Stereoselective syntheses of the antihistaminic drug olopatadine and its E-isomer

Article abstract of DOI:10.1021/jo300925c

Practical stereoselective synthetic routes to the antihistaminic drug olopatadine and its E-isomer have been developed, the key steps being a trans stereoselective Wittig olefination using a nonstabilized phosphorus ylide and a stereoselective Heck cyclization. The stereoselectivity of the Wittig reaction depends on both the phosphonium salt anion and the cation present in the base used to generate the ylide.

Full text of DOI:10.1021/jo300925c

Note
pubs.acs.org/joc
Stereoselective Syntheses of the Antihistaminic Drug Olopatadine
and Its E-Isomer
Joan Bosch,* Jordi Bachs, Antonia M. Gomez, Rosa Griera, Marta Ecija, and Mercedes Amat
†Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan
XXIII s/n, 08028 Barcelona, Spain
‡Urquima, S.A., Arnau de Vilanova 22-42, 08105 Sant Fost de Campsentelles, Barcelona, Spain
,†
‡
†
†
†
†
́
́
S
* Supporting Information
ABSTRACT: Practical stereoselective synthetic routes to the
antihistaminic drug olopatadine and its E-isomer have been
developed, the key steps being a trans stereoselective Wittig
olefination using a nonstabilized phosphorus ylide and a
stereoselective Heck cyclization. The stereoselectivity of the
Wittig reaction depends on both the phosphonium salt anion
and the cation present in the base used to generate the ylide.
lopatadine is a nonsedating histamine H1-receptor
antagonist with mast cell stabilizing properties. This
Scheme 1. Synthetic Strategy: A Wittig/Heck Approach to
Olopatadine and Its E-Isomer
O
dual action allows seasonal allergic conjunctivitis and rhinitis
signs and symptoms to be controlled.1 Structurally, olopatadine
is a dibenzo[b,e]oxepin derivative bearing a Z-configurated
(dimethylamino)propylidene substituent and an acetic acid
chain at the C-11 and C-2 positions, respectively, of the tricyclic
system. Previous synthetic approaches to olopatadine2 involve
the generation of the trisubstituted exocyclic double bond from
a tricyclic dibenz[b,e]oxepin ketone, which represents a
drawback in terms of Z/E stereoselectivity.3
We herein report short and practical stereoselective
syntheses of olopatadine and its E-isomer (trans-olopatadine),
based on a common strategy involving successive stereo-
selective Wittig and intramolecular Heck reactions as the key
steps.4 After a Williamson reaction to assemble the benzyl aryl
ether moiety, the Wittig olefination would lead to the key
intermediates 1 or 2, depending on the aromatic aldehyde and
aryl iodide derivatives used as the starting materials (Scheme
1). Taking into account that in particular cases, by choosing the
appropriate reaction conditions, high selectivity for (E)- and/or
(Z)-alkene can be attained in the Wittig reaction of
nonstabilized phosphorus ylides with aldehydes5 and that the
Heck reaction usually involves a syn-addition/syn-elimination
mechanism,6 the above Williamson−Wittig−Heck strategy
could provide stereoselective access to both olopatadine and
its E-isomer.
The starting aldehyde 5 was prepared from 2-iodobenzyl
chloride 3 and 3-formyl-4-hydroxyphenylacetic ester 47 under
the reaction conditions indicated in Scheme 2. The Wittig
reaction from 5 was initially performed using the ylide
generated from the commercially available phosphonium
bromide 6 (X = Br) by treatment with KHMDS in toluene
(Table 1, entry 1),8 giving a mixture of E/Z alkenes in a 1:3
ratio. Similar results were obtained starting from the iodide salt
6 (X = I)9 (entry 2). Notably, the use of the lithium base
LHMDS to generate the ylide from phosphonium iodide 6 (X
= I) produced a dramatic change in the stereoselectivity of the
Wittig reaction, leading to a 9:1 E/Z ratio of alkenes 1 in 73%
yield (entry 3).10 A similar effect, although less pronounced
(4:1 E/Z ratio), was observed from the bromide salt 6 (X = Br)
(entry 4). In contrast, the use of phosphonium chloride 6 (X =
Received: May 14, 2012
Published: June 25, 2012
© 2012 American Chemical Society
6340
dx.doi.org/10.1021/jo300925c | J. Org. Chem. 2012, 77, 6340−6344

The Journal of Organic Chemistry
Note
Scheme 2. Wittig Reaction from Aldehyde 5
Scheme 3. Wittig Reaction from Aldehyde 9
Table 1. Stereochemistry Dependence on the Cation in the
Wittig Reaction
a
Table 2. Stereochemistry Dependence on the Cation in the
Wittig Reaction
a
b
entry
base, M
6, X
E/Z ratio
1, yield (%)
b
c
entry
base, M
6, X
solvent
E/Z ratio
2, yield (%)
1
2
3
4
5
K
Br
I
1:3
60
c
K
1:3
85
1
2
3
4
K
K
K
Li
I
toluene
THF
1:3
1:4
73
64
86
88
Li
Li
Li
I
9:1
73
I
c
Br
Cl
4:1
77
Br
I
toluene
toluene
1:3
c
1:1.5
37
3.5:1
a
a
Reaction conditions: aldehyde 5 (0.02 M in anhydrous toluene),
Reaction conditions: aldehyde 9 (0.02 M in anhydrous toluene or
THF), phosphonium salt 6 (4.2 equiv), MHMDS (4.2 equiv), rt.
Calculated by H NMR and HPLC. Calculated by HPLC from the
b
phosphonium salt 6 (4.2 equiv), MHMDS (4.2 equiv), rt. Calculated
c
b
c
by 1H NMR and HPLC. Calculated by HPLC from the crude
1
reaction mixture.
crude reaction mixture.
Cl)11 as the ylide precursor gave poor results in terms of both
selectivity and chemical yield (entry 5).
reaction from iodo alkene E-1 was performed under solid−
liquid phase transfer conditions, using a stoichiometric quantity
of Bu4NCl as the transfer agent16 and K2CO3 as the base,17 in
the presence of a catalytic amount of Pd(OAc)2 (without
The above trans selectivity is worthy of comment, as Wittig
olefination reactions of nonstabilized phosphorus ylides with
aromatic aldehydes usually produce the thermodynamically less
stable cis isomer as the major product.5 The presence of a
nucleophilic group (for instance, amino) in the side chain of
these ylides causes a shift in the stereochemistry of the alkene
product toward the trans isomer,12 whose production is also
increased by lithium ions.13
The pronounced effect of the lithium cation on alkene
stereochemistry was also observed in the Wittig reaction from
benzaldehyde 9, which was prepared from 2-formylbenzyl
bromide 714 and 4-hydroxy-3-iodophenylacetic ester 815
(Scheme 3). Thus, alkenes 2 were produced in an E/Z ratio
of 1:3 when the ylide was generated in toluene solution from
phosphonium iodide 6 (X =I) using KHMDS as the base
(Table 2, entry 1). Neither the use of THF as the solvent
(entry 2) nor starting from the bromide salt (entry 3)
substantially modified the E/Z ratio. However, when using the
lithium base LHMDS to generate the ylide from iodide 6 (X =
I), the stereoselectivity was reversed, with a significant
enhancement of E stereochemistry, leading to an E/Z ratio of
3.5:1 (entry 4).
phosphine ligands18) in an acetonitrile−water mixture.19
A
single dibenzoxepin derivative 10, bearing a Z-configurated
double bond, was formed with complete stereoselectivity in
60% yield.20 A similar Pd-catalyzed cyclization from iodo alkene
E-2 stereoselectively afforded E dibenzoxepin 11 in 55% yield.
The above results were not unexpected and are consistent with
a syn-addition of the initially formed arylpalladium intermediate
to the alkene, with a subsequent syn β-elimination of a
hydridopalladium halide, as outlined in Scheme 4.
However, in contrast with the high stereoselectivity observed
in the above Heck arylations from trans alkenes E-1 and E-2,
the Heck cyclization from cis alkenes Z-1 and Z-2 was not
stereoselective, leading to mixtures of the cyclized products 10
and 11 (approximate ratios 3:2), probably as a consequence of
a competitive Pd(II)-promoted isomerization of the starting Z-
configurated alkenes to the more stable E-isomers.
Finally, alkaline hydrolysis of the cyclized products 10 and 11
furnished the target drug olopatadine and its E-isomer,
respectively.
In summary, we have developed practical synthetic routes to
the antihistaminic drug olopatadine and its E-isomer based on a
common strategy involving successive highly stereoselective
Wittig olefination and Heck cyclization reactions as the key
steps.
From the synthetic standpoint, with four different alkenes
now in hand, prepared in acceptable yield and good (E-1) to
acceptable (Z-1, E-2, Z-2) stereoselectivity, we were ready to
tackle the key Heck cyclization. The intramolecular Heck
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Note
The combined organic extracts were dried and concentrated to give an
oil, which was cooled in the refrigerator for 2 days to afford 6, (X =Cl)
as a hygroscopic white solid (12.4 g, 90%): mp 188−191 °C; 1H NMR
(300 MHz, CDCl3) δ 1.74−1.87 (m, 2H), 2.12 (s, 6H), 2.53 (t, J = 6.0
Hz, 2H), 3.77−3.89 (m, 2H), 7.69−7.89 (m, 15H); 13C NMR (75.4
MHz, CDCl3) δ 19.9 (d, J = 52.2 Hz), 20.5 (d, J = 3.3 Hz), 45.0 (s),
58.2 (d, J = 16.0 Hz), 118.0 (d, J = 86.2 Hz), 130.2 (d, J = 12.6 Hz),
133.2 (d, J = 9.9 Hz), 134.7 (d, J = 2.8 Hz); IR (KBr) 995, 1112, 1434
cm−1. Anal. Calcd for C23H27NClP: C, 71.96; H, 7.09; N, 3.65; Cl,
9.24. Found: C, 71.93; H, 7.15; N, 3.52; Cl, 9.45.
Scheme 4. Stereoselective Heck Reactions
Methyl [3-Formyl-4-(2-iodobenzyloxy)phenyl]acetate (5). A
solution of methyl (3-formyl-4-hydroxyphenyl)acetate (16.7 g, 85.9
mmol) in acetonitrile (68 mL) was slowly added at rt to a mixture of
1-(chloromethyl)-2-iodobenzene (21.7 g, 85.9 mmol), K2CO3 (13.1 g,
94.5 mmol), and NaI (3.22 g, 21.5 mmol) in acetonitrile (273 mL),
and the mixture was heated at reflux for 3 h. The solid was separated
by filtration, and the filtrate was concentrated. The resulting residue
was dissolved in toluene (330 mL), and the organic solution was
washed with 0.1 N aqueous NaOH and H2O, dried, and concentrated.
The residue was dissolved in acetone (330 mL) and poured into H2O
(500 mL). The mixture was filtered, and the resulting solid was
crystallized from toluene−cyclohexane to afford 5 (24.7 g, 70%): mp
68−70 °C; 1H NMR (300 MHz, CDCl3) δ 3.61 (s, 2H), 3.70 (s, 3H),
5.15 (s, 2H), 7.00−7.10 (m, 2H), 7.37−7.42 (m, 1H), 7.48−7.51 (m,
2H), 7.77 (d, J = 2.1 Hz, 1H), 7.90 (dd, J = 7.8, 1.2 Hz, 1H), 10.55 (s,
1H); 13C NMR (75.4 MHz, CDCl3) δ 39.9 (CH2), 52.1 (CH3), 74.4
(CH2), 97.2 (C), 113.3 (CH), 124.9 (C), 126.9 (C), 128.4 (CH),
128.6 (CH), 129.2 (CH), 129.8 (CH), 136.6 (CH), 138.0 (C), 139.4
(CH), 159.6 (C), 171.5 (C), 189.2 (CH); IR (NaCl) 1158, 1249,
1683, 1736, 2700, 2900 cm−1. Anal. Calcd for C17H15IO4: C, 49.78; H,
3.69. Found: C, 49.67; H, 3.66.
Methyl [4-(2-Formylbenzyloxy)-3-iodophenyl]acetate (9).
Operating as above, from 2-(bromomethyl)benzaldehyde (11 g, 55.3
mmol), methyl (4-hydroxy-3-iodophenyl)acetate (16.1 g, 55 mmol),
K2CO3 (8.36 g, 60.5 mmol), and NaI (2.07 g, 13.8 mmol) in
acetonitrile (220 mL), compound 9 (18 g, 80%) was obtained after
crystallization from acetone−H2O: mp 93−97 °C; 1H NMR (300
MHz, CDCl3) δ 3.54 (s, 2H), 3.70 (s, 3H), 5.55 (s, 2H), 6.90 (d, J =
8.4 Hz, 1H), 7.46 (dd, J = 8.2, 2.2 Hz, 1H), 7.54 (dd, J = 7.8, 7.5 Hz,
1H), 7.67−7.74 (m, 2H), 7.88 (dd, J = 6.0, 1.3 Hz, 1H), 8.08 (d, J =
7.8 Hz, 1H), 10.15 (s, 1H); 13C NMR (75.4 MHz, CDCl3) δ 39.6
(CH2), 52.1 (CH3), 68.6 (CH2), 86.4 (C), 112.3 (CH), 127.4 (CH),
127.7 (CH), 128.4 (C), 130.4 (CH), 132.4 (C), 134.2 (CH), 134.5
(CH), 138.8 (C), 140.0 (CH), 156.0 (C), 171.6 (C), 193.4 (CH); IR
(KBr) 1252, 1691, 1731, 2750, 2833 cm−1. Anal. Calcd for C17H15IO4:
C, 49.78; H, 3.69; I, 30.94. Found: C, 49.81; H, 3.53; I, 31.24.
Methyl 3-[4-(Dimethylamino)but-1-enyl]-4-(2-
iodobenzyloxy)phenylacetate (1). LHMDS (1 M in THF, 51.5
mL, 51.5 mmol) was added dropwise to a suspension of 6 (X = I)
(24.3, 51.2 mmol) in anhydrous toluene (300 mL), and the resulting
mixture was stirred at rt for 1 h. A solution of 5 (5.00 g, 12.2 mmol) in
anhydrous toluene (170 mL) was added, and the resulting mixture was
stirred at rt for 2.5 h. The reaction was quenched with H2O (150 mL),
and the aqueous layer was extracted with toluene. The combined
organic extracts were extracted with 2 N aqueous HCl (150 mL), and
then solid K2CO3 was added to the aqueous phase until pH 9. The
alkaline solution was extracted with EtOAc, and the extracts were dried
and concentrated. Column chromatography (Al2O3, hexane−EtOAc
95:5 to 75:25) afforded compound 1 (4.26 g, 73%; E/Z 9:1) as an oil.
Pure samples of both isomers were obtained after additional column
chromatography.
EXPERIMENTAL SECTION
■
(3-Dimethylaminopropyl)triphenylphosphonium Iodide (6,
X = I). A mixture of 3-(dimethylamino)-1-propyl chloride hydro-
chloride (20 g, 126 mmol), PPh3 (33 g, 126 mmol), and NaI (19 g,
126 mol) in acetonitrile (80 mL) was heated at reflux for 5.5 days.
After cooling at rt, H2O−acetonitrile (2:1, 360 mL) was added, and
the mixture was stirred at 45 °C for 0.5 h. The resulting suspension
was filtered, solid K2CO3 was added to the filtrate until pH 9−10, and
the solution was extracted with CH2Cl2 (3 × 150 mL). The combined
organic extracts were dried and concentrated, and the resulting oil was
dissolved in CH2Cl2 (25 mL). AcOEt (120 mL) was added, and the
mixture was stirred until the formation of a white solid, which was
1
collected by filtration (52 g, 87%): mp 138−141 °C; H NMR (300
MHz, CDCl3) δ 1.75−1.87 (m, 2H), 2.13 (s, 6H), 2.54 (t, J = 5.9 Hz,
2H), 3.65−3.75 (m, 2H), 7.70−7.87 (m, 15H); 13C NMR (75.4 MHz,
CDCl3) δ 20.4 (d, J = 52.2 Hz), 20.5 (d, J = 3.3 Hz), 45.2 (s), 58.2 (d,
J = 16.0 Hz), 117.9 (d, J = 86.2 Hz), 130.3 (d, J = 12.6 Hz), 133.3 (d, J
= 10.5 Hz), 134.9 (d, J = 2.7 Hz); IR (KBr) 995, 1111, 1438 cm−1.
Anal. Calcd for C23H27NIP: C, 58.11; H, 5.73; N, 2.95; I, 26.70.
Found: C, 58.13; H, 5.66; N, 2.90; I, 26.58.
1
Data for E-1: H NMR (300 MHz, CDCl3) δ 2.27 (s, 6H), 2.39−
(3-Dimethylaminopropyl)triphenylphosphonium Chloride
(6, X = Cl). A mixture of 3-(dimethylamino)-1-propyl chloride
hydrochloride (10 g, 63 mmol) and PPh3 (16.5 g, 63 mmol) in 1-
butanol (40 mL) was heated at reflux for 4 days. The mixture was
cooled at rt, toluene−Et2O (1:1, 50 mL) was added, and the solution
was kept in the refrigerator for a night. The solid formed was filtered
and washed with toluene−Et2O and Et2O to give pure 6·HCl (X = Cl)
(15.6 g, 59%) as a white powder. A solution of this hydrochloride in 2
N aqueous K2CO3 (50 mL) was extracted with CH2Cl2 (3 × 30 mL).
2.45 (m, 4H), 3.55 (s, 2H), 3.68 (s, 3H), 5.04 (s, 2H), 6.18−6.29 (m,
1H), 6.81 (d, J = 8.7 Hz, 1H), 6.84 (d, J = 16.2 Hz, 1H), 6.99−7.09
(m, 2H), 7.34−7.39 (m, 2H), 7.50 (dd, J = 7.5, 1.8 Hz, 1H), 7.86 (dd,
J = 7.9, 1.2 Hz, 1H); 13C NMR (75.4 MHz, CDCl3) δ 31.8 (CH2);
40.4 (CH2), 45.4 (2CH3); 52.0 (CH3), 59.4 (CH2), 74.4 (CH2), 96.9
(C), 112.8 (CH), 125.1 (CH), 126.6 (C), 127.2 (C), 127.3 (CH),
128.3 (CH), 128.4 (CH), 128.6 (CH), 129.3 (CH), 129.4 (CH),
139.1 (CH), 139.2 (C), 154.1 (C), 172.2 (C); IR (NaCl) 1245, 1737
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Note
cm−1. Anal. Calcd for C22H26NIO3: C, 55.12; H, 5.47; N, 2.92. Found:
C, 55.12; H, 5.48; N, 2.83.
Data for Z-1: H NMR (300 MHz, CDCl3) δ 2.22 (s, 6H), 2.36−
(CH3), 59.2 (CH2), 70.0 (CH2), 119.3 (CH), 126.1 (C), 127.2 (C),
127.7 (CH), 127.8 (CH), 128.1 (CH), 128.4 (CH), 129.6 (CH),
130.2 (CH), 130.7 (CH), 134.1 (C), 139.6 (C), 141.0 (C), 154.1 (C),
172.2 (C); IR (NaCl) 1224, 1489, 1738 cm−1. Anal. Calcd for
C22H25NO3: C, 75.19; H, 7.17; N, 3.99. Found: C, 74.82; H, 7.14; N,
3.81.
1
2.51 (m, 4H), 3.57 (s, 2H), 3.68 (s, 3H), 5.02 (s, 2H), 5.74 (dt, J =
11.4, 6.8 Hz, 1H), 6.67 (d, J = 11.4 Hz, 1H); 6.84 (d, J = 8.7 Hz, 1H),
6.97−7.13 (m, 2H), 7.20 (d, J = 1.8 Hz, 1H), 7.32−7.40 (m, 1H),
7.48−7.51 (m, 1H), 7.84 (dd, J = 7.8, 1.2 Hz, 1H); 13C NMR (75.4
MHz, CDCl3) δ 27.1 (CH2), 40.4 (CH2), 45.3 (2CH3), 52.0 (CH3),
59.4 (CH2), 74.2 (CH2), 96.7 (C), 112.3 (CH), 125.2 (CH), 126.0
(C), 127.0 (C), 128.3 (2CH), 128.7 (CH), 129.3 (CH), 130.4 (CH),
130.9 (CH), 139.0 (CH), 139.2 (C), 154.9 (C), 172.1 (C); IR (NaCl)
1244, 1738 cm−1. Anal. Calcd for C22H26NIO3: C, 55.12; H, 5.47; N,
2.92. Found: C, 55.17; H, 5.54; N, 2.87.
( Z ) - 1 1 - [ 3 - ( D i m e t h y l a m i n o ) p r o p y l i d e n e ] - 6 , 1 1 -
dihydrodibenz[b,e]oxepin-2-acetic Acid Hydrochloride. 5 N
aqueous NaOH (6.2 mL, 31.0 mmol) was added to a solution of 10
(3.32 g, 9.45 mmol) in MeOH (105 mL) and H2O (21 mL). The
mixture was stirred at rt for 3 h, neutralized with 2 N aqueous HCl,
and concentrated to dryness. The resulting residue was dissolved in
H2O, and the solution was filtered through an ionic exchange resin
DIAION HP-20 (H2O until negative test of AgNO3 and then MeOH
as eluents). The methanolic fractions gave olopatadine (2.64 g, 83%).
37% HCl (1 mL, 12.0 mmol) was added to a stirred solution of the
above olopatadine in THF (65 mL), and the mixture was stirred for 5
min. The solid formed was filtered and suspended in acetone (60 mL).
The suspension was refluxed for 30 min, cooled, and filtered to give
olopatadine hydrochloride as a solid (2.33 g, 66% overall): mp 231−
Methyl 4-{2-[4-(Dimethylamino)but-1-enyl]benzyloxy}-3-io-
dophenylacetate (2). Operating as above, from aldehyde 9, under
the reaction conditions of Table 2, mixtures of E-2 and Z-2 were
obtained. Column chromatography (Al2O3, hexane−EtOAc 95:5 to
75:25) afforded the pure isomers as oils.
1
Data for E-2: H NMR (300 MHz, CDCl3) δ 2.27 (s, 6H), 2.41−
2.44 (m, 4H), 3.52 (s, 2H), 3.69 (s, 3H), 5.14 (s, 2H), 6.08−6.19 (m,
1H), 6.72 (d, J = 15.6 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 7.18−7.31
(m, 3H), 7.46−7.53 (m, 2H), 7.71 (d, J = 2.1 Hz, 1H); 13C NMR
(75.4 MHz, CDCl3) δ 31.8 (CH2), 39.6 (CH2), 45.5 (2CH3), 52.1
(CH3), 59.3 (CH2), 69.4 (CH2), 86.7 (C), 112.5 (CH), 126.1 (CH),
127.0 (CH), 127.5 (CH), 128.2 (CH), 128.2 (C), 128.4 (CH), 130.2
(CH), 131.5 (CH), 132.6 (C), 136.6 (C), 140.1 (CH), 156.3 (C),
171.7 (C); IR (NaCl) 1249, 1488, 1738 cm−1. Anal. Calcd for
C22H26NIO3: C, 55.12; H, 5.47; I, 26.47; N, 2.92. Found: C, 54.97; H,
5.43; I, 26.63; N, 2.85.
1
233 °C (dec); H NMR (300 MHz, CD3OD) δ 2.86 (s, 6H), 2.83−
2.91 (m, 2H), 3.28−3.34 (m, 2H), 3.57 (s, 2H), 5.19 (br, 2H), 5.67 (t,
J = 7.3 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 7.07−7.13 (m, 2H), 7.26−
7.37 (m, 4H); 13C NMR (75.4 MHz, CD3OD) δ 26.4 (CH2), 40.5
(CH2), 43.4 (2CH3), 58.0 (CH2), 71.5 (CH2), 120.3 (CH), 124.8 (C),
126.5 (CH), 127.0 (CH), 128.4 (C), 128.5 (CH), 129.0 (CH), 130.1
(CH), 131.7 (CH), 132.8 (CH), 135.1 (C), 144.5 (C), 145.6 (C),
155.9 (C), 175.7 (C); IR (KBr) 1225, 1491, 1716, 2927 cm−1. Anal.
Calcd for C21H24NClO3·H2O: C, 64.36; H, 6.69; N, 3.57. Found: C,
64.59; H, 6.30; N, 3.63.
1
Data for Z-2: H NMR (300 MHz, CDCl3) δ 2.17 (s, 6H), 2.29−
( E ) - 1 1 - [ 3 - ( D i m e t h y l a m i n o ) p r o p y l i d e n e ] - 6 , 1 1 -
dihydrodibenz[b,e]oxepin-2-acetic Acid Hydrochloride. Oper-
ating as above, from ester 11 (973 mg, 2.77 mmol), trans-olopatadine
hydrochloride was obtained as a white solid (728 mg, 70%): mp 170−
173 °C; 1H NMR (300 MHz, CD3OD) δ 2.56−2.63 (m, 2H), 2.75 (s,
6H), 3.13 (t, J = 7.6 Hz, 2H), 3.53 (s, 2H), 4.78 (br, 1H), 5.51 (br,
1H), 5.98 (t, J = 7.2 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 7.06 (dd, J =
8.3, 2.3 Hz, 1H), 7.25−7.44 (m, 5H); 13C NMR (75.4 MHz, CD3OD)
δ 26.0 (CH2), 40.8 (CH2), 43.3 (2CH3), 57.9 (CH2), 70.9 (CH2),
120.3 (CH), 125.9 (CH), 127.6 (C), 128.5 (C), 128.6 (CH), 129.5
(2CH), 130.0 (CH), 131.5 (CH), 132.0 (CH), 135.8 (C), 141.3 (C),
144.2 (C), 155.6 (C), 175.7 (C); IR (KBr) 1223, 1484, 1725, 2960
cm−1. Anal. Calcd for C21H24NClO3·H2O: C, 64.36; H, 6.69; N, 3.57.
Found: C, 64.66; H, 6.47; N, 3.56.
2.35 (m, 4H), 3.51 (s, 2H), 3.68 (s, 3H), 5.05 (s, 2H), 5.76−5.85 (m,
1H), 6.60 (d, J = 11.40 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 7.16−7.31
(m, 4H), 7.63−7.66 (m, 1H), 7.70 (d, J = 2.4 Hz, 1H); 13C NMR
(75.4 MHz, CDCl3) δ 26.9 (CH2), 39.6 (CH2), 45.3 (2CH3), 52.0
(CH3), 59.3 (CH2), 68.9 (CH2), 86.6 (C), 112.2 (CH), 127.1 (CH),
127.4 (2CH), 127.5 (CH), 128.1 (C), 129.1 (CH), 130.1 (CH), 131.8
(CH), 134.0 (C), 135.6 (C), 140.0 (CH), 156.3 (C), 171.6 (C); IR
(NaCl) 1250, 1489, 1738 cm−1. Anal. Calcd for C22H26NIO3: C,
55.12; H, 5.47; I, 26.47; N, 2.92. Found: C, 55.21; H, 5.68; I, 25.16; N,
2.87.
(Z)-Methyl 11-[3-(Dimethylamino)propylidene]-6,11-
dihydrodibenz[b,e]oxepin-2-acetate (10). A mixture of the
compound of E-1 (600 mg, 1.25 mmol), K2CO3 (436 mg, 3.15
mmol), and Bu4NCl (349 mg, 1.25 mmol) in 10:1 acetonitrile−H2O
(24 mL) was stirred at rt for 15 min, Pd(OAc)2 (57 mg, 0.25 mmol)
was added, and the mixture was stirred at 60 °C for 24 h. The solvent
was removed under reduced pressure, and the resulting residue was
dissolved in EtOAc (40 mL) and washed with saturated aqueous
NaHCO3 and aqueous NaCl solutions. The organic phase was dried,
filtered, and concentrated. Column chromatography (Al2O3, hexane−
EtOAc 95:5 to 75:25) of the residue afforded 10 (264 mg, 60%) as an
oil: 1H NMR (300 MHz, CDCl3) δ 2.22 (s, 6H), 2.41−2.46 (m, 2H),
2.56−2.63 (m, 2H), 3.52 (s, 2H), 3.66 (s, 3H), 5.18 (br, 2H), 5.71 (t, J
= 7.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 7.02−7.09 (m, 2H), 7.22−
7.30 (m, 4H); 13C NMR (75.4 MHz, CDCl3) δ 28.0 (CH2), 40.2
(CH2), 45.4 (2CH3), 51.9 (CH3), 59.4 (CH2), 70.3 (CH2), 119.6
(CH), 123.8 (C), 125.5 (C), 126.1 (CH), 127.3 (2CH), 128.9 (CH),
129.8 (CH), 130.7 (CH), 131.9 (CH), 133.5 (C), 139.5 (C), 145.5
(C), 154.4 (C), 172.0 (C); IR (NaCl) 1225, 1489, 1739 cm−1. Anal.
Calcd for C22H25NO3·1/4H2O: C, 74.24; H, 7.22; N, 3.94. Found: C,
74.59; H, 7.14; N, 3.77.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of the 1H and 13C NMR spectra of all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: joanbosch@ub.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(E)-Methyl 11-[3-(Dimethylamino)propylidene]-6,11-
dihydrodibenz[b,e]oxepin-2-acetate (11). Operating as in the
above preparation of 10, from E-2 (100 mg, 0.21 mmol), compound
11 (40 mg, 55%) was obtained as an oil after column chromatography
(Al2O3, hexane−EtOAc 95:5 to 75:25): 1H NMR (300 MHz, CDCl3)
δ 2.16 (s, 6H), 2.28−2.43 (m, 4H), 3.53 (s, 2H), 3.67 (s, 3H), 4.78
(br, 1H), 5.54 (br, 1H), 6.03 (t, J = 6.9 Hz, 1H), 6.70 (d, J = 8.4 Hz,
1H), 7.20 (dd, J = 8.5, 2.2 Hz, 1H), 7.17−7.37 (m, 5H); 13C NMR
(75.4 MHz, CDCl3) δ 27.7 (CH2), 40.2 (CH2), 45.3 (2CH3), 52.0
We thank the AGAUR, Generalitat de Catalunya, for Grant
2009-SGR-1111. This study was partially funded by Urquima,
S.A.
DEDICATION
■
Dedicated to Prof. Miguel A. Miranda on the occasion of his
60th birthday.
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The Journal of Organic Chemistry
Note
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