An expedient synthesis of 1-[3-(dimethylamino)propyl]-5-methyl-3-phenyl1H-indazole (FS-32) - an antidepressant

Article abstract of DOI:10.1055/s-2001-17517

Intramolecular 1,3-dipolar cycloaddition of functionalized sydnone leading to the synthesis of 1-[3-(dimethylamino)propyl] -5-methyl-3-phenyl-1H-indazole (FS-32), an antidepressant drug candidate, is described.

Full text of DOI:10.1055/s-2001-17517

SHORT PAPER
1775
An Expedient Synthesis of 1-[3-(Dimethylamino)propyl]-5-methyl-3-phenyl-
1H-indazole (FS-32) - An Antidepressant
Synthesis
e
of 1-[(Dime
n
thylamino)p
g
ropyl]-5-me
-
P
enyl-1
H
-
i nda
z
ole ng Yeu, Jia-Tzong Yeh, Teng-Yueh Chen,* Biing-Jiun Uang*
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 300, Peoples Republic of China
Fax +886(3)5711082; E-mail: bjuang@mx.nthu.edu.tw
Received 16 May 2001; revised 2 July 2001
R
N
O
Abstract: Intramolecular 1,3-dipolar cycloaddition of functional-
ized sydnone leading to the synthesis of 1-[3-(dimethylamino)pro-
pyl]-5-methyl-3-phenyl-lH-indazole (FS-32), an antidepressant
drug candidate, is described.
H
N
N
i
N
OC2H5
O
O
2
3
Keywords: intramolecular 1,3-dipolar cycloaddition, sydnones,
antidepressant, FS-32
O
CH3
4
Ph
ii
H
CH3
CH3
O
R
N
OH CH3
R
Ph
Intramolecular 1,3-dipolar cycloaddition reaction offers a
remarkably wide range of utility in the synthesis of com-
plex cyclic natural products and macrocycles in less num-
ber of steps.1–3 Sydnones are easily accessible aromatic
compounds and versatile synthetic intermediates with a
masked azomethine imine unit. Their 1,3-dipolar cycload-
dition with dipolarophiles such as alkenes and alkynes is
a convenient synthetic procedure for pyrazoles4–7 and
fused heterocycles.8 Though there are limited reports9–11
on the intramolecular 1,3-dipolar cycloadditions using
functionalized 3-arylsydnones in the synthesis of fused
heterocycles, 3-alkylsydnones are not studied in such re-
actions. We wanted to explore the potential of sydnones as
Ph
iii
N
N
N
O
O
O
O
6
5
iv
H3C
Ph
H3C
Ph
v
N
N
N
N
R
O
R
H3C
7
1
R = (CH2)3N(CH3)2
1,3-dipoles and develop a methodology for the synthesis Scheme Reagents and conditions: i) 1. NaOH/MeOH, 2. NaNO2/
HCl, 3. Ac2O; ii) BuLi/THF/–70 °C; iii) NaH/MeI/0 °C iv) xylene/
130 °C v) Pt/C, air, HClO4/AcOH/130 °C
of bioactive molecules.
Several indazole derivatives have gained significant im-
portance in view of their promising pharmacological pro-
perties.12 In this paper, we describe a convenient and new
synthesis of a potent antidepressant drug candidate, 1-[3-
(dimethylamino)propyl]-5-methyl-3-phenyl-1H-indazo-
nation at C-4 of sydnone 3 in the presence of butyllithium
at –70 °C in THF followed by slow addition of aldehyde
le (FS-32) (1) using intramolecular 1,3-dipolar cycloaddi-
4 to the reaction medium yielded sydnone 5 as an insepa-
tion as the key step (Scheme). Compound 113–15 antago-
rable mixture of two diastereomers in 65% yield. As the
configuration at the chiral centers of 5 does not affect the
subsequent steps and target molecule, we have proceeded
further with the same mixture of 5. 3-Arylsydnones hav-
nizes reserpine-induced effects and potentiates amphe-
tamine-induced self-stimulation and L-dopa induced in-
crease in motor activity.
ing C-1 hydroxyl group in the alkenyl side chain are
known to get decomposed to cyclohexenonyl derivatives
on refluxing in xylene.17 Hence, protection of hydroxyl
group was required before we subject the substrate 5 to
1,3-dipolar cycloaddition. Hydroxyl group of 5 was meth-
ylated with methyl iodide at 0 °C to provide the corre-
sponding methyl derivative 6 in quantitative yield.
Cyclization of 6 was carried out, by heating in xylene at
130 °C to afford the corresponding tetrahydroindazole de-
rivative 7 in 46% yield. The moderate yield in this step is
attributed to the lower stability of 3-alkylsydnone 6,
which partly gets decomposed before cyclization to 7. Ini-
tial rate determining 1,3-dipolar cycloaddition followed
by rapid rearomatization with ejection of carbon dioxide
Sydnone 5 with preattached alkenyl side chain is chosen
as an appropriate intermediate for 1,3-dipolar cycloaddi-
tion in our synthetic protocol. Preparation of functional-
ized sydnone
5
is envisaged from 3-[3-
(dimethylamino)propyl]sydnone (3) and (E)-3-methyl-6-
phenylhex-5-enal16 (4). Condensation of ethyl bromoace-
tate with N,N-dimethylpropane-1,3-diamine and subse-
quent sequential hydrolysis, nitrosation and dehydrative
cyclization of the resulted ethyl 2-[3-(dimethylamino)pro-
pylamino]ethanoate (2) produced compound 3. Deproto-
Synthesis 2001, No. 12, 25 09 2001. Article Identifier:
1437-210X,E;2001,0,12,1775,1777ftx,en;F04401ss.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1776
J.-P. Yeu et al.
SHORT PAPER
MS (EI, 70 eV): m/z (%): 171 (M+, 1), 58 (100)
is the proposed mechanistic pathway for such reactions.18
The target molecule 1 is accomplished by the aromatiza-
tion of 7 on refluxing in acetic acid containing a small
amount of perchloric acid in the presence of a catalytic
amount of platinum.
HRMS: m/z Calcd for C7H13N3O2 171.1008. Found 171.1000.
3-[3-(Dimethylamino)propyl]-4-[(1-hydroxy-3-methyl-6-
phenyl)-5-hexyl]sydnone (5)
To a solution of 3 (0.17 g, 1.0 mmol) in THF (10 mL) was added a
solution of BuLi in hexanes (2.0 M, 0.5 mL) under argon at –78 °C
and the mixture was stirred for 30 min. Aldehyde 4 (0.187 mL, 1.0
mmol) dissolved in THF (5 mL) was added dropwise to the above
solution over a period of 10 min. The mixture was allowed to warm
to r.t. and stirred for 4 h. To this mixture, H2O (20 mL) was added
and the mixture was extracted with EtOAc (2 ¥ 10 mL). EtOAc
fractions were treated with aq HCl to pH 3–4. The aqueous layer
was separated from this and adjusted to pH 10 by adding aq NaOH
solution and extracted with EtOAc (2 ¥ 10 mL). The combined ex-
In conclusion, we have demonstrated the application of
intramolecular 1,3-dipolar cycloaddition methodology in
the synthesis of a bioactive molecule. It is noteworthy
that, in earlier intramolecular 1,3-dipolar cycloaddi-
tions,9–11 relatively more stable 3-arylsydnones were used
as substrates. We could make use of a 3-alkylsydnone in
intramolecular 1,3-dipolar cycloaddition for the first time,
though overall yield of our synthesis is moderate. The
synthetic strategy described here has significant potential tracts were dried (MgSO4), concentrated and passed through a silica
for wider application by choosing the appropriate sub-
strate. Currently studies are in progress in this direction.
gel column eluting with MeOH. Compound 5 (0.232 g, 65%) was
obtained as a pale yellow liquid.
IR (neat): 3386 (br), 1729 cm–1.
1H NMR: d = 1.04 (d, J = 6.5 Hz, 3 H), 1.70–2.50 (m, 9 H), 2.16 (s,
IR spectra were recorded on a Bomen MB 100FT spectrometer. The
NMR spectra were run at 400 MHz for 1H NMR, 100 MHz for 13
C
6 H), 4.30–4.50 (m, 2 H), 4.68 (br, 1 H), 4.87 (m, l H), 6.25 (dt,
J = 15.6, 6.8 Hz, 1 H), 6.45 (d, J = 15.6 Hz, 1 H), 7.29–7.38 (m, 5
H).
MS (EI, 70 eV): m/z (%) = 359 (M+, 1), 58 (100).
NMR and are referenced to internal standard TMS in ppm units on
a Varian Unity-400 NMR spectrometer using CDCl3 as solvent.
HRMS were recorded on a Jeol HX 100 spectrometer and elemental
analyses were carried out with a Heraeus CHNO Rapid analyzer.
HRMS: m/z Calcd for C20H29N3O3 359.2209. Found 359.2200
Ethyl 2-[3-(Dimethylamino)propylamino]ethanoate (2)
N,N-Dimethylpropane-1,3-diamine (37.9 g, 0.37 mol) was dis-
solved in benzene (100 mL) and K2CO3 (46.0 g, 0.33 mol) was add-
ed. Ethyl bromoacetate (31.0 g, 0.186 mol) dissolved in benzene
(100 mL) was added dropwise to the above solution while stirring.
After the addition, stirring was continued for 10 h, the mixture was
then filtered and the filtrate concentrated. Distillation of the residue
at reduced pressure (90–100 °C/0.05 torr) yielded compound 2
(23.8 g, 68%) as a colorless oil.
3-[3-(Dimethylamino)propyl]-4-[(1-methoxy-3-methyl-6-
phenyl)-5-hexyl]sydnone (6)
NaH (50%, 10 mg, 0.21 mmol) was washed with hexane twice and
cooled in an ice bath under argon. Compound 5 (50 mg) dissolved
in THF (5 mL) was added to this and the mixture was stirred for 30
min. MeI (11.7 mmol) was added to the above solution and the mix-
ture was allowed to warm to r.t. and was stirred for 1 h. This solu-
tion was diluted with H2O (10 mL) and extracted with EtOAc
(3 ¥ 10 mL). EtOAc extracts were dried (MgSO4), concentrated and
purified by passing through a basic alumina column to furnish com-
pound 6 (47 mg, 90%) as a pale yellow liquid.
IR (neat): 1739 cm–1.
1H NMR: d = 0.97 (d, J = 6.7 Hz, 3 H), 1.40–2.40 (m, 9 H), 2.16 (s,
6 H), 3.24 (s, 3 H), 4.42 (m, 3 H), 6.1–6.4 (m, 2 H), 7.1–7.4 (m, 5 H).
IR (neat): 3447(br), 1739 cm–1.
1H NMR: d = 1.15 (t, J = 7.2 Hz, 3 H), 1.54 (tt, J = 7.1, 7.3 Hz, 2
H), 2.08 (s, 6 H), 2.20 (t, J = 7.1 Hz, 2 H), 2.52 (t, J = 7.3 Hz, 2 H),
3.26 (s, 2 H), 4.05 (q, J = 7.2 Hz, 2 H).
13C NMR: d = 13.9 (CH3), 27.8 (CH2), 45.2 (CH3), 47.8 (CH2), 50.8
(CH2), 57.6 (CH2), 60.3 (CH2), 172.2 (C).
MS (EI, 70 eV): m/z (%) = 373 (M+, 1), 58 (100).
MS (EI, 20 eV): m/z (%) = 188 (M+, 2), 58 (100).
HRMS: m/z Calcd for C21H31N3O3 373.2365. Found 373.2358
HRMS: m/z Calcd for C9H20N2O2 188.1525. Found 188.1522.
1-[3-(Dimethylamino)propyl]-7-methoxy-5-methyl-3-phenyl-
1H-4,5,6,7-tetrahydroindazole (7)
Compound 6 (0.165 g, 0.44 mmol) was dissolved in xylene (2 mL)
and heated at 130 °C for 22 h. Xylene was removed by distillation
and residue was submitted to chromatography using MeOH and
Et3N (50:1) to provide compound 6 (66 mg, 46%).
3- [3-(Dimethylamino)propyl]sydnone (3)
NaOH (5.6 g, 0.139 mol) was added to a solution of 2 (20.0 g, 0.154
mol) in MeOH (150 mL) and the mixture was refluxed for 2 h. The
mixture was concentrated and treated with H2O (20 mL). HCl (37%,
51 mL) was slowly added to the above solution and to this, NaNO2
(12.8 g, 0.185 mol) dissolved in H2O (50 mL) was added over a pe-
riod of 45 min. The mixture was stirred for 45 min and then concen-
trated. Ac2O (100 mL) was added to the residue and heated at 90 °C
for 2 h. The solution was concentrated and aq NaHCO3 solution was
added until pH 7 and the mixture was extracted with CH2Cl2 (3 ¥ 50
mL). Organic layer was concentrated and the residue was passed
through a silica gel column eluting with MeOH to provide 3 (11.0
g, 42%) as a pale yellow liquid.
IR (neat): 3040, 2936, 2818, 1605, 1453, 1084 cm–1.
1H NMR: d = 1.10 (d, J = 6.7 Hz, 3 H), 1.40–1.55 (m, 1 H),1.70–
2.40 (m,7 H), 2.18 (s, 6 H), 2,79 (dd, J = 15.0, 4.5 Hz, 1 H), 3.40 (s,
3 H), 4.08–4.28 (m, 2 H), 4.40–4.60 (m, 1 H), 7.20–7.30 (m, 1 H),
7.32–7.40 (m, 2 H), 7.61–7.65 (m, 2 H).
13C NMR: d = 21.1 (CH3), 27.9 (CH2), 29.8 (CH), 30.5 (CH2), 36.4
(CH2), 44.9 (CH), 8.1 (CH2), 54.3 (CH3), 56.4 (CH2), 71.8 (CH),
115.2 (C), 125.5 (CH), 127.9 (CH), 133.8 (C), 139.1 (C), 143.2 (C).
IR (neat): 3141, 1743 cm–1.
MS (EI, 70 eV): m/z (%) = 327 (M+,14), 312 (M – 15, 39).
1H NMR: d = 2.04 (tt, J = 6.4, 7.0 Hz, 2 H), 2.18 (s, 6 H), 2.30 (t,
J = 6.4 Hz, 2 H), 4.32 (t, J = 7.0 Hz, 2 H), 6.32 (s, 1 H).
13C NMR: d = 26.4 (CH2), 44.8 (CH3), 51.0 (CH2), 54.8 (CH2), 94.9
(CH) 169.0 (C).
HRMS: m/z Calcd for C20H29N3O 327.2311. Found 327.2310.
Synthesis 2001, No. 12, 1775–1777 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of 1-[3-(Dimethylamino)propyl]-5-methyl-3-phenyl-1H-indazole
1777
1-[3-(Dimethylamino)propyl]-5-methyl-3-phenyl-1H-indazole
(1)
(2) Yip, C.; Handerson, S.; Tranmer, G. K. J. Org. Chem. 2001,
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To a solution of 7 (48 mg, 0.147 mmol) dissolved in AcOH (3 mL)
were added 10% Pt/C (3 mg, 0.0147 mmol) and HClO4 (0.3 mL)
and the mixture was refluxed for 40 h. Aq sat. NaHCO3 solution (10
mL) was added and the mixture was extracted with EtOAc (2 ¥ 20
mL), dried (MgSO4), filtered and concentrated. The residue was pu-
rified by passing it through a silica gel column and eluting with
MeOH–Et3N (50:1) to yield compound l (11 mg, 26%).
(3) Reiser, U.; Jauch, J.; Herdtweck, E. Tetrahedron:
Asymmetry 2000, 11, 3345.
(4) Huisgen, R.; Gotthardt, H.; Grashey, R. Angew. Chem., Int.
Ed. Engl. 1962, 1, 48.
(5) Huisgen, R.; Gotthardt, H.; Grashey, R. Angew. Chem., Int.
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33, 5697.
IR (neat): 3040, 2960, 2875, 2805, 1606, 1499, 1456, 1260 cm–1.
1H NMR: d = 2.12 (tt, J = 7.0, 6.9 Hz, 3 H), 2.21 (s, 6 H), 2.30 (t,
J = 7.0 Hz, 2 H), 2.47 (s, 3 H), 4.45 (t, J = 6.9 Hz, 2 H), 7.23 (m, 1
H), 7.37 (m, 2 H), 7.48 (t, J = 7.8 Hz, 2 H), 7.75 (s, 1 H), 7.93 (d,
J = 3 Hz, 2 H).
13C NMR: d = 21.4 (CH3), 27.9 (CH2), 45.3 (CH3), 46.64 (CH2),
56.5 (CH2),109.1 (CH), 120.2 (CH),121.8 (C),127.4 (CH), 127.6
(CH), 128.2 (CH), 128.7 (CH), 130.3 (C), 133.9 (C), 139.8 (C),
143.1 (C).
(12) Caron, S.; Vazquez, E. Synthesis 1999, 4, 588; and
references cited therein.
(13) Ikeda, Y.; Takano, N.; Matsushita, H.; Shiraki, Y.; Koide,
T.; Nagashima, R.; Fugimura, Y.; Shindo, M.; Suziki, S.;
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Ed.; Pergamon: Oxford, 1984, 167–303.
MS (EI, 70 eV): m/z (%) = 293 (M+, 26), 235 (100).
HRMS: m/z Calcd for C19H23N3 293.1892. Found 293.1900
Acknowledgement
This work was supported by the National Science Council of Repu-
blic of China.
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References
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Synthesis 2001, No. 12, 1775–1777 ISSN 0039-7881 © Thieme Stuttgart · New York