYNTHESIS OF KEY PRECURSOR FOR PET AGENTS
2741
Figure 1. Monodentate 18F Ab-plaque-imaging agent AV-45.
In 2011, researchers[3] reported a new series of multidentate18F styrylpyridine
derivatives for selectively targeting Ab plaques in the blood vessels of the human
brain (Fig. 2). Their research[3] suggested that [18F] 2a may be a useful PET imaging
agent in the brain.
As shown in Scheme 1, TEG-substituted 4-(N-methyl-N-Boc-amino)styrylpyr-
idine (5) is the key precursor for the synthesis of monodentate PET imaging agent
1[4a] and other multidentate PET imaging agents (2a, 2b, 2c, 3, 4).[3]
RESULTS AND DISCUSSION
Although TEG-substituted 4-(N-methyl-N-Boc-amino)styrylpyridine (5) is very
important, only one protocol[3] has been reported concerning its synthesis. The
reported method involved the air- and moisture-sensitive Heck reaction and micro-
wave reaction in which a special microwave synthesizer (Biotage microwave reaction
vial) and harsh reaction conditions (high temperature and high pressure) were
required. Herein, we report a new method for the synthesis of TEG-substituted
4-(N-methyl-N-Boc-amino) styrylpyridine (5) without microwave irradiation or
air- and moisture-sensitive metal catalytic reactions (Scheme 2).
Figure 2. Multidentate 18F Ab-plaque-imaging agents.

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Z. LI ET AL.
Scheme 1. Synthesis of monodentate and multidentate PET imaging agents from TEG-substituted4-
(N-methyl-N-Boc-amino)styrylpyridine (5).
Scheme 2. Synthesis of TEG-substituted 4-(N-methyl-N-Boc-amino)styrylpyridine (5).

SYNTHESIS OF KEY PRECURSOR FOR PET AGENTS
2743
Scheme 3. Synthesis of AV 105 from TEG-substituted 4-(N-methyl-N-Boc-amino)styrylpyridine (5).
First, (bromomethyl)-4-nitrobenzene (10) was transformed into 11 smoothly by
the Wittig–Horner reaction.[2f,5,6] Second, substitution of 11 with mono-tetrahydro-
2H-pyran (THP)-protected triethylene glycol (12) in the presence of NaH afforded
13 in 95% yield. Subsequently, reduction of 13 by Na2S · 10H2O[7] in EtOH=H2O
(v=v ¼ 2:1) solution afforded 14 in 68% yield. It is worth noting that reduction of 13
should be carried out under basic conditions to avoid deprotection of the THP group.
Na2S ·10H2O was therefore selected as reductant. Next, 14 was allowed to react with
paraformaldehyde and 4-methylbenzenethiol in refluxing MeOH. After removal of
[2f,8]
MeOH, the residue reacted with NaBH4
in dichloroethane (DME) at 100 °C to
afford 15 in 65% yield. Protection of 15 with Boc2O afforded 16 in 67% yield. Finally,
the TEG-substituted 4-(N-methyl-N-Boc-amino)styrylpyridine (5) was obtained in 72%
yield after selective deprotection of the THP group. CuSO4 · 5H2O[9] was employed in
this step because it can promote depyranylation of alcohol efficiently while keeping
the Boc group intact.
As described previously, all starting materials and reagents employed in our new
method were cheap and readily available. All reactions were simple and easy to
handle: (a) No special reactor or harsh reaction conditions (e.g., high temperature
and high pressure) were required. (b) No microwave irradiation or air- or moisture-
sensitive metal catalytic reactions were involved. Our new method can be employed
for mass production of TEG-substituted 4-(N-methyl-N-Boc-amino)styrylpyridine (5).
With 5 in hand, we further tried to synthesize the key precursor 6 (AV 105)[3]
for the monodentate imaging agent 1 (AV-45). As shown in Scheme 3, 6 was
obtained in 65% yield by the reaction of 5 with TsCl in the presence of Et3N and
dimethylaminopyridine (DMAP).
CONCLUSION
In summary, TEG-substituted 4-(N-methyl-N-Boc-amino)styrylpyridine (5),
which can serve as key precursor for many monodentate and multidentate imaging
agents for Ab plaques in the human brain, has been synthesized with cheap starting
materials via simple reactions. The key precursor 6 (AV-105) for 1 (AV-45) has also
been prepared in good yield from 5. Our new method could be employed for mass
production of monodentate imaging agent AV-45 and other multidentate imaging
agents. This work is under research in our laboratory and further results will be
reported in due course.
EXPERIMENTAL
All commercially available reagents were used without further purification.
1
Column chromatography was performed on silica gel (200–300 mesh). H NMR

2744
Z. LI ET AL.
and 13C NMR spectra were recorded in CDCl3 at 400 MHz on a Bruker NMR spec-
trometer. All chemical shifts are reported in parts per million (ppm) downfield from
tetramethylsilane (TMS) and peak multiplicities are referred to as singlet (s), doublet
(d), quartet (q), and multiplet (m).
Compound 13
NaH (312 mg, 7.81 mmol) was added to a solution of mono-THP-protected
triethylene glycol (12) (1.83 g, 7.81 mmol) in 16 mL dioxane at rt. The mixture was
stirred for 3 h. To the mixture (E)-2-chloro-5-(4-nitrostyryl)pyridine (11) (750 mg,
2.92 mmol) was added. After stirring at rt for 12 h, the mixture was poured into water
and extracted 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 chromatography (SiO2, PE=AcOEt ¼ 1:1) to afford 13 (1.21 g, yield: 95%) as
a yellow oil. 1H NMR (CDCl3): d 8.26 (1H, s), 8.22 (2H, d, J ¼ 8.8 Hz), 7.87 (1H, dd,
J ¼ 8.8 Hz, J ¼ 2.4 Hz), 7.62 (2H, d, J ¼ 8.8 Hz), 7.19 (1H, d, J ¼ 16.4 Hz), 7.04 (1H,
d, J ¼ 16.4 Hz), 6.89–6.88 (1H, m), 4.63 (1H, t, J ¼ 3.6 Hz), 4.57–4.53 (2H, m),
3.89–3.84 (4H, m), 3.73–3.67 (7H, m), 3.63–3.58 (1H, m), 1.86–1.78 (1H, m),
1.75–1.69 (1H, m), 1.61–1.52 (4H, m). 13C NMR (CDCl3): d 163.9, 146.8, 143.7,
135.6, 129.5, 126.8, 125.7, 125.4, 124.2, 111.8, 99.0, 70.8, 70.7, 70.6, 70.6, 69.7,
66.7, 65.6, 62.3, 30.6, 25.5, 19.6. HRMS (FAB) calcd. for C24H30N2O7 (MHþ):
458.2053; found: 458.2055.
Compound 14
Compound 13 (1.0 g, 2.2 mmol) and Na2S · 10H2O (1.72 g, 22 mmol) were dis-
solved in a mixture of EtOH and H2O (15 mL, VEtOH=VH2O ¼ 2:1). The mixture
was heated to reflux for 2 h. After cooling to rt, the mixture was diluted with H2O
and extracted 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 chromatography (SiO2, PE=EtOAc ¼ 1:1) to afford 14 (0.63 g, yield: 68%) as
1
a yellow oil. H NMR (CDCl3): d 8.06 (1H, d, J ¼ 2 Hz), 7.67 (1H, dd, J ¼ 8.4 Hz,
J ¼ 2.0 Hz), 7.22 (2H, d, J ¼ 8.0 Hz), 6.77 (2H, q, J ¼ 16.0 Hz), 6.69 (1H, d, J ¼ 8.8
Hz), 6.58 (2H, d, J ¼ 8.4 Hz), 4.56 (1H, t, J ¼ 3.6 Hz), 4.40 (2H, t, J ¼ 4.8 Hz),
3.81–3.77 (4H, m), 3.74 (2H, s), 3.63–3.60 (6H, m), 3.56–3.51 (1H, m), 3.43–3.39
(1H, m), 1.78–1.71 (1H, m), 1.66–1.61 (1H, m), 1.55–1.41 (4H, m). 13C NMR
(CDCl3): d 162.7, 146.4, 145.1, 135.2, 128.2, 127.7, 127.7, 127.4, 121.0, 115.2,
111.4, 99.0, 70.8, 70.7, 70.7, 69.9, 66.7, 65.3, 62.3, 30.7, 25.5, 19.6. HRMS (FAB)
calcd. for C24H32N2O5 (MHþ): 428.2311; found: 428.2310.
Compound 15
Compound 14 (500 mg, 0.25 mmol) and paraformaldehyde (120 mg, 0.30 mmol)
in 10 mL MeOH was heated to reflux for 30 min. 4-Methylbenzenethiol (160 mg,
0.25 mmol) in 5 mL MeOH was added to the mixture. After 2 h, the mixture was
cooled to rt and MeOH was removed under vacuum. The residue was dissolved in
5 mL DME. NaBH4 (100 mg, 0.76 mmol) was added to the solution and the mixture

SYNTHESIS OF KEY PRECURSOR FOR PET AGENTS
2745
was heated to 100 °C for 1 h. After cooling to rt, the mixture was poured into water.
The mixture was extracted by EtOAc and the combined organic layer was dried over
Na2SO4. After filtration, the filtrate was concentrated under vacuum and the residue
was purified by column chromatography (SiO2, PE=EtOAc ¼ 1:1) to afford com-
pound 15 (371 mg, yield: 65%) as yellow oil. 1H NMR (CDCl3): d 8.13 (1H, d, J ¼ 2.4
Hz), 7.75 (1H, dd, J ¼ 2.4 Hz, J ¼ 8.8 Hz), 7.35 (2H, d, J ¼ 8.8 Hz), 6.92–6.65 (5H,
m), 4.63 (1H, t, J ¼ 3.6 Hz), 4.47 (2H, t, J ¼ 4.8 Hz), 3.88–3.83 (4H, m), 3.71–3.67
(7H, m), 3.63–3.58 (1H, m), 3.50–3.46 (1H, m), 2.87 (3H, s), 1.85–1.78 (1H, m),
1.74–1.68 (1H, m), 1.62–1.52 (4H, m).13C NMR (CDCl3): d 162.6, 149.2, 145.1,
135.1, 128.4, 127.7, 126.4, 120.3, 112.5, 111.4, 100.1, 99.1, 70.8, 70.8, 70.7, 69.9,
66.8, 65.3, 62.3, 58.3, 30.7, 25.6, 19.6. HRMS (FAB) calcd. for C25H34N2O5
(MHþ): 442.2468; found: 442.2469.
Compound 16
Compound 15 (600 mg, 1.5 mmol) and (Boc)2O (410 mg, 2.2 mmol) were dis-
solved in a mixture of EtOH and H2O (10 mL VEtOH,=VH2O ¼ 2:1). The mixture
was stirred at rt for 12 h. The mixture was diluted with water and extracted by
EtOAc. The combined organic layer was dried over Na2SO4. After filtration, the fil-
trate was concentrated under vacuum and the residue was purified by column chro-
matography (SiO2, PE=EtOAc ¼ 1:1) to afford compound 16 (500 mg, yield: 67%)
as yellow oil. 1H NMR (CDCl3): d 8.16 (1H, d, J ¼ 2.0 Hz), 7.77 (1H, dd, J ¼ 2.0 Hz,
J ¼ 8.4 Hz), 7.43 (2H, d, J ¼ 8.8 Hz), 7.21 (2H, d, J ¼ 8.0 Hz), 6.99–6.90 (2H, m), 6.78
(1H, d, J ¼ 8.8 Hz), 4.62 (1H, t, J ¼ 3.6 Hz), 4.48 (2H, t, J ¼ 4.8 Hz), 3.87–3.83
(4H, m), 3.70–3.66 (6H, m), 3.62–3.57 (1H, m), 3.49–3.45 (1H, m), 3.25 (3H, s),
1.89–1.78 (1H, m), 1.73–1.67 (1H, m), 1.62–1.53, (2H, m), 1.51–1.47 (2H, m), 1.45
(9H, s). 13C NMR (CDCl3): d 163.2, 154.8, 145.8, 143.3, 135.4, 134.3, 127.4, 126.8,
126.6, 125.6, 124.6, 111.6, 99.1, 80.6, 70.9, 70.8, 70.7, 69.9, 66.8, 65.5, 62.3, 37.3,
30.7, 28.5, 25.6, 19.6. HRMS (FAB) calcd. for C30H42N2O7 (MHþ): 542.2992;
found: 542.2993.
TEG-Substituted 4-(N-Methyl-N-Boc-amino)styrylpyridine (5)
A mixture of compound 16 (1.5 g, 2.9 mmol) and CuSO4 · 5H2O (9.0 g,
36 mmol) in 20 mL MeOH was stirred at rt for 12 h. The mixture was diluted with
water and extracted 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 chromatography (SiO2, EtOAc) to afford TEG-substituted
4-(N-methyl-N-Boc-amino)styrylpyridine (5) (1.2 g, yield: 72%) as a white solid.
1H NMR (CDCl3): d 8.15 (1H, d, J ¼ 2.0 Hz), 7.76 (1H, dd, J ¼ 2.4 Hz, J ¼ 8.4 Hz),
7.41 (2H, d, J ¼ 8.4 Hz), 7.20 (2H, d, J ¼ 8.4 Hz), 6.98–6.89 (2H, m), 6.77 (1H, d,
J ¼ 8.8 Hz), 4.48 (2H, t, J ¼ 4.8 Hz), 3.84 (2H, t, J ¼ 4.8 Hz), 3.71–3.68 (6H, m),
3.60–3.58 (2H, m), 3.24 (3H, s), 2.71 (1H, t, J ¼ 6.0 Hz), 1.44 (9H, s). 13C NMR
(CDCl3): d 163.1, 154.8, 145.7, 143.3, 135.5, 134.2, 127.4, 126.9, 126.6, 125.6,
124.6, 111.6, 80.6, 72.6, 70.8, 70.5, 69.8, 65.3, 61.9, 37.3, 28.5. HRMS (FAB) calcd.
for C25H34N2O6(MHþ): 458.2417; found: 458.2415. The data are identical with
those reported in the literature.[3]

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Z. LI ET AL.
FUNDING
This work is supported by National Science Foundation of China (NSFC
21302011) and Beijing Higher Education Young Elite Teacher Project (YETP0571).
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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