Intramolecular nonbonded S...N interaction in rabeprazole

Article abstract of DOI:10.1248/cpb.56.802

Intramolecular nonbonded S...N interactions in the crystal structures of the derivatives (7a-d) of sodium rabeprazole (1) and an intermolecular nonbonded S...N interaction between ethylmethylsulfoxide and pyridine in a solution were recognized. These results made us estimate that the intramolecular nonbonded S...N interaction existed in 1 and its derivatives in a solution, and formed the 4-membered quasi-ring in 2 (Fig. 1) followed by the increase of the reactivity of 2 to give the putative spiro sulfoxide 3, which is the key intermediate in the reaction cascade of 1 (Chart 1).

Full text of DOI:10.1248/cpb.56.802

802
Chem. Pharm. Bull. 56(6) 802—806 (2008)
Vol. 56, No. 6
Intramolecular Nonbonded S···N Interaction in Rabeprazole
Kazuhiko HAYASHI,*,a Shiho OGAWA,b Shigeki SANO,b Motoo SHIRO,c Kentaro YAMAGUCHI,d
Yoshihisa SEI,d and Yoshimitsu NAGAO*,b
a College of Pharmacy, Kinjo Gakuin University; 2–1723 Omori, Moriyama-ku, Nagoya 463–8521, Japan: b Graduate
School of Pharmaceutical Sciences, The University of Tokushima; Sho-machi, Tokushima 770–8505, Japan: c Rigaku
Corporation; 3–9–12 Matsubara-cho, Akishima, Tokyo 196–8666, Japan: and d Faculty of Pharmaceutical Sciences at
Kagawa Campus, Tokushima Bunnri University; 1314–1 Shido, Sanuki, Kagawa 769–2193, Japan.
Received January 8, 2008; accepted March 21, 2008; published online April 1, 2008
Intramolecular nonbonded S···N interactions in the crystal structures of the derivatives (7a—d) of sodium
rabeprazole (1) and an intermolecular nonbonded S···N interaction between ethylmethylsulfoxide and pyridine
in a solution were recognized. These results made us estimate that the intramolecular nonbonded S···N interac-
tion existed in 1 and its derivatives in a solution, and formed the 4-membered quasi-ring in 2 (Fig. 1) followed by
the increase of the reactivity of 2 to give the putative spiro sulfoxide 3, which is the key intermediate in the reac-
tion cascade of 1 (Chart 1).
Key words nonbonded interaction; rabeprazole; X-ray crystallographic analysis; proton pump inhibitor; close contact
Intramolecular nonbonded S···X (XꢀS, O, N, etc.) inter- electrophilic position of benzimidazole moiety, as shown in
actions have been observed in a large number of organosulfur Fig. 1. Therefore, in order to make clear the presence of the
compounds controlling the conformation of small and large intramoleculer nonbonded S···N interaction in 1, we charac-
molecules.1—12) Some of these compounds showed the strong terized the crystal structures of derivatives of 1 at first, since
bioactivity, and we suggested that the intramolecular non- 1 itself could hardly be crystallized.21)
bonded S···X interactions play an important role on the
The reactions of 1 with various electrophiles in the pres-
mechanism of several biological effects.1,2,6—12) For example, ence of amines gave the corresponding derivatives of 1 in
the clear S···O close contact in the complex crystalline 36—92% yields, as shown in Chart 2. The resultant deriva-
structure of carbonic anhydrase I and acetazolamide was rec- tives 7a—d were recrystallized from suitable solvents to ob-
ognized.12) The same nonbonded interaction was observed in tain the corresponding crystals available for X-ray crystallo-
the crystalline structure of acyliminothiadiazoline, which has graphic analysis. The computer-generated drawings of the
potent angiotensin II receptor antagonistic activity.6,11) It is crystal structures of derivatives 7a—d are shown in Fig. 2.
estimated that the ring structure consisted of the intramolecu- As we expected, the S···N close contact between sulfoxide S
lar nonbonded S···X interactions was more flexible than that and N of the pyridine moiety was recognized in crystal struc-
of covalent bonding, and this flexibility increased the binding tures of all derivatives. In crystallographic structures 7a—c,
affinity of the active compound to the flexible pocket of the the distances (2.815, 2.806, 2.709 Å) between nonbonded
enzyme or the receptor. These results prompted us to dis- S···N atoms were clearly shorter than the sum (S and N:
close the new roles of intramolecular nonbonded S···X in-
teractions in other drugs. Herein, we focus on rabepra-
zole,13—16) and discuss the intramolecular nonbonded S···N
interaction in rabeprazole and its role.
Sodium rabeprazole (1) is one of the inhibitors of the gas-
tric (Hꢁ-Kꢁ)-ATPase.13,14) As a result of the investigations on
the mechanism of action of these inhibitors, it has been
expected that 1 will be activated by protonation in the pari-
etal cell (intermediate 2), converted into the sulfenamide 5
via the spiro sulfoxide 3 and sulfenic acid 4, and the active
principle 5 can react with the accessible cysteines of the gas-
tric (Hꢁ-Kꢁ)-ATPase followed by the inhibition of the
enzyme (compound 6), as shown in Chart 1.14,17—20) In this
reaction cascade, the key step is the formation of the putative
spiro sulfoxide 3 arising from nucleophilic attack of the pyri-
dine nitrogen on the activated 2-position of the benzimida-
zole moiety.18) The fact that the nucleophilic attack of the
Chart 1
pyridine nitrogen smoothly proceeds despite the week nucle-
ophilicity is very interest, and made us guess that the in-
tramoleculer nonbonded S···N interaction influenced this
step. Because, if such intramoleculer nonbonded S···N
interaction is possible in rabeplazole, the 4-membered quasi-
ring in 2 containing the rabeplazole structure would be
Fig. 1. Probable Nonbonded S···N Interaction in 2
© 2008 Pharmaceutical Society of Japan
formed and bring the nitrogen atom of pyridine close to the
∗ To whom correspondence should be addressed. e-mail: hayashi@kinjo-u.ac.jp

June 2008
803
3.35 Å)22) of the corresponding van der Waals radii, and the a nonbonded S···N interaction was formed between ethyl-
planarities of S–C–C–N (see torsion angles in 7a—c) moi- methylsulfoxide molecule and pyridine molecule in a MeOH
eties were determined. And, the S···N close contact solution and the same nonbonded S···N interaction can also
(S1···N3: 3.229 Å, 3.235 Å) can also be observed in the be formed within a molecule. Therefore, we estimate that the
crystallographic structure of 7d, though the planarity of the intramolecular nonbonded S···N interaction is formed in 1
S1–C16–C17–N3 moiety was not recognized. These results itself even in a solution, and the 4-membered quasi-ring
make us estimate that the S···N close contact is formed in formed by the nonbonded interaction in 2 containing the
the crystal structure of 1, and get us interested in this S···N rabeplazole structure accelerates the reaction of 2 to 3.
close contact in a solution. In previous studies, we have
Subsequently, the intermediates, which were formed in the
reported the evidence for intermolecular nonbonded S···O reaction cascade17—20) to inhibit the gastric (Hꢁ-Kꢁ)-ATPase,
interactions in a solution by utilizing cold-spray ionization were isolated in order to make clear that the action mecha-
mass spectrometry (CSI-MS).23) Thus, we attempted detec- nism of 1 was the same as that of the other inhibitors of the
tion of a week complex of ethylmethylsulfoxide with pyri- gastric (Hꢁ-Kꢁ)-ATPase. The sulfenamide 8e was obtained
dine by an intermolecular nonbonded S···N interaction in a in 86% yield by the treatment of 1 with 48% aqueous HBF4
MeOH solution in a similar manner, since a nonbonded in methanolic solution.18) Using 60% HClO4, the perchlorate
S···N interaction has not been detected in a solution.
salt 8f was obtained in a quantitative yield, as shown in Chart
The CSI-MS spectra were taken by using mixture (1 : 1) of 3. The reaction of 8e with ethanethiol gave the desired disul-
ethylmethylsulfoxide with an equimolecular amount of pyri- fide 9 in 99% yield, as shown in Chart 4. The structures of
1
dine in MeOH at room temperature, and the corresponding these compounds were identified by H-NMR, IR spectra,
molecular ion peak, m/z 172 due to [ethylmethylsulfox- mass spectra, and elementary analysis. Interestingly, the reac-
ide···pyridine complexꢁH]ꢁ (for C8H13NOSꢁH), were tion of 8e with cysteine afforded cystine in 72% yield, as
clearly observed, as shown in Fig. 3. This result suggests that shown in Chart 4. In preceding paper, it has been reported
that the S–S bond in 9 can be cleaved by thiols yielding
another disulfides.17) In this reaction, the rate of nucleophilic
attack of cysteine to disulfide 10, which should be generated
by the reaction of 8e with cysteine, would be much faster
than that to 8e, as shown in Fig. 4. The generation of 8e, 8f,
9, and cystine definitely suggest that sodium rabeprazole (1)
also inhibits the gastric (Hꢁ-Kꢁ)-ATPase in the action mech-
anism reported previously,18—20) and the same intramoleculer
nonbonded S···N interactions will also exist in the other in-
hibitors of the gastric (Hꢁ-Kꢁ)-ATPase such as lansopra-
Reagents and conditions: (i) 4-nitrobenzylbromide (1.2 mol eq), N,N-diisopropyl-
ethylamine (2.2 mol eq), 18 h; (ii) 2,5-dichlorobenzensulfonyl chloride (1.1 mol eq),
Et3N (3.0 mol eq), 13 h; (iii) cinnanyl bromide (1.2 mol eq), Et3N (2.2 mol eq), 20.5 h;
(iv) 2-bromoacetophenone (1.1 mol eq), Et3N (3.0 mol eq), 17.5 h.
zole24) and omeprazole.25)
In conclusion, the intramoleculer nonbonded S···N inter-
Chart 2
actions in the crystal structures of rabeplazole derivatives
Fig. 2. Computer-Generated Drawing Derived from the X-Ray Coordinates of Compounds 7a—d

804
Vol. 56, No. 6
Fig. 3. CSI Mass Spectrum of Ethylmethylsulfoxide and Pyridine
using tetramethylsilane (TMS) as an internal standard. Fast atom bombard-
ment mass spectra (FAB-MS) were recorded on a JEOL JMS SX-102A
spectrometer. Cold-spray ionization mass spectra (CSI-MS) were measured
by JEOL JMS-700 spectrometer equipped with CSI source. Elementary
combustion analyses were performed on a Yanaco CHN CORDER MT-5.
All reactions were monitored by TLC employing 0.25-mm silica gel plates
(Merck 5715; 60 F254). Column chromatography was carried out on silica
gel [Kanto Chemical 60N; 63—210 mm]. Anhydrous THF was commer-
cially obtained from Kanto Chemical. All reagents were used as purchased.
Typical Procedure for the Preparation of Rabeprazole Derivatives
7a—d 4-Nitorobenzylbromide (1.36 g, 6.30 mmol) was added to a solution
of N,N-diisopropylethylamine (2.00 ml, 11.5 mmol) and 1 (2.00 g, 5.24 mmol)
in anhydrous THF (2.0 ml) at ꢂ26 °C. After being stirred at room tempera-
ture for 18 h, the reaction mixture was treated with water and then extracted
with CHCl3. The extract was washed with saturated NaHCO3 solution, satu-
rated NH4Cl solution, and brine, and then dried over anhydrous MgSO4. The
organic layer was evaporated in vacuo to afford a crude product, which was
purified by chromatography on a silica gel column [CHCl3 and CHCl3/MeOH
(97 : 3)], giving 7a (2.13 g, 82%) as colorless powder. The single crystals of
7a were obtained by recrystallization from THF as colorless prisms.
1-(4-Nitrobenzyl)-2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-
yl]methylsulfinyl}-1H-benzimidazole (7a): Colorless prisms, mp 143 °C
(THF). 1H-NMR (400 MHz, CDCl3) d: 2.0—2.1 (2H, m), 2.23 (3H, s), 3.35
(3H, s), 3.55 (2H, t, Jꢀ6.1 Hz), 4.08 (2H, t, Jꢀ6.1 Hz), 4.99 (1H, d,
Jꢀ13.7 Hz), 5.12 (1H, d, Jꢀ13.7 Hz), 5.79 (1H, d, Jꢀ16.4 Hz), 5.86 (1H, d,
Jꢀ16.4 Hz), 6.66 (1H, d, Jꢀ5.6 Hz), 7.23 (1H, d, Jꢀ7.6 Hz), 7.3—7.4 (4H,
m), 7.86 (1H, d, Jꢀ7.6 Hz), 8.10 (1H, d, Jꢀ5.6 Hz), 8.16 (2H, d, Jꢀ8.6 Hz).
IR (KBr) cmꢂ1: 2875, 1585, 1521, 1341, 1341, 1038, 744, 429. FAB-MS
m/z: 495.1700 [Mꢁ1]ꢁ (Calcd for C25H27N4O5S: 495.1702). Anal. Calcd for
C25H26N4O5S: C, 60.71; H, 5.30; N, 11.33. Found: C, 60.47; H, 5.28; N,
11.04.
1-(2,4-Dichlorophenylsulfonyl)-2-{[4-(3-methoxypropoxy)-3-meth-
ylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole (7b): Colorless needles,
mp 124—125 °C (AcOEt). 1H-NMR (400 MHz, CDCl3) d: 2.0—2.1 (2H,
m), 2.26 (3H, s), 3.36 (3H, s), 3.55 (2H, t, Jꢀ6.1 Hz), 4.08 (2H, t, Jꢀ
6.1 Hz), 4.78 (1H, d, Jꢀ13.4 Hz), 4.96 (1H, d, Jꢀ13.4 Hz), 6.63 (1H, d,
Jꢀ5.6 Hz), 7.4—7.5 (3H, m) , 7.56 (1H, dd, Jꢀ2.4, 8.3 Hz), 7.7—7.8 (1H,
m), 7.8—7.9 (1H, m), 8.10 (1H, d, Jꢀ5.6 Hz), 8.41 (1H, d, Jꢀ2.4 Hz). IR
(KBr) cmꢂ1: 1583, 1454, 1387, 1296, 1171, 1055, 823, 688, 584, 523. FAB-
MS m/z: 568.0530 [Mꢁ1]ꢁ (Calcd for C24H24Cl2N3O3S2: 568.0534). Anal.
Calcd for C24H23Cl2N3O3S2·1/4AcOEt: C, 50.85; H, 4.27; N, 7.12. Found: C,
50.62; H, 4.18; N, 6.95.
1-Cinnamyl-2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl-
sulfinyl}-1H-benzimidazole (7c): Colorless plates, mp 97—98 °C (Et2O).
1H-NMR (400 MHz, CDCl3) d: 2.0—2.1 (2H, m), 2.22 (3H, s), 3.34 (3H, s),
3.53 (2H, t, Jꢀ6.1 Hz), 4.04 (2H, t, Jꢀ6.1 Hz), 4.97 (1H, d, Jꢀ13.6 Hz),
5.04 (1H, d, Jꢀ13.6 Hz), 5.25 (1H, ddd, Jꢀ1.2, 5.9, 16.4 Hz), 5.30 (1H, ddd,
Reagents and conditions: (i) aq. HBF4 (3.3 mol eq), MeOH, 14 h; (ii) aq. HClO4
(3.3 mol eq), MeOH, 16 h.
Chart 3
Reagents and conditions: (i) EtSH (1.0 mol eq), MeCN, 1 N HCl (cat.), r.t., 1.5 h; (ii)
cysteine (1.0 mol eq), 50% aq. MeCN, 1 N HCl (cat.), r.t., 17 h.
Chart 4
Fig. 4. Plausible Cystine-Generating Pathway from 8e
7a—d and the intermolecular nonbonded S···N interaction
between ethylmethylsulfoxide S and N of the pyridine moiety
in a solution were recognized. From these results, it is as-
sumed that the nonbonded S···N interaction in 1 is formed
in a solution, and increase the reactivity of 2 to give the puta-
tive spiro sulfoxide 3 by the formation of the 4-membered
quasi-ring in 2 containing the rabeplazole structure, as shown
in Chart 1 and Fig. 1. Further, the mechanism of action of
sodium rabeprazole (1) was confirmed by the isolation of the
intermediates (8e, 8f, 9, and cystine) in the reaction cascade
of 1.
Experimental
All melting points were determined on a Yanaco micro melting point ap-
paratus and are uncorrected. IR spectra were obtained on a JASCO FT/IR- Jꢀ1.2, 5.9, 16.4 Hz), 6.32 (1H, dt, Jꢀ15.9, 5.9 Hz), 6.59 (1H, d,
1
420 IR Fourier transform spectrometer. H-NMR (400 MHz) spectra were Jꢀ15.9 Hz), 6.63 (1H, d, Jꢀ5.9 Hz), 7.2—7.4 (7H, m), 7.4—7.5 (1H, m),
recorded on JEOL JNM-AL400. Chemical shifts are given in d values (ppm)
7.8—7.9 (1H, m), 8.17 (1H, d, Jꢀ5.6 Hz). IR (KBr) cmꢂ1: 2939, 1581,

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Table 1. Summary of X-Ray Crystallographic Analyses of Compounds 7a—d
7a
7b
7c
7d
Formula
C25H26N4O5S
494.56
Colorless, block
Monoclinic
P21/c
C26H27Cl2N3O6S2
612.54
Colorless, platelet
Triclinic
¯
P1
C27H29N3O3S
475.60
Colorless, platelet
Monoclinic
P21/c
C26H27N3O4S
477.58
Colorless, block
Triclinic
¯
P1
Formula weight
Crystal description
Crystal system
Space group
Lattice constants
a, Å
10.063(5)
8.448(4)
27.950(1)
7.880(11)
12.902(16)
14.304(17)
96.63(8)
103.56(8)
96.05(9)
1391(3)
2
12.216(8)
8.772(5)
23.000(18)
8.451(4)
15.885(7)
17.750(8)
89.54(3)
86.08(3)
85.90(3)
2371(18)
4
b, Å
c, Å
a, deg.
b, deg.
94.82(2)
90.16(5)
g, deg.
Volume, Å3
Z
2366(1)
4
1.388
0.043, 0.083
1.065
2465(3)
4
1.282
0.134, 0.187
0.917
Density (calcd), g/cm3
Residual R, Rw
Goodness of Fit Indicator
1.462
0.069, 0.182
1.146
1.338
0.098, 0.247
1.203
7.89 (1H, d, Jꢀ7.6 Hz), 9.55 (1H, d, Jꢀ7.6 Hz). IR (KBr) cmꢂ1: 1621,
1564, 1520, 1475, 1415, 1317, 1101, 1068, 762, 623. FAB-MS m/z:
342.1251 [M]ꢁ (Calcd for C18H20N3O2S: 342.1276). Anal. Calcd for
C18H20N3O2S·ClO4·1/2CH3OH: C, 48.53; H, 4.84; N, 9.18. Found: C,
48.21; H, 4.54; N, 9.52.
Reaction of 8e with Ethanthiol 1 N HCl (0.2 ml) and ethanthiol (35 ml,
0.94 mmol) were added to a solution of 8e (400 mg, 0.94 mmol) in MeCN
(4 ml) at room temperature. After being stirred at room temperature for
30 min, the reaction mixture was treated with saturated NaHCO3 solution,
concentrated in vacuo, and then extracted with AcOEt. The extract was dried
over anhydrous MgSO4 and evaporated in vacuo to afford an residue, which
was crystallized from AcOEt to give 9 (381 mg, 99%).
1458, 1296, 1088, 1041, 756. FAB-MS m/z: 476.1982 [Mꢁ1]ꢁ (Calcd for
C27H30N3O3S: 476.2008). Anal. Calcd for C27H29N3O3S: C, 68.18; H, 6.15;
N, 8.84. Found: C, 68.21; H, 6.19; N, 8.71.
1-Phenacyl-2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl-
sulfinyl}-1H-benzimidazole (7d): Colorless needles, mp 108—109 °C
1
(AcOEt). H-NMR (400 MHz, CDCl3) d: 2.0—2.1 (2H, m), 2.16 (3H, s),
3.34 (3H, s), 3.53 (2H, t, Jꢀ6.1 Hz), 4.07 (2H, t, Jꢀ6.1 Hz), 4.87 (1H, d,
Jꢀ13.9 Hz), 4.95 (1H, d, Jꢀ13.9 Hz), 5.94 (1H, d, Jꢀ18.3 Hz), 6.21 (1H, d,
Jꢀ18.3 Hz), 6.68 (1H, d, Jꢀ5.6 Hz), 7.2—7.3 (1H, m), 7.3—7.4 (2H, m),
7.54 (2H, t, Jꢀ7.3 Hz), 7.67 (1H, t, Jꢀ7.3 Hz), 7.8—7.9 (1H, m), 8.04 (2H,
d, Jꢀ7.3 Hz), 8.23 (1H, d, Jꢀ5.6 Hz). IR (KBr) cmꢂ1: 2939, 2877, 1689,
1581, 1458, 1234, 1088, 748. FAB-MS m/z: 478.1790 [Mꢁ1]ꢁ (Calcd for
C26H28N3O4S: 478.1807). Anal. Calcd for C26H27N3O4S: C, 65.39; H, 5.70;
N, 8.80. Found: C, 65.19; H, 5.70; N, 8.78.
2-[2-(Ethyldithiomethyl)-4-(3-methoxypropoxy)-3-methyl-1-pyri-
1
dinio]benzimidazolide (9): Yellow powder, mp 92 °C. H-NMR (400 MHz,
CDCl3) d: 1.02 (3H, t, Jꢀ7.3 Hz), 2.2—2.3 (2H, m), 2.31 (2H, q, Jꢀ7.3 Hz),
2.48 (3H, s), 3.39 (3H, s), 3.59 (2H, t, Jꢀ6.4 Hz), 4.42 (2H, t, Jꢀ6.4 Hz),
4.89 (2H, s), 7.12 (1H, d, Jꢀ7.3 Hz), 7.1—7.2 (2H, m), 7.7—7.8 (2H,m),
8.96 (1H, d, Jꢀ7.1 Hz). IR (KBr) cmꢂ1: 2880, 1619, 1307, 1091, 750;
FAB-MS m/z: 404.1473 [M]ꢁ (Calcd for C20H25N3O2S2: 404.1466). Anal.
Calcd for C20H25N3O2S2·1/4H2O: C, 58.09; H, 6.46; N, 10.16. Found: C,
58.36; H, 6.13; N, 10.10.
X-Ray Crystallographic Analysis of Rabeprazole Derivatives 7a—d
The measurement was made on a Rigaku RAXIS-RAPID Imaging Plate dif-
fractometer with graphite monochromated MoKa radiation. The data were
processed using the PROCESS-AUTO program package. The linear absorp-
tion coefficient, m, for MoKa radiation is 1.0 cmꢂ1. A symmetry-related ab-
sorption correction using the program ABSCOR was applied.26) The data
were corrected for Lorentz and polarization effects. The structure was solved
by directed methods and expanded using Fourier techniques.27,28) The non-
hydrogen atoms were refined anisotropically. Hydrogen atoms were included
but not refined. Natural atom scattering factors were taken from Cromer and
Waber.29) The values for the mass attenuation coefficients are those of
Creagh and Hubbel.30) All calculation were performed using the teXsan
crystallographic software package.31) The crystal data are listed in Table 1.
Determination Condition for CSI-MS (Cold-Spray Ionization Mass
Spectrometry)23) Needle voltage: 3.9 kV, orifice voltage: 30 V, ring lens
voltage: 10 V, spray temp.: r.t., resolution: 6000, flow rate: 0.5 ml/h, sol-
vent: MeOH, CSI mass spectra of ethylmethylsulfoxide and pyridine:
[C8H13NOSꢁH]ꢁ, exact mass: 172.0649.
Reaction of 8e with Cysteine32) 1 N HCl (0.25 ml) and a solution of L-
cysteine (142 mg, 1.17 mmol) in water (2.5 ml) were added to a solution of
8e (500 mg, 1.17 mmol) in MeCN (2.5 ml) at room temperature. After being
stirred at room temperature for 16.5 h, the precipitated colorless powder was
collected by filtration, washed with water, and then dried in vacuo to give
cystine (101 mg, 72%).
Cystine: Colorless powder, 258—261 °C (dec.) [lit.33) 260—261 °C
(dec.)]. 1H-NMR (400 MHz, D2OꢁNaOD) d: 2.90 (2H, dd, Jꢀ7.6, 13.7 Hz),
3.10 (2H, dd, Jꢀ4.6, 13.7 Hz), 3.58 (2H, dd, Jꢀ4.6, 7.6 Hz); IR (KBr) cmꢂ1
:
1585, 1484, 1408, 1194, 1127, 963, 847, 541.
Acknowledgement We thank Eisai Co., Ltd., for the provision of
sodium rabeprazole (1). This work was supported by a Grant-in-Aid for Sci-
entific Reserch (B) (2) (14370723 and 16390008) and Scientific Research
(C) (20550102) from the Japan Society for the Promotion of Science.
Typical Procedure for the Preparation of Sulfenamide 8e, f 48%
aqueous HBF4 (1.4 ml, 10.7 mmol) was added to a solution of 1 (2.00 g,
5.24 mmol) in MeOH (60 ml) at ꢂ25 °C. After being stirred for 14 h, the
precipitated yellow powder was collected by filtration, washed with cold
MeOH and then dried in vacuo to give 8e (1.92 g, 86%).
References and Notes
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Experimental Advances,” ed. by Bernardi F., Csizmadia I. G., Mangini
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3-(3-Methoxypropoxy)-4-methyl-5H-pirido[1ꢃ.2ꢃ:4.5][1.2.4]thiadi-
azino[2.3-a]benzimidazol-13-ium Tetrafluoroborate (8e): Yellow powder, mp
123 °C (dec.). 1H-NMR (400 MHz, DMSO-d6) d: 2.0—2.2 (2H, m), 2.42
(3H, s), 3.29 (3H, s), 3.55 (2H, t, Jꢀ6.1 Hz), 4.62 (2H, t, Jꢀ6.4 Hz), 5.11
(2H, s), 7.3—7.5 (2H, m), 7.70 (1H, d, Jꢀ7.8 Hz), 7.86 (1H, d, Jꢀ7.8 Hz),
7.89 (1H, d, Jꢀ7.8 Hz), 9.56 (1H, d, Jꢀ7.8 Hz). IR (KBr) cmꢂ1: 3433, 1624,
1450, 1315, 1084, 756. FAB-MS m/z: 342.1293 [M]ꢁ (Calcd for
C18H20N3O2S: 342.1276). Anal. Calcd for C18H20N3O2S·BF4·CH3OH: C,
49.80; H, 4.62; N, 9.17. Found: C, 49.54; H, 4.64; N, 9.54.
3-(3-Methoxypropoxy)-4-methyl-5H-pirido[1ꢃ.2ꢃ:4.5][1.2.4]thiadi-
azino[2.3-a]benzimidazol-13-ium Perchlorate (8f): Colorless powder, mp
123 °C (dec.). 1H-NMR (400 MHz, DMSO-d6) d: 2.1—2.2 (2H, m), 2.42
(3H, s), 3.28 (3H, s), 3.55 (2H, t, Jꢀ6.1 Hz), 4.62 (2H, t, Jꢀ6.1 Hz), 5.10
(2H, s), 7.4—7.5 (2H, m), 7.70 (1H, d, Jꢀ7.6 Hz), 7.86 (1H, d, Jꢀ8.1 Hz),

806
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