Synthesis of metabolites and related substances of rabeprazole, an anti-ulcerative drug

Article abstract of DOI:10.1080/00397910802372541

Rabeprazole sodium (Aciphex) is a gastric proton pump inhibitor used for the prevention and treatment of gastric acid-related diseases. During the synthesis of bulk drug of rabeprazole sodium, we have observed metabolites rabeprazole sulfide and rabeprazole sulfone and related substances rabeprazole-N-oxide, rabeprazole sulfone-N-oxide, N-aralkyl rabeprazole, chloro rabeprazole, and methoxy rabeprazole as impurities in the drug substance. The present work describes the synthesis and characterization of these compounds. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802372541

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Synthesis of Metabolites
and Related Substances
of Rabeprazole, an Anti-
Ulcerative Drug
Ganta Madhusudhan Reddy a b , Kaga Mukkanti b ,
Boluggodu Vijaya Bhaskar a & Padi Pratap Reddy a
a Research and Development, Integrated Product
Development , Dr. Reddy's Laboratories Ltd ,
Bachupally, India
b Institute of Science and Technology , J. N. T.
University , Kukatpally, Hyderabad, India
Published online: 22 Dec 2008.
To cite this article: Ganta Madhusudhan Reddy , Kaga Mukkanti , Boluggodu Vijaya
Bhaskar & Padi Pratap Reddy (2008) Synthesis of Metabolites and Related Substances
of Rabeprazole, an Anti-Ulcerative Drug, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 39:2, 278-290, DOI:
10.1080/00397910802372541
To link to this article: http://dx.doi.org/10.1080/00397910802372541
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Synthetic Communications1, 39: 278–290, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802372541
Synthesis of Metabolites and Related Substances
of Rabeprazole, an Anti-Ulcerative Drug
Ganta Madhusudhan Reddy,1,2 Kaga Mukkanti,2
Boluggodu Vijaya Bhaskar,1 and Padi Pratap Reddy1
1Research and Development, Integrated Product Development,
Dr. Reddy’s Laboratories Ltd, Bachupally, India
2Institute of Science and Technology, J. N. T. University,
Kukatpally, Hyderabad, India
Abstract: Rabeprazole sodium (Aciphex1) is a gastric proton pump inhibitor
used for the prevention and treatment of gastric acid–related diseases. During
the synthesis of bulk drug of rabeprazole sodium, we have observed metabolites
rabeprazole sulfide and rabeprazole sulfone and related substances rabeprazole-
N-oxide, rabeprazole sulfone-N-oxide, N-aralkyl rabeprazole, chloro rabeprazole,
and methoxy rabeprazole as impurities in the drug substance. The present work
describes the synthesis and characterization of these compounds.
Keywords: Impurities, metabolites, rabeprazole Na, spectral characterization,
synthesis
INTRODUCTION
Rabeprazole sodium, 2-[([4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-
methyl)sulfinyl]-1H-benzimidazole sodium (1), is a proton pump inhibi-
tor, inhibits the action of Hþ-Kþ ATPase in parietal cells,[1–5] and is
Received April 29, 2008.
DRL Communication No. IPDO-IPM-00022
Address correspondence to Padi Pratap Reddy, Research and Development,
Integrated Product Development, Innovation Plaza, Dr. Reddy’s Laboratories
Ltd., Survey Nos. 42, 45, 46 and 54, Bachupally, Qutubullapur, R. R. Dist.
500 072, India. E-mail: prataprp@drreddys.com
278

Related Substances of Rabeprazole
279
used for the prevention and treatment of gastric acid–related diseases. It
has also demonstrated efficacy in healing and symptom relief of gastric
and duodenal ulcers and has shown a high eradication rate of the
microorganism Helicobacter pylori when associated with antimicrobial
therapy.[6,7]
The presence of impurities (related substances) in an active pharma-
ceutical ingredient (API) can have a significant impact on the quality and
safety of the drug products. International conference on harmonization
(ICH) guidelines recommend identifying and characterizing all impurities
present in API at a level of ꢀ0.10%.[8] These impurities are required in
pure form to check the analytical performance characteristics such as
specificity, linearity, range, accuracy, precision, limit of detection
(LOD), limit of quantification (LOQ), robustness, system suitability test-
ing, and relative retention factor.[9] These related substances are also used
to check the accuracy of the analytical method of API.
In our manufacturing process of rabeprazole sodium (1), we have iden-
tified following seven impurities: 2-[([4-(3-methoxypropoxy)-3-methyl-2-pyr-
idinyl]methyl)thio]-1H-benzimidazole (sulfide, 2), 2-[([4-(3-methoxypropoxy)
-3-methyl-2-pyridinyl]methyl)sulfonyl]-1H-benzimidazole
[([4-chloro-3-methylpyridine-2-yl]methyl)thio]-1H-benzimidazole
(sulfone,
3),
(chloro
rabeprazole, 4), 2-[([4-methoxy-3-methyl-2-pyridinyl]methyl)sulfinyl]-1H-
benzimidazole (methoxy rabeprazole, 5), 2-[([4-(3-methoxypropoxy)-3-
methyl-2-pyridinyl-1-oxide]methyl)sulfonyl)-1H-benzimidazole (sulfone-
N-oxide, 6), 2-[([4-(3-methoxypropoxy)-3-methyl-2-pyridine-1-oxide]-
methyl)sulfinyl]-1H-benzimidazole (N-oxide, 7) and 2-[([4-(3-methoxypro-
poxy)-3-methyl]pyridin-2-yl)methanesulfinyl]-1-([4-(3-methoxypropoxy)-3-
methyl]pyridin-2-ylmethyl)-1H-benzimidazole (N-aralkyl rabeprazole, 8)
(Fig. 1). Although rabeprazole sulfide 2 and sulfone 3 were known as
metabolites,[2,10] synthesis and characterization of chloro rabeprazole 4
and methoxy rabeprazole 5 were reported.[11,12] An increasing number
of publications on development of analytical methods for rabeprazole
bulk drug analysis indicated the significance of impurities of rabepra-
zole.[12–26] Except for chloro rabeprazole 4 and methoxy rabeprazole 5,
a detailed synthetic procedure has not been reported for rest of the related
substances. In our present investigation, we have taken up the synthesis
and characterization of these impurities.
RESULTS AND DISCUSSION
Synthesis of rabeprazole sodium 1 involved condensation of chloro-
methylpyridine derivative 9 with the 2-mercapto benzimidazole 10 in
the presence of NaOH and oxidation of the resulting compound 2 using

280
G. M. Reddy et al.
Figure 1. Structure of rabeprazole and its related substances Structural frame-
work of rabeprazole sodium (1), rabeprazole sulfide (2), rabeprazole sulfone
(3), chloro rabeprazole (4), methoxy rabeprazole (5), rabeprazole sulfone-N-oxide
(6), rabeprazole N-oxide (7), and N-aralkyl rabeprazole (8).
meta chloro perbenzoic acid (m-CPBA).[27] Rabeprazole free base 1a
was converted into its sodium salt 1 (Scheme 1) and was purified from
methanol and methyl tert-butylether (MTBE).
Scheme 1. Synthetic scheme of rabeprazole sodium (1)). Reagents and conditions:
(a) NaOH, water–acetone (2:1), 25–30 ꢁC; (b) m-CPBA, CHCI3, ꢂ10 to ꢂ15 ꢁC,
3 h; (c) NaOH, MeOH–MTBE (1:10), 25–30 ꢁC, 8 h.

Related Substances of Rabeprazole
281
Scheme 2. Synthetic scheme of rabeprazole sulfone (3). Reagents and conditions:
m-CPBA, CHCI3–MeOH (2:1), ꢂ20 to ꢂ25 ꢁC, 45 min, 80%.
Rabeprazole sulfide 2 was obtained from the synthetic sequence fol-
lowed for rabeprazole (Scheme 1). Infrared (IR), 1H NMR, and mass spec-
tral data of compound 2 are identical with those of reference sample.[27]
Rabeprazole sulfone 3 was prepared by the controlled oxidation of
rabeprazole sulfide 2, using an optimal amount of m-CPBA (Scheme 2).
The protonated molecular ion appeared at 376.0, and sodium adduct
appeared as the base peak at 398.1 in the mass spectra. In the 1H
NMR, a deuterium-exchangeable singlet at d 13.80 corresponded to
benzimidazole-NH proton. Two singlets due to O-methyl and 3-methyl
group of pyridine ring are displayed at d 3.25 and d 2.18, respectively.
Aromatic protons of benzimidazole moiety appeared as multiplets at d
7.36–7.41 and 7.66–7.71, while those of pyridine ring are seen as two
doublets at d 8.0 and 6.90. Two triplets and one quintet at d 4.10, 3.48,
and 1.97 corresponded to O-propyloxy group protons.
Rabeprazole sulfone-N-oxide 6 is the overoxidized by-product formed
in the synthesis of rabeprazole. We have prepared this compound by the
oxidation of rabeprazole 1a using excess of m-CPBA (2.2 equiv) in chloro-
form (Scheme 3). The protonated molecular ion of 6 appeared at 391.9, and
sodium adduct appeared as the base peak at 414.3 in the mass spectrum. IR
spectrum of 6 showed the presence of O¼S¼O stretching (1324 cmꢂ1),
CꢂN stretching (1301 cmꢂ1), and C–O arylalkyl stretching (1094 cmꢂ1).
1H NMR spectral data of compound 6 is similar to that of compound 3.
Rabeprazole-N-oxide 7 was prepared starting from 2-chloromethyl-
3-methyl-4-(3-methoxy propoxy)pyridine hydrochloride (9). Conversion
of hydrochloride 9 into its free base by reacting with ammonia and
Scheme 3. Synthetic scheme of rabeprazole sulfone-N-oxide (6). Reagents and
conditions: m-CPBA, MeOH–CHCI3 (1:3), ꢂ5 to ꢂ10 ꢁC, 45 min, 80%.

282
G. M. Reddy et al.
subsequent oxidation using m-CPBA gave the corresponding N-oxide 12.
Condensation of 12 with mercapto derivative 10 in aqueous alkali fol-
lowed by m-CPBA oxidation of resulted sulfide 13 furnished the desired
N-oxide impurity 7 (Scheme 4). Mass spectrum of the N-oxide showed
peaks at m=z 376.2 and 398.0 corresponding to the adduct ions (Mþ þ H)
and (Mþ þ Na), respectively. IR spectrum displayed characteristic absorp-
tions at 1098 and 1059 cmꢂ1 corresponding to C–O stretching and S¼O
1
stretching, respectively. H NMR spectrum of rabeprazole-N-oxide 7 is
similar to that of rabeprazole sulfone-N-oxide 6.
N-Aralkyl rabeprazole 8 was prepared following the rabeprazole
synthetic pathway with a slight modification of reaction conditions.
Thus, condensation of two equivalents of 9 with mercapto benzimidazole
10 in aqueous alkali at 70–75 ꢁC, followed by oxidation of resulted sulfide
14 with m-CPBA, yielded the desired N-aralkyl rabeprazole 8 in 23%
yield (Scheme 5, path I). Compound 8 was obtained in a better yield
by the direct aralkylation of rabeprazole 1a using 2-chloromehtylpyridine
derivative 9 (Scheme 5, path II). Assigned structure of compound 8 was
1
confirmed from its mass, IR, and H NMR spectra. The protonated
molecular ion of 8 appeared at 553.6 in the mass spectrum. IR spectrum
of 8 showed the presence of S¼O stretching at 1046 cmꢂ1. 1H NMR spec-
trum is devoid of benzimidazole NH signal. It is evidenced the presence
of two methoxy groups (d 3.17, s, 3H; d 3.3, s, 3H), two methyl groups (d
2.27, s, 6H), eight aromatic protons (d 7.76–7.81, m, 2H; d 7.28–7.38, m,
Scheme 4. Synthetic scheme of rabeprazole N-oxide (7). Reagents and conditions:
(a) NaOH, water–CHCI3 (2:3), 25 ꢁC; (b) m-CPBA, CHCI3, 35 ꢁC, 2.5 h, 71% (c)
NaOH, water–Acetone (1:1), 25 ꢁC, 1 h; (d) m-CPBA, CHCI3, ꢂ10 ꢁC, 45min, 72%.

Related Substances of Rabeprazole
283
Scheme 5. Synthetic scheme of rabeprazole N-aralkyl impurity (8). Reagents and
conditions: (a) NaOH, water 70–75 ꢁC, 4 h, 79% (b) m-CPBA, MeOH–CHCI3
(1:2), 0–5 ꢁC, 45 min, 23% (c) NaOH, water, 70–75 ꢁC, 4 h, 78%.
2H; d 8.22, d, 1H; d 8.03, d, 1H; d 6.90, d, 1H; d 6.94, d, 1H), S-CH2
group (d 4.67, d, 1H; d 4.98, d, 1H), N-CH2 group (d 5.81, q, 2H), and
three multiplets at d 4.08–4.09, 3.43–3.53 and 1.66–2.02 corresponding
to O-propyloxy group protons.
CONCLUSION
Information of the different possible impurities, metabolites, and their
synthetic routes is a prerequisite for thorough understanding of impurity
profile in the manufacturing of the anti-ulcerative drug rabeprazole.
Keeping in view this regulatory requirement of rabeprazole impurities,
the process-related impurities and metabolites in rabeprazole bulk drug
were identified, synthesized, and characterized using mass, IR and
NMR spectral data.
EXPERIMENTAL
The 1H NMR spectra were recorded on Varian Mercury plus and
Gemini-2000 at 400 MHz and 200 MHz, respectively. The infrared
spectra were recorded in the solid sate as KBr dispersion medium

284
G. M. Reddy et al.
using a Perkin-Elmer Spectrum One Fourier transform infrared (FT-IR)
spectrophotometer. The mass analysis was performed on AB-4000 Q-trap
LC-MS=MS mass spectrometer MDS SCIEX, Applied Bio Systems,
California, USA. Melting points were determined on a Polmon digital
capillary melting-point apparatus MP96 and are uncorrected. The sol-
vents and reagents were used without further purification.
2-[([4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl)thio]-1H-
benzimidazole (Rabeprazole Sulfide, 2)
To a stirred solution of 10 (6.7 g, 44.6 mmol), sodium hydroxide (3.75 g,
93.7 mmol) in acetone (50.0 mL), and water (50.0 mL), a solution of
9 (10.0 g, 37.6 mmol) in water (50.0 mL) was added dropwise over a period
of 45 min at 15–20 ꢁC. The precipitated solid was filtered at 25–30 ꢁC,
washed with 1:1 mixture of acetone and water (20.0 mL), and dried to a
constant weight at 55ꢁC to provide compound 2 (11.0 g, 85% yield). Mp:
116–118 ꢁC; IR (KBr, cmꢂ1) 3049 (Ar-H), 2888 (Ali-H), 1585 (aromatic
C ¼ C), 1303 (C–N), 1092 (C–O arylalkylether), 746 (Ar-H bending); mass
(EI) þve ES-MS: 344 (Mþ þ H), 687 (2Mþ þ H), ꢂve ES-MS: 342
1
(Mꢂ ꢂ H) 378.1 (Mꢂ þ Cl); H NMR (200MHz, DMSO-d6): d 12.61 (s,
NH), 8.23 (d, J ¼ 5.6 Hz, 1H), 7.39–7.52 (m, 2H), 7.11–7.16 (m, 2H), 6.95
(d, J ¼ 5.6 Hz, 1H), 4.70 (s, 2H), 4.10 (t, J ¼ 6.2 Hz, 2H), 3.49 (t, J ¼ 6.4 Hz,
Hz, 2H), 3.25 (s, 3H), 2.22 (s, 3H), 1.98 (qn,J ¼ 6, 2H); 13C NMR
(200MHz, DMSO-d6) d 162.68, 154.68, 150.29, 147.74, 121.35, 119.75,
117.39, 110.51, 106.22, 68.28, 65.04, 57.92, 36.28, 28.66, 10.35.
2-[([4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl)sulfonyl]-1H-
benzimidazole (Rabeprazole Sulfone, 3)
A solution of m-CPBA (15.0 g, 60.8 mmol, 70% w=w) in CHCl3 (50.0 mL)
was added to a solution of 2 (10.0 g, 29.1 mmol) in CHCl3 (50.0 mL) and
MeOH (25.0 mL) dropwise over a period of 45 min at ꢂ20 to ꢂ 25 ꢁC.
On completion of reaction (vide Thin Layer Chromatography, TLC), reac-
tion mass was poured in to the NaOH solution (5.0 g of NaOH in 100.0 mL
of water), pH was adjusted to 7–7.5 with AcOH, chloroform layer was
separated, and product was extracted into basic water (2.0 g of NaOH in
70.0 mL of water). This alkaline solution containing the product was given
CHCl3 washings (3 ꢃ 25 mL). Acetone (25.0 mL) was charged to the aqu-
eous phase and cooled to 5–10 ꢁC. pH was adjusted to 8–8.5 with AcOH;
the isolated solid was filtered, washed with 1:1 mixture of water and
acetone (20.0 mL), and dried to a constant weight at 50 ꢁC to provide com-
pound 3 (8.3 g, 80% yield). Mp: 138–142 ꢁC; IR (KBr, cmꢂ1): 3063 (Ar-H),

Related Substances of Rabeprazole
285
2933 (Ali-H), 1339 (O¼S¼O), 1301 (C–N), 1095 (C–O), 756 (Ar-H
bending); mass (EI): +ve ES-MS: 376.0 (Mþ þ H), 398.1 (Mþ þ Na). ꢂve
ES-MS: 373.9 (Mꢂ ꢂH);1H NMR (200 MHz, DMSO-d6]: d 13.80 (s,
NH), 8.00 (d, J ¼ 5.6 Hz, 1H), 7.66–7.71 (m, 2H), 7.36–7.41 (m, 2H),
6.90 (d, J ¼ 5.6 Hz, 1H), 5.07 (s, 2H), 4.10 (t, J ¼ 6.2 Hz, 2H), 3.48 (t,
J ¼ 6.2 Hz, 2H), 3.25 (s, 3H), 2.18 (s, 3H), 1.97 (qn, J ¼ 6, 2H); 13C
NMR (200 MHz, DMSO-d6) d 162.95, 148.04, 147.91, 147.09, 138.04,
124.40, 123.14, 116.84, 106.83, 68.24, 65.12, 60.51, 57.93, 28.59, 11.02.
2-[([4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl-1-oxide]methyl)sulfonyl]-
1H-benzimidazole (Rabeprazole Sulfone-N-oxide, 6)
A solution of m-CPBA (30.0 g, 121.7 mmol, 70% w=w) in CHCl3
(110.0 mL) was added to a solution of 1a (20.0 g, 55.7 mmol) in CHCl3
(120.0 mL) and MeOH (40.0 mL) over a period of 45 min at ꢂ5 to ꢂ10 ꢁC.
On completion of reaction (vide TLC), reaction mass was poured into the
NaOH solution (15.0 g NaOH in 200.0 mL of water), pH was adjusted to
7–7.5 with AcOH, and two layers were separated. Product was extracted
from the CHCl3 phase into basic water (5.0 g of NaOH in 150.0 mL of
water), and this alkaline solution was given CHCl3 washings
(2 ꢃ 30 mL). Acetone (50.0 mL) was charged to the water phase, solution
was cooled to 5–10 ꢁC, and pH was adjusted to 8–8.5 using AcOH. Iso-
lated solid was filtered, washed with 1:1 mixture of H2O and acetone
(20.0 mL), and purified from the acetone to give compound 6 as a white
solid (17.4 g, 80% yield). Mp: 170–174 ꢁC; IR (KBr, cmꢂ1): 3058 (Ar-H),
2927 (Ali-H), 1324 (O¼S¼O), 1301 (C–N), 1094 (C–O arylalkyl ether),
747 (Ar-H bending); mass (EI): þve ES-MS: 391.9 (Mþ þ H), 783.8
(2Mþ þ H), 414.3 (Mþ þ Na), 805.8 (2Mþ þ Na), 430.9 (Mþ þ K), ꢂve
1
ES-MS: 390.2 (Mꢂ ꢂ H); H NMR (200 MHz, DMSO-d6]: d 13.9 0 (s,
NH), 8.03 (d, J ¼ 7.2 Hz, 1H), 7.67–7.68 (br, 2H), 7.35–7.41 (m, 2H),
7.08 (d, J ¼ 7.6 Hz, 1H), 5.44 (s, 2H), 4.12 (t, J ¼ 6.2 Hz, 2H), 3.49
(t, J ¼ 6.2 Hz, 2H), 3.25 (s, 3H), 2.20 (s, 3H), 1.98 (qn, J ¼ 5.8, 2H); 13C
NMR (200 MHz, DMSO-d6) d 153.89, 148.52, 138.86, 138.32, 136.61,
126.45, 124.27, 116.96, 108.94, 68.22, 65.88, 57.95, 54.09, 28.62, 12.12.
2-[([4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl-1-oxide]methyl)sulfinyl]-
1H-benzimidazole (Rabeprazole-N-oxide, 7)
2-Chloromethyl-3-methyl-4-(3-methoxypropoxy)pyridine-1-oxide (12)
The pH of a stirred solution of 9 (15.0 g, 56.3 mmol) in CHCl3 (75.0 mL)
and H2O (50.0 mL) was adjusted to 7.5 using aq. NH3, and solution

286
G. M. Reddy et al.
was stirred for 10 min. Organic layer was separated and washed with water
(50.0 mL), and to this solution was added a solution of m-CPBA (15.0 g,
60.8 mmol, 70% w=w) in CHCl3 (80.0 mL) over a period of 2 h at 35 ꢁC
and stirred for 30 min. Progress of the reaction was monitored by (TLC),
and on completion of reaction, reaction mass was cooled to 25 ꢁC, water
(100.0 mL) was added, and pH adjusted to 7.5–8.0 with aq. NH3 solution.
The organic phase was separated and washed with water (2 ꢃ 50.0 mL) and
concentrated under reduced pressure at less then 40 ꢁC to give compound
12 as a semisolid (9.8 g, 71% yield). IR (KBr, cmꢂ1): 2959 (Ali-H), 1103 (C–
O arylalkylether), 1304 (N-O); mass (EI): 246.2 (Mþ þ H), 230 (245-Cl); 1H
NMR (400 MHz, CDCl3) d 8.22 (d, J ¼ 7.2 Hz, 1H), 6.80 (d, J ¼ 7.6 Hz,
1H), 4.96 (s, 2H), 4.12 (t, J ¼ 6.4 Hz, 2H), 3.54 (t, J ¼ 6.0 Hz, 2H), 3.34
(s, 3H), 2.30 (s, 3H), 2.06–2.15 (m, 2H).
2-[([4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl-1-oxide]methyl)-
sulfinyl]-1H-benzimidazole (7)
To a stirred solution of 10 (10.0 g, 66.6 mmol) in water (50.0 mL) and
NaOH (5.9 g, 147.5 mmol), a solution of 2-chloromethyl-3-methyl-4-
(3-methoxypropoxy)pyridine-1-oxide (12, 15.5 g, 63.1 mmol) in acetone
(50.0 mL) was added and the reaction mixture was stirred over a
period of 1 h. On completion of reaction (vide TLC), product 13 was
extracted with chloroform (40 mL), and the solution was used as such
in the next step.
To the stirred and cooled solution of 13 in chloroform, a solution of
m-CPBA (8.20 g, 33.4 mmol, 70% w=w) in chloroform (30.0 mL) was
added drop by drop at ꢂ10 ꢁC over a period of 30 min. On completion
of the reaction (vide TLC), the reaction mass was poured into the solu-
tion of NaOH (8.24 g, 206.0 mmol) in water (100.0 mL), and pH was
adjusted to 8–8.5 using acetic acid. The chloroform layer was separated,
and the product was extracted into the aq. NaOH solution (2.75 g in
100.0 mL water). This alkali solution containing the product was washed
with chloroform (2 ꢃ 30 mL) to remove unreacted sulfide 13. pH was
adjusted to 8.5–9.0 using acetic acid and then extracted with chloroform
(3 ꢃ 20 mL). The chloroform layer was concentrated under reduced
pressure; the product was isolated from methanol (30 mL) and dried at
50 ꢁC to yield compound 7 as a white solid (11.10 g, 72% yield). Mp:
158–164 ꢁC; IR (KBr, cmꢂ1): 3035 (Ar-H), 2984 (Ali-H), 1098 (C–O aryl-
alkylether), 1059 (S¼O), 742 (Ar-H bending); mass: þ ve ES-MS: 376.2
(Mþ þ H), 398 (Mþ þ Na), 1148.7 (3Mþ þ Na), 414.2 (Mþ þ K);
1H NMR (200 MHz, DMSO-d6]: d 8.21 (d, J ¼ 7.0 Hz, 1H), 7.67–7.71
(m, 2H), 7.30–7.35 (m, 2H), 6.75 (d, J ¼ 7.2 Hz, 1H), 5.21 (d, J ¼ 12.8 Hz,

Related Substances of Rabeprazole
287
Hz, 1H), 4.97 (d, J ¼ 12.6 Hz, 1H), 4.08 (t, J ¼ 6.2 Hz, 2H), 3.51
(t, J ¼ 6 Hz, 2H), 3.33 (s, 3H), 2.24 (s, 3H), 2.06 (qn, J ¼ 6 Hz, 2H); 13C
NMR (200 MHz, DMSO-d6) d156.23, 153.93, 141.47, 139.23, 137.35,
126.91, 123.40, 116.32, 107.44, 65.89, 58.58, 54.23, 28.96, 12.01.
2-[([4-(3-Methoxypropoxy)-3-methyl]pyridinyl)methyl]sulfinyl-1-[([4-
(3-methoxypropoxy)-3-methyl]pyridinyl)methyl]-1H-benzimidazole
(N-Aralkyl Rabeprazole, 8)
2-[([4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl)thio]-1-([4-(3-
methoxypropoxy)-3-methyl-2-pyridinyl]methyl)-1H-benzimidazole (14)
A solution of 9 (28.2 g, 106.0 mmol) in water (100.0 mL) was added to a
stirred solution of 10 (8.0 g, 53.3 mmol) and NaOH (5.3 g, 132.5 mmol) in
water (50.0 mL) over a period of 45 min at 15–20 ꢁC. The resulting solu-
tion was then heated to 70–75 ꢁC, and after being stirred at 70–75 ꢁC for
4 h, the precipitated solid was filtered at 25–30 ꢁC, washed with 1:1 mix-
ture of MeOH and H2O (20.0 mL), and dried to a constant weight at
50 ꢁC to yield 14 (23.4 g, 79% yield). IR (KBr, cmꢂ1): 2927 (Ali-H),
1290 (C–N), 1083 (C–O), 743 (Ar-H bending); mass (EI): þve ES-MS:
537.0 (Mþ þ H), 559.2 (Mþ þ Na), 575.2 (Mþ þ K);1H NMR
(400 MHz, CDCl3]: d 8.29 (d, J ¼ 6.0 Hz, 1H), 8.23 (d, J ¼ 5.6 Hz, 1H),
7.69 (d, J ¼ 8 Hz, 1H), 7.14–7.18 (m, 2H), 7.06 (d, J ¼ 4 Hz, 1H), 6.67–
6.70 (m, 2H), 5.40 (s, 2H), 4.84 (s, 2H), 4.04–4.11 (m, 4H), 3.50–3.57
(m, 4H), 3.35 (s, 6H), 2.28 (s, 6H), 2.01–2.10 (m, 4H).
2-[([4-(3-Methoxypropoxy)-3-methyl]pyridinyl)methyl]sulfinyl-1-[([4-(3-
methoxypropoxy)-3-methyl]pyridinyl)methyl]-1H-benzimidazole (8)
A solution of m-CPBA (5.0 g, 20.2 mmol, 70% w=w) in CHCl3
(110.0 mL) was added to a stirred solution of 14 (10.0 g, 18.6 mmol)
in CHCl3 (50.0 mL) and MeOH (25.0 mL) dropwise over a period of
45 min at 0–5 ꢁC. On completion of reaction (vide TLC), reaction mass
was poured into NaOH solution (2.0 g of NaOH in 100.0 mL of water),
pH was adjusted to 8–8.5 using AcOH and the aqueous phase was sepa-
rated and extracted with CHCl3 (2 ꢃ 50.0 mL). Combined organics were
concentrated under reduced pressure to yield a brown color liquid 8
(2.4 g, 23% yield). IR (neat, cmꢂ1): 3057 (Ar-H), 2923 (Ali-H), 1291
(C–N), 1065 (C–O), 1046 (S¼O), 743 (Ar-H bending); mass (EI): þve
ES-MS: 553.6 (Mþ þ H); 1H NMR (200 MHz, DMSO-d6]: d 8.22 (d,
J ¼ 6.0, 1H), 8.03 (d, J ¼ 5.6 Hz, 1H), 7.76–7.81 (m, 2H), 7.28–7.38 (m,

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G. M. Reddy et al.
2H), 5.81 (q, J ¼ 6, 17.2 Hz, 2H), 6.94 (d, J ¼ 5.6 Hz, 1H), 6.90 (d,
J ¼ 5.6 Hz, 1H), 4.98 (d, J ¼ 13.6 Hz, 1H), 4.67 (d, 13.6, 1H), 4.08–
4.09 (m, 4H), 3.43–3.53 (m, 4H), 3.3 (s, 3H), 3.17 (s, 3H), 2.27 (s,
6H), 1.66–2.02 (m, 4H);13C NMR (200 MHz, DMSO-d6) d 162.89,
162.70, 154.19, 153.27, 150.72, 148.06, 147.79, 141.84, 136.25, 123.99,
122.81, 121.85, 120.10, 111.20, 106.30, 68.39, 65.14, 57.94, 56.58,
48.67, 45.95, 28.78, 10.45, 9.47.
Alternative Procedure for 8
A solution of 9 (5.92 g, 22.2 mmol) in water (30.0 mL) was added to
a stirred solution of 1a (8.0 g, 22.2 mmol) and NaOH (2.0 g, 50.0 mmol)
in water (40.0 mL) at 25–30 ꢁC. The resulting solution was then heated
to 70–75 ꢁC and maintained for 5 h. On completion of reaction (vide
TLC), solution was extracted with chloroform (2 ꢃ 25 mL), and the
chloroform layer was concentrated under reduced pressure to yield a
brown liquid 8 (9.6 g, 78% yield).
ACKNOWLEDGMENTS
The authors are grateful to colleagues of the Analytical Research
Department of Integrated Product Development Operations, Discovery
Research, and the management of Dr. Reddy’s Laboratories Ltd. for
providing necessary support.
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