A simple synthesis of the novel antihistaminic drug olopatadine hydrochloride

Article abstract of DOI:10.1055/s-0033-1340008

A new alternative route for the synthesis of olopatadine is described. The present strategy involves a Lewis acid mediated ring opening of a cyclic ether to introduce 3-(dimethylamino)propylidene group as the side chain. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0033-1340008

PAPER
▌3399
paper
A Simple Synthesis of the Novel Antihistaminic Drug Olopatadine
Hydrochloride
Synthesis of the Antihistaminic Drug Olopatadine
Subhash P. Chavan,* Pradeep B. Lasonkar
Division of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune 411008, India
Fax +91(20)5892629; E-mail: sp.chavan@ncl.res.in
Received: 04.07.2013; Accepted after revision: 18.09.2013
O
Abstract: A new alternative route for the synthesis of olopatadine
is described. The present strategy involves a Lewis acid mediated
ring opening of a cyclic ether to introduce 3-(dimethylamino)pro-
pylidene group as the side chain.
O
11
2
OH
NMe2
Key words: antihistaminic drugs, chelates, zinc, spiro compounds,
Lewis acids
1
Figure 1 Structure of olopatadine
Olopatadine hydrochloride is a top selling antihistaminic
drug ranked in the ‘Top 200 Brand Name Drugs by total
US prescriptions in 2010’.1 It is a selective histamine H1
receptor (H1R) antagonist. Olopatadine (1) is used for the
treatment of ocular symptoms of seasonal allergic con-
junctivitis. The compound may be administered in a solid
oral dosage form such as ‘allelock®’ tablets, as ophthal-
mic solution form ‘pataday®’, ‘patanol®’ and nasal spray
‘patanase®’. Olopatadine was developed by Kyowa Hakko
Kirin Co. Ltd. and is produced commercially using Wittig
reaction as the key step.2 Structure–activity relationship
studies have revealed that the key structural features re-
quired for the enhanced antiallergic activities are: a 3-(di-
methylamino)propylidene group as the side chain at C-11,
a terminal carboxyl moiety at C-2, and a dibenzoxepin
ring system. Although both Z- and E-isomers of 1 show
similar H1R affinities,3 only the Z-isomer is marketed as a
drug. Because of the potent antiallergic activity of 1, there
is a huge interest for the stereoselective generation of the
Z-isomer of olopatadine (Figure 1).
Literature review reveals a number of synthetic strategies
to access olopatadine, mostly in the form of patents.4 In
most of the syntheses, the key side chain has been intro-
duced via ‘Grignard reaction’ or ‘Wittig olefination’.2a,4d
In most of the previous approaches, the main drawback
has been the low E/Z stereoselectivity. Recently, Bosch et
al. have utilized a stereoselective Heck reaction for the se-
lective generation of Z-isomer via the intramolecular cy-
clization of an E-alkene intermediate.5 Nishimura et al.
also reported a stereospecific route to 1 under palladium
catalysis. In their synthetic route, the Z-stereoselectivity
was controlled by an intramolecular stereospecific seven-
membered ring cyclization from an alkyne intermediate
using palladium catalyst.6 Unfortunately most of the re-
ported syntheses involve expensive reagents and harsh re-
action conditions, which are operationally difficult to
perform on a large scale. Herein we describe a new and
simple synthetic route for olopatadine.
The envisaged retrosynthetic strategy for (1) is delineated
in Scheme 1. A linear synthetic strategy was invoked
wherein homoallyl alcohol 2 was conceived as the ideal
O
O
O
O
O
O
O
OH
OMe
OMe
NMe2
OH
2
3
1
O
O
O
O
OMe
HO
OH
O
4
5
Scheme 1 Retrosynthetic analysis of olopatadine (1)
SYNTHESIS 2013, 45, 3399–3403
Advanced online publication: 23.10.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1340008; Art ID: SS-2013-T0457-OP
© Georg Thieme Verlag Stuttgart · New York

3400
S. P. Chavan, P. B. Lasonkar
PAPER
O
O
i) SOCl2, MeOH
24 h, r.t., >99%
9-BBN
NaOH, H2O2
O
O
OH
ii) Zn, allyl bromide
DMF, 2 h, 91%
THF, 24 h, 84%
HO
O
5
OMe
4
O
O
O
O
O
O
Table 1
+
O
HO
OMe
OMe
OMe
OH
OH
6
2
3
Scheme 2 Synthesis of diol 6 and its acid-mediated dehydration
precursor to 1. Homoallyl alcohol 2 upon mesylation, di- the undesired E-olefin along with the generation of the
methylamination, and hydrochlorination would lead to spiroether 3 (Scheme 2).
olopatadine hydrochloride salt. Homoallyl alcohol 2 in
turn could be prepared from the cyclic spiroether 3 by
Lewis acid mediated ether ring opening. Cyclic spiroether
3 in turn could be obtained from known intermediate 2-
(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid
(5, also known as isoxepac) through routine functional
The diol 6 was treated with both protic as well as Lewis
acids. It was found that inorganic protic acids led to the
formation of cyclic ether 3 as the major or exclusive prod-
uct (Table 1, entries 1 and 2), while organic acids fur-
nished the olefin as the major product (entries 3 and 4). It
was observed that treatment of diol 6 with catalytic p-tol-
group manipulations such as Barbier reaction to introduce
uenesulfonic acid (PTSA) at ambient temperature instant-
the allyl group, followed by hydroboration and ether for-
ly formed a spirotetrahydrofuran ring 3 in almost
quantitative yield (entry 5) whereas the treatment of 6
mation.
According to the proposed plan, synthesis of olopatadine with Lewis acid (Et2O·BF3) at room temperature led to the
(1) started from isoxepac (5),7 which on treatment with formation of cyclic ether 3 along with the formation of
thionyl chloride in methanol gave the corresponding isox- olefin 2 as the minor product (entry 6).
epac methyl ester in quantitative yield. Barbier reaction
on the methyl ester with allyl bromide in the presence of
However, when the reaction was carried out at elevated
temperature the olefin 2 was the only product formed (Ta-
ble 1, entry 7). In both the cases the E/Z ratio was 3:2, in
favor of the unwanted isomer. From this it was clear that
zinc powder in DMF as the solvent furnished the allylic
alcohol 4 in 91% yield8 (Scheme 2).
Hydroboration of 4 with 9-BBN followed by quenching diol 6 was transformed to spiroether 3 under the influence
with sodium hydroxide and hydrogen peroxide afforded of Lewis acid, and then the spiroether 3 opened to give the
the diol 6.9 In order to introduce the exocyclic double olefin 2. Since the olefin 2 obtained from diol 6 gave at
bond by acid-mediated dehydration of diol 6, several con- best a ratio of E/Z = 3:2, it was decided to study the behav-
ditions were screened as shown in Table 1. Almost all the ior of spiroether 3 under the influence of a variety of
reaction conditions led to the predominant formation of Lewis acids.
Table 1 Acid-Mediated Dehydration of Diol 6
Entry
Reagenta
Time (h)
Temp
Yield 2 (%)
Yield 3 (%)
E/Zb of 2
1
2
3
4
5
6
7
HCl
24
24
32
14
0.25
6
r.t.
none
30
90
–
H2SO4
HCO2H
PPTSc
r.t.
53
4:1
4:1
4:1
–
r.t.
45
32
80 °C
r.t.
59
10
PTSA
none
22
99
Et2O·BF3
Et2O·BF3
0 °C
50 °C
64
3:2
3:2
0.5
95
none
a CH2Cl2 was used as solvent.
b E/Z ratio was confirmed by 1H NMR spectroscopy and HPLC.
c EtOH was used as solvent.
Synthesis 2013, 45, 3399–3403
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of the Antihistaminic Drug Olopatadine
3401
O
O
i) MsCl
pyridine, 2 h
Table 2
ref. 2a
O
O
3
1
ii) Me2NH (50%)
MeOH, 3 h
OMe
OMe
OH
NMe2
84% over two steps
2
7
Scheme 3 Lewis acid mediated ether opening of spiroether 3 and the formation of 7
In order to improve the Z-selectivity, we screened differ-
6
4
O
ent Lewis acids and their combination with base as sum-
marized in Table 2. Amongst various Lewis acids
screened, we observed that AlCl3 gave the best result.
Thus, spiroether 3 on treatment with 2.5 equivalents of
AlCl3 resulted in the formation of homoallyl alcohol 2 in
2
11
1'
O
12
13
3'
M
H
5'
O
OMe
Figure 2 Plausible mechanism for the stereoselectivity towards Z-
isomer
95% yield with an E/Z ratio of 2:3 (Scheme 3). Attempts
to separate the isomers by AgNO3 column chromatogra-
phy failed. As compound 2 was solid, we attempted to
separate the isomers by preferential recrystallization. The
E/Z ratio could be improved to 1:9 after two recrystalliza-
tions.10
To complete the synthesis, the isomeric mixture (E/Z =
1:9) of homoallyl alcohol 2 was subjected to mesylation
and dimethylamination resulting in compound 7 in 84%
yield (Scheme 3). Ohshima et al.2a have reported the sa-
ponification of 7 and E/Z-isomer separation of the corre-
sponding acid. The spectroscopic data of 7 was in good
agreement with the reported values.2,5,6
Table 2 Lewis Acid Mediated Ether Opening of Spiroether 3
Reagenta
Time
Temp
Yield (%) E/Zb
Et2O·BF3
AlCl3
AlCl3
TiCl4
6 h
0 °C to r.t.
r.t.
93
96
95
39
81
82
60
83
92
91
3:2
1:1
2:3
4:1
2:1
3:2
3:2
2:1
1:1
4:1
In summary, we have developed a novel and concise syn-
thetic route to the antihistaminic drug, olopatadine hydro-
chloride, in seven steps with 59% overall yield. Lewis
acid mediated ring opening of the cyclic ether 3 resulted
in the formation of the desired Z-isomer of 2 (E/Z = 2:3)
as the major component, which could be improved to E/Z
= 1:9 after two recrystallizations. The present method is
operationally simple and has several advantages com-
pared to the conventional methods of manufacturing
olopatadine hydrochloride,2a where a large excess of the
reagent is required and the reaction has to be performed
under strict anhydrous conditions.
10 min
7 h
0 °C to r.t.
0 °C to r.t.
0 °C to r.t.
0 °C to r.t.
0 °C to r.t.
MW
12 h
SnCl4
SbF5
5 h
30 min
24 h
InCl3
AlCl3
6 min
AlCl3 + PhNMe2 18 h
r.t.
AlCl3 + DBU
30 min
0 °C to r.t.
All reagents and solvents were used as received from the manufac-
turer. Petroleum ether (PE) used refers to the fraction boiling in the
range of 60–80 °C. Melting points are recorded using Büchi B-540
melting point apparatus in capillary tubes and are uncorrected. IR
spectra were recorded on a PerkinElmer IR spectrophotometer
Model 68B or on a PerkinElmer 1615 FT IR spectrophotometer. 1H
(200, 400, and 500 MHz) and 13C (50, 100, and 125 MHz) NMR
spectra were recorded on Bruker and Bruker Avance 400 spectrom-
eters, using a 1:1 mixture of CDCl3 and CCl4 as solvent. The chem-
ical shifts (δ) and coupling constants (Hz) are reported in the
a CH2Cl2 was used as solvent.
b E/Z ratio was confirmed by 1H NMR spectroscopy and HPLC.
Although the exact mechanism of this reaction remains to
be elucidated, the plausible mechanism for the stereose-
lectivity towards Z-isomer (major) could be explained by
considering the metal coordination. The Lewis acid first
chelates with the 1′-oxygen of furan ring and the metal co-
ordinates with oxygen of C-13 (Figure 2). Opening of the
furan ring results in the formation of Z-isomer as the ma-
jor isomer.
1
standard fashion with reference to CHCl3 (δ = 7.26, for H) or the
central line (δ = 77.0 of CDCl3 for 13C). In the 13C NMR spectra, the
nature of the carbons (C, CH, CH2, or CH3) was determined by re-
cording the DEPT-135 spectra. HRMS (ESI) were taken on Orbi-
trap (quadrupole plus ion trap) and TOF mass analyzer. Standard
abbreviations were used to explain the multiplicities of the signals.
The reaction progress was monitored by the TLC analysis on TLC
plates precoated with silica gel 60 F254 (Merck) and visualized by
fluorescence quenching or I2 or by charring after treatment with p-
anisaldehyde and also 2,4-DNP. Merck’s flash silica gel (230–400
mesh) was used for column chromatography.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3399–3403

3402
S. P. Chavan, P. B. Lasonkar
PAPER
Methyl 2-(11-Allyl-11-hydroxy-6,11-dihydrodibenzo[b,e]oxe-
pin-2-yl)acetate (4)
CH2Cl2 (3 × 20 mL), and the combined organic layers were washed
with brine (30 mL), dried (Na2SO4), filtered, and concentrated un-
der reduced pressure. The crude product was column-purified over
silica gel (PE–EtOAc, 9:1) to furnish the spiroether 3 (2.81 g, 99%)
as a colorless liquid; Rf = 0.7 (PE–EtOAc, 8:2).
2-(11-Oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid (5;
5.00 g, 18.65 mmol) was dissolved in MeOH (100 mL) and cooled
to 0 °C. SOCl2 (2.06 mL, 27.98 mmol) was added dropwise over 30
min and the resulting solution was stirred at r.t. for 24 h. The solvent
was evaporated almost to dryness and the residue was partitioned
between CH2Cl2 (50 mL) and sat. aq NaHCO3 (50 mL). The organic
layer was separated, dried (Na2SO4), filtered, and concentrated un-
der reduced pressure to give isoxepac ester, which was used without
further purification. To a stirred mixture of isoxepac ester (5.00 g,
17.66 mmol) and Zn (3.44 g, 53 mmol) in DMF (50 mL) was added
allyl bromide (1.66 mL, 19.43 mmol) at 0 °C. After 2 h, the mixture
was filtered to remove the excess Zn. Aq 10% HCl (20 mL) was
added and the organic layer was separated. The aqueous layer was
extracted with small portions of EtOAc (3 × 20 mL), the combined
organic extracts were dried (Na2SO4), filtered, and concentrated un-
der reduced pressure. The resulting liquid was purified by column
chromatography (PE–EtOAc, 8:2) to give 4 (5.2 g, 91% over two
steps) as a thick colorless liquid; Rf = 0.5 (PE–EtOAc, 8:2).
IR (CHCl3): 2926, 1738, 1488 cm–1.
1H NMR (400 MHz, CDCl3 + CCl4): δ = 1.87–1.99 (m, 2 H), 2.56–
2.72 (m, 2 H), 3.59 (s, 2 H), 3.69 (s, 3 H), 4.33–4.17 (m, 2 H), 5.02
(d, J = 15.3 Hz, 1 H), 5.56 (d, J = 15.3 Hz, 1 H), 6.97 (d, J = 7.2 Hz,
1 H), 7.03 (d, J = 8.03 Hz, 1 H), 7.10–7.26 (m, 3 H), 7.51 (s, 1 H),
7.74 (d, J = 7.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3 + CCl4): δ = 25.9, 40.7, 42.6, 51.9,
68.9, 72.9, 85.1, 121.4, 124.5, 126.2 (2C), 126.9, 127.0, 129.21,
129.27, 133.6, 140.2, 143.4, 153.9, 172.0.
HRMS (ESI): m/z [M + H]+ calcd for C20H21O4: 325.1434; found:
325.1437.
Methyl 2-[11-(3-Hydroxypropylidene)-6,11-dihydrodiben-
zo[b,e]oxepin-2-yl]acetate (2)
IR (CHCl3): 3482, 3073, 2951, 1735, 1490 cm–1.
To an ice cold (0 °C), magnetically stirred solution of spiroether 3
(2.00 g, 6.12 mmol) in anhydrous CH2Cl2 (25 mL) was added anhy-
drous crystalline AlCl3 (2.05 g, 15.43 mmol) in one portion under
N2. The resulting mixture was warmed to r.t. and the red-orange re-
action mixture was stirred at r.t. until the completion of reaction (7
h, by TLC, eluent: PE–EtOAc, 6:4). The mixture was then poured
into an ice cooled 10% aq HCl (20 mL) and the aqueous layer was
extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts
were dried (Na2SO4), filtered, and concentrated under reduced pres-
sure. The crude mixture was purified by silica gel column chroma-
tography (PE–EtOAc, 7:3) to afford 2 (1.9 g, 95%) as a white solid;
mp 102–104 °C; Rf = 0.4 (PE–EtOAc, 6:4).
1H NMR (200 MHz, CDCl3 + CCl4): δ = 2.86–2.97 (m, 1 H), 3.34–
3.44 (m, 1 H), 3.60 (s, 2 H), 3.68 (s, 3 H), 5.04 (d, J = 15.5 Hz, 1 H),
5.09–5.18 (m, 2 H), 5.47 (d, J = 15.5 Hz, 1 H), 5.35–5.56 (m, 1 H),
6.90–7.00 (m, 1 H), 7.06 (d, J = 8.1 Hz, 1 H), 7.15–7.31 (m, 3 H),
7.56 (d, J = 2.2 Hz, 1 H), 7.94–7.84 (m, 1 H).
13C NMR (50 MHz, CDCl3 + CCl4): δ = 40.5, 48.7, 51.8, 73.6, 75.7,
119.4, 121.3, 125.8, 125.9, 126.8, 127.0, 127.5, 129.5 (2 C), 133.5,
134.5, 139.0, 142.1, 154.7, 171.9.
HRMS (ESI): m/z [M + H]+ calcd for C20H21O4: 325.1434; found:
325.1433.
IR (CHCl3): 3446, 2921, 1736, 1463 cm–1.
Methyl 2-[11-Hydroxy-11-(3-hydroxypropyl)-6,11-dihydro-
dibenzo[b,e]oxepin-2-yl]acetate (6)
1H NMR (200 MHz, CDCl3 + CCl4): δ = 2.38–2.49 (m, 0.8 H, E-
isomer), 2.63–2.73 (m, 1.2 H, Z-isomer), 3.53 (s, 2 H), 3.68 (s, 3 H),
3.69–3.75 (m, 0.8 H, E-isomer), 3.81 (t, J = 6.3 Hz, 1.2 H, Z-iso-
mer), 5.19 (br s, 2 H), 5.73 (t, J = 7.8 Hz, 0.6 H, Z-isomer), 6.06 (t,
J = 7.8 Hz, 0.4 H, E-isomer), 6.70 (d, J = 8.2 Hz, 0.4 H, E-isomer),
6.79 (d, J = 8.2 Hz, 0.6 H, Z-isomer), 7.00–7.34 (m, 6 H).
9-BBN (1.80 g, 14.81 mmol) was added to a well-stirred solution of
olefin 4 (4.00 g, 12.34 mmol) in anhydrous THF (40 mL) at r.t. and
the reaction mixture was stirred for 24 h at 70 °C. The mixture was
quenched with aq 3 M NaOH (0.54 g, 13.50 mmol) at 0 °C, fol-
lowed by the dropwise addition of 30% H2O2 (3.50 mL, 37.03
mmol). The resulting solution was stirred for 6 h at r.t. to cleave the
boron complex. The organic phase was separated and the aqueous
layer extracted with EtOAc (3 × 20 mL). The combined organic
phases were washed with brine (30 mL), dried (Na2SO4), filtered,
and concentrated under reduced pressure. The crude product was
purified by column chromatography (PE–EtOAc, 7:3) to afford diol
6 (3.54 g, 84%) as a colorless liquid; Rf = 0.4 (PE–EtOAc, 1:1).
HRMS (ESI): m/z [M + H]+ calcd for C20H21O4: 325.1434; found:
325.1437.
Methyl 2-{11-[3-(Dimethylamino)propylidene]-6,11-dihydro-
dibenzo[b,e]oxepin-2-yl}acetate (7)
To homoallyl alcohol 2 (1.00 g, 3.08 mmol) in pyridine (16 mL)
was added MsCl (0.95 mL, 11.72 mmol) gradually at 0 °C. The re-
action mixture was allowed to come to r.t. and stirred for further 2
h. The mixture was quenched with H2O (5 mL) and then extracted
with EtOAc (2 × 20 mL). The combined organic layers were
washed with brine (10 mL) and concentrated. To a solution of the
resulting oil in MeOH (20 mL) was added 50% aq Me2NH (5.20
mL, 18.0 equiv) and the mixture was stirred under reflux for 3 h.
The solvent was evaporated and the residue extracted with EtOAc
(2 × 20 mL). The combined organic layers were washed with brine
(10 mL), dried (Na2SO4), filtered, and concentrated under reduced
pressure. The crude reaction mixture was purified by silica gel col-
umn chromatography (CH2Cl2–MeOH, 97:3) to give 7 (0.91 g, 84%
over two steps) as a pale yellow liquid; Rf = 0.4 (MeOH).
IR (CHCl3): 3502, 2949, 1735, 1491 cm–1.
1H NMR (200 MHz, CDCl3 + CCl4): δ = 1.20–1.56 (m, 2 H), 2.08–
2.28 (m, 1 H), 2.64–2.89 (m, 1 H), 3.36–3.64 (m, 4 H), 3.67 (s, 3 H),
4.84 (br s, 1 H), 5.01 (d, J = 15.4 Hz, 1 H), 5.43 (d, J = 15.4 Hz, 1
H), 6.93 (d, J = 7.2 Hz, 1 H), 6.98–7.32 (m, 4 H), 7.62 (d, J = 2.2
Hz, 1 H), 7.97 (d, J = 7.5 Hz, 1 H).
13C NMR (50 MHz, CDCl3 + CCl4): δ = 27.3, 40.4, 41.9, 52.0, 62.7,
73.7, 76.6, 121.2, 125.8, 126.2, 126.9 (2 C), 128.3, 129.3 (2 C),
134.4, 139.7, 143.4, 154.9, 172.6.
HRMS (ESI): m/z [M + Na]+ calcd for C20H22O5 + Na: 365.1359;
found: 365.1360.
IR (CHCl3): 1740, 1495, 1221 cm–1.
Methyl 2-[4′,5′-Dihydro-3′H,6H-spiro(dibenzo[b,e]oxepine-
11,2′-furan)-2-yl]acetate (3)
1H NMR (200 MHz, CDCl3 + CCl4): δ = 2.15 (s, 2 H), 2.24 (s, 4 H),
2.31–2.62 (m, 4 H), 3.51 (s, 2 H), 3.67 (s, 3 H), 4.73 (br s, 1 H), 5.45
(br s, 1 H), 5.69 (t, J = 7.1 Hz, 0.6 H, Z-isomer), 6.02 (t, J = 6.9 Hz,
0.4 H, E-isomer), 6.69 (d, J = 8.3 Hz, 0.4 H, E-isomer), 6.78 (d, J =
8.3 Hz, 0.6 H, Z-isomer), 6.98–7.37 (m, 6 H).
To a solution of the diol 6 (3.00 g, 2.50 mmol) in anhydrous CH2Cl2
(30 mL) in an oven-dried flask under a N2 atmosphere was added
PTSA (83 mg, 0.43 mmol) at r.t. The solution was stirred for an ad-
ditional 10 min and then the reaction was quenched by the addition
of H2O (20 mL). The resulting organic mass was extracted with
Synthesis 2013, 45, 3399–3403
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of the Antihistaminic Drug Olopatadine
3403
(4) For synthetic processes, see: (a) Oshima, E.; Kumazawa, T.;
Otaki, S.; Obase, H.; Ohmori, K.; Ishii, H.; Manabe, H.;
Tamura, T.; Shuto, K. US Patent US005116863, 1992;
Chem Abstr. 1988, 108, 167330. (b) Lever, W.; Leighton, H.
European Patent EP0214779, 1990; Chem Abstr. 1987, 107,
58673. (c) Bosch, C.; Bachs, R.; Gomez, A.; Alonso, M.;
Bessa, A. Patent WO2006/010459, 2006; Chem Abstr. 2006,
144, 192128. (d) Tarur, V.; Bhise, N.; Sathe, D.; Naidu, A.;
Aher, U.; Patil, S.; Verma, S.; Sawant, K.; Naik, T.; Amre,
R. WO2007/105234 A2, 2007; Chem Abstr. 2007, 147,
371628. (e) Castellin, A.; Ferrari, C.; Galvagni, M. U.S.
Patent US 2011/0065936 A1, 2011; Chem Abstr. 2010, 153,
554939.
Acknowledgment
P.L. would like to thank CSIR, New Delhi, India, for a fellowship.
S.P.C. is grateful to the Council of Scientific and Industrial Re-
search (CSIR)-New Delhi for research funding under the ACT pro-
gramme of the 12th five year plan. We are thankful to Dr. U. R.
Kalkote and Dr. H. B. Borate for helpful discussions and Centaur
Pharmaceuticals Pvt. Ltd. for providing the starting material.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are copies of 1H and 13C NMR spectra for all new compounds and
the HPLC chromatogram of 2.SunogIopitfrmanrtuSnIpgifop
o
nr
irtat
(5) Bosch, J.; Bachs, J.; Gómez, A. M.; Griera, R.; Écija, M.;
Amat, M. J. Org. Chem. 2012, 77, 6340.
(6) Nishimura, K.; Kinugawa, M. Org. Process Res. Dev. 2012,
16, 225.
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(10) Recrystallization details: after two recrystallization using
PE–EtOAc (9:1) system, compound 2 with E/Z = 2:3 ratio
could be improved to E/Z = 1:9 ratio.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3399–3403