Synthesis and characterization of metabolites and potential impurities of lansoprazole, an antiulcerative drug

Article abstract of DOI:10.1080/00397910802162934

Lansoprazole (Prevacid) is an antiulcerative drug used for the treatment of duodenal and gastric ulcers, reflux oesophagitis, and Zollinger-Ellison syndrome. During the bulk synthesis of lansoprazole, we have observed five impurities: lansoprazole N-oxide, lansoprazole sulfone N-oxide, lansoprazole sulfide, lansoprazole sulfone and N-aralkyl lansoprazole. The present work describes the synthesis and characterization of these impurities. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802162934

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Synthesis and Characterization
of Metabolites and Potential
Impurities of Lansoprazole, an
Antiulcerative Drug
Ganta Madhusudhan Reddy a b , K. Mukkanti b , T.
Laxmi Kumar a , J. Moses Babu a & Padi Pratap Reddy
a
a Research and Development, Active Pharmaceutical
Ingredients, Dr. Reddy's Laboratories Ltd. ,
Hyderabad, India
b Institute of Science and Technology, J.N.T.
University , Kukatpally, Hyderabad, India
Published online: 29 Sep 2008.
To cite this article: Ganta Madhusudhan Reddy , K. Mukkanti , T. Laxmi Kumar ,
J. Moses Babu & Padi Pratap Reddy (2008) Synthesis and Characterization of
Metabolites and Potential Impurities of Lansoprazole, an Antiulcerative Drug,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 38:20, 3477-3489, DOI: 10.1080/00397910802162934
To link to this article: http://dx.doi.org/10.1080/00397910802162934
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Synthetic Communications1, 38: 3477–3489, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802162934
Synthesis and Characterization of Metabolites
and Potential Impurities of Lansoprazole,
an Antiulcerative Drug
Ganta Madhusudhan Reddy,1,2 K. Mukkanti,2 T. Laxmi Kumar,1
J. Moses Babu,1 and Padi Pratap Reddy1
1Research and Development, Active Pharmaceutical Ingredients,
Dr. Reddy’s Laboratories Ltd., Hyderabad, India
2Institute of Science and Technology, J.N.T. University, Kukatpally,
Hyderabad, India
Abstract: Lansoprazole (Prevacid) is an antiulcerative drug used for the treat-
ment of duodenal and gastric ulcers, reflux oesophagitis, and Zollinger–Ellison
syndrome. During the bulk synthesis of lansoprazole, we have observed five
impurities: lansoprazole N-oxide, lansoprazole sulfone N-oxide, lansoprazole sul-
fide, lansoprazole sulfone and N-aralkyl lansoprazole. The present work describes
the synthesis and characterization of these impurities.
Keywords: HR-MS, impurities, lansoprazole, spectral characterization, synthesis
INTRODUCTION
[(Pyridylmethyl)sulfinyl]benzimidazoles (PSBs) are highly active inhibi-
tors of the gastric (Hþ, Kþ)-ATPase both in vitro and in vivo with high
and long-lasting antisecretory activity.[1,2] Lansoprazole is the generic
Received December 26, 2007.
Address correspondence to Padi Pratap Reddy, Research and Development,
Active Pharmaceutical Ingredients, Integrated Product Development, Innovation
Plaza, Dr. Reddy’s Laboratries Ltd., Survey Nos. 42, 45, 46 & 54, Bachupally, Qutu-
bullapur mandal, Hyderabad 500 072, Andhrapradesh, India. E-mail: prataprp@
drreddys.com
3477

3478
G. M. Reddy et al.
name of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-
1H-benzimidazole (1). It has been demonstrated to be effective in the
treatment of duodenal and gastric ulcers, reflux oesophagitis, and Zollinger–
Ellison syndrome.[3,4] Current evidence indicates that lansoprazole 1 is an
alternative to omeprazole and H2-receptor antagonists in the short-term
treatment of duodenal and gastric ulcer and reflux oesophagitis, particu-
larly in the light of the potential of lansoprazole for faster healing and
more rapid symptom resolution.[5]
The presence of impurities in an active pharmaceutical ingredient
(API) can have a significant impact on the quality and safety of the drug
products. Therefore, it is necessary to study the impurity profile of the
API to be used in the manufacturing of a drug product. International
conference on Harmonization (ICH) guidelines recommend identifying
and characterizing all impurities that are present at a level of ꢀ0.10%.[6]
In this context, a comprehensive study was undertaken to synthesize
and characterize the following five impurities:[7] 2-[[[3-methyl-4-(2,2,2-
trifluoroethoxy)-1-oxide-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole
(N-oxide, 2); 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-1-oxide-2-pyridyl]-
methyl]sulfonyl]-1H-benzimidazole (sulfone N-oxide, 3); 2-[[[3-methyl-4-
(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]-1H-benzimidazole (sulfide,
4);
2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfonyl]-1
H-benzimidazole (sulfone, 5), and 1-[[3-methyl-4-(2,2,2-trifluoroethoxy)-
2-pyridyl]methyl]-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]-
sulfinyl]-1H-benzimidazole (N-aralkyl lansoprazole, 6).
Several analytical methods have been reported for the determination
of lansoprazole and pantoprazole in biological fluids and pharmaceutical
formulations.[8] Two of the lansoprazole impurities, lansoprazole sulfide
4 and sulfone 5, were earlier reported as metabolites.[9] However, except
for sulfide impurity 4, a detailed synthetic procedure is not reported for
other impurities. Among these five impurities, sulfone N-oxide 3 and
N-aralkyl 6 impurities are reported here for the first time.
RESULTS AND DISCUSSION
Lansoprazole 1 has been synthesized (Fig. 1) by an oxidation of sulfide 4,
which is produced from a condensation reaction between 2-mercaptoben-
zimidazole
8 and 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)-
pyridine (7). The transformation of sulfide 4 into lansoprazole 1 was
conducted using peroxy acid such as m-chloroperbenzoic acid (m-CPBA)
or hydrogen peroxide.[10]
Lansoprazole-N-oxide 2 was prepared from 2-chloromethyl-3-methyl-
4-(2,2,2-trifluoroethoxy) pyridine hydrochloride (7). Reaction of 7 with

Metabolites and Impurities of Lansoprazole
3479
Figure 1. Synthesis of lansoprazole.
alkali and subsequent oxidation using m-CPBA gave the corresponding
N-oxide 10. Condensation of 10 with mercapto benzimidazole derivative
8 in aqueous alkali followed by m-CPBA oxidation of resulting sulfide 11
furnished the desired N-oxide impurity 2 (Fig. 2). High-resolution
mass spectrometry (HRMS): m=z calcd. for C16H15N3O3F3S (Mþ þ H):
386.0786; found: 386.0792; calcd. for C16H14N3O3F3NaS (Mþ þ Na):
408.0606; found: 408.0615; m=z calcd. for C16H13N3O3F3S (Mꢁ ꢁ H):
384.0630; found: 384.0638. IR (NH)3436 cmꢁ1, Ar-H 3066 cmꢁ1
,
1
aromatic C ¼ C 1585, 1480, 1449 cmꢁ1, S ¼ O 1069 cmꢁ1. HNMR (d
Figure 2. Synthesis of lansoprazole N-oxide.

3480
G. M. Reddy et al.
Figure 3. Synthesis of lansoprazole sulfone N-oxide.
ppm) 13.68 (br, NH), 8.34 (d, J ¼ 7.2, 1H, Py-H), 7.66 (m, 2H), 7.32 (m,
2H, Ar-H), 7.27 (d, J ¼ 7.2, 1H, Py-H), 4.92 (m, 2H, Py-CH2), 4.92 (m,
2H, OCH2–CF3), 2.05 (s, 3H, Py-CH3).
Lansoprazole sulfone N-oxide 3 is the overoxidized by-product
formed in the synthesis of lansoprazole. Lansoprazole sulfide 4, on treat-
ment with m-CPBA in chloroform, smoothly afforded lansoprazole sul-
fone N-oxide 3 (Fig. 3). The protonated molecular ion of 3 appeared at
402.0, and the sodium adduct appeared as the base peak at 424.1 in
the EI spectrum. HRMS m=z calcd. for C16H14N3O4F3NaS (Mþ þ Na):
424.0555; found: 424.0558; m=z calcd. for C16H13N3O4F3S (Mꢁꢁ H):
400.0579; found: 400.0579. This is consistent with the assigned structure
of 3. IR spectrum of 3 showed the presence of O ¼ S ¼ O stretching
(1335 cmꢁ1), C–N stretching (1109 cmꢁ1), and C–O aryl alkyl stretching
1
(1016 cmꢁ1). The HNMR spectral data of compound 3 are similar to
that of compound 2.
Lansoprazole sulfide 4 was obtained using the synthetic sequence
followed for lansoprazole (Fig. 1). HRMS m=z calcd. for C16H15N3OF3S
(Mþ þ H): 354.0888; found: 354.0894; m=z calcd. for C16H13N3OF3S
(Mꢁ ꢁ H) 352.0731; found: 352.0726. Data of 4 are consistent with that
1
of sulfide. IR, mass, and HNMR spectral data of 4 are identical with
that of the reference sample.[10]
Lansoprazole sulfone 5 was prepared by the controlled oxidation of
lansoprazole sulfide 4, using an optimal amount of m-CPBA (Fig. 4). The
protonated molecular ion appeared at 386.0 and a sodium adduct
Figure 4. Synthesis of lansoprazole sulfone.

Metabolites and Impurities of Lansoprazole
3481
appeared as the base peak at 408.0 in the EI spectrum. HRMS (EI), m=z
calcd. for C16H15N3O3F3S (Mþ þ H): 386.0786; found: 386.0791; calcd.
for C16H14N3O3F3NaS (Mþ þ Na): 408.0606; found: 408.0626; m=z
calcd. for C16H13N3O3F3S (Mꢁ ꢁ H): 384.0630; found: 384.0628). IR
O ¼ S ¼ O stretching (1329 cmꢁ1), C–O stretching (1227, 1086 cmꢁ1), C–
1
N stretching (1165 cmꢁ1). The HNMR spectral data of compound 5 is
similar to that of compound 2.
Synthesis of lansoprazole N-aralkyl impurity commenced from 2-
chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine hydrochloride
(7). Condensation of 7 with mercapto derivative 8 in the presence of
alkali and subsequent oxidation using m-CPBA gave the corresponding
lansoprazole N-aralkyl impurity 6 in poor yield but better yield was
obtained from the reaction of lansoprazole 1 with chloro compound 7
(Fig. 5). HRMS m=z calcd. for C25H23N4O3F6S (Mþ þ H): 573.1395;
found: 573.1399; calcd. for C25H22N4O3F6NaS (Mþ þ Na): 595.1215;
found: 595.1243. IR spectrum with S ¼ O absorption (1040 cmꢁ1
)
1HNMR d ppm: 8.28 (d, J ¼ 5.6, 1H, Py-H), 8.09 (d, J ¼ 5.6, 1H,
Py-H), 7.78 (m, 1H, Ar-H), 7.56 (m, 1H, Ar-H), 7.30 (m, 2H, Ar-H),
7.07 (d, J ¼ 5.6, 1H, Py-H), 7.03 (d, J ¼ 5.6, 1H, Py-H), 5.91 (d,
Figure 5. Synthesis of N-aralkyl lansoprazole.

3482
G. M. Reddy et al.
J ¼ 17.2, 1H, Py-CH2), 5.80 (d, J ¼ 17.2, 1H, Py-CH2), 5.00 (d, J ¼ 13.6,
1H, Py-CH2), 4.88 (m, 4H, OCH2CF3), 4.71 (d, J ¼ 13.6, 1H, Py-CH2),
2.30 (s, 3H, Py-CH3), 2.08 (s, 3H, Py-CH3). This further supports the
assigned structure 6.
CONCLUSION
Information about the different possible impurities, metabolites, and
their synthetic routes is a prerequisite for a thorough understanding of
the impurity formation pathway of the antiulcerative drug lansoprazole.
Keeping in view this regulatory importance of lansoprazole impurities,
the process-related impurities and metabolites in bulk lansoprazole were
identified, synthesized and characterized using mass, HRMS, IR, and
NMR techniques.
EXPERIMENTAL
1
The HNMR spectra data were recorded at 200 MHz on Varian and
400 MHz on Varian, Gemini-2000, FT NMR spectrometers; the chemical
shifts were reported in d ppm relative to TMS. The infrared spectra were
obtained using a Perkin-Elmer, Spectrum One Fourier transform infrared
(FT-IR) spectrophotometer, with substances being pressed in KBr pel-
lets. The mass analysis was performed on a AB-4000 Q-trap LC-MS=MS
mass spectrometer. The high resolution mass spectroscopy (HRMS)
analysis was performed on the Micromass LCT Premier XE mass spec-
trometer equipped with an ESI Lock spray source for accurate mass
values (Water Corporation, Milford, MA, USA). Solvent removal
was accomplished by a rotary evaporator operating at house vacuum
(40–50 Torr). The solvents and reagents were used without further puri-
fication. m-CPBA was used in the reaction, having the assay of 70% w=w.
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-1-oxide-2-pyridyl]methyl]
sulfinyl]-1H-benzimida-zole (Lansoprazole-N-Oxide, 2)
2-Chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine-1-oxide (10)
In the solution of 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyri-
dine hydrochloride (20.0 g, 72 mmol, 7) in CHCl3 (100.0 mL) and H2O
(100.0 mL), pH was adjusted to 8.0 with aq. ammonia and stirred for
10 min. The chloroform layer was separated and washed with H2O
(2 ꢂ 100 mL). To this solution of free base 2-chloromethyl-3-methyl-
4-(2,2,2-trifluoroethoxy)pyridine (9), a solution of m-CPBA (43.0 g,

Metabolites and Impurities of Lansoprazole
3483
175 mmol) in CHCl3 (250.0 mL) was added at reflux temperature for 1 h
and stirred for 1.5 h for reaction completion. pH was adjusted to 8.5 with
ꢃ
aq. ammonia at 15–20 C. The organic and aqueous layers were sepa-
rated, and the organic layer was washed with water (2 ꢂ 50.0 mL). The
organic layer was concentrated under reduced pressure at less than 45
ꢃC; the solid was isolated in n-hexane and dried to get the brown solid
10. Yield 17.4 g, 83%); IR (KBr, cmꢁ1): 3027 (Ar-H), 1572, 1473 (aror-
matic C ¼ C), 1246 (CꢁO aryl alkylether), 1170 (C–N), 780 (Ar-H bend-
ing); 1HNMR (DMSO-d6, 400 MHz, d ppm): 8.30 (d, J ¼ 7.6, 1H, Py-H)
7.27 (d, J ¼ 7.2, 1H, Py-H), 5.0 (s, 2H, –CH2Cl), 4.96–4.79 (m, 2H,
OCH2CF3), 2.27 (s, 3H, Py-CH3); MS m=z (EI): 256.0 (Mþ þ H).
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-1-oxide-2-pyridyl]methyl]thio]-
1H-benzimidazole (11)
To the solution of 2-mercapto-1H-benzimidazole (10.3 g, 68 mmol, 8) in
water (50.0 mL) and NaOH (4 g, 100 mmol), a solution of 2-chloro-
methyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine-1-oxide (16 g, 62 mmol,
10) in acetone (50.0 mL) was added and stirred for 1 h to reaction comple-
tion. The isolated solid was filtered, washed with a 1:1 mixture of water
ꢃ
and acetone (20.0 mL), and dried at 40–45 C to get a white solid. Yield
18.6 g, 80.5%; IR (KBr, cmꢁ1): 3037 (Py-H), 2958, 2938 (Ali-H), 1613
(C ¼ N), 1574, 1442 (aromatic C ¼ C), 1270, 1049 (arylalkylether), 1174
1
(C–N), 762 (Ar-H bending); HNMR (DMSO-d6 þ CHCl3-d, 400 MHz,
d ppm): 13.24 (s, benzimidazole-NH), 8.24 (d, J ¼ 7.2, 1H, Py-H), 7.48–
7.50 (m, 1H, Ar-H), 7.33–7.36 (m, 1H, Ar-H), 7.14 (d, J ¼ 7.2, 1H, Py-
H), 7.08–7.15 (m, 2H, Ar-H), 4.86 (s, 2H, PyCH2Cl), 2.39 (s, 3H,
PyCH3), 4.63–4.69 (m, 2H, OCH2CF3); MS m=z (EI): 370.0 (Mþ þ H),
392.1 (Mþ þ Na).
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-1-oxide-2-pyridyl]methyl]
sulfinyl]-1H-benzimidazole (Lansoprazole N-Oxide, 2)
To a cooled solution of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-1-oxide-
2-pyridyl]methyl]thio]-1H-benzimidazole (6.0 g, 16 mmol, 11) in chloro-
form (30.0 mL), a solution of m-CPBA (4.0 g, 16 mmol) in chloroform
ꢃ
(30.0 mL) was added slowly at ꢁ10 to ꢁ15 C over a period of 30 min.
The reaction mass was poured into the solution of NaOH (2.0 g,
50 mmol) in water (50.0 mL), and pH was adjusted to 8–8.5 using acetic
acid. The organic and aqueous layers were separated. The organic layer
was extracted with aq. NaOH solution (1.5 g in 30.0 mL water), and
the resulting aq. layer was washed with chloroform (2 ꢂ 15.0 mL) to
remove unreacted sulfide 11. Methanol (15.0 mL) was added, and then

3484
G. M. Reddy et al.
pH was adjusted with acetic acid to 7–7.5. The isolated product was
ꢃ
filtered and dried at 50 C to yield a white solid 2. Yield 6.2 g, 67%;
mp 196–200 ꢃC (dec.). IR (KBr, cmꢁ1): 3436 (moisture O–H), 3066
(Ar–H), 2941, 2864 (Ali–H), 1615 (C ¼ N), 1585, 1470, 1449, 1408 (Ar
C ¼ C), 1255 (arylalkylether), 1174 (C–N), 1155 (C–F), 1069 (S ¼ O);
1HNMR (DMSO-d6, 400 MHz, d ppm): 13.68 (br, benzimidazole-NH),
8.34 (d, J ¼ 7.2, 1H, Py-H), 7.66 (m, 2H, Ar-H), 7.32 (m, 2H, Ar-H),
7.27 (d, J ¼ 7.2, 1H, Py-H), 4.92 (s, 2H, Py-CH2–Cl), 2.05 (s, 3H, Py-
CH3), 4.92 (m, 2H, –CH2CF3); 13CNMR (DMSO-d6, 400 MHz, d ppm)
154.71, 136.78, 123.59 (q, 275.7, splitting due to coupling between 19F
and 13C), 123.30, 117.35, 109.98, 65.33 (q, 34.4, splitting due to coupling
between 19F and 13C), 54.30, 11.55; MS: þve. HRMS: m=z calcd. for
(Mþ þ H) C16H15N3O3F3S: 386.0786; found: 386.0792 (1.6 ppm); calcd.
for(Mþ þ Na)C16H14N3O3F3Na S: 408.0606; found: 408.0615 (2.2 ppm).
ꢁve HRMS: m=z calcd. for (Mꢁ ꢁ H). C16H13N3O3F3S: 384.0630; found:
384.0638 (2.1 ppm).
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-1-oxide-2-pyridyl]methyl]
sulfonyl]-1H-benzimidazole (3)
To a solution of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]-
thio]-1H-benzimidazole (10.0 g, 28.3 mmol, 4) in CHCl3 (50.0 mL) at ꢁ 20
to ꢁ 25 ꢃC, a solution of m-CPBA (40.0 g, 162 mmol) in CHCl3 (60.0 mL)
was added slowly for 45 min. The reaction was maintained for 1 h, and
then the temperature was raised to 0 ꢃC and maintained for 1 h. The reac-
tion mass was poured into the aq. NaOH solution (12.0 g NaOH in
100.0 mL of water), pH was adjusted to 8.0 with AcOH, and the organic
layer was separated. This CHCl3 layer was extracted with basic water
(1.5 g of NaOH in 50.0 mL of water) and washed with CHCl3
(2 ꢂ 20.0 mL). Methanol (25.0 mL) was added, and the solution was
cooled to 10 ꢃC. pH was adjusted to 7.0 with AcOH, temperature cooled
to 5ꢃC, and the isolated solid was filtered. The solid was washed with the
1:1 mixture of H2O and methanol (10.0 mL) and purꢃified from the acet-
one to yield white solid 3, 7.4 g, 68%; mp: 239–244 C. IR (KBr, cmꢁ1):
3415 (moisture O–H), 3079 (Ar–H), 2954 (Ali–H), 1612, 1456 (aromatic
C ¼ C), 1397 (Ali-H bending), 1335 (O ¼ S ¼ O), 1135 (C–F), 1109 (C–N),
1
1016 (C–O aryl alkyl ether), 750 (Ar-H bending); HNMR (DMSO-d6,
400 M Hz, d ppm): 13.85 (br, benzimidazole-NH), 8.12 (d, J ¼ 7.2, 1H,
Py-H), 7.74 (br, 1H, Ar-H), 7.61 (br, 1H, Ar-H), 7.38 (br, 2H, Ar-H),
7.22 (d, J ¼ 7.2, 1H, Py-H), 5.44 (s, 2H, PyCH2), 4.93 (q, J ¼ 8.8, 2H,
OCH2–CF3), 2.25 (s, 3H, PyCH3); 13CNMR (DMSO-d6, 400 MHz, d
ppm) 151.79, 148.41, 142.14, 139.45, 136.68, 134.21, 126.81, 125.26,

Metabolites and Impurities of Lansoprazole
3485
123.61 (q, 276.5, splitting due to coupling between 19F and 13C), 123.43,
120.63, 113.13, 110.19, 65.29 (q, 34.4, splitting due to coupling between
19F and 13C), 54.05, 11.97. Mass (Mþ þ H) 402.0, (Mþ þ Na) 424.1,
(EI): þ ve HRMS: m=z calcd. for (Mþ þ Na) C16H14N3O4F3NaS:
424.0555; found: 424.0558 (0.7 ppm); ꢁve HRMS: m=z calcd. for
(Mꢁ ꢁ H). C16H13N3O4F3S: 400.0579; found: 400.0579 (0.0 ppm).
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]-1H-
benzimidazole (4)
To the solution of 2-mercapto-1H-benzimidazole (7.8 g, 52 mmol, 8) and
sodium hydroxide (3.8 g, 95 mmol) in water (60.0 mL) and acetone
(60.0 mL) at 15–20 ꢃC, a solution of 2-chloromethyl-3-methyl-4-(2,2,2-tri-
fluoroethoxy)pyridine hydrochloride (12.0 g, 43 mmol, 7) in water
(30.0 mL) was added slowly for 45 min. The precipitated solid was filtered
ꢃ
at 25–30 C, washed with a 1:1 mixture (20.0 mL) of acetone and water,
and dried to a constant weight at 60 ꢃC to yield off-white solid 4. Yield
12.3 g, 80%; mp 111–116 ꢃC; IR (KBr, cmꢁ1) 3551 (moisture O–H),
3054 (Ar–H), 2984, 2898 (Ali–H), 1662 (C ¼ N), 1590, 1509, 1445 (aro-
matic C ¼ C), 1380, 1363 (Ali-H bending), 1256, 1175 (C–N), 1163 (C-
F), 1009 (arylalkylether), 762, 746 (Ar-H bending). Mass (EI) þ ve
HRMS: m=z calcd. for (Mþ þ H) C16H15N3OF3S: 354.0888; found:
354.0894 (1.7 ppm); ꢁve HRMS: m=z calcd. for (Mꢁ ꢁ H) C16H13N3OF3S:
352.0731; found: 352.0726 (ꢁ1.4 ppm); 1HNMR (DMSO-d6, 200 MHz, d
ppm]: 12.59 (s, benzimidazole-NH), 8.31 (d, J ¼ 5.6, 1H, Py-H), 7.53 (m,
1H, Ar-H), 7.38 (m, 1H, Ar-H), 7.13 (m, 2H, Ar-H), 7.09 (d, J ¼ 5.6, 1H,
1
Py-H), 4.90 (q, J ¼ 8.8, 2H, splitting due to coupling between H and
19F), 4.73 (s, 2H, Py-CH2), 2.25 (s, 3H, Py-CH3); 13CNMR (DMSO-d6,
200 M Hz, d ppm) 161.19, 155.55, 150.05, 147.78, 142.65, 136.33,
123.76 (q, 275.7, splitting due to coupling between 19F and 13C),
121.40, 120.12, 117.05, 110.12, 106.86, 64.70 (q, 34.4, splitting due to
coupling between 19F and 13C), 36.19, 10.23.
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfonyl]-1H-
benzimidazole (5)
To the solution of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]-
methyl]thio]-1H-benzimi-dazole (8.0 g, 22.6 mmol, 4) in CHCl3 (40.0 mL)
and MeOH (15.0 mL), a solution of meta chloroperbenzoic acid
(m-CPBA) (11.5 g, 46.9 mmꢃol) in CHCl3 (50.0 mL) was added for
45 min to 1 h at ꢁ10 to ꢁ15 C. The reaction mass was poured into the

3486
G. M. Reddy et al.
solution of aq. NaOH (5.0 g of NaOH in 100.0 mL of water). pH was
adjusted to 8 with AcOH, and then the organic layer was separated. It
was extracted with basic water (2.0 g of NaOH in 60.0 mL of water)
and washed with CHCl3 (2 ꢂ 20.0 mL). Acetone (20.0 mL) was charged
to the aqueous layer and cooled to 5–10 ꢃC. pH was adjusted with AcOH
to 8, and the isolated solid was filtered and washed with the 1:1 mixture
of water and acetone (20.0 mL), then purified from methanol and dried to
a constant weight at 60–65 ꢃC to yield white solid 5. Yield 6.2 g, 71%; mp
206–210 C; IR (KBr, cmꢁ1): 3437 (moisture O–H), 3091 (Ar–H), 2964,
ꢃ
(Ali–H), 1586, 1480, 1456 (aromatic C ¼ C), 1442, 1386 (Ali-H bending),
1329 (O ¼ S ¼ O), 1227, 1086 (arylalkylether), 1165 (C–N), 1143 (C–F),
1
744 (Ar–H bending); H NMR (DMSO-d6, 400 M Hz, d ppm]: 12.00
(br, benzimidazole-NH), 8.14 (d, J ¼ 5.6, 1H, Py-H), 7.68 (m, 2H, Ar-
H), 7.35 (m, 2H, Ar-H), 7.08 (d, J ¼ 5.6, 1H, Py-H), 5.10 (s, 2H, Py-
CH2), 4.90 (q, J ¼ 8.4, 2H, OCH2CF3), 2.23 (s, 3H, Py-CH3); 13CNMR
(DMSO-d6, 400 MHz, d ppm) 161.47, 148.77, 148.04, 138.94, 123.98,
123.72 (q, 275.7, splitting due to coupling between 19F and 13C),
123.32, 117.04, 107.41, 64.70 (q, 33.8, splitting due to coupling between
19F and 13C), 60.39, 10.90. Mass (EI) þve HRMS: m=z calcd.
for (Mþ þ H) C16H15N3O3F3S: 386.0786; found: 386.0791 (1.3 ppm);
calcd. for (Mþ þ Na) C16H14N3O3F3NaS: 408.0606; found: 408.0626
(4.9 ppm); ꢁve HRMS: m=z calcd. for (Mꢁ ꢁ H) C16H13N3O3F3S:
384.0630; found: 384.0628 (ꢁ 0.5 ppm).
1-[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]-2-[[[3-methyl-
4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (6)
1-[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]-2-[[[3-methyl-4-
(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]-1H-benzimidazole (12)
To a solution of 2-mercapto-1H-benzimidazole (6.0 g, ꢃ40 mmol, 8) and
NaOH (12.75 g, 318 mmol) in H2O (30.0 mL) at 25–30 C, a solution of
2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine HCl (22.0 g,
80 mmol, 7) in H2O (65.0 mL) was added for 30–45 min. Reaction mass
was heated to 70–75 ꢃC and maintained at 70–75 ꢃC for 4 h. The precipi-
tated solid was filtered at 25–30 ꢃC and washed with a 1:1 mixture of
MeOH and H2O (20.0 mL), the recrystallized from ethyl acetate and
dried to a constant weight at 55 ꢃC to yield 12. Yield 17.5 g, 79%. MS
1
m=z (Mþ þ H) 557.2, (Mþ þ Na) 579.2; HNMR (DMSO-d6, 400 MHz,
d ppm): 8.28 (dd, J ¼ 8, 20, 1H, Py-H), 8.10 (d, J ¼ 6, 1H, Py0-H),
7.58–7.60 (m, 1H, Ar-H), 7.29–7.38 (m, 1H, Ar-H), 7.01–7.17 (m, 2H,
Ar-H), 7.02 (d, J ¼ 6, 2H, Py-H), 5.48 (s, 2H, Py’-CH2), 4.70–4.92 (m,

Metabolites and Impurities of Lansoprazole
3487
4H, Py-CH2), 4.71 (d, J ¼ 6.8, 2H, Py-CH2), 2.25 (s, 3H, Py-CH3), 2.20 (s,
3H, Py0-CH3).
1-[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]-2-[[[3-methyl-4-
(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (6)
To the solution of 1-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]-
methyl]-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]-1H-
benzimidazole (12.0 g, 21.5 mmol, 12) in CHCl3 (60.0 mL) and MeOH
(30.0 mL) at 20–25ꢃC, a solution of m-CPBA (6.0 g, 24.4 mmol) in CHCl3
(50.0 mL) was added slowly for 30 min. The reaction was maintained for
4 h, and the reaction mass was poured into the solution of NaOH (2.0 g of
NaOH in 100.0 mL of water). pH was adjusted to 8.5 with AcOH, and
then the both layers were separated. Aq. layer was extracted with CHCl3
(2 ꢂ 50.0 mL), and the combined organics were concentrated under
reduced pressure. A solid was recrystallized from MeOH (30.0 mL) and
dried to a constant weight at 50 ꢃC to yield a white solid 6. Yield
3.64 g, 29.5%; mp 155–160 ꢃC. IR (KBr, cmꢁ1): 3411 (moisture O–H),
3086 (Ar–H), 2949, 2805 (Ali–H), 1583, 1476, 1459 (aromatic C ¼ C),
1382 (Ali–H bending), 1040 (S ¼ O), 1263 (arylalkylether), 1165 (C–N),
748 (Ar–H bending); mass (EI): þve HRMS: m=z calcd. for (Mþ þ H)
C25H23N4O3F6S: 573.1395; found: 573.1399 (0.7 ppm); calcd. for
(Mþ þ Na) C25H22N4O3F6NaS: 595.1215; found: 595.1243, (4.7 ppm);
1HNMR (DMSO-d6, 400 MHz, d ppm): 8.28 (d, J ¼ 5.6, 1H, Py-H),
8.09 (d, J ¼ 5.6, 1H, Py0-H), 7.75–7.80 (m, 1H, Ar-H), 7.70–7.60 (m,
1H, Ar-H), 7.25–38 (m, 2H, Ar-H), 7.07 (d, J ¼ 5.6, 1H, Py-H), 7.03
(d, J ¼ 5.6, 1H, Py0-H), 5.80 (dd, J ¼ 8, 17.2, 1H, Py’-CH2), 5.00 (d,
J ¼ 13.6, 1H, Py-CH2), 4.82–4.90 (m, 4H, Py-CH2), 4.71 (d, J ¼ 13.6,
1H, Py-CH2), 2.30 (s, 3H, Py-CH3), 2.08 (s, 3H, Py’-CH3); 13CNMR
(DMSO-d6, 400 MHz, d ppm) 161.30, 161.11, 154.08, 153.98, 151.51,
148.03, 147.77, 141.71, 136.16, 124.00, 123.76 (q, 277.0, splitting due to
coupling between 19F and 13C), 123.71 (q, 277.4, splitting due to coupling
between 19F and 13C), 122.82, 121.96, 120.08, 118.86, 111.21, 106.94,
64.62 (q, 32.4, splitting due to coupling between 19F and 13C), 59.33,
45.85, 10.31, 9.31.
Alternative Procedure to Prepare 6
To a solution of lansoprazole (5.0 g, 13.5 mmol, 1) and NaOH (1.2 g,
30 mmol) in H2O (30.0 mL) at 25–30 ꢃC, a solution of 2-chloromethyl-
3-methyl-4-(2,2,2-trifluoroethoxy)pyridine HCl (3.73 g, 13.5 mmol, 7) in

3488
G. M. Reddy et al.
H2O (15.0 mL) was added. The reaction mass was heated to 70–75 ꢃC and
maintained at 70–75 ꢃC with the completion of the reaction. The precipi-
tated solid was filtered at 25 ꢃC, washed with a 1:1 mixture of MeOH and
H2O (20.0 mL), then purified in ethyl acetate and dried to a constant
ꢃ
weight at 50–55 C to yield, 6. Yield 6.2 g, 80%.
ACKNOWLEDGMENTS
The authors are grateful to colleagues in the Analytical Research Depart-
ment of Integrated Product Development Operations, Discovery
Research, and the management of Dr. Reddy’s Laboratories Ltd. for
providing the necessary support.
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