A simple and efficient asymmetric synthesis of anxiolytic drug enciprazine

Article abstract of DOI:10.1055/s-0030-1258173

A straightforward and efficient asymmetric synthesis of (S)-1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(3,4,5-trimethoxyphenoxy) propan-2-ol is described. The key intermediate, (S)-2-[(3,4,5-trimethoxyphenoxy) methyl]oxirane, was obtained by a hydrolytic kinetic resolution method using the catalyst (R,R)-salen-cobalt(III) complex. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258173

SHORT PAPER
2705
A Simple and Efficient Asymmetric Synthesis of Anxiolytic Drug Enciprazine
Synthesis of
A
nxio
.
lytic
Drug
E
V
nciprazine enkat Narsaiah,* B. Nagaiah
Organic Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160387; E-mail: vnakkirala2001@yahoo.com
Received 23 March 2010; revised 21 April 2010
derivatives with various heterocycles in the hydrophilic
Abstract: A straightforward and efficient asymmetric synthesis of
(S)-1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(3,4,5-trimethoxyphen-
oxy)propan-2-ol is described. The key intermediate, (S)-2-[(3,4,5-
trimethoxyphenoxy)methyl]oxirane, was obtained by a hydrolytic
part of the molecule have shown the highest anticonvul-
sive activity. Enciprazine [(S)-1-[4-(2-methoxyphe-
nyl)piperazin-1-yl]-3-(3,4,5-trimethoxyphenoxy)propan-
kinetic resolution method using the catalyst (R,R)-salen–cobalt(III) 2-ol, 1] is a non-benzodiazepine anxiolytic drug. As a
complex.
(phenoxy)(phenylpiperazinyl)propanol derivative, it ex-
hibits a broad spectrum of pharmacological activity, such
as cardiovascular, hypotensive, neurotropic, and local an-
esthetic properties (Figure 1).1e,2
Key words: trimethoxyphenol, resolution, chiral epoxide, meth-
oxybenzenamine
As part of our research program in the design and synthe-
sis of b-adrenoceptor antagonist molecules,3 herein we re-
port the asymmetric synthesis of (S)-enciprazine (1) using
the hydrolytic kinetic resolution method introduced by
Jacobsen.4 Advantages of this protocol are the ready
availability of the catalyst [(R,R)-salen–Co(III) complex],
the catalyst would be used in small quantities (0.5 mol%)
and is recyclable, and the use of 0.55 equivalents of water
as the solvent as well as reactant (Figure 1).
The aryloxyaminopropanol moiety is a general feature of
various b-adrenoreceptor blocking drugs (b-blockers).
Different substitution on the lipophilic or hydrophilic
parts of the molecule can modify the pharmacologic pro-
file as well as pharmacokinetics of the compounds. The
main clinical indications of b-blockers are in the area of
cardiovascular diseases, such as hypertension, angina
pectoris, myocardial infarction, and cardiac arrhythmias.1
However, some b-blockers readily access the brain be-
cause of their lipophilicity and can influence some central
nervous system functions.
OH
N
CHO
N
OMe
MeO
MeO
O
H
H
MeO
OMe
N
O
N
O
OMe
2
OMe
1
Co
OAc
Scheme 1
(R,R)-salen–Co(III) complex
As shown in the retrosynthetic analysis (Scheme 1), the
synthetic approach started from commercially available
3,4,5-trimethoxybenzaldehyde (2), which was treated
with 3-chloroperoxybenzoic acid in dichloromethane to
afford the 3,4,5-trimethoxyphenyl formate (3) in very
good yield. The thus obtained formate compound 3 was
reacted with potassium hydroxide in methanol to obtain
the hydrolysis product, 3,4,5-trimethoxyphenol (4), in ex-
cellent yield. Phenol compound 4 was reacted with epi-
chlorohydrin in presence of potassium carbonate to yield
rac-2-[(3,4,5-trimethoxyphenoxy)methyl]oxirane (5) in
very good yields (Scheme 2). This racemic epoxide is a
free-flowing liquid, which is an advantage when using the
hydrolytic kinetic resolution method which was used to
separate the enantioselective isomers of (S)-epoxide 6 and
(R)-1,2-diol 7 with excellent enantioselectivity.
OH
N
N
OMe
MeO
MeO
O
OMe
1
Figure 1
Therefore, propranolol has been used for treatment of
anxiety syndromes, prophylaxis of migraine headaches,
schizophrenia, alcohol withdrawal, and tremors. In a sim-
ilar manner, the newly developed aryloxyaminopropanol
Thus, the racemic epoxide 5 was treated with Jacobsen
catalyst (R,R)-salen–Co(OAc) (0.5 mol%) and water
(0.55 equiv) at room temperature for eight hours; the reac-
SYNTHESIS 2010, No. 16, pp 2705–2707
Advanced online publication: 12.07.2010
DOI: 10.1055/s-0030-1258173; Art ID: Z07610SS
x
x.
x
x
.
2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

2706
A. V. Narsaiah, B. Nagaiah
SHORT PAPER
1, CHCl3).2b All the products were characterized by their
1H NMR, IR, and mass spectroscopy data.
CHO
OCHO
b
a
In summary, we have described, a concise asymmetric
synthesis of (S)-enciprazine (1) in a highly enantioselec-
tive fashion. The key intermediate, the chiral epoxide 6,
was achieved by hydrolytic kinetic resolution method us-
ing Jacobsen’s catalyst with excellent enantioselectivity.
This method can be applied for large-scale preparation of
(S)-enciprazine.
MeO
OMe
MeO
OMe
O
OMe
2
OMe
3
OH
O
MeO
MeO
c
d
MeO
OMe
O
OMe
5
OMe
4
Melting points were recorded on Buchi R-535 apparatus. IR spectra
were recorded on a Perkin-Elmer FT-IR 240-c spectrophotometer
OH
1
O
using KBr optics. H NMR spectra were recorded on Bruker-300
O
OH
MeO
MeO
MeO
MeO
MHz spectrometer in CDCl3 using TMS as internal standard. Mass
spectra were recorded on a Finnigan MAT 1020 mass spectrometer
operating at 70 eV.
+
OMe
OMe
6
7
3,4,5-Trimethoxyphenyl Formate (3)
To a stirred soln of 3,4,5-trimethoxybenzaldehyde (2, 2 g, 10.2
mmol) in anhyd CH2Cl2 (20 mL) was added MCPBA (2.64 g, 15.3
mmol) in portions at 0 °C for a period of 30 min. After 1 h, cooling
was removed and the mixture was stirred at r.t. for 8 h (TLC moni-
toring). When no starting material remained (TLC), the mixture was
diluted with CH2Cl2 (40 mL) and washed with sat. NaHCO3 (2 × 20
mL). The organic layer was washed with brine (10 mL), dried
(Na2SO4), and concentrated under reduced pressure. The crude
product was obtained as red syrup; yield: 2 g (93%).
OMe
NH
OMe
Cl
Cl
+
NH2
HO
OH
N
e
f
N
N
H•HCl
H
11
10
9
8
O
HN
OMe
MeO
MeO
O
g
N
+
1
3,4,5-Trimethoxyphenol (4)
To a stirred soln of 3 (2 g, 9.43 mmol) in MeOH (10 mL) was added
KOH (0.5 g, 9.43 mmol) at 0 °C. The resulting mixture was stirred
at r.t. for 30 min. When the reaction was complete (TLC), the sol-
vent was removed under reduced pressure and washed with hexane
(20 mL). The residue obtained was dissolved in H2O (25 mL) and
acidified with dilute (1 M) HCl (to pH 5–6) with cooling to give a
solid that was filtered and dried; yield: 1.38 g (80%); mp 143–
145 °C.
OMe
6
11
Scheme 2 Reagents and conditions: (a) MCPBA, CH2Cl2, r.t., 8 h,
93%; (b) KOH, MeOH, r.t., 30 min, 80%; (c) epichlorohydrin,
K2CO3, TBAB (cat.), MeCN, reflux, 6 h, 90%; (d) (R,R)-salen–
Co(III) catalyst, H2O, 0 °C to r.t., 10 h, 46% (6), 48% (7); (e) SOCl2,
benzene, reflux, 5 h, 95%; (f) Na2CO3, H2O, reflux 24 h, 90%; (g)
i-PrOH, reflux, 15 h, 93%.
IR (KBr): 3270, 2999, 2957, 2843, 1611, 1515, 1485, 1432, 1342,
1272, 1225, 1184, 1130, 996, 814, 777, 740, 703 cm–1.
tion was monitored by HPLC (ODS-Column, UV:
225nm, 60% MeCN–H2O). When the reaction was com-
plete, the mixture was chromatographed on silica gel (60–
120 mesh) to give the enantioselective epoxide (S)-2-
[(3,4,5-trimethoxyphenoxy)methyl]oxirane (6) in 46%
yield with 94% ee with [a]D21 +3.5 (c 1, CHCl3). On fur-
ther elution of the column by increasing the polarity of the
mobile phase, (R)-3-(3,4,5-trimethoxyphenoxy)propane-
1,2-diol (7) was obtained in 48% yield with 97% ee with
[a]D21 –3.6 (c 1, CHCl3).
1H NMR (CDCl3): d = 3.61 (s, 3 H), 3.80 (s, 6 H), 6.01 (s, 2 H), 8.65
(br s, 1 H, OH).
MS (EI): m/z (%) = 184 (75) [M]+, 169 (100), 154 (10), 141 (50),
126 (25), 111 (30), 85 (15), 71 (10), 69 (40), 55 (20).
2-[(3,4,5-Trimethoxyphenoxy)methyl]oxirane (5)
To a stirred soln of 4 (1.3 g, 7 mmol) in anhyd MeCN (10 mL) was
added anhyd K2CO3 (2 g, 14 mmol) and epichlorohydrin (0.65 g, 7
mmol) and TBAB (cat.) at r.t. The resulting mixture was stirred at
reflux for 6 h (TLC monitoring). When the reaction was complete,
the solvent was removed under reduced pressure. The residue was
dissolved in H2O and extracted with EtOAc (2 × 20 mL). The com-
bined organic layers were washed with brine (10 mL) and dried
(Na2SO4) and concentrated under reduced pressure. The obtained
crude product was purified by column chromatography (silica gel,
60–120 mesh, EtOAc–hexane, 3:7) to give pure 5 as light-colored
liquid; yield: 1.52 g (90%).
In a similar manner, diethanolamine 8 was treated with
thionyl chloride in benzene at reflux condition to afford
the corresponding derivative of bis(2-chloroethyl)amine
hydrochloride (9) in very good yields. This hydrochloride
was reacted with o-ansidine in presence of a base to yield
1-(2-methoxyphenyl)piperazine (11) in good yields. The
chiral epoxide, (S)-2-[(3,4,5-trimethoxyphenoxy)meth-
yl]oxirane (6), and the amine, 1-(2-methoxyphenyl)piper-
IR (neat): 2936, 2838, 1598, 1506, 1459, 1423, 1344, 1231, 1194,
1128, 1056, 1007, 911, 814, 779, 629 cm–1.
azine (11), were refluxed in isopropyl alcohol for 15 hours 1H NMR (CDCl3): d = 2.69 (q, J = 2.3 Hz, 1 H), 2.88 (t, J = 4.5 Hz,
1 H), 3.20–3.30 (m, 1 H), 3.71 (s, 3 H), 3.80 (s, 6 H), 3.90 (q, J = 5.5
to afford the desired product (S)-1-[4-(2-methylphe-
Hz, 1 H), 4.12 (dd, J = 3.8, 3.8 Hz, 1 H), 6.12 (s, 2 H).
MS (EI): m/z (%) = 242 (100) [M + 2]+, 223 (10), 183 (10), 168 (12),
152 (20), 121 (15), 90 (22), 65 (20).
nyl)piperazin-1-yl]-3-(3,4,5-trimethoxyphenoxy)propan-
2-ol (enciprazine, 1) in excellent yields with [a]D21 +3.0 (c
Synthesis 2010, No. 16, 2705–2707 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of Anxiolytic Drug Enciprazine
2707
(S)-2-[(3,4,5-Trimethoxyphenoxy)methyl]oxirane (6)
13C NMR (75 MHz, CDCl3): d = 146.5, 137.3, 120.9, 116.5, 109.3,
A mixture of racemic epoxide 5 (3 g, 12.5 mmol) and (R,R)-salen–
Co(III)OAc complex (0.036 g, 0.062 mmol) was vigorously stirred
for 15 min at r.t. Then mixture was cooled to 0 °C and H2O (0.12
mL, 6.86 mmol) was added over a period of 30 min through syringe
pump. After complete addition of H2O, the cooling was removed
and stirring was continued at r.t. for 10 h [monitored by HPLC
(ODS-column, UV 225 nm, 60% MeCN–H2O)]. When the reaction
was complete, the mixture was diluted with EtOAc (30 mL), dried
(Na2SO4), and evaporated under reduced pressure. The residue was
chromatographed (silica gel, 60–120 mesh, EtOAc–hexane, 1:9).
The less polar epoxide 6 eluted first as light-colored liquid; yield:
1.3 g (46%); 94% ee; [a]D21 +3.5 (c 1, CHCl3). The chiral epoxide 6
was confirmed by its spectral data and similar to the racemic ep-
oxide 5. Changing the column eluent to EtOAc–hexane (4:6) pro-
vided the (R)-diol 7, which was obtained as a light-colored thick
syrup; yield: 1.5 g (48%); 97% ee.
61.8, 55.1, 45.7, 44.8, 43.5, 41.3.
MS (EI): m/z (%) = 192 (10) [M]+, 177 (10), 161 (10), 149 (15), 136
(100), 120 (60), 100 (20), 93 (10), 77 (15), 56 (20), 42 (10).
(S)-1-[4-(2-Methylphenyl)piperazin-1-yl]-3-(3,4,5-trimethoxy-
phenoxy)propan-2-ol ((S)-Enciprazine, 1)
To a stirred mixture of 6 (0.2 g, 0.83 mmol) in anhyd i-PrOH (5 mL)
was added 11 (0.19 g, 1 mmol) at r.t. The resulting mixture was re-
fluxed for 15 h (TLC monitoring). When the reaction was complete,
the solvent was removed under reduced pressure and residue was
dissolved in a minimal amount of EtOAc and adsorbed on silica gel,
and eluted with EtOAc–hexane (4:6). The pure product was ob-
tained as syrup; yield: 0.33 g (93%).
[a]D21 +3.0 (c 1, CHCl3).
IR (neat): 3456, 2925, 2854, 1746, 1461, 1375, 1163, 723 cm–1.
1H NMR (CDCl3): d = 3.30–3.40 (m, 2 H), 3.45–3.55 (m, 5 H), 3.70
(s, 3 H), 3.80 (s, 6 H), 3.88 (s, 4 H), 3.90–3.98 (m, 3 H), 4.15 (t,
J = 6.0 Hz, 2 H), 6.11 (s, 2 H), 6.91 (d, J = 6.5 Hz, 2 H), 7.01–7.10
(m, 1 H), 7.20–7.30 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 132.3, 129.8, 125.4, 124.1, 121.1,
111.7, 96.0, 92.3, 70.3, 67.1, 61.6, 60.7, 57.7, 55.3, 51.3, 44.4, 42.4.
MS (EI): m/z (%) = 433 (20) [M + 1]+, 418 (12), 326 (25), 250 (100),
242 (25), 184 (15), 169 (10), 154 (15), 138 (10), 123 (0), 92 (20),
84 (10), 76 (15), 56 (20), 42 (10).
(R)-3-(3,4,5-Trimethoxyphenoxy)propane-1,2-diol (7)
[a]D21 –3.6 (c 1, CHCl3).
IR (neat): 3409, 2937, 1599, 1506, 1459, 1423, 1346, 1230, 1194,
1157, 1126, 1056, 1006, 813, 778, 628 cm–1.
1H NMR (CDCl3): d = 3.60 (dd, J = 5.3, 6.0 Hz, 1 H), 3.68 (s, 3 H),
3.76 (d, J = 3.5 Hz, 1 H), 3.81 (s, 3 H), 3.80 (s, 3 H), 3.92 (d, J = 5.4
Hz, 2 H), 3.98–4.12 (m, 1 H), 6.12 (s, 2 H).
MS (EI): m/z (%) = 259 (100) [M + 1]+, 238 (10), 221 (15), 199 (10),
131 (10), 122 (25), 100 (52), 76 (10).
Bis(2-chloroethyl)amine Hydrochloride (9)
Acknowledgment
To a stirred mixture of diethanolamine (2 g, 19 mmol) in benzene
(10 mL) was added SOCl2 (6.8 g, 57 mmol) at 0 °C. The resulting
mixture was refluxed for 5 h and the solvent was distilled off under
reduced pressure. To the residue was added benzene (10 mL) and
the mixture was stirred for a period and then distilled again. A white
solid was obtained (3.23 g, 95%) and used directly.
B.N. is thankful to UGC-New Delhi for providing a fellowship.
References
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1-(2-Methoxyphenyl)piperazine (11)
To a stirred mixture of 9 (2.5 g, 14 mmol) and 10 (1.72 g, 14 mmol)
was added Na2CO3 soln [Na2CO3 (3 g) dissolved in H2O (15 mL)]
and TBAB (cat.) at r.t. The resulting mixture was refluxed for 24 h
(TLC monitoring). When the reaction was complete, the mixture
was cooled to r.t. and extracted with EtOAc (2 × 20 mL). The com-
bined organic layers were washed with brine (10 mL) and dried
(Na2SO4) and concentrated under reduced pressure. The crude prod-
uct was purified by column chromatography (silica gel, 60–120
mesh, EtOAc–hexane, 4:6) to give pure 11 as a light-colored, low-
melting solid; yield: 2.42 g (90%).
IR (KBr): 3405, 2931, 1748, 1601, 1519, 1486, 1436, 1364, 1320,
1267, 1223, 1178, 1136, 1096, 1044, 974, 903, 763, 740, 699, 663,
630 cm–1.
1H NMR (CDCl3): d = 3.35–3.45 (m, 2 H), 3.50–3.68 (m, 4 H), 3.84
(s, 3 H), 4.25–4.35 (m, 2 H), 6.55–6.88 (m, 4 H).
Synthesis 2010, No. 16, 2705–2707 © Thieme Stuttgart · New York