A simple and efficient synthesis of the antimigraine drug lomerizine

Article abstract of DOI:10.1055/s-0029-1218749

The synthesis of the antimigraine drug 1-[bis(4-fluorophenyl)methyl]-4-(2, 3,4-trimethoxybenzyl)piperazine has been carried out in very good yields. The five-step synthesis started from bis(4-fluorophenyl)methanone. This route can be applied for large-scale preparation of lomerizine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218749

SHORT PAPER
1989
A Simple and Efficient Synthesis of the Antimigraine Drug Lomerizine
Synthesis of the
A
.
ntimigraine
D
V
rug Lomerizine enkat Narsaiah,* J. Kranthi Kumar
Organic Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160387; E-mail: vnakkirala2001@yahoo.com
Received 24 February 2010; revised 3 March 2010
Abstract: The synthesis of the antimigraine drug 1-[bis(4-fluo-
OMe
rophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)piperazine has been
carried out in very good yields. The five-step synthesis started from
bis(4-fluorophenyl)methanone. This route can be applied for large-
scale preparation of lomerizine.
OMe
N
N
OMe
N
N
Key words: keto reduction, calcium chloride, trimethoxybenzyl
bromide, piperazine
F
F
Migraine is an inherited or acquired clinical syndrome
consisting of a variable combination of moderate-to-
severe pulsatile headache, gastrointestinal disturbance,
photophobia, phonophobia, and malaise. Migraine has
traditionally been considered to be associated with chang-
es in the caliber of blood vessels in the head. Several in-
F
F
lomerizine
flunarizine
N
N
O
vestigators have reported findings that imply
a
pathophysiological and epidemiological relationship be-
tween migraine and glaucoma. Glaucoma is the second
leading cause of preventable blindness in the world and an
important risk factor for the disease is increased pressure
within the eye, which is thought to damage the optic nerve
and eventually lead to blindness.
F
lidoflazine
F
Figure 1 Structures of lomerizine and other related piperazine deri-
The successful development of a product capable of di-
rectly protecting the retina and optic nerve from glauco-
matous damage would represent a significant advance in
the treatment of this sight-threatening disease.1 1-[Bis(4-
fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)pipera-
zine dihydrochloride (lomerizine, Figure 1) is a newly
synthesized Ca2+ channel blocker developed for use as a
potential antimigraine drug. Indeed, among the existing
Ca2+ channel blockers, lomerizine is one of the most se-
lective for the CNS and cerebral arteries. Furthermore, it
has been reported to inhibit both T-type and L-type Ca2+
currents to prevent glutamate-induced neurotoxicity and
to exhibit protective effects of migraine, ischemia, and hy-
poxia. These characteristics suggest that lomerizine is bet-
ter suited than other Ca2+ channel blockers for ophthalmic
use.2 The literature reports3 for the synthesis of lomerizine
show that it was carried out by the reductive amination of
trimethoxybenzaldehyde with a piperazine derivative at
high temperature in the presence of formic acid. As part of
our research program in design and synthesis of biologi-
cally active molecules,4 herein we report a highly efficient
route for the synthesis of lomerizine as shown in
Scheme 1.
vatives
Our synthetic strategy started from commercially avail-
able bis(4-fluorophenyl)methanone (2), which on reduc-
tion with sodium borohydride in methanol5 at room
temperature afforded the corresponding product, bis(4-
fluorophenyl)methanol (3), in excellent yield. Bis(4-fluo-
rophenyl)methanol (3) was treated with hydrochloric acid
at reflux to yield the corresponding chloro derivative,
4,4¢-(chloromethylene)bis(fluorobenzene) (4), in very
good yield. This chloro compound was used for further re-
action without purification. The thus-obtained chloro
compound 4 was subjected to further reaction with piper-
azine in the presence of potassium carbonate at THF
reflux to yield the corresponding product, 1-[bis(4-fluo-
rophenyl)methyl]piperazine (5), in very good yield. This
was reacted with 2,3,4-trimethoxybenzyl bromide (7)6 in
the presence of potassium carbonate in acetonitrile at
reflux to afford the target molecule, 1-[bis(4-fluorophe-
nyl)methyl]-4-(2,3,4-trimethoxybenzyl)piperazine (1), in
very good yields. All the products were characterized by
1H NMR and IR spectroscopy and mass spectrometry.
In conclusion, we have reported a simple and efficient
synthetic pathway for the preparation of antimigraine
drug lomerizine. This route is very convenient for the
large-scale preparation of lomerizine.
SYNTHESIS 2010, No. 12, pp 1989–1991
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2
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0
Advanced online publication: 19.04.2010
DOI: 10.1055/s-0029-1218749; Art ID: Z04510SS
© Georg Thieme Verlag Stuttgart · New York

1990
A. V. Narsaiah, J. K. Kumar
SHORT PAPER
H
N
OH
O
Cl
N
a
b
c
F
F
F
F
F
F
F
F
2
3
4
5
OMe
OMe
N
OMe
OH
OMe
Br
OMe
N
d
e
MeO
+
5
MeO
OMe
OMe
F
F
7
6
1
Scheme 1 Reagents and conditions: (a) NaBH4, MeOH, 0 °C to r.t., 2 h, 96%; (b) CaCl2, concd HCl, reflux, 10 h, 96%; (c) piperazine, K2CO3,
THF, reflux, 8 h, 90%; (d) PBr3, Et2O, 0 °C to r.t., 1 h, 93%; (e) 2,3,4-trimethoxybenzyl bromide, MeCN, K2CO3, reflux, 10 h, 90%.
IR spectra were recorded on a Perkin-Elmer FT-IR 240-c spectro-
photometer using KBr optics. 1H NMR spectra were recorded on a
Bruker Avance-300 spectrometer in CDCl3 using TMS as internal
standard. Mass spectra were recorded on a Finnigan MAT 1020
mass spectrometer operating at 70 eV.
tert-butylammonium iodide (PTC) at r.t. The resulting reaction
mixture was refluxed for 8 h. After completion of the starting mate-
rial as indicated by TLC, the solvent was removed under reduced
pressure. The afforded residue was extracted with EtOAc (2 × 30
mL). The combined organic layers were washed with brine (20
mL), dried (Na2SO4), and concentrated under reduced pressure to
obtain the crude product, which was purified by column chromatog-
raphy on silica gel using EtOAc–hexane (3:7) as eluent. The pure
product was obtained as a thick liquid; yield: 2.24 g (90%).
Bis(4-fluorophenyl)methanol (3)
To a stirred solution of bis(4-fluorophenyl)methanone (2; 2.0 g,
9.16 mmol) in MeOH (20 mL) was added NaBH4 (0.52 g, 13.76
mmol) at 0 °C in portions. The resulting reaction mixture was
stirred at r.t. for 2 h. After completion of the reaction as indicated
by TLC, the mixture was quenched by adding crushed ice. Then, the
solvent was removed under reduced pressure and extracted with
EtOAc (2 × 30 mL). The combined organic layers were washed
with brine (20 mL), dried (Na2SO4), and concentrated under re-
duced pressure. The obtained crude product was purified by column
chromatography on silica gel using EtOAc–hexane (2:8) as eluent;
yield: 1.92 g (96%); colorless thick syrup.
IR (KBr): 3428, 2924, 2850, 1603, 1567, 1506, 1385, 1220, 1152,
1092, 1046, 1005, 871, 826, 783, 717 cm–1.
1H NMR (CDCl3): d = 2.35 (br s, 1 H, OH), 5.68 (s, 1 H), 6.90–7.02
(m, 4 H), 7.20–7.30 (m, 4 H).
EIMS: m/z (%) = 289 (M+ + 1, 60), 242 (27), 204 (42), 203 (100),
95 (10), 76 (20), 51 (10).
1-[Bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)pip-
erazine (1, Lomerizine)
IR (neat): 3379, 2884, 1604, 1508, 1414, 1298, 1226, 1182, 1157,
1099, 1015, 865, 833, 778 cm–1.
1H NMR (CDCl3): d = 2.35 (br s, 1 H, OH), 5.68 (s, 1 H), 6.90–7.02
(m, 4 H), 7.20–7.30 (m, 4 H).
To a stirred solution of compound 5 (1.0 g, 3.47 mmol) in MeCN
(10 mL) was added 1-(bromomethyl)-2,3,4-trimethoxybenzene (7;
0.9 g, 3.47 mmol) and K2CO3 (1.0 g, 6.94 mmol) and a catalytic
amount (100 mg) of tert-butylammonium iodide at r.t. The resulting
reaction mixture was refluxed for 10 h. After completion of the
starting material as indicated by TLC, the solvent was removed un-
der reduced pressure. The afforded residue was extracted with
EtOAc (2 × 15 mL). The combined organic layers were washed
with brine (20 mL), dried (Na2SO4), and concentrated under re-
duced pressure to obtain the crude product, which was purified by
column chromatography on silica gel using EtOAc–hexane (2:8) as
eluent. The pure product was obtained as a syrup; yield: 1.5 g
(90%).
EIMS: m/z (%) = 220 (10), 203 (15), 186 (10), 173 (12), 130 (10),
118 (25), 102 (100).
4,4¢-(Chloromethylene)bis(fluorobenzene) (4)
To a mixture of alcohol 3 (1.92 g, 8.72 mmol) in concd HCl (10 mL)
was added CaCl2 (1.34 g, 12.2 mmol) at r.t. The resulting reaction
mixture was heated at 95–100 °C for 10 h. Then, the mixture was
cooled to r.t. and extracted with EtOAc (2 × 30 mL). The combined
organic layers were washed with brine (20 mL), dried (Na2SO4),
and concentrated under reduced pressure to obtain the crude prod-
uct; yield: 2.0 g (96%).
IR (neat): 3443, 2938, 2825, 1650, 1602, 1502, 1464, 1418, 1286,
1224, 1155, 1098, 1046, 1010, 964, 902, 827, 755, 667 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.35 (br s, 4 H), 2. 48 (br s, 4 H),
3.48 (s, 2 H), 3.81 (s, 6 H), 3.83 (s, 3 H), 4.18 (s, 1 H), 6.55 (d,
J = 8.3 Hz, 1 H), 6.92 (t, J = 8.3 Hz, 5 H), 7.25–7.35 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 162.7, 160.3, 152.8, 152.4, 138.1,
129.0, 125.1, 123.1, 115.2, 106.7, 74.3, 60.9, 56.0, 55.7, 52.8, 51.5.
1H NMR (CDCl3): d = 6.18 (s, 1 H), 7.03 (t, J = 7.8 Hz, 4 H), 7.33
(t, J = 7.8 Hz, 4 H).
1-[Bis(4-fluorophenyl)methyl]piperazine (5)
To a stirred mixture of the above chloro compound 4 (2.0 g, 8.4
mmol) in THF (20 mL) was added piperazine (0.72 g, 8.4 mmol)
and K2CO3 (2.32 g, 16.8 mmol) and a catalytic amount (100 mg) of
Synthesis 2010, No. 12, 1989–1991 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of the Antimigraine Drug Lomerizine
1991
EIMS: m/z (%) = 470 (M+ + 2, 30), 469 (M+ + 1, 100), 201 (10), 181
(25).
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Acknowledgment
The author J.K.K. is thankful to UGC-New Delhi for providing a
fellowship.
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Synthesis 2010, No. 12, 1989–1991 © Thieme Stuttgart · New York