Novel and Efficient Synthesis of Deuterium-Labeled Olopatadine-d6

Article abstract of DOI:10.1134/S1070428019090197

A novel and highly efficient synthetic approach has been developed for the synthesis of deuterium-labeled olopatadine-d₆ using inexpensive and commercially available dimethyl sulfate-d₆ at the stage of alkylation of primary amine intermediate. The proposed synthetic path makes it possible to avoid the use of expensive labeled reagents such as dimethyl amine-d₆ used as labeled precursor in the traditional synthetic route. The structure of the obtained olapatadine-d₆ has been confirmed by ¹H NMR and mass spectral data.

Full text of DOI:10.1134/S1070428019090197

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 9, pp. 1387–1393. © Pleiades Publishing, Ltd., 2019.
Novel and Efficient Synthesis
of Deuterium-Labeled Olopatadine-d6
S. Endooria, K. Ch. Gulipallia, S. Bodigea, and N. Seelama*
a Department of Chemistry, K L University, Green fields, Vaddeswaram, Guntur, India
*e-mail: nareshvarma.klu@gmail.com
Received April 3, 2019; revised June 27, 2019; accepted July 2, 2019
Abstract—A novel and highly efficient synthetic approach has been developed for the synthesis of deuterium-
labeled olopatadine-d6 using inexpensive and commercially available dimethyl sulfate-d6 at the stage of
alkylation of primary amine intermediate. The proposed synthetic path makes it possible to avoid the use of
expensive labeled reagents such as dimethyl amine-d6 used as labeled precursor in the traditional synthetic
route. The structure of the obtained olapatadine-d6 has been confirmed by 1H NMR and mass spectral data.
Keywords: olapatadine, olopatadine-d6, antihistamine, deuterium-labeled compounds.
DOI: 10.1134/S1070428019090197
Since the discovery of highly active deuterium-
labeled therapeutic organic molecules, the chemistry of
deuterium substituted compounds has been grabbing
attention from every nook and corner of chemical
world [1]. Due to isotope effect, the stability and
efficiency of existing drugs has been enhanced by
substitution of deuterium for hydrogen. It is generally
observed that carbon–deuterium (C–D) bonds are more
resistant to chemical or enzymatic cleavage than
carbon–hydrogen (C–H) bonds [2–3]. Moreover, the
recent literature survey revealed that therapeutic
activities of some clinical medicines have been notably
improved by H–D displacements which could be
noticed from the following remarkable examples.
Deuterium-labeled amphetamines were more rapidly
transported into the brain and were more persistent,
and their activity was maintained for a longer time [4];
halogenated anesthetics such as selvoflane cease
oxidation to form toxic metabolites within the body [5]
through deuterium labeling; deuterium-labeled fluoro-
D-phenylalanine and long-chain fatty acids were
resistant to breakdown by their target microorganisms
[6]. More recently, deuterium-labeled clinical medi-
cines such as paroxetine (antidepressant), [7] ataza-
navir (HIV drug) [8], and venlafaxine (antidepressant)
[9] were synthesized as long-lasting drug candidates
by the pharmaceutical industry. Furthermore, olopata-
dine is an antihistamine as well as anticholinergic and
mast cell stabilizer which has been developed by
Kyowa Hakko Kirin Co. Ltd. [10] and is widely used
as an eye solution for allergic conjunctivitis [11–13]
and as an oral treatment for allergic rhinitis and skin
diseases [14–16]. In general, both Z and E isomers of
olopatadine show similar H1R affinities [17], but in
fact the Z isomer of olopatadine is only being con-
sidered as a therapeutic drug because of the potent
anti-allergic activity. Nevertheless, these deuterium-
labeled drugs are being used as human drug metabo-
lism investigation tracers and as internal standards for
quantitative analysis using GC/MS or LC/MS [18, 19].
In view of the above mentioned facts, it was con-
templated to design an inexpensive and facile synthetic
path for the synthesis of deuterium-labeled olopata-
dine to enhance the efficiency and stability by incor-
porating deuterium in place of hydrogen atoms so that
it could be used as an internal standard for quantitative
analysis.
Literature review revealed a number of strategies
for the synthesis of olopatadine [20–26]. In most of the
reported syntheses, the key side chain has been intro-
duced via Grignard reaction or Wittig olefination, and
stereoselective synthesis of the Z isomer is a challeng-
ing issue. Nishimura et al. [27] reported a stereoselec-
tive route shown in Scheme 1. In this route, the
Z stereoselectivity was controlled by palladium-cata-
lyzed intramolecular closure of seven-membered ring
in alkyne intermediate 5 to form dihydrodibenzo[b,e]-
oxepine 6. The same synthetic strategy was success-
fully applied to the synthesis of olopatadine-d6
(Scheme 2). However, this synthetic strategy suffers
1387

ENDOORI et al.
1388
Scheme 1.
OMe
Br
OMe
i
Br
O
+
O
O
HO
Br
1
2
3
OMe
OMe
Br
Br
ii
iii
O
O
O
O
I
OH
4
5
OMe
OMe
O
OMe
OH
OMs
NMe2
iv
v
vi
O
O
O
O
O
6
7
8
OH
O
NMe2
vii
O
Olopatadine
Reagents and conditions: i: K2CO3 (2.5 equiv), DMF, room temperature, 3 h, yield 97%; ii: I2 (1.0 equiv), Ag2SO4 (1.0 equiv),
MeOH, room temperature, 2 h, 87%; iii: but-3-yn-1-ol (2.0 equiv), PdCl2(PPh3)2 (0.05 equiv), CuI (0.1 equiv), Et3N (4.0 equiv),
DMF, room temperature, 4 h, 93.6%; iv: Pd(OAc)2 (0.1 equiv), tri-o-tolylphosphine (0.25 equiv), piperidine (7.0 equiv), formic acid
(1.1 equiv), DMF, 95°C, 4 h, 74.8%; v: MsCl (1.2 equiv), pyridine, 90°C, 2 h, 89%; vi: 50% aqueous dimethylamine (18.0 equiv),
MeOH, reflux, 3 h, 76%; vii: NaOH (1.5 equiv), MeOH–water (2:1), room temperature, 3 h, 88%.
18.0 equiv of 50% aqueous dimethylamine. These
limitations led us to try an alternative approach for the
synthesis of olopatadine-d6.
The retro-synthetic analysis for olopatadine-d6 is
outlined in Scheme 3. According to this approach,
primary amine 12 could be the late stage intermediate
which would give rise to olopatadine-d6 via treatment
with commercially available dimethyl sulfate-d6, fol-
from several limitations such as: (1) labeled dimethyl-
amine-d6 in D2O is less commercially accessible and
highly expensive; therefore, it was replaced by
dimethylamine-d6 hydrochloride; (2) replacement of
the mesyl group by dimethylamine-d6 hydrochloride
was low yielding (~25%), because only 2.0 equiv of
the reagent was used owing to its high cost, whereas in
the synthesis of non-deuterated olopatadine we used
Scheme 2.
OMe
OMe
OH
N(CD3)2
OMs
N(CD3)2
viii
ix
O
O
O
O
O
O
7
9
Olopatadine-d6
Reagents and conditions: viii: dimethylamine-d6 hydrochloride (2.0 equiv), Et3N (3.0 equiv), MeOH, reflux, 5 h, 25%;
ix: NaOH (1.5 equiv), MeOH–water (2:1), room temperature, 3 h, 87%.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

NOVEL AND EFFICIENT SYNTHESIS OF DEUTERIUM-LABELED OLOPATADINE-d6
1389
Scheme 3.
OH
OMe
OMe
N(CD3)2
NH2
N3
O
O
O
O
O
O
Olopatadine-d6
12
OMe
11
OMe
Cl
OH
O
O
O
O
10
6
lowed by ester hydrolysis. Primary amine 12, in turn,
could be obtained by reduction of azide 11, which
could be prepared from alcohol 6 through chloro
derivative 10.
thus formed was reacted with 50% aqueous dimethyl-
amine (Scheme 1) and dimethylamine hydrochlo-
ride-d6 (Scheme 2) in MeOH at 70°C to give tertiary
amines 8 and 9, respectively; and final alkaline hy-
drolysis in aqueous methanol afforded olopatadine and
olopatadine-d6 in separate experiments.
According to Scheme 4, methyl 2-{11-[(Z)-3-hy-
droxypropylidene]-6,11-dihydrodibenzo[b,e]oxepin-2-
yl)acetate (6) was treated with SOCl2 in toluene at
90°C to give chloro derivative 10 which was converted
to azide 11 by reaction with sodium azide in DMF at
70°C. Azide 11 was reduced with triphenylphosphine
in aqueous THF to access primary amine derivative 12.
The subsequent N-alkylation of 12 with dimethyl
sulfate-d6 in THF at 70°C furnished tertiary amine 13
in 62% yield, and basic hydrolysis of the latter in
aqueous methanol afforded the desired olopatadine-d6.
According to Scheme 1, methyl 2-(4-hydroxy-
phenyl)acetate (1) was alkylated with 1-bromo-2-
(bromomethyl)benzene (2) in DMF in the presence
of K2CO3 to give methyl 2-{4-[(2-bromobenzyl)-
oxy]phenyl}acetate (3) which was selectively
iodinated with Ag2SO4/I2 in MeOH to afford methyl
2-{4-[(2-bromobenzyl)oxy]-3-iodophenyl}acetate (4).
Sonogashira coupling of 4 with but-3-yn-1-ol produced
methyl 2-{4-[(2-bromobenzyl)oxy]-3-(4-hydroxybut-
1-yn-1-yl)phenyl}acetate (5) in a good yield. Com-
pound 5 was used in the key step (stereoselective
palladium-catalyzed cyclization) to obtain methyl
2-{11-[(Z)-3-hydroxypropylidene]-6,11-dihydrodi-
benzo[b,e]oxepin-2-yl}acetate (6) which was treated
with mesyl chloride in pyridine. Mesyl derivative 7
The structure and purity of olopatadine-d6 synthe-
1
sized by both routes was confirmed by H NMR and
Scheme 4.
OMe
OMe
OMe
OH
Cl
N3
O
O
O
x
xi
O
O
O
6
10
11
OMe
OMe
NH2
N(CD3)2
O
O
xii
xiii
xiv
Olopatadine-d6
O
O
12
9
Reagents and conditions: x: SOCl2 (1.2 equiv), toluene, 90°C, 2 h, 90.5%; xi: NaN3 (1.2 equiv), DMF, 70°C, 3 h, 89%; xii: PPh3
(2.0 equiv), THF–water, room temperature, 6 h, 75%; xiii: dimethyl sulfate-d6 (2.2 equiv), NaOH (3.0 equiv), THF, reflux, 4 h, 62%;
xiv: NaOH (1.5 equiv), MeOH–water (2:1), room temperature, 3 h, 87%.
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ENDOORI et al.
1390
mass spectra and HPLC analyses. The deuterium in-
corporation in [2H6]olopatadine was >98%. This corre-
sponds well to the reported deuterium abundance for
the labeled starting material (dimethyl sulfate-d6,
>98% D) and indicates that there was no loss of
deuterium by exchange during the syntheses. These
compounds were considered to be of acceptable
quality for use as internal standards in bioanalytical
studies.
mixture was filtered through celite, and the sorbent
was washed with ethyl acetate (300 mL). The filtrate
was concentrated under reduced pressure to give
yellow solid which was triturated with methanol, and
the precipitate was filtered off and dried under reduced
pressure. Yield 11.9 g (87%), colorless crystals.
1H NMR spectrum (CDCl3, 300 MHz), δ, ppm: 7.74 t
(2H, J = 6.9 Hz), 7.57 d (1H, J = 8.1 Hz), 7.37 t (1H,
J = 7.5 Hz), 7.23–7.17 m (2H), 6.82 d (1H, J =
8.4 Hz), 5.17 s (2H), 3.69 s (3H), 3.54 s (2H). Mass
spectrum: m/z 463/461 [M + H]+.
EXPERIMENTAL
Methyl 2-{4-[(2-bromobenzyl)oxy]-3-(4-hydroxy-
but-1-yn-1-yl)phenyl}acetate (5). A solution of 4
(5.0 g, 10.9 mmol), but-3-yn-1-ol (1.85 mL,
21.8 mmol), and triethylamine (6.1 mL, 43.6 mmol) in
DMF (50 mL) was degassed with argon for 10 min,
and PdCl2(PPh3)2 (382 mg, 0.545 mmol) and CuI
(103 mg, 1.09 mmol) were added under argon atmo-
sphere at room temperature. The mixture was stirred
for 4 h (TLC), quenched with water (150 mL), and
extracted with ethyl acetate (2×200 mL). The organic
layer was washed with water (50 mL) and brine
(50 mL), dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column
chromatography (CombiFlash), using ethyl acetate–
hexane (1 : 1). Yield 4.10 g, 93.6%), amber oil.
1H NMR (CDCl3, 300 MHz), δ, ppm: 7.64 d (1H, J =
6.9), 7.58 d (1H, J = 7.2 Hz), 7.37–7.32 m (2H), 7.21–
7.13 m (2H), 6.85 d (1H, J = 8.7 Hz), 5.18 s (2H),
3.80 q (2H, J = 6.0 Hz), 3.69 s (3H), 3.53 s (2H), 2.73 t
(2H, J = 6.3 Hz), 2.01 t (1H, J = 5.7 Hz). Mass
spectrum: m/z 405/403 [M + H]+.
[2H6]Dimethyl sulfate (98% D) was obtained from
CDN Isotopes, and all other chemicals and solvents
were purchased from Sigma–Aldrich, Merck, and
Combi-Blocks and were used without further purifica-
1
tion. The H NMR spectra were recorded on a Bruker
AMX 300 spectrometer operating at 300 MHz or on
a Bruker Avance 400 spectrometer at 400 MHz; the
chemical shifts are referenced to tetramethylsilane as
internal standard. The mass spectra were recorded on
an Agilent Technologies instrument (multimode ion
source, positive ion detection). Thin-layer chromatog-
raphy (TLC) was performed using Whatman no. 4500-
101 (Diamond No. MK6F silica gel 60 Å) plates;
visualization under UV light (λ 254 nm).
Methyl 2-{4-[(2-bromobenzyl)oxy]phenyl}-
acetate (3). Methyl 2-(4-hydroxyphenyl)acetate (1,
10.0 g, 60.2 mmol), was dispersed in DMF (100 mL),
and 2-bromobenzyl bromide (2) (15.75 g, 63.2 mmol)
and K2CO3 (20.77 g, 150.5 mmol) were added with
stirring at room temperature. The mixture was stirred
at room temperature for 3 h (TLC), diluted with water
(300 mL), and extracted with tert-butyl methyl ether
(MTBE, 3×300 mL). The combined extracts were
washed with water (200 mL) and brine (200 mL), dried
over Na2SO4, and concentrated under reduced pres-
Methyl 11-{[(Z)-3-hydroxypropylidene]-6,11-di-
hydrodibenzo[b,e]oxepin-2-yl}acetate (6). A solution
of 5 (4.0 g, 9.95 mmol), piperidine (6.88 mL,
69.6 mmol), and formic acid (0.42 mL, 10.94 mmol) in
DMF (40.0 mL) was degassed with argon for 10 min,
and Pd(OAc)2 (223.0 mg, 0.995 mmol) and tri-o-tolyl-
phosphine (754 mg, 2.48 mmol) were added at room
temperature. The mixture was stirred for 4 h at 95°C
(TLC), cooled to room temperature, diluted with water
(150 mL), and extracted with ethyl acetate (2×
300 mL). The combined organic extracts were washed
with water (100 mL) and brine (100 mL), dried over
Na2SO4, and concentrated under reduced pressure. The
crude material was purified by column chromatog-
raphy (CombiFlash, ethyl acetate–hexane, 2:1). Yield
1
sure. Yield 19.8 g (97%), pale yellow oil. H NMR
spectrum (CDCl3, 300 MHz), δ, ppm: 7.59–7.52 m
(2H), 7.32 t (1H, J = 7.7 Hz), 7.25–7.15 m (3H), 6.93 d
(2H, J = 8.7 Hz), 5.11 s (2H), 3.68 s (3H), 3.57 s (2H).
Mass spectrum: m/z 337/335 [M + H]+.
Methyl 2-{4-[(2-bromobenzyl)oxy]-3-iodo-
phenyl}acetate (4). Iodine (7.56 g, 29.8 mmol) was
added with stirring to a suspension of Ag2SO4 (9.29 g,
29.8 mmol) in methanol (30 mL), and the mixture was
stirred until iodine dissolved completely. A solution of
3 (10.0 g, 29.8 mmol) in methanol (30 mL) was then
added over a period of 15 min at room temperature,
and the mixture was stirred for 2 h at room tempera-
ture. When the reaction was complete (TLC), the
1
2.41 g (74.8%), white solid. H NMR (CDCl3,
300 MHz), δ, ppm: 7.21–7.16 m (4H), 6.95 d (1H, J =
8.1 Hz), 6.72 d (1H, J = 8.1 Hz), 5.65 t (1H, J =
7.5 Hz), 5.05–5.60 br.s (2H), 3.71 t (2H, J = 6.3 Hz),
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NOVEL AND EFFICIENT SYNTHESIS OF DEUTERIUM-LABELED OLOPATADINE-d6
1391
3.60 s (3H), 3.45 s (2H), 2.59 q (2H, J = 6.9 Hz),
1.92 br.s (1H). Mass spectrum: m/z 325.1 [M + H]+.
(30 mL) and brine (30 mL), dried over Na2SO4, and
concentrated under reduced pressure, and the crude
material was purified by column chromatography
(CombiFlash, CH2Cl2–MeOH, 95:5). Yield 22.0 mg
(25%), light brown solid. 1H NMR (CDCl3, 300 MHz),
δ, ppm: 7.32–7.24 m (4H), 7.04 d (2H, J = 10.2 Hz),
6.80 d (1H, J = 8.1 Hz), 5.70 t (1H, J = 6.9 Hz), 4.80–
5.60 br.s (2H), 3.67 s (3H), 3.52 s (2H), 2.59 q (2H,
J = 7.2 Hz), 2.44 t (2H, J = 7.2 Hz). Mass spectrum:
m/z 358.3 [M + H]+.
Methyl 2-{11-[(Z)-3-(methanesulfonyloxy)-
propylidene]-6,11-dihydrodibenzo[b,e]oxepin-2-yl}-
acetate (7). A solution of 6 (500 mg, 1.54 mmol) in
pyridine (5.0 mL) was cooled to 0–5°C, methanesul-
fonyl chloride (0.24 mL, 3.08 mmol) was added
dropwise over a period of 15 min, and the mixture was
stirred for 3 h at 90°C. The mixture was cooled to
room temperature, quenched with water (20 mL), and
extracted with ethyl acetate (2×50 mL). The combined
extracts were washed with brine (20 mL), dried over
Na2SO4, and concentrated under reduced pressure.
Methyl 2-{11-[(Z)-3-chloropropylidene]-6,11-di-
hydrodibenzo[b,e]oxepin-2-yl}acetate (10). A solu-
tion of 6 (2.20 g, 6.79 mmol) in toluene was cooled to
0°C, and thionyl chloride (0.59 mL, 8.15 mmol) was
added dropwise over a period of 5 min. The mixture
was heated at 90°C for 2 h (TLC), cooled to 0°C,
slowly diluted with ice-cold water (100 mL), and ex-
tracted with ethyl acetate (2×200 mL). The combined
extracts were washed with a saturated solution of
NaHCO3 (30 mL) and brine (100 mL), dried over
Na2SO4, and concentrated under reduced pressure.
1
Yield 550 mg (89%), light brown oil. H NMR spec-
trum (CDCl3, 300 MHz), δ, ppm: 7.35–7.27 m (4H),
7.08 d (2H, J = 7.5 Hz), 6.82 d (1H, J = 8.4 Hz), 5.74 t
(1H, J = 7.2 Hz), 5.05–5.50 br.s (2H), 3.70 s (3H),
3.65 t (2H, J = 6.6 Hz), 3.55 s (2H), 3.04 s (3H), 2.92 q
(2H, J = 6.6 Hz).
Methyl 2-{11-[(Z)-3-(dimethylamino)propyli-
dene]-6,11-dihydrodibenzo[b,e]oxepin-2-yl}acetate
(8). Compound 7 (300 mg, 0.746 mmol) was dissolved
in methanol (5.0 mL), 50% aqueous dimethylamine
(2.2 mL, 13.43 mmol) was added, and the mixture was
stirred under reflux for 3 h. When the reaction was
complete (TLC), the mixture was cooled to room tem-
perature and concentrated under reduced pressure, and
the residue was diluted with water (20 mL) and
extracted with ethyl acetate (3×50 mL). The combined
extracts were washed with a saturated solution of
NaHCO3 (30 mL) and brine (30 mL), dried over
Na2SO4, and concentrated under reduced pressure, and
the residue was purified by column chromatography
(CombiFlash, CH2Cl2–MeOH, 95:5). Yield 200 mg
1
Yield 2.10 g (90.5%), light yellow oil. H NMR spec-
trum (CDCl3, 300 MHz), δ, ppm: 7.31–7.26 m (4H),
7.06 d (2H, J = 7.5 Hz), 6.81 d (1H, J = 8.4 Hz), 5.72 t
(1H, J = 7.2 Hz), 5.05–5.60 br.s (2H), 3.68 s (3H),
3.65 t (2H, J = 6.6 Hz), 3.53 s (2H), 2.90 q (2H, J =
6.6 Hz). Mass spectrum: m/z 343.1 [M + H]+.
Methyl 2-{11-[(Z)-3-azidopropylidene]-6,11-di-
hydrodibenzo[b,e]oxepin-2-yl}acetate (11). Sodium
azide (597 mg, 9.18 mmol) was added to a solution of
10 (2.10 g, 6.12 mmol) in DMF (20 mL), and the
mixture was heated at 70°C for 3 h. When the reaction
was complete (TLC), the mixture was cooled to room
temperature, diluted with water (60 mL), and extracted
with ethyl acetate (3×100 mL). The combined extracts
were washed with water (2 × 100 mL) and brine
(100 mL), dried over Na2SO4, and concentrated under
reduced pressure. Yield 1.91 g, 89%), off-white solid.
1H NMR spectrum (CDCl3, 300 MHz), δ, ppm: 7.33–
7.26 m (4H), 7.06 d (2H, J = 3.3 Hz), 6.82 d (1H,
J = 9.0 Hz), 5.68 t (1H, J = 7.2 Hz), 5.00–5.50 br.s
(2H), 3.68 s (3H), 3.54 s (2H), 3.44 t (2H, J =
6.90 Hz), 2.73 q (2H, J = 6.90 Hz). Mass spectrum:
m/z 350.1 [M + H]+.
1
(76%), light brown solid. H NMR spectrum (CDCl3,
300 MHz), δ, ppm: 7.32–7.24 m (4H), 7.04 d (2H, J =
10.2 Hz), 6.80 d (1H, J = 8.1 Hz), 5.70 t (1H, J =
6.9 Hz), 4.75–5.60 br.s (2H), 3.67 s (3H), 3.52 s (2H),
2.59 q (2H, J = 7.2 Hz), 2.44 t (2H, J = 7.2 Hz), 2.23 s
(6H). Mass spectrum: m/z 352.1 [M + H]+.
Methyl 2-{11-[(Z)-3-((2H6)dimethylamino)-
propylidene]-6,11-dihydrodibenzo[b,e]oxepin-2-yl}-
acetate (9). Dimethylamine-d6 hydrochloride
(43.0 mg, 0.496 mmol) and triethylamine (0.10 mL,
0.744 mmol) were added to a solution of 7 (100 mg,
0.248 mmol) in methanol (3.0 mL). The mixture was
stirred under reflux for 5 h, cooled to room tempera-
ture, and concentrated under reduced pressure. The
residue was diluted with water (20 mL) and extracted
with ethyl acetate (3×20 mL), the combined extracts
were washed with a saturated solution of NaHCO3
Methyl 2-{11-[(Z)-3-aminopropylidene]-6,11-di-
hydrodibenzo[b,e]oxepin-2-yl}acetate (12). Tri-
phenylphospine (2.86 g, 10.9 mmol) was added to
a solution of 11 (1.91 g, 5.47 mmol) in THF–water
(2:1, 30 mL), and the mixture was stirred at room
temperature for 6 h. When the reaction was complete
(TLC), the mixture was diluted with water (50 mL)
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ENDOORI et al.
1392
and extracted with ethyl acetate (2×50 mL). The com-
bined extracts were washed with brine (10 mL), dried
over Na2SO4, and concentrated under reduced pres-
sure, and the crude product was purified by column
chromatography (CombiFlash, CH2Cl2–MeOH,
J = 7.2 Hz), 2.63 q (2H, J = 7.2 Hz), 2.34 s (6H). Mass
spectrum: m/z 338.1 [M + H]+.
2-{11-[(Z)-3-((2H6)Dimethylamino)propylidene]-
6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid
(olopatadine-d6) was synthesized in a similar way
from 300 mg (0.854 mmol) of 9 using 50.4 mg
(1.26 mmol) of sodium hydroxide. Yield 250 mg
1
90:10). Yield 1.41 g, 75%), light brown gel. H NMR
spectrum (CDCl3, 300 MHz), δ, ppm: 7.22–7.15 m
(6H), 6.92 d (2H, J = 10.5 Hz), 6.72 d (1H, J =
8.4 Hz), 5.58 t (1H, J = 7.2 Hz), 4.45–5.50 br.s (2H),
3.57 s (3H), 3.47 s (2H), 3.10 t (2H, J = 7.2 Hz), 2.78 q
(2H, J = 6.9 Hz). Mass spectrum: m/z 324.1 [M + H]+.
1
(87%), off-white solid. H NMR spectrum (DMSO-d6,
400 MHz), δ, ppm: 7.38–7.26 m (4H), 7.06 d (2H, J =
2.4 Hz), 6.77 d (1H, J = 5.6 Hz), 5.65 t (1H, J =
9.6 Hz), 4.95–5.50 br.s (2H), 3.50 s (3H), 2.82 t (2H,
J = 9.6 Hz), 2.64 q (2H, J = 9.6 Hz). Mass spectrum:
m/z 343.9 [M + H]+.
Alternative synthesis of 2-{11-[(Z)-3-((2H6)di-
methylamino)propylidene]-6,11-dihydrodibenzo-
[b,e]oxepin-2-yl}acetate (9). Dimethyl sulfate-d6
(233 mg, 1.70 mmol) and a solution of NaOH
(186 mg, 4.65 mmol) in water (1.0 mL) were added
with stirring to a solution of 12 (500 mg, 1.55 mmol)
in THF (10 mL). The mixture was heated at 70°C for
2 h and cooled to 0°C, and an additional portion of
dimethyl sulfate-d6 (233 mg, 1.70 mmol) was added.
The reaction mixture was refluxed for 2 h until the
reaction was complete (MeOH–CH2Cl2, 5:95), cooled
to room temperature, diluted with water (20 mL), and
extracted with ethyl acetate (2×50 mL). The combined
extracts were dried over anhydrous Na2SO4 and con-
centrated under reduced pressure, and the crude
product was purified by column chromatography
(CombiFlash; CH2Cl2–MeOH, 0 to 5% of the latter).
Yield 340 mg (62%), light brown solid. 1H NMR spec-
trum (CDCl3, 300 MHz), δ, ppm: 7.32–7.24 m (4H),
7.04 d (2H, J = 10.2 Hz), 6.80 d (1H, J = 8.1 Hz),
5.70 t (1H, J = 6.9 Hz), 4.80–5.60 br.s (2H), 3.67 s
(3H), 3.52 s (2H), 2.59 q (2H, J = 7.2 Hz), 2.44 t (2H,
J = 7.2 Hz). Mass spectrum: m/z 358.3 [M + H]+.
ACKNOWLEDGMENTS
The authors thank the management of AMRI
Hyderabad Research Center for giving an opportunity
to carry out this research.
CONFLICT OF INTERESTS
The authors declare the absence of conflict of
interests.
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