Accidental discovery of a 'longer-range' vinylogous Pummerer-type lactonization: Formation of sulindac sulfide lactone from sulindac

Article abstract of DOI:10.1016/j.tetlet.2011.01.008

Unexpected formation of sulindac sulfide lactone occurred when sulindac was treated with oxalyl chloride and triethylamine. Structurally analogous sulindac sulfide and indomethacin did not undergo such lactonization under similar reaction conditions. We b

Full text of DOI:10.1016/j.tetlet.2011.01.008

Tetrahedron Letters 52 (2011) 1179–1182
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Tetrahedron Letters
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Accidental discovery of a ‘longer-range’ vinylogous Pummerer-type
lactonization: formation of sulindac sulfide lactone from sulindac
⇑
Somnath Halder, Apparao Satyam
R&D Special Projects Department, Medicinal Chemistry Division, Piramal Life Sciences Limited, Goregaon (E), Mumbai 400063, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Unexpected formation of sulindac sulfide lactone occurred when sulindac was treated with oxalyl chlo-
ride and triethylamine. Structurally analogous sulindac sulfide and indomethacin did not undergo such
lactonization under similar reaction conditions. We believe that the sulfoxide function in sulindac plays
a pivotal role possibly via a ‘longer-range’ vinylogous Pummerer-type reaction as a driving force for the
observed lactonization. The structure of the lactone was confirmed by single crystal X-ray analysis.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 28 October 2010
Revised 21 December 2010
Accepted 6 January 2011
Available online 13 January 2011
Keywords:
Sulindac sulfide
Sulindac sulfide lactone
Longer-range vinylogous Pummerer-type
lactonization
As an extension of our mission to discover new gastric-sparing
nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-
NSAIDs) as potentially ‘safe NSAIDs’,1,2 we wanted to synthesize
and evaluate the NO-sulindac (3a) from sulindac (1), which is a
widely used non-steroidal anti-inflammatory drug for acute or
long term treatment of osteoarthritis, rheumatoid arthritis, anky-
losing spondylitis, acute painful shoulder, and acute gouty arthri-
tis.3 When we attempted to synthesize NO-sulindac (3a) from
sulindac (1) by an established method as shown in Scheme 1 for
the synthesis of such NO-NSAIDs,1 the desired ester compound
3a was not obtained. However, to our surprise, the major product
isolated from the above reaction was found to be the sulindac sul-
fide lactone (4) on the basis of its analytical and spectroscopic data.
To rule out any ambiguity associated with the structural assign-
ment, we have further confirmed the structure of lactone 4 by sin-
gle crystal X-ray analysis (Fig. 1).
Obviously, the reduction of sulindac sulfoxide to sulindac sul-
fide along with concomitant lactonization has occurred in the
above reaction. Surprised by the non-participation of 2-
((2-hydroxyethyl)disulfanyl)ethyl nitrate (L1) in the above reac-
tion, we have repeated the above reaction twice with slight modi-
fications as stated below to verify whether the formation of
anticipated sulindac acid chloride (2) has really occurred: using
ethanol in place of 2-((2-hydroxyethyl)disulfanyl)ethyl nitrate
(L1) in the first reaction and in the absence of any alcoholic reac-
tant in the second reaction. In both the experiments, lactone 4
was obtained as the major product and the expected ethyl ester
of sulindac (3b) was not formed in the first reaction. These results
confirmed our doubt that the formation of sulindac acid chloride
(2) is indeed not occurring under the reaction conditions.
Intrigued by the above unique transformation, we have sub-
jected structurally analogous compounds, such as sulindac sulfide
(5) and indomethacin (6) to similar reaction conditions, but this
time in the presence of ethanol as alcoholic reactant and observed
that the respective sulindac sulfide lactone (4) and indomethacin
lactone (9) were not formed (Schemes 2 and 3, respectively).
However, the corresponding sulindac sulfide ethyl ester (10)
and indomethacin ethyl ester (11) were obtained as major prod-
ucts from the above reactions thereby confirming the formation
of acid chlorides (7) and (8), respectively, in these reactions
(Schemes 2 and 3, respectively).
The above results clearly demonstrate that the sulfoxide present
in sulindac (1) plays a pivotal role in this unique transformation
probably via a plausible mechanism, as depicted in Scheme 4,
involving a ‘longer-range’ vinylogous Pummerer-type thionium
ion-assisted lactonization.4 Thus, in the initial step, the oxalyl chlo-
ride is expected to preferentially acylate the sulfoxide oxygen in
sulindac to give an acyloxysulfonium salt (A). In the second step,
the base is expected to abstract an acidic methylene proton, which
is connected to the sulfonium group via a conjugated chain of
‘nine-carbon atoms’ (marked in blue) consisting of a phenyl ring
and two indene double bonds, to yield a carbanion, which passes
through the said conjugated nine carbon atom chain to assist the
cleavage of sulfur-oxygen bond to yield a thionium ion (B). In the
third step, the thionium ion (B) pulls the electrons through the con-
jugated chain of ‘seven carbon atoms’ (marked in blue) consisting
⇑
Corresponding author. Tel.: +91 22 40032903; fax: +91 22 3081 8036.
E-mail address: apparaosvgk@hotmail.com (A. Satyam).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.008

1180
S. Halder, A. Satyam / Tetrahedron Letters 52 (2011) 1179–1182
CO2R
Sulindac sulfide lactone (4)
CO2Et
CH3
F
F
CH3
CH3CH2OH
TEA, DCM
(COCl)2
H3C
S
H3C
S
10
O
CH3CH2OH
3a, R = CH2CH2SSCH2CH2ONO2
TEA, DCM
3b, R = CH2CH3
CO2H
CH3
COCl
CH3
F
F
R-OH = O2NOCH2CH2SSCH2CH2OH (L1)
R-OH
(COCl)2
or CH3CH2OH
TEA, DCM
CO2H
CH3
COCl
CH3
F
F
H3C
H3C
S
S
7
5
(COCl)2
Scheme 2. Attempted synthesis of sulindac sulfide lactone (4) from sulindac sulfide
(5) and formation of sulindac sulfide ethyl ester (10).
H3C
H3C
S
S
O
O
1
2
O
(COCl)2
TEA, DCM
With or Without R-OH
CO2Et
CH3
MeO
MeO
O
CH3
N
N
O
F
O
O
O
CH3
Cl
Cl
9
11
CH3CH2OH
TEA, DCM
H3C
S
TEA, DCM
(COCl)2
CH3CH2OH
4
CO2H
COCl
MeO
MeO
Scheme 1. Formation of sulindac sulfide lactone (4) from sulindac (1).
CH3
N
CH3
N
(COCl)2
O
O
Cl
Cl
8
6
Scheme 3. Attempted synthesis of indomethacin lactone (9) from indomethacin (6)
and formation of indomethacin ethyl ester (11).
co-workers reported the synthesis of unsaturated d-lactones (19)
via the application of vinylogous Pummerer-type lactonization of
the thionium ion intermediate (18).8
Figure 1. X-ray structure of sulindac sulfide lactone (4).
However, we have not come across any known example involv-
ing such a ‘longer-range’ (i.e., consisting of a conjugated chain of 7
or 9 carbon atoms) vinylogous Pummerer-type cyclization. We,
therefore, believe that ours is the first example of its kind.
Earlier, Sperl et al. reported the synthesis of sulindac sulfide lac-
tone (4) form sulindac sulfide (5) and used the same as an interme-
diate for the synthesis of 14C-labeled compounds.9 However, its
structure was not fully established and its biological activity was
not evaluated. We have now evaluated the anti-inflammatory
and anti-cancer activities of sulindac sulfide lactone 4 as well as
its sulfoxide (12) and sulfone (13) derivatives (Fig. 2) and those re-
sults will be reported elsewhere in due course.
In summary, we have accidentally discovered an interesting
‘longer-range’ vinylogous Pummerer-type lactonization process
wherein we obtained the sulindac sulfide lactone (4) as the major
product when sulindac (1) was treated with oxalyl chloride and
triethylamine. Although a few examples of extended or ‘long-range’
of an indene double bond and the sulfonium quinone methide
probably via a ‘longer-range’ vinylogous Pummerer-type lactoniza-
tion of carboxylic acid and gets reduced to sulfide thereby yielding
the sulindac sulfide lactone (4).
Literature survey on Pummerer-type reactions5 revealed the
following known examples involving such extended or long range
(i.e., consisting of a conjugated chain of 3–5 atoms) vinylogous
Pummerer-type reactions (Scheme 5): (1) Feldman et al. reported
the synthesis of spirocyclic indole compounds (15) from indole-
2-sulfoxides and proposed the intermediate thionium ion (14),
which undergoes vinylogous extended Pummerer-type reaction;6
(2) Zhou and co-workers synthesized 5-phenylthiovinyl-1,3-
oxazoles (17) via the application of ‘long-range’ Pummerer-type
cyclization of thionium ion intermediate (16);7 (3) Wang and

S. Halder, A. Satyam / Tetrahedron Letters 52 (2011) 1179–1182
1181
Et3N:
O
O
H
O
O
F
F
O
O
F
F
OH
CH3
OH
CH3
(COCl)2
H3C
Et3N, CH2Cl2
H3C
S
S
O
H3C
O
O
S
12
13
H3C S+
1
Cl-
O
O
O
Figure 2. Structures of sulindac sulfoxide lactone (12) and sulindac sulfone lactone
(13).
Cl
O
Cl
Cl
O
O
Acyloxysulfonium salt (A)
Acknowledgments
We are grateful to Piramal Life Sciences management for their
support and encouragement. We also thank all our colleagues from
Special Projects department, Patents department, and analytical
department for their technical help and cooperation. We thank
Mr. M. Mobin Shaikh for generating X-ray crystal structure at
National Single Crystal X-ray Diffraction Facility, and Sophisticated
Analytical Instrument Facility (SAIF) for FT-IR data, IIT-Bombay,
India.
O
H
O
F
F
O
Et3N:
O
CH3
CH3
H3C
S
H3C S+
Thionium ion (B)
Supplementary data
4
X-ray crystallographic data (excluding structure factors) have
been deposited with the Cambridge Crystallographic Data Centre
as supplementary Publication No. CCDC 742703. Supplementary
data (scanned copies of spectral data and HPLC chromatograms
for all the reported compounds) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2011.01.008.
Scheme 4. A plausible mechanism for the formation of sulindac sulfide lactone (4)
from sulindac (1) via a longer-range vinylogous Pummerer-type thionium ion-
induced lactonization.
References and notes
Nu
S+
Nu
1. Nemmani, K. V. S.; Mali, S. V.; Borhade, N.; Pathan, A. R.; Karwa, M.;
Pamidiboina, V.; SenthilKumar, S. P.; Gund, M.; Jain, A. K.; Mangu, N. K.;
Dubash, N. P.; Desai, D.; Sharma, S.; Satyam, A. Bioorg. Med. Chem. Lett. 2009, 19,
5297.
2. Pathan, A. R.; Karwa, M.; Pamidiboina, V.; Deshattiwar, J. J.; Deshmukh, N. J.;
Gaikwad, P. P.; Mali, S. V.; Desai, D. C.; Dhiman, M.; Mariappan, T. T.; Sharma, S.
D.; Satyam, A.; Nemmani, K. V. S. Inflammopharmacol. 2010, 18, 157.
3. Official FDA Information on sulindac at www.drugs.com.
4. We sincerely thank the reviewer for giving useful comments and suggestions
on the mechanism of this unique transformation.
5. (a) Smith, L. H. S.; Coote, S. C.; Sneddon, H. F.; Procter, D. J. Angew. Chem., Int.
Ed. 2010, 49, 5832; (b) Bur, S. K.; Padwa, A. Chem. Rev. 2004, 104, 2401; (c)
Feldman, K. S. Tetrahedron 2006, 62, 5003; (d) Akai, S.; Kita, Y. Top. Curr. Chem.
2007, 274, 35.
S
N
Ph
N
Ph
15
14
Prn
N
Prn
O
S
H
Ph
N
O
S+
CH3
CH3
Ph
17
16
S+
6. (a) Feldman, K. S.; Nuriye, A. Y. Tetrahedron Lett. 2009, 50, 1914; (b) Feldman, K.
S.; Karatjas, A. G. Org. Lett. 2006, 8, 4137; (c) Feldman, K. S.; Fodor, M. D. J. Am.
Chem. Soc. 2008, 130, 14964.
S
7. Xu, G.; Chen, K.; Zhou, H. Synthesis 2009, 3565.
8. Liu, J.; Wang, M.; Li, B.; Liu, Q.; Zhao, Y. J. Org. Chem. 2007, 72, 4401.
9. Sperl, G. J.; Pamukcu, R.; Brendel, K.; Gross, P. H. J. Labelled Compd. Radiopharm.
1999, 42, 877.
S
S
H
10. Experimental procedures and compound characterization data for all the
compounds reported in this article are presented below: Synthesis of (E)-
5-fluoro-8a-methyl-8-(4-(methylthio)benzylidene)-8,8a-dihydro-2H-indeno-
[2,1-b]furan-2-one (sulindac sulfide lactone 4) in the presence of
HOCH2CH2SSCH2CH2ONO2 (LI): To a solution of sulindac (1) (2 g, 5.61 mmol)
in dichloromethane (15 mL) at room temperature was added oxalyl chloride
(0.58 mL, 6.71 mmol) and the mixture was stirred for 2 h. The solvent was
removed under reduced pressure and the residue was re-dissolved in
dichloromethane (15 mL). A solution of 2-((2-hydroxyethyl)disulfanyl)ethyl
nitrate (L1, 1.5 gm, 7.50 mmol) and triethylamine (1 mL, 7.20 mmol) in
dichloromethane (10 mL) was added drop-wise and the solution was stirred
at RT for 4 h. The solvent was evaporated and the residue was extracted with
ethyl acetate (3 Â 25 mL), washed with water (2 Â 25 mL) and brine (25 mL),
dried over anhydrous Na2SO4, and concentrated. The crude material was
purified by silica gel column chromatography using 5–10% ethyl acetate/
petroleum ether as eluent to afford lactone 4 (400 mg, 21%) as a yellow solid.
Formation of the expected NO-sulindac (3a) was not observed. Mp 148 °C. IR
O
O
O
R
O
R
18
19
Scheme 5. Some known examples of extended or ‘long-range’ vinylogous Pum-
merer-type thionium ion-triggered cyclizations.
(i.e., involving a conjugated chain of 3–5 atoms) vinylogous Pum-
merer-type cyclizations are reported in the literature, as far as
we know, ours is the first example of a vinylogous Pummerer-type
lactonization wherein such a ‘longer-range’ (i.e., consisting of a
conjugated chain of 7 or 9 carbon atoms) process is involved. We
have also confirmed the structure of lactone 4 by a single crystal
X-ray analysis.10
(KBr): 1759, 1658, 1471, 1202 cmÀ1 1H NMR (300 MHz, CDCl3): d 1.67 (s, 3H),
.

1182
S. Halder, A. Satyam / Tetrahedron Letters 52 (2011) 1179–1182
2.50 (s, 3H), 5.99 (s, 1H), 6.71 (s, 1H), 6.95–7.43 (m, 7H). 13C NMR (125.7 MHz,
CDCl3): d 15.4, 27.2, 94.7, 108.8, 111.6, 111.8, 118.6, 118.8, 123.8, 126.2, 127.6,
128.4, 134.9, 137.9, 138.4, 138.8, 161.9, 163.9, 173.0, 173.8. HRMS ESI (m/z):
[M+Na]+ calculated for C20H15FNaO2S: 361.0669; found: 361.0660 (mass
J2 = 8.85 Hz, 1H), 6.90 (dd, J1 = 2.4 Hz, J2 = 9.1 Hz, 1H), 7.15 (s, 1H), 7.29–7.47
(m, 5H). 13C NMR (75.4 MHz, CDCl3) d 10.9, 14.5, 15.7, 32.2, 61.4, 105.9, 106.3,
110.7, 110.9, 123.9, 124.0, 126.2, 130.1, 130.2, 131.2, 133.3, 138.7, 139.4, 140.5,
146.8, 170.7; HRMS, ESI (m/z): [M+H]+ calculated for C22H22FO2S 369.1319,
found 369.1319. Synthesis of ethyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-
accuracy:
2.49 ppm).
Synthesis
of
(E)-5-fluoro-8a-methyl-8-(4-
(methylthio)benzylidene)-8,8a-dihydro-2H-indeno[2,1-b]furan-2-one
(sulindac
1H-indol-3-yl)acetate (Indomethacin ethyl ester) (11): To
a solution of
sulfide lactone 4) in presence of alcohol (EtOH): To a solution of sulindac (1)
(357 mg, 1 mmol) in dichloromethane (5 mL) at room temperature was added
oxalyl chloride (0.12 mL, 1.38 mmol) and the mixture was stirred for 2 h. The
solvent was removed under reduced pressure and the residue was re-dissolved
in dichloromethane (5 mL). A solution of absolute EtOH (0.08 mL, 1.37 mmol)
and triethylamine (0.19 mL, 1.37 mmol) in dichloromethane (2 mL) was added
drop-wise and the solution was stirred at rt for 4 h. The reaction mixture was
washed with water (5 mL) and brine (5 mL), dried over anhydrous Na2SO4, and
concentrated. The crude material was purified by silica gel column
chromatography using 40% dichloromethane/petroleum ether as eluent to
afford the lactone 4 (222 mg, 65.5%) as a yellow solid. The formation of expected
ester compound 3b was not observed. Analytical and spectral data of the
product are identical to those reported above. Synthesis of (E)-5-fluoro-
8a-methyl-8-(4-(methylthio)benzylidene)-8,8a-dihydro-2H-indeno[2,1-b]furan-2-
one (sulindac sulfide lactone 4) in absence of an alcoholic reactant: To a solution
of sulindac (1) (5 g, 14.02 mmol) in dichloromethane (50 mL) at room
temperature was added oxalyl chloride (1.45 mL, 16.79 mmol) and the
mixture was stirred for 2 h. The solvent was removed under reduced
pressure and the residue was re-dissolved in dichloromethane (50 mL).
Triethylamine (3.5 mL, 25.8 mmol) was added drop-wise and the solution
was stirred for 4 h. The reaction mixture was washed with water (2 Â 50 mL)
and brine (2 Â 50 mL), dried over anhydrous Na2SO4, and concentrated. The
crude material was purified by silica gel column chromatography using 50%
dichloromethane/petroleum ether as eluent to afford lactone 4 (3.2 g, 67%) as a
yellow solid, which was recrystallized from methanol to get yellow crystals for
X-ray analysis. Analytical and spectral data are identical to those obtained
indomethacin (6) (500 mg, 1.39 mmol) in dichloromethane (8 mL) was added
oxalyl chloride (0.144 mL, 1.67 mmol) and the solution was stirred at room
temperature for 2 h. The solvent was removed under reduced pressure and the
crude material was re-dissolved in dichloromethane (8 mL). A solution of
absolute EtOH (0.098 mL, 1.67 mmol) and triethylamine (0.23 mL, 1.67 mmol)
in dichloromethane (1 mL) was added drop-wise, and the reaction mixture was
stirred for 30 min. The reaction mixture was diluted with dichloromethane
(25 mL), washed with water (2 Â 25 mL) and brine (25 mL), dried over
anhydrous Na2SO4, and concentrated to afford ester 11 (500 mg, 93%) as a
white solid. Mp 85–87 °C (lit.11 mp 82–83 °C). IR (KBr): 1728, 1680, 1602, 1467,
1183 cmÀ1 1H NMR (300 MHz, CDCl3): d 1.30 (t, J = 6.9 Hz, 3H), 2.40 (s, 3H),
.
3.67 (s, 2H), 3.85 (s, 3H), 4.16 (q, J = 7.2 Hz, 2H), 6.67 (dd, J1 = 2.4 Hz, J2 = 9.0 Hz,
1H), 6.87 (d, J = 9 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H) 7.45–7.50 (m, 2H), 7.63–7.69
(m, 2H). MS m/z ESI (+ve): 386.1 [M+H]+, 408.1 [M+Na]+. Synthesis of (E)-5-
fluoro-8a-methyl-8-(4-(methylsulfinyl)benzylidene)-8,8a-dihydro-2H-indeno[2,1-
b]furan-2-one (sulindac sulfoxide lactone) (12): The lactone
4 (500 mg,
1.47 mmol) was dissolved in a mixture of methanol (35 mL) and acetone
(16 mL). A solution of sodium periodate (650 mg, 3.03 mmol) in water (9 mL)
was added and the mixture was stirred for 40 h. The solvent was removed
under reduced pressure and the white precipitate obtained was filtered,
washed with water, and dried to afford the corresponding sulfoxide 12
(370 mg, 70%) as a white solid. Mp 83–84 °C (lit.12 mp 84 °C). IR (KBr): 1763,
1661, 1471, 1205, 1048 cmÀ1 1H NMR (300 MHz, CDCl3): d 1.71 (s, 3H), 2.79 (s,
.
3H), 6.04 (s,1H), 6.80 (s, 1H), 7.00 - 7.73 (m, 7H). 13C NMR (75.4 MHz, CDCl3): d
26.6, 43.9, 93.9, 108.8, 111.4, 111.7, 118.4, 118.7, 121.2, 127.3, 128.5, 134.8,
134.9, 139.4, 140.3, 140.8, 161.2, 164.6, 172.1, 172.4. HRMS ESI (m/z): [M+Na]+
calculated for C20H15FNaO3S: 377.0618; found: 377.0602 (mass accuracy:
above. X-ray analysis for compound 4: Formula
C20H15FO2S, unit cell
parameters a 7.317(5) b 18.346(5) c 12.347(5), 90, b 107.07(5),
group P21/a monoclinic, CCDC No. 742703. Synthesis of (E)-ethyl 2-((Z)-6-
fluoro-2-methyl-3-(4-(methylthio)benzylidene)-2,3-dihydro-1H-inden-1-ylidene)-
a
c
90, space
4.24 ppm).
benzylidene)-8,8a-dihydro-2H-indeno[2,1-b]furan-2-one
lactone) (13): The lactone (100 mg, 0.29 mmol) was dissolved in THF
Synthesis
of
(E)-5-fluoro-8a-methyl-8-(4-(methylsulfonyl)-
(sulindac sulfone
4
acetate (Sulindac sulfide ethyl ester) (10): Sulindac sulfide
5
(50 mg,
(5 mL) and cooled to 0 °C. A solution of oxone (218 mg, 0.35 mmol) in water
(4 mL) was added drop-wise and the reaction mixture was stirred at room
temperature for 20 h. The solvent was removed under reduced pressure and
the white precipitate obtained was filtered, washed with water, and dried to
afford the corresponding sulfone 13 (90 mg, 82%) as a white solid. Mp: 191–
0.147 mmol) was dissolved in dichloromethane (5 mL) by warming on a hot
water bath. Oxalyl chloride (0.018 mL, 0.20 mmol) was added at room
temperature under nitrogen and the reaction mixture was stirred for 2 h. The
solvent was removed under reduced pressure. The crude material was re-
dissolved in dichloromethane (5 mL) and
a
solution of absolute EtOH
192 °C (lit.12 mp 193 °C). IR (KBr): 1762, 1591, 1468, 1311, 1144 cmÀ1 1H NMR
.
(0.012 mL, 0.20 mmol) and triethylamine (0.028 mL, 0.20 mmol) in
dichloromethane (2 mL) was added drop-wise. The reaction mixture was
stirred at rt for 30 min, diluted with dichloromethane (25 mL), washed with
water (25 mL) and brine (25 mL), and dried over anhydrous Na2SO4 and
concentrated. The crude material was purified by silica gel column
chromatography using 5% ethyl acetate/petroleum ether as eluent to obtain
ester 10 (48 mg, 89%) as a yellow solid. Mp 95–97 °C. IR (KBr): 1722, 1605,
(300 MHz, CDCl3): d 1.69 (s, 3H), 3.09 (s, 3H), 6.04 (s,1H), 6.77 (s, 1H), 6.98–
7.94 (m, 7H). 13C NMR (125.7 MHz, CDCl3): d 26.6, 43.9, 93.9, 108.8, 111.4,
111.8, 118.4, 118.7, 121.2, 127.3, 128.5, 134.8, 136.7, 139.3, 140.3, 140.7, 161.2,
164.6, 172.1, 172.4. HRMS ESI (m/z): [M+Na]+ calculated for C20H15FNaO4S:
393.0567; found: 393.0553 (mass accuracy: 3.56 ppm).
11. Cattani, V. B.; Fiel, L. A.; Jäger, A.; Jäger, E.; Colomé, L. M.; Uchoa, F.; Stefani, V.;
Costa, T. D.; Guterres, S. S.; Pohlmann, A. R. Eur. J. Pharm. Sci. 2010, 39, 116.
12. Gross, P.; Sperl, G.; Pamukcu, R.; Brendel, K. U.S. Patent 5776,962, 1998; Chem.
Abstr. 1998, 129, 122563.
1465, 1166 cmÀ1 1H NMR (300 MHz, CDCl3): d 1.28 (t, J = 7.2 Hz, 3H), 2.22 (s,
.
3H), 2.56 (s, 3H), 3.57 (s, 2H), 4.19 (t, J = 7.2 Hz, 2H), 6.60 (dt, J1 = 3.0 Hz,