Efficient synthesis of N-Oxide derivatives: Substituted 2-(2-(pyridyl-N-oxide)methylsulphinyl)benzimidazoles

Article abstract of DOI:10.1080/00397910701470693

Different substituted 2-chloromethylpyridyl derivatives (6a-d) were oxidized with mCPBA to give the respective 2-chloromethylpyridine-N-oxide derivatives (7a-d) at low temperature, which on condensation with 2-mercapto-1H-benzimidazole (8a-c) in the presence of aprotic solvents give the 2-[[(pyridin-2-yl-1-oxide)methyl]sulfanyl]-1H-benzimidazole (9a-d) in good yield. Finally, 9a-d oxidized with mCPBA in chlorinated solvent gives a mixture of 2-[[(pyridin-2-yl-1-oxide)methyl]sulfonyl]-1H-benzimidazole (3a-d, 10%) and 2-[[(pyridin-2-yl-1-oxide) methyl]sulfinyl]-1H-benzimidazole (4a-d, 90%) derivatives. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701470693

This article was downloaded by: [Loyola University Libraries]
On: 26 September 2013, At: 02:48
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Efficient Synthesis of N‐Oxide
Derivatives: Substituted
2
‐(2‐(Pyridyl‐N‐oxide)methylsulphinyl)benzimidaz
a a a a
Purna C. Ray , Vasantha Mittapelli , Amit Rohatgi & Om Dutt Tyagi
a
Matrix Laboratories Limited, Medak Dist, India
Published online: 30 Aug 2007.
To cite this article: Purna C. Ray , Vasantha Mittapelli , Amit Rohatgi & Om Dutt Tyagi (2007) Efficient
Synthesis of N‐Oxide Derivatives: Substituted 2‐(2‐(Pyridyl‐N‐oxide)methylsulphinyl)benzimidazoles, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:17,
2861-2868, DOI: 10.1080/00397910701470693
To link to this article: http://dx.doi.org/10.1080/00397910701470693
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

w
Synthetic Communications , 37: 2861–2868, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701470693
Efficient Synthesis of N-Oxide Derivatives:
Substituted 2-(2-(Pyridyl-N-
oxide)methylsulphinyl)benzimidazoles
Purna C. Ray, Vasantha Mittapelli, Amit Rohatgi, and
Om Dutt Tyagi
Matrix Laboratories Limited, Medak Dist, India
Abstract: Different substituted 2-chloromethylpyridyl derivatives (6a–d) were
oxidized with mCPBA to give the respective 2-chloromethylpyridine-N-oxide derivatives
(
7a–d) at low temperature, which on condensation with 2-mercapto-1H-benzimidazole
8a–c) in the presence of aprotic solvents give the 2-[[(pyridin-2-yl-1-oxide)methyl]-
(
sulfanyl]-1H-benzimidazole (9a–d) in good yield. Finally, 9a–d oxidized with
mCPBA in chlorinated solvent gives a mixture of 2-[[(pyridin-2-yl-1-oxide)methyl]-
sulfonyl]-1H-benzimidazole (3a–d, 10%) and 2-[[(pyridin-2-yl-1-oxide) methyl]sulfinyl]-
1H-benzimidazole (4a–d, 90%) derivatives.
Keywords: lansoprazole N-oxide, mCPBA, omeprazole N-oxide, pantoprazole
N-oxide, rabeprazole N-oxide
Several substituted 2-(2-pyridylmethyl)sulphinyl-1H-benzimidazoles deriva-
tives such as esomeprazole, omeprazole, lansoprazole, pantoprazole, and rabe-
[1]
prazole are well-known proton pump inhibitors. Generally, 2-(2-pyridyl
methylsulphanyl)-1H-benzimidazoles (1) are oxidized to prepare 2-(2-
pyridylmethylsulphinyl)-1H-benzimidazoles (2) using different oxidizing
[
2]
reagents such as H O , mCPBA, and NaOCl on a commercial scale. Use
2
2
of these oxidizing reagents results in the formation of many by-products
Received January 22, 2007
Address correspondence to Purna C. Ray, Matrix Laboratories Ltd., Plot No. 34 A,
Anrich Industrial Estate, Bollaram, Jinnaram (Mandal), Medak Dist 502 325, AP,
India. E-mail: pcray@matrixlabsindia.com
2
861

2
862
P. C. Ray et al.
such as 2-(2-(pyridyl-N-oxide)methylsulphonyl)-1H-benzimidazoles (3),
-(2-(pyridyl-N-oxide)methylsulphinyl)-1H-benzimidazoles (4) and 2-(2-pyr-
2
[2]
idylmethylsulphonyl) benzimidazoles (5). Isolation of these by-products is
very cumbersome and requires expensive techniques such as preparative
high performance liquid chromatography (HPLC) and thin-layer chromato-
graphy (TLC). Compounds 3 and 5 can be prepared by oxidation of 2, but
compound 4 is difficult. Compound 4a was isolated as a metabolite on a pre-
[
3]
parative scale. Direct synthesis of 4a is reported, but it consists of several
steps and uses hazardous chemicals such as carbondisulphide, cyclohexyliso-
[
4]
cyanate, and bromine. The present investigation provides a simple synthetic
method to prepare different substituted N-oxides using nonhazardous
reagents/solvents on a multigram scale.
RESULTS AND DISCUSSION
The free base of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine (6a) was
reacted with m-chloroperbenzoic acid (mCPBA) in chloroform medium at
5
8C to give 2-chloromethyl-3,5-dimethyl-4-methoxypyridine-N-oxide (7a).
The compound 7a was condensed with 5-methoxy-2-mercapto-1H-benzimi-
dazole (8a) in N,N-dimethylformamide containing potassium carbonate to
yield a chlorine-free compound characterized as 5-methoxy-2-[[(4-methoxy-
3
,5-dimethylpyridin-2-yl-1-oxide)methyl]sulfanyl]-1H-benzimidazole (9a)
1
2
1
[
IR (KBr, cm ): 3062 (NH). H NMR (CDCl , d ppm): 2.26 (s, 3H, CH ),
3 3
2.39 (s, 3H, CH ), 3.77 (s, 3H, OCH ), 3.83 (s, 3H, OCH ), 4.69 (s, 2H,
CH ), 6.77–8.12 (m, 4H, Ar-H), 13.75 (sbr, 1H, NH), DIP MS,
3 3 3
2
m/z(%)-346(M þ H)].
The compound 9a was oxidized with mCPBA in dichloromethane at 08C.
Isolated mixture of two compounds (less polar (3a)/more polar (4a) 210:90
on HPLC) was separated from column chromatography using chloroform/
methanol (98:2) as eluent. The infrared spectrum of compound 3a showed
peaks at 3106 (NH), 1328, and 1153 (SO ), and for 4a showed peaks at
2
3
060 (NH), 1065 (S 55 O). The direct insertion probe (DIP) mass spectra of
a and 4a displayed molecular ion peaks at m/z 362 (M þ H), 378 (M þ H)
3
respectively. In addition, in the C NMR spectrum, shielding of the proton
containing pyridine carbon (d 137.28) indicated the presence of pyridine-N-
1
oxide. The H NMR spectra of 3a and 4a are similar to 9a. Based on this
1
3
spectral data, the structures of 3a and 4a were confirmed as 5-methoxy-2-
[
[(4-methoxy-3,5-dimethylpyridin-2-yl-1-oxide)methyl]sulfonyl]-1H-benzimi-
dazole (3a) and 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl-1-oxide)-
methyl]sulfinyl]-1H-benzimidazole (omeprazole N-oxide, 4a).
This method extended to three other derivatives (i.e., lansoprazole, pan-
toprazole, and rabeprazole). In all these cases, the corresponding N-oxides
(
Table 1, Scheme 1) were obtained as final products in the ratio of ꢀ10%

Table 1. Preparation of substituted pyridine N-oxides (3a–d, 4a–d, 7a–d, 9a–d)
S. no.
R
1
R
2
R
3
R
4
Mp (8C)
Yield (%)
7
7
7
7
9
9
9
9
3
3
3
3
4
4
4
4
a
b
c
CH
H
3
3
3
OCH
OCH CF
OCH3
CH CH
OCH
CF
OCH3
CH CH
OCH
3
CH
CH
3
3
—
—
—
—
52.5
98.45
84
2
3
H
OCH3
—
—
d
a
b
c
H
OCH
OCH
OCH
2
2
2
2
OCH
3
3
3
3
CH
CH
CH
3
3
3
—
—
72
88
CH
H
3
OCH
H
3
186–188
225–226
120 (dec)
153–155
206–207
189–190 (dec)
170–171
153–156
171–173
183–185
158–159
153–156 (dec)
OCH
2
3
21
H
OCH3
OCHF2
H
98.44
96
d
a
b
c
H
2
2
OCH
CH
CH
3
3
CH
H
3
OCH
H
3
93.59 (mix)
88.90 (mix)
96.15 (mix)
73 (mix)
93.59 (mix)
88.90 (mix)
96.15 (mix)
73 (mix)
OCH CF
2
CH3
OCH3
3
H
OCH3
CH CH
OCHF
H
2
d
a
b
c
H
2
2
2
OCH
CH
CH3
CH
3
CH3
H
OCH3
OCH CF
OCH3
OCH3
H
2
3
3
H
OCH3
CH3
OCHF
H
2
d
H
OCH CH CH OCH
2 2 2

2
864
P. C. Ray et al.
Scheme 1. Solvents and reagents: (i) CHCl
K CO , (iv) MDC/mCPBA.
3
/NaHCO
3
, (ii) mCPBA, (iii) DMF/
2
3
(
3) and ꢀ90% (4) on HPLC, thus providing a general method for the synthesis
of the title compounds.
EXPERIMENTAL
Melting points were determineded in capillaries using a Polman digital melting-
point apparatus (model no. Mp 96) and are uncorrected. Infrared spectra were
recorded on a Perkin-Elmer Spectrum FT-IR spectrophotometer using 1%
1
13
potassium bromide pellet. H and C NMR spectra were recorded on a Bruker
3
1
00-MHz Advance NMR spectrometer at 300 MHz for H NMR and 75 MHz
13
for C NMR. Mass spectra were recorded on a LC-MSD-Trap-SL system.
The high performance liquid chromatography (Waters 2414-Alliance) is
equipped with a 285 nm detector and a Develosil ODS UGS, 4.6 ꢀ 150 nm, 5
micrometers. The flow rate is about 0.8 mL per minute. The chromatogram
programmed as 60 minutes run time and injuction volume 40 microliters.
The mobile phase used is water and buffer (prepared a filtered and degassed
mixture of acetonitrile, water and triethylamine, (160:40:1) and adjusted the
pH to 7.0 with orthophosphoric acid) in the ratio of 9:1.
General Procedure for the Preparation of Substituted
2-Chloromethyl-pyridine-N-oxides (7a–d)
2-Chloromethyl-pyridine hydrochloride derivative (6) was dissolved in
chloroform (9V). This clear solution was washed with sodium bicarbonate

Synthesis of N-oxide Derivatives
2865
solution and DM water, dried, and filtered. m-Chloroperbenzoic acid (1.1 molar
ratio) was added portion wise at 58C for 85 min and maintained for 1 h. Then,
the reaction mixture was washed with sodium bicarbonate solution and DM
water, dried, and concentrated in vacuo. The obtained residue of 7a was tritu-
rated with ethyl acetate; the separated solid was filtered and dried at 408C
overnight. Remaining derivatives 7b–7d were not isolated because of their
stability and were immediately used for the next step.
Data
2
solid (yield 52.47%). H NMR (CDCl ) (d ppm): 2.24 (s, 3H, CH ), 2.36
-Chloromethyl-3,5-dimethyl-4-methoxypyridine-N-oxide (7a). White
1
3
3
(s, 3H, CH ), 3.77 (s, 3H, OCH ), 4.93 (s, 2H, CH ), 8.06 (s, 1H, Ar-H).
3 3 2
DIP MS: m/z (%) 202 (M þ 1,60).
General Procedure for the Preparation of Substituted 2-[[(Pyridin-
-yl-1-oxide)methyl]sulfanyl]-1H-benzimidazoles (9a–d)
2
Pyridine derivative 7 (1 mol) was dissolved in dry DMF (12.22 V) and
-mercapto-1H-benzimidazole derivative (8. 1.0 mol); anhydrous potassium
2
carbonate (2.5 mol) was added subsequently. The resulting mixture was
stirred at ambient temperature for 12–18 h. The reaction mixture was
poured into ice-cold water, and the separated solid was extracted with chloro-
form. The extract was washed with DM water, dried over anhy. Sodium
sulphate, and filtered. The solvent distilled out completely. The obtained
solid was filtered with the help of hexane and dried at 408C for 15 h. Charac-
1
terization of the 9 was confirmed by IR, H NMR, and mass.
Data
5
fanyl]-1H benzimidazole (9a). White solid. IR (cm ): 3062 (NH). H NMR
-Methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl-1-oxide)methyl]sul-
2
1
1
(CDCl ) (d ppm): 2.26 (s, 3H, CH ), 2.39 (s, 3H, CH ), 3.77 (s, 3H, OCH ),
3 3 3 3
3
.83 (s, 3H, OCH ), 4.69 (s, 2H, CH ), 6.77–8.12 (m, 4H, Ar-H), 13.75 (sb,
3 2
1
H, NH, D O exchangeable). DIP MS: m/z (%) 346 (M þ 1,75).
2
2
-[[(3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-1-oxide)methyl]sulfa-
2
1
1
nyl]-1H-benzoimidazole (9b). White solid. IR (cm ): 3108 (NH). H NMR
CDCl ) (d ppm): 2.33 (s, 3H, CH ), 4.81 (s, 2H, CH S), 4.89 (q, 2H,
(
3
3
2
J ¼ 8.71 Hz, OCH CF ), 7.06–8.33 (m, 6H, Ar-H). DIP MS: m/z (%) 370
2
3
(M þ 1,100).
5
fanyl]-1H-benzoimidazole (9c). White solid. IR (cm ): 3109 (NH). H
-(Difluoromethoxy)-2-[[(3,4-dimethoxypyridin-2-yl-1-oxide) methyl]sul-
1
2
1

2
866
P. C. Ray et al.
NMR (CDCl ) (d ppm): 3.94 (s, 3H, OCH ), 4.06 (s, 3H, OCH ), 4.65 (s, 2H,
3
3
3
CH ), 6.49 (t, 1H, J ¼ 74.7 Hz, OCHF ), 6.83–8.17 (m, 5H, Ar-H), 14.36 (sb,
2
2
1
H, NH, D O exchangeable). DIP MS: m/z (%) 384 (M þ 1,100).
2
2
nyl]-1H-benzoimidazole (9d). White solid. IR (cm ): 3107 (NH). H NMR
-[[(4-(3-Methoxypropoxy)-3-methyl-pyridin-2-yl-1-oxide)methyl]sulfa-
2
1
1
(
CDCl ), (d ppm): 2.09 (m, 2H, OCH CH CH OCH ), 2.34 (s, 3H, CH ), 3.34
3 2 2 2 3 3
(
s, 3H, OCH ), 3.54 (t, 2H, J ¼ 5.89 Hz, OCH CH CH OCH ), 4.14 (t, 2H,
3
2
2
2
3
J ¼ 6.24 Hz, OCH CH CH OCH ), 4.76 (s, 2H, CH S), 6.78–8.23 (m, 6H,
2
2
2
3
2
Ar-H), 14.29 (sb, 1H, NH, D O exchangeable). DIP MS: m/z (%) 360
2
(
M þ 1,100).
General Procedure for the Preparation of Substituted 2-[[(Pyridin-
2-yl-1-oxide)methyl]sulfonyl]-1H-benzimidazoles (3a–d) and
Substituted 2-[[(Pyridin-2-yl-1-oxide)methyl]sulfinyl]-1H-
benzimidazoles (4a–d)
The compound 9 (1 mol) was dissolved in dichloromethane (30 V) and
cooled on an ice bath to 08C. m-Chloroperbenzoic acid (1.0 mol) was added
portionwise at 08C for 145 min and maintained for 15 min. Then, the
reaction mixture was washed with sodium bicarbonate solution and DM
water, dried, and concentrated in vacuo. The obtained semisolid with
compound is 3 is about 10% and with 4 about 90% by HPLC. The products
3
and 4 were separated by column chromatography over silica gel (60–120
mesh) using a mixture of chloroform and methanol (98:2) as eluent and
confirmed by IR, NMR, and mass spectra.
Data
5
fonyl]-1H-benzimidazole (3a). White solid. IR (cm ): 3106 (NH), 1328 and
-Methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl-1-oxide)methyl]sul-
2
1
1
1153 (SO ). H NMR (DMSO-d ) (d ppm): 2.17 (s, 3H, CH ), 2.20 (s, 3H,
CH ), 3.70 (s, 3H, OCH ), 3.82 (s, 3H, OCH ), 5.33 (s, 2H, CH ), 6.99–
2 6 3
3
3
3
2
1
.06 (m, 4H, Ar-H), 13.69 (sb, 1H, NH, D O exchangeable). C NMR
3
8
2
(
DMSO-d ) (d ppm): 12.17 (CH ), 12.81 (CH ), 54.21 (C8), 55.51 (OCH ),
6 3 3 3
60.27 (OCH ), 94.38 (C4), 101.97 (C10), 114.36 (C6), 121.44 (C7), 129.66
3
(
C12), 130.86 (3a), 135.15 (C7a), 137.48 (C13), 137.57 (C9), 147.18 (5C),
153.87 (C11), 157.92 (C2). DIP MS: m/z (%) 378 (M þ 1,75).
2
nyl]-1H-benzoimidazole (3b). White solid. IR (cm ): 3114 (NH), 1333 and
-[(3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-1-oxide)methylsulfo-
2
1
1
1
169 (SO ). H NMR (DMSO-d ), (d ppm): 2.50 (s, 3H, CH ), 4.94 (q, 2H,
2 6 3
J ¼ 8.70 Hz, OCH ), 5.44 (s, 2H, CH SO ), 7.20–8.32 (m, 6H, Ar-H),
2
2
2
1
3
1
3.87 (sb, 1H, NH, D O exchangeable). C NMR (DMSO-d ), (d ppm):
2
6

Synthesis of N-oxide Derivatives
2867
1
1.99 (CH ), 54.05 (C8), 65.27 (q, J ¼ 34.4 Hz, OCH ), 110.20 (C12), 113.08
3
2
(
C7), 120.76 (C5), 123.39 (C6), 123.63 (q, J ¼ 276, CF ), 125.47 (C4), 126.79
3
(
C10), 134.24 (C3a), 136.69 (C13), 139.44 (C9), 142.31 (C7a), 148.39 (C11),
51.77 (C2). DIP MS: m/z (%) 402 (M þ 1,80).
1
5
nyl]-1H-benzoimidazole (3c). White solid. IR (cm ): 3104 (NH), 1336 and
-(Difluoromethoxy)-2-[(3,4-dimethoxypyridin-2-yl-1-oxide)methylsulfo-
2
1
1
1
131 (SO ). H NMR (DMSO-d ) (d ppm): 3.81 (s, 3H, OCH ), 3.91 (s, 3H,
2 6 3
OCH ), 5.22 (s, 2H, CH ), 7.04–8.03 (m, 6H, Ar-5H þ OCHF2), 14.00 (sb,
3
2
1
H, NH, D O exchangeable). DIP MS: m/z (%) 416 (M þ 1,100).
2
2
-[(4-(3-Methoxypropoxy)-3-methyl-pyridin-2-yl-1-oxide)methylsulfo-
nyl]-1H-benzoimidazole (3d). DIP MS: m/z (%) 391 (M þ 1,100).
5-Methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl-1-oxide)methyl]sul-
finyl]-1H-benzimidazole (Omeprazole N-oxide, 4a). White solid. IR (cm ):
21
1
3
060 (NH), 1065 (S 55 O). H NMR (DMSO-d ), (d ppm): 2.01 (s, 3H, CH ),
6 3
2.19 (s, 3H, CH ), 3.63 (s, 3H, OCH ), 3.81 (s, 3H, OCH ), 4.81 (s, 2H,
CH ), 6.94–8.24 (m, 4H, Ar-H), 13.55 (sb, 1H, NH, D O exchangeable).
3
3
3
1
3
C
NMR (DMSO-d ) (d ppm): 11.85 (CH ), 12.83 (CH ), 54.45 (C8), 55.48
2
2
6
3
3
(OCH ), 60.24 (OCH ), 94.53 (C4), 101.51 (C10), 113.06 (C6), 120.39 (C7),
3 3
129.29 (C12), 130.50 (C7a), 135.10 (3a), 137.58 (C13), 139.40 (C9), 152.95
(5C), 153.98 (C11), 157.01 (C2). DIP MS: m/z (%) 362 (M þ 1,80).
2-[(3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-1-oxide)methylsulfi-
nyl]-1H-benzoimidazole (Lansoprazole N-oxide, 4b). White solid. IR
2
cm ): 3093 (NH), 1058 (S 55 O). H NMR (DMSO-d ), (d ppm): 2.07
1
1
(
6
(
s, 3H, CH ), 4.91 (m, 4H, 2 ꢀ CH ), 7.26–8.36 (m, 6H, Ar-H), 13.70 (sb,
3
2
1
H, NH, D O exchangeable). C NMR (DMSO-d ) (d ppm): 12.04 (CH ),
2 6 3
3
1
5
1
1
1
4.79 (C8), 65.81 (q, J ¼ 34.5 Hz, OCH ), 110.46 (C12), 112.87 (C7),
2
20.20 (C5), 123.25 (C6), 124.08 (q, J ¼ 276 Hz, CF ), 124.41 (C4),
3
27.00 (C10), 135.06 (C3a), 137.28 (C13), 141.95 (C9), 143.43 (C7a),
52.47 (C11), 155.17 (C2). DIP MS: m/z (%) 386 (M þ 1,100).
5-(Difluoromethoxy)-2-[(3,4-dimethoxypyridin-2-yl-1-oxide)methylsulfi-
nyl]-1H-benzoimidazole (Pantoprazole N-oxide, 4c). White solid. IR
2
cm ): 3095 (NH), 1057 (S 55 O). H NMR (DMSO-d ) (d ppm): 3.72
1
1
(
(
6
s, 3H, OCH ), 3.90 (s, 3H, OCH ), 4.79 (s, 2H, CH ), 7.01–8.21 (m, 6H,
2
3
3
Ar-5H þ OCHF2), 13.85 (sb, 1H, NH, D O exchangeable). DIP MS: m/z
2
(%) 400 (M þ 1,100).
2-[(4-(3-Methoxypropoxy)-3-methyl-pyridin-2-yl-1-oxide)methylsulfi-
nyl]-1H-benzoimidazole (Rabeprazole N-oxide, 4d). White solid. IR
2
1
cm ): 3034 (NH, br), 1060 (S 55 O). H NMR (DMSO-d ), (d ppm): 1.96
1
(
6

2
868
P. C. Ray et al.
(
(
m, 2H, OCH CH CH OCH ), 2.03 (s, 3H, CH ), 3.24 (s, 3H, OCH ), 3.45
2
2
2
3
3
3
t, 2H, J ¼ 6.17 Hz, OCH CH CH OCH ), 4.11 (t, 2H, J ¼ 6.14 Hz, OCH
2
2
2
3
2-
CH CH OCH ), 4.90 (AB , 2H, J ¼ 12.22 Hz, CH SO), 7.11–8.24 (m, 6H,
2
2
3
q
2
1
3
Ar-H), 13.72 (sb, 1H, NH, D O exchangeable). C NMR (DMSO-d ), (d
2
6
ppm): 11.59 (CH ), 28.56 (OCH CH CH OCH ), 54.28 (CH SO), 57.94
3
2
2
2
3
2
(
OCH ), 65.85 (OCH CH CH OCH ), 68.21 (OCH CH CH OCH ), 108.83
3 2 2 2 3 2 2 2 3
(
C12), 112.4 5 (C7), 119.73 (C5), 122.67 (C6), 123.91 (C4), 126.10 (C10),
1
1
34.70 (C3a), 136.66 (C13), 140.83 (C9), 143.09 (C7a), 153.84 (C11),
54.81 (C2). DIP MS: m/z (%) 376 (M þ 1,100).
ACKNOWLEDGMENTS
We are grateful to the Analytical Division of Matrix Laboratories Limited for
providing analytical and spectral data. We also thank G. Jyothi for analytical
support and discussion.
REFERENCES
1
. Miner, P.; Jr; Katz, P. O.; Chen, Y.; Sostek, M. Gastric acid control with esomepra-
zole, omeprazole, lansoprazole, pantoprazole and rabeprazole: A five-way
crossover study. Am. J. Gastroenterology 2003, 98 (12), 2616.
2
3
4
. Moon, Y.-H.; Si, S.; Lee, K.-I.; Si, A.; Lee, G.-S. High yield method for preparing
lansoprazole 2002, US6423846.
. Shiraga, P.; Shimatani, K.; Sato, A.; Iwasaki, K.; Tozuka, Z.; Hata, T. Identification
of metabolites of omeprazole in rats. Yakubutsu Dosai 1996, 11 (1), 45.
. (a) Clausen, F. P. Process for the preparation of 2-[[(2-pyridinyl)methyl] sulfinyl]-
1H-benzimidazoles and novel compounds of use for such purpose 1998,
WO9840377; (b) Clausen, F. P.; Mccluskey, K. K.; Preikschat, H. F.;
Pedersen, S. B. Process for the preparation of 2-[[(2-pyridinyl)methyl]sulfinyl]-
1H-benzimidazoles and novel compounds of use for such purpose 1998,
WO9840378.