The synthesis of precursor of FP- (+) DTBZ

Article abstract of DOI:10.1080/00397911.2019.1663539

A synthetic route to the precursor of FP- (+) DTBZ was disclosed, in which 3-hydroxy-4-methoxybenzaldehyde was employed as a starting material. In the method, the benzyl-protecting protocol and the in-situ Diels-Alder reaction made the procedure more practical because of the mild conditions for selectively deprotection and the accelerated reaction process.

Full text of DOI:10.1080/00397911.2019.1663539

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
The synthesis of precursor of FP- (+) DTBZ
Caijiao Wu, Hui Li, Feiyang Sun, Changshun Bao, Xuefei Bao & Guoliang Chen
To cite this article: Caijiao Wu, Hui Li, Feiyang Sun, Changshun Bao, Xuefei Bao & Guoliang
Chen (2019): The synthesis of precursor of FP- (+) DTBZ, Synthetic Communications, DOI:
10.1080/00397911.2019.1663539
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https://doi.org/10.1080/00397911.2019.1663539
The synthesis of precursor of FP- (þ) DTBZ
Caijiao Wu, Hui Li, Feiyang Sun, Changshun Bao, Xuefei Bao, and Guoliang Chen
Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang
Pharmaceutical University, No.103 Wenhua Road, Shenhe District, Shenyang, 110016, P. R. of China
ABSTRACT
ARTICLE HISTORY
Received 26 March 2019
A synthetic route to the precursor of FP- (þ) DTBZ was disclosed, in
which 3-hydroxy-4-methoxybenzaldehyde was employed as a start-
ing material. In the method, the benzyl-protecting protocol and the
in-situ Diels-Alder reaction made the procedure more practical
because of the mild conditions for selectively deprotection and the
accelerated reaction process.
KEYWORDS
Positron Emission
Computed Tomography;
VMAT2 imaging agents;
precursor of FP- (þ)
DTBZ; synthesis
GRAPHICAL ABSTRACT
Introduction
Studies have shown the early detection and monitoring of neurodegenerative diseases
including Parkinson’s disease (PD), Alzheimer’s disease (AD), dementia with Lewy
bodies (DLB), other dementias, and movement disorders are a very significant unmet
medical need. The brain positron emission computed tomography (PET) can be used
for diagnosis of Parkinson’s disease.[1]
Vesicular Monoamine Transporter 2 (VMAT2), a membrane bound protein, is a bio-
marker for Parkinson’s disease.[2] DTBZ and its derivatives (Figure 1), labeled with
positron emitting isotopes such as [11C] and [18F], were used as PET radioligands for
examining VMAT2[3,4] and the density of VMAT2 determined by [18F] DTBZ was well,
CONTACT Xuefei Bao
bxf551@163.com; Guoliang Chen
chenguoliang@syphu.edu.cn
Key Laboratory of
Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, No.103
Wenhua Road, Shenhe District, Shenyang, 110016, P. R. of China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website
ß 2019 Taylor & Francis Group, LLC

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C. WU ET AL.
Figure 1. Structures of DTBZ, [11C] DTBZ, FP- (þ) DTBZ and precursor 1.
inversely correlated with the severity of Parkinson’s disease.[5] 9-[18F] fluoropropyl-
(þ)-dihydrotetrabenazine ([18F] AV-133, FP- (þ) DTBZ) targeting VMAT2 was
employed as brain PET tracer. FP- (þ) DTBZ is currently under Phase II/III clinical tri-
als to verify its validity in the diagnosis of neurodegenerative diseases including demen-
tia with Lewy bodies and Parkinson’s disease.[5–7] In this paper, we described a
procedure for the synthesis of the precursor of FP- (þ) DTBZ.
Results and discussion
About its synthesis, Hank et al. reported a route (Scheme 1, Route A)[8] using 6,7-dime-
thoxy-3,4-dihydroisoquinoline as the starting material, which was not commercially
available. Besides, the second step required seven days with yield only of 30%. In add-
ition, harsh condition was employed to remove the methoxyl group and it was difficult
to remove the mono 3-methoxyl selectively. Therefore, we optimized an economical and
practical synthetic route based on Liu’s work (Scheme 1, Route B[9]). This synthetic
route from commercially available 3-hydroxy-4-methoxy benzaldehyde involved benzyl
protection, Henry reaction, reduction, Pictet–Spengler reaction, in-situ Diels–Alder cyc-
lization, resolution of chiral isomers, debenzylation, and etherification.
The substituted 2-nitrovinyl benzene 5 was prepared via the benzyl protocol and the
Henry reaction, which converted to the substituted phenyl ethanamine 6 via the reduc-
tion. Initially, we attempted to prepare the intermediate 5 under the conditions of Aldol
condensation, but no satisfactory result was obtained (Table 1, entries 1–4). After
repeatedly exploration, Henry reaction was employed to achieve this goal and the inter-
mediate 5 was obtained by adding 4, ammonium acetate, and nitromethane into a solv-
ent of acetic acid at 93 ꢀC (entry 6). As for the next step of reduction, strong reductant
of lithium aluminum hydride (LAH) was selected to reduce the double bond and nitro
group simultaneously. Much lower yield was obtained when adding LAH at ambient
temperature because of the generation of impurities (Table 2, entry 1). However, when
decreasing feeding temperature and reaction temperature, no product was obtained

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3
Route A:
Route B:
Scheme 1. Reported and modified synthetic routes of precursor 1.

4
C. WU ET AL.
Table 1. Optimization of solvents, base and temperature for the formation of intermediate 5a.
Entry
CH3NO3 (equie)
Solvent
Base (equie)
Temp (oC)
Yield (%)
1
2
3
4
5
6
1.1
1.1
1.1
1.5
3
toluene
MeOH
MeOH
MeOH
CH3COOH
CH3COOH
Piperidine (0.15)
NaOH (1.0)
NaOH (1.0)
NaOH (2.0)
CH3COONH4 (2.4)
CH3COONH4 (2.4)
110
0
0!10
0!10
50
<10%
<10%
<10%
<10%
NDb
3
93
70.0%
aStandard conditions: 4 (40.6 g, 167.7 mmol); bnot detected by TLC analysis.
Table 2. Optimization of temperature for the formation of intermediate 6a.
Entry
Temp (oC)
Yield (%)
1
2
3
33!66
0!25
0!66
17.3
NDb
84.0
aStandard conditions: 5 (19.3 g, 67.7 mmol), the THF solution of LiAlH4 (2.5 M, 108 mL, 270 mmol). bNot detected by
TLC analysis.
(entry 2). An attempt at reducing the feeding temperature and raising the reaction tem-
perature step by step was success to obtain a higher yield (entry 3).
The Bischler–Napieralski reaction was employed to synthesize dihydro isoquinoline
intermediate 7, but we abandoned the approach after several failed attempts due to the
low yield (Table 3, entries 1–6). Eventually, intermediate 7 was obtained with acceptable
yield of 62.9% via the Pictet–Spengler reaction with urotropine. In the process, the yield
was increased by 10% by raising the reaction temperature from 60 to 90 ꢀC (entries 7,
8). We tried to increase the yield by further raising the temperature, but the impurity
7 A was increased when the temperature raised to 110–120 ꢀC (entry 9). Isomerization
may occur easily during high reaction temperature, therefore, 90 ꢀC was selected as the
optimal condition.
Tertiary amine 7-1 was synthesized via Mannich reaction, but the reaction always pro-
duced isomer 7-1-1 which could not be reduced by changing reaction time, reaction tem-
perature, or feeding amount of dimethylamine and polyformaldehyde (Scheme 2).
However, the isomer 7-1-1 would increase when reducing the reaction temperature to
ambient temperature or below. Compound 12-1 was synthesized from propane-1,3-diol
and p-toluenesulfonyl chloride, but when the reaction was carried out at the ambient tem-
perature, the monosulfonate 12-1-1 was the major product (Scheme 2). Therefore, we
obtained 12-1 with an acceptable yield when the reaction was carried out below 0 ꢀC.

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Table 3. Optimization of temperature for the formation of intermediate 7a.
Entry
Method
Dehydrant (equie)
Solvent
Temp (oC)
Yield (%)
1
2
3
4
5
6
7
8
9
A
A
A
A
A
A
B
B
B
POCl3 (3.3)
POCl3 (3.3)
POCl3 (1.5)
PCl5 (1.5)
PCl5 (1.5)
PCl5 (1.5)
–
–
DCM
DCM
DCM
DCM
105
60
25
<5
<5
<10
<5
<10
<10
55.7
64.5
26.9
25
ꢁ5!25
ꢁ5!44
60
90
120
aStandard conditions for method A: 6 (7.9 g, 30 mmol); standard conditions for method B: 6 (7.9 g, 30 mmol), trifluoro-
acetic acid (12 mL), hexamethylenetetramine (12.9 g, 92 mmol), acetic acid (48 mL).
Scheme 2. The synthesis of intermediates 7-1 and 12-1.
The in-situ Diels-Alder cyclization followed by the elimination of the quaternary
ammonium 7-2 salt furnished ketone 8. Compared with the route reported by Hank
et al.[8], tertiary amine 7-1 first reacts with iodomethane to form quaternary ammonium
7-2 instead of directly reacting with the intermediate 7, which greatly accelerated the
reaction process for the preparation of ketone 8. Also, the possible mechanism for
the formation of ketone 8 was shown in Scheme 3. After the reduction of the ketone 8,
the racemic compound 11 was carefully resoluted with di-p-toluoyl-L-tartaricdi-p-
toluoyl-L-tartaric acid in acetone. Under normal pressure and room temperature
conditions, the 3-OBn of the optical pure 11 was selectively deprotected to give the key
intermediate 12 via Pd-catalysed hydrogenation while keeping the C–N bond of the
benzylamine structure in the substituted isoquinoline undestroyed. The intermediate 12
could be easily converted to the final key precursor 1 via reacted with 12-1.

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C. WU ET AL.
Scheme 3. The possible mechanism for the formation of ketone 8.
Conclusion
We provide an economical and practical route to synthesize the key precursor of FP-
(þ) DTBZ and it is acceptable from both reaction conditions and yield standpoint. The
advantages of the method are the benzyl ether protecting group removed selectively
under mild conditions and the in-situ Diels–Alder reaction accelerating the process of
cyclization.
Experimental section
General
Reagents and solvents were obtained from commercial suppliers and used without fur-
ther purification. Melting points were determined with a X-4 digital apparatus and were
1
uncorrected. Specific rotation was determined with a WZZ-automatic polarimeter. H
nuclear magnetic resonance (NMR) spectra were collected using a Bruker ARX-600
apparatus and using tetramethylsilane (TMS) as an internal standard. Electrospray ion-
ization mass spectrometry (ESI-MS) data were obtained using an Agilent 1100 Series
MSD Trap (SL) apparatus. The reactions were monitored by thin-layer chromatography
(TLC; HG/T2354-92, GF254) and compounds septated by TLC were visualized with
UV light.
Synthesis of 9-(benzyloxy)-3-isobutyl-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-
pyrido[2,1-a]isoquinolin-2-one (8)
The intermediate 7 (4.3 g, 16.0 mmol) and quaternary ammonium 7-2 (6.5 g, 20.7 mmol)
were added to a solution of methanol (40 mL) and the mixture was stirred at reflux for
31 h. Then, the mixture was cooled to ambient temperature and dissolved in DCM
(100 mL) and H2O (50 mL), then organic phase was collected and washed with brine
(100 mL) before being dried over anhydrous sodium sulfate. The sodium sulfate was fil-
tered off and the filtrate was concentrated in vacuum to afford white solid 8þ(4.3 g,
1
68.1%). Mp 119–121 ꢀC (Lit.[3] Mp 133–135 ꢀC). MS(ESI): m/z ¼ 394.3 [M þ H] . H-
NMR (600 MHz, CDCl3): d (ppm) 7.43 (d, J ¼ 7.4 Hz, 2H), 7.38–7.34 (m, 2H), 7.32–7.28

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(m, 1H), 6.65 (s, 1H), 6.58 (s, 1H), 5.12 (s, 2H), 3.84 (s, 3H), 3.49 (s, 1H), 3.27 (s, 1H),
3.08 (d, 2H), 2.91 (d, J ¼ 13.3 Hz, 1 H), 2.66 (dd, 4H), 2.35 (s, 1H), 1.83–1.78 (m, 1H),
1.69–1.62 (m, 1H), 1.06–1.01 (m, 1H), 0.91 (t, J ¼ 6.6 Hz, 6H).
Synthesis of (2 R,3R,11bR)-9-(benzyloxy)-3-isobutyl-10-methoxy-1,3,4,6,7,11b-
hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol.di-P-toluoyl-L-tartrate (10) and
(2 R,3R,11bR)-9-(benzyloxy)-3-isobutyl-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-
pyrido[2,1-a]isoquinolin-2-ol (11)
The intermediate 9 (3.6 g, 9.0 mmol) was added to a solution of methanol (140 mL) and
the mixture was stirred. When the reaction temperature rose to 45 ꢀC, di-p-toluoyl-tar-
taric acid（3.5 g, 9.0 mmol）was added and the mixture was stirred at 45 ꢀC for 0.5 h.
Then, the mixture was cooled to ambient temperature and concentrated in vacuum to
afford white solid (7.5 g), which was recrystallized twice from acetone to afford
(2 R,3R,11bR)-9-(benzyloxy)-3-isobutyl-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyr-
ido[2,1-a]isoquinolin-2-ol.di-P-toluoyl-L-tartrate 10.
The tartrate 10 (2.4 g, 3.1 mmol) was dissolved in H2O (200 mL) and the pH was
adjusted to 10 with 25% ammonium hydroxide, then the solution was extracted with
DCM (200 mL). Organic phase was washed with brine (200 mL) before being dried over
anhydrous sodium sulfate. The sodium sulfate was filtered off and the filtrate was con-
centrated in vacuum to afford white solid 11 (1.3 g, 35.8%). Mp 133–136 ꢀC (Lit.[3]
20
20
Mp 139–141 ꢀC). [a]D
(c ¼ 1, chloroform)).
¼ þ53.3ꢀ (c ¼ 1, chloroform) (lit[9]. [a]D
¼ þ58.3ꢀ
Synthesis of (2 R,3R,11bR)-3-isobutyl-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-
pyrido[2,1-a]isoquinoline-2,9-diol (12)
The intermediate 11 (1.3 g, 3.2 mmol) and 5% Pd-C (0.1 g) were added to a solution of
anhydrous ethanol (50 mL) and the mixture was stirred at 25 ꢀC for 48 h at a hydrogen
atmosphere. Then the mixture was concentrated in vacuum to remove ethanol to afford
white solid 12 (0.8 g, 83.0%). Mp 216–218 ꢀC (Lit.[4] Mp 206–208 ꢀC). MS(ESI):
1
m/z ¼ 306.3 [M þ H]þ. H-NMR (600 MHz, CDCl3): d (ppm) 6.65 (s, 2H), 3.85 (s, 3H),
3.40 (td, J ¼ 10.5, 4.6 Hz, 1H), 3.16 (s, 1H), 3.07 (d, J ¼ 10.5 Hz, 2H), 3.01 (s, 1H),
2.67–2.53 (m, 2H), 2.47 (s, 1H), 2.07–1.96 (m, 1H), 1.77 (s, 1H), 1.72–1.67 (m, 2H),
1.62–1.49 (m, 2–H), 1.25 (s, 1H), 1.09–1.04 (m, 1H), 0.93 (dd, J ¼ 13.0, 6.5 Hz, 6H).
Synthesis of 3-(((2 R,3R,11bR)-2-hydroxy-3-isobutyl-10-methoxy-1,3,4,6,7,11b-
hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)propyl 4-
methylbenzenesulfonate (1)
The intermediate 12 (0.53 g, 1.74 mmol), 12-1 (1.50 g, 5.21 mmol) and potassium car-
bonate (0.60 g, 4.34 mmol) were added to a solution of acetone (50.0 mL). After stirred
at 65 ꢀC for 48 h,the mixture was cooled to ambient temperature and concentrated in
vacuum to remove acetone. The residue was dissolved in DCM (80 mL) and the organic
phase was washed with H2O (50 mL) and brine (100 mL) before being dried over

8
C. WU ET AL.
anhydrous sodium sulfate. The sodium sulfate was filtered off and the filtrate was con-
centrated in vacuum to afford white solid 1 (0.50 g, 55.6%). Mp 115–120 ꢀC. MS(ESI):
m/z ¼ 518.3 [M þ H]þ. HRMS (ESI): m/z [M þ H]þ calcd for C28H39NO6S 518.2498,
20
1
found 518.2594. [a]D ¼ þ29.09ꢀ (c ¼ 1, chloroform). H-NMR (600 MHz, CDCl3): d
(ppm) 7.76 (d, J ¼ 8.2 Hz, 2H), 7.28 (s, 2H), 6.65 (s, 1H), 6.52 (s, 1H), 4.29–4.23
(m, 2H), 4.00–3.96 (m, 2H), 3.76 (s, 3H), 3.40 (s, 1H), 3.08 (t, 4H), 2.60 (t, J ¼ 17.8 Hz,
2H), 2.48 (s, 1H), 2.40 (s, 3H), 2.14 (p, J ¼ 6.1 Hz, 2H), 2.04–1.98 (m, 1H), 1.73–1.68
(m, 2H), 1.58 (d, J ¼ 10.7 Hz, 2H), 1.09–1.05 (m, 1H), 0.94 (dd, J ¼ 12.5, 6.5 Hz, 6H).
1
Full experimental detail, H spectra, MS spectra are explained in the supplemen-
tary material.
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