A practical one pot synthesis of 2-[2-(pridylmethyl)-thio]-1H-benzimidazoles

Article abstract of DOI:10.1081/SCC-120003612

A combination of Et₃N and pTSCl was found to be far superior than pTSCl or benzene sulfonyl chloride alone in convert ing substituted 2-picoline-N-oxides to the corresponding 2-chloromethylpyridines and has been exploited for the synthesis of a variety of 2-[2-(pyridylmethyl)-thio]-1H-benzimidazoles, key intermediates in the manufacture of H⁺/K⁺-ATPase inhibitors in a single pot.

Full text of DOI:10.1081/SCC-120003612

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A PRACTICAL ONE POT SYNTHESIS OF 2-[2-
(
PYRIDYLMETHYL)-THIO]-1H-BENZIMIDAZOLES
a a a a
a
R. A. Rane , R. K. Pathak , C. P. Kaushik , K. V. V. Prasad Rao & Ashok Kumar
a
Lupin Laboratories Limited, 198-202, New Industrial Area No. 2, Mandideep, M.P., 462 046,
India
Published online: 16 Aug 2006.
To cite this article: R. A. Rane , R. K. Pathak , C. P. Kaushik , K. V. V. Prasad Rao & Ashok Kumar (2002): A PRACTICAL ONE
POT SYNTHESIS OF 2-[2-(PYRIDYLMETHYL)-THIO]-1H-BENZIMIDAZOLES, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 32:8, 1211-1217
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SYNTHETIC COMMUNICATIONS, 32(8), 1211–1217 (2002)
A PRACTICAL ONE POT SYNTHESIS
OF 2-[2-(PYRIDYLMETHYL)-THIO]-1H-
BENZIMIDAZOLES
R. A. Rane, R. K. Pathak, C. P. Kaushik,
K. V. V. Prasad Rao, and Ashok Kumar*
Lupin Laboratories Limited, 198-202, New Industrial
Area No. 2, Mandideep, 462 046, M.P., India
ABSTRACT
A combination of Et N and pTSCl was found to be far
3
superior than pTSCl or benzene sulfonyl chloride alone in
converting substituted 2-picoline-N-oxides to the correspond-
ing 2-chloromethylpyridines and has been exploited for
the synthesis of a variety of 2-[2-(pyridylmethyl)-thio]-1H-
benzimidazoles, key intermediates in the manufacture of
þ
þ
H /K -ATPase inhibitors in a single pot.
Key Words: Omeprazole; Lansoprazole; Benzimidazole; 2-
Halomethylpyridines; Pyridylmethylthiobenzimidazoles
The search for a practical yet efficient synthesis of bioactive molecules
1
has always been the focus of our interest. In this direction, synthesis of
þ
þ
H /K -ATPase irreversible inhibitors such as omeprazole, lansoprazole
*
Corresponding author. Fax: (91-22) 8683589; E-mail: guptaak1@hotmail.com
211
1
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

1
212
RANE ET AL.
and pantoprazole (1a,1b,1d), which have regained their position as leading
candidates in ulcer chemotherapy, were chosen as target molecules.
2
The reported synthesis of the prazoles 1a–c involves the condensa-
tion of 2-halomethylpyridines (3a–c) with 2-mercaptobenzimidazoles (4)
and the subsequent oxidation of the resulted sulfides (2a–c). The synthesis
2
e,3
of 2-halomethylpyridines in turn is performed by subjecting 2-methyl-
pyridine-N-oxides to Bockethide rearrangement in the presence of acetic
anhydride, followed by saponification and transformation of the resulting
2-hydroxymethylpyridines to the corresponding halo derivatives (3a–c)
by reacting with halogenating agents such as SOCl , POCl , P Br etc.
2
3
3
This method, however, suffers from drawbacks such as poor material
efficiency, involvement of multisteps and formation of ring acetoxy
products.
Quite a few single-step conversions of 2-picoline-N-oxide to give
-chloromethylpyridine in the presence of reagents such as p-toluene-
2
sulfonyl chloride, benzenesulfonyl chloride and phosphoryl chloride
4
5
6
are also reported in the literature; however, the extension of this method-
ology to substituted pyridines proved to be futile in our hands. The
present report describes a mild, general and convenient single-step syn-
thesis of various 2-chloromethylpyridines and their in-situ condensation
with 2-mercaptobenzimidazoles to get the desired sulfides in reasonably
good yields (Scheme 1).
Scheme 1.
The new conditions discovered involve condensation of p-TSCl with
various substituted 2-methylpyridine-N-oxides in the presence of an
ꢀ
organic base such as triethylamine at moderate temperature (40–65 C) to
give the corresponding 2-chloromethylpyridines, 3, in high yield. The iso-
lation of the latter is practically possible and was successfully achieved in a

Q Q
SYNTHESIS OF H /K -ATPase INHIBITORS
1213
few cases; however, since 2-halomethylpyridines are known to be very
7
unstable, the isolations of these intermediates was found to be unnecessary
and therefore in-situ reactions with 2-mercaptobenzimidazoles to give 2
were preferred. The consumption of 2-mercaptobenzimidazoles in the
condensation step was also found to be a good measure for the strength
8
of 3 in the reaction mixture. The synthesis of 2-chloromethylpyridines
(
3) can be performed under different conditions (see table); however,
since the formation of 1 : 1 adduct of pyridine N-oxides with pTSCl (as
1
9
analysed by H NMR ) appears to be the initial step, addition of triethy-
lamine to the substrate: pTSCl complex (Method A) was found to give
better results.
The formation of 2-methylthiobenzimidazole (6) in the reaction of
-mercaptobenzimidazole with 5c under the conditions disclosed herewith
2
is worth highlighting.
1
0b
Although all attempts to isolate 3-hydroxy-4-
methoxy-2-chloromethylpyridine (7) or the corresponding 2-[{3-(hydroxy-
-methoxy)-2-pyridylmethyl}-thio]-1H-benzimidazole (8) from the reaction
4
mixture were unsuccessful, the formation of 6, however, can be rationalized
based on the mechanism where thiolate anion of 4 attacks the activated
3-methoxy group of 3c, as depicted in the Scheme 2. Cleavage of arylalkyl
ethers by thiolates and thiophenolate anions is very well documented in the
1
1,12
literature.
Scheme 2.
The attempted generalization of the reaction using mesyl chloride
MsCl) in the place of pTSCl under the reaction conditions led to quick
(
deoxygenations of the pyridine-N-oxides to give the corresponding sub-
1
3
stituted pyridines in high yields. Similar N-deoxygenations are reported
to take place in the presence of large amounts of MsCl (9 mol. Eq.) and
Et N (12 mol. Eq.).
3
In conclusion, the work compiled in this communication has been able
to exemplify the potential of the new conditions in the synthesis of the title
þ
þ
compounds (2), key intermediates in the manufacture of H /K -ATPase
inhibitors such as omeprazole and lansoprazole.

1
214
RANE ET AL.

Q Q
SYNTHESIS OF H /K -ATPase INHIBITORS
1215
EXPERIMENTAL SECTION
Melting points are uncorrected. The elemental analysis of C, H, N was
1
performed by a Carlo Erba 1106 elemental analyser. H NMR spectra
were recorded on a Brucker 200 MHz in CDCl with TMS as an internal
3
indicator. Column chromatography was done with Labochemie SiO2
(
60–120 mesh). The CH Cl was distilled from calcium hydride and toluene
2 2
was dried over sodium before used. All experiments were carried out with
exclusion of moisture.
Typical Procedure
Preparation of a sulfide derivative (2a) (Table, Entry 2): A mixture of
4
1
2,3,5-trimethyl-4-methoxypyridine-N-oxide
p-toluenesulfonyl chloride 2.85 g (15 mmol) was stirred in CH Cl (1 ml)
(5a, 1.67 g, 10 mmol) and
2
2
ꢀ
at 40 C for 2 h under nitrogen atmosphere. To the resulting mixture was
added dropwise, a solution of 2.1 ml (15 mmol) Et N in 10 ml of CH Cl at
0 C. The reaction mixture was kept under stirring for another 3 h,
3
2
2
ꢀ
4
neutralized with NaHCO3 (1 g), and was concentrated under reduced
pressure. To the methanol (20 ml) solution of the residue thus obtained
was added a suspension of 1.44 g (8 mmol) of 5-methoxy-2-mercapto-1H-
benzimidazole (4) in MeOH (10 ml). The reaction mixture was heated
under reflux for 4 h and MeOH was distilled off to give a residue which
was dissolved in EtOAc (60 ml). The organic layer was washed with 5%
NaOH solution (20 ml) and then with water followed by removal of EtOAc
to yield 2.4 g of 2-[{3-(5-dimethyl-4-methoxy)-2-pyridymethyl}-thio]-1H-5-
methoxybenzimidazole, 2a, as oily liquid. The crude product was subjected
to silica gel column chromatography using CHCl /MeOH as eluent and
3
crystallized from methanol/isopropyl ether to give 2.1 g (63%) of the title
ꢀ
16
compound; assay by HPLC ꢁ 98%; m.p. 155 C (lit. m.p. 155–156 C).
ꢀ
2b (Table, Entry 7): Prepared in 59.4% isolated yield starting from
,3-dimethyl-4-(2,2,2-trifluoroethoxy) pyridine N-oxide (5b); m.p. 144 C
1
4
ꢀ
2
(
1
5
ꢀ
lit. m.p. 144–145 C).
c (Table, Entry 9): Prepared in 55% isolated yield starting from
2
-methyl-3,4-dimethoxypyridine-N-oxide (5c) followed by crystallization
1
5
2
from chloroform/diethylether to give a white solid, m.p. 121 C,
ꢀ
17,18
assay
8
by HPLC ꢁ 98%.
2
-Methylthiobenzimidazole (6): Isolated by column chromatography as
ꢀ
ꢀ
11
a white solid, m.p. 201 C (lit. 201 C).

1
216
RANE ET AL.
ACKNOWLEDGMENT
The authors wish to thank Dr. N. L. Gupta and Dr. B. N. Roy for
constant encouragement and Mr. Ajay K. Tiwari and Mr. Charles D’souza
for their expert assistance in the preparation of the manuscript.
REFERENCES
1. (a) Singh, D.; Wani, M.J.; Kumar, A. J. Org. Chem. 1999, 64, 4665; (b)
Kumar, A.; Rane, R.A.; Dike, S.Y.; Ravindran, V.K. Synth. Commun.
1997, 27, 1133; (c) Kumar, A.; Rane, R.A.; Master, H.E.; Newadkar,
R.V. Tetrahedron Lett. 1997, 38, 8753; (d) Kumar, A.; Ner, D.H.; Dike,
S.Y. Indian J. Chem. 1992, 31B, 803; (e) Kumar, A.; Salunkhe, R.V.;
Rane, R.A.; Dike, S.Y. J. Chem. Soc., Chem. Commun. 1991, 483.
. (a) Singh, J.; Cho, E.W. Eur. Pat. Appl. No. 176,308; Chem. Abstr.
2
1986, 105, 60604w; (b) Lindberg, P.; Brandstrone, A.; Wallamar, B.
Trends Pharmacol. Sci. 1987, 8, 399; (c) Rosener, M.; Herling, A.;
Bickel, M. Ger. Offen. 3,509,333; Chem. Abstr. 1986, 106, 5044j; (d)
Masaki, H.; Susumu, N.; Fumio, N.; Kenji, M.; Hiroshi, T. Eur. Pat.
Appl. No. 194,458; Chem. Abstr. 1986, 105, 226353r; (e) Kohl, B.;
Strum, E.; Senn-Bilfinger, J.; Simon, W.A.; Kruger, U.; Schaefer, H.;
Rainer, G.; Figala, V.; Klemm, K. J. Med. Chem. 1992, 35, 1049.
. Mckillop, A.; Bhagrath, M.K. Hetrocycles 1985, 1697 and reference
cited therein.
3
4
5
6
7
. Matsmura, E. J. Chem. Soc. Jpn. 1953, 74, 353.
. Vozza, J.F. J. Org. Chem. 1962, 27, 3856.
. Yash, M.L.; Pews, R.G. J. Hetrocyclic Chem. 1962, 27, 3856.
. Bohlmann, R. In Comprehensive Organic Synthesis. Trost, B.M.,
Flaming, I., Eds.; Vol. 6, pp. 203–223.
8
. HPLC Conditions ¼ Column : Novapak C (reverse phase); Mobile
1
8
Phase 0.01 M Na HPO ; H O CH CN (70 : 30) Adjusted to pH 7
3
2
4
2
using H PO ; Flow rate: 1.5 ml/min; detector: UV l220 nm (Shimadzu
3
4
SPD-10A).
1
9
. 5a : pTSCl (1 : 1 adduct) ¼ H NMR(200 MHz, CDCl ) d: 2.05 (3H, s,
3
Me), 2.22 (6H, s, Me), 2.58 (3H, s, Me), 3.84 (3H, s, OMe), 7.06 (2H, d,
1
J ¼ 8 Hz), 7.6 (2H, d, J ¼ 8 Hz), 9.35 (9H, s, ArH); 5a: H NMR
(
(
CDCl ) d: 2.1 (3H, s, Me), 2.19 (3H, s, Me), 2.4 (3H, s, Me), 4.7
3
3H, s, OMe), 7.95 (1H, s, ArH).
1
1
0. 6. H NMR (DMSO-d ) d: 2.7 (3H, s, CH ), 7.15 (2H, m, 5, 6-H), 7.38
6
3
1
3
(
2H, m, 4, 7-H); C NMR (DMSO-d 50 MHz) d: 151.4, 139.9, 121.5,
6
,
113.9, 14.

Q Q
SYNTHESIS OF H /K -ATPase INHIBITORS
1217
1
1
1. Dictionary of Organic Compounds, 5th Ed.; Vol. 4 by Chapman and
Hall, p. 3663.
2. (a) Testaferri, L.; Tieco, M.; Tingoli, M.; Chianeli, D.; Montanucci, M.
Tetrahedron 1982, 38, 3687; (b) ibid. 1983, 39, 193; (c) Testaferri, L.;
Tieco, M.; Tingoli, M.; Chianelli, D.; Maiolo, P. ibid. 1982, 38, 2721;
(
(
d) Testaferri, L.; Tieco, M.; Tingoli, M. J. Org. Chem. 1980, 45, 4376;
e) Nayak, M.K.; Chakraborty, A.K. Tetrahedron Lett. 1997, 38, 8749.
1
1
1
1
3. Moromoto, Y.; Kunihar, H.; Vokoe, C.; Kinoshita, T. Chem. Lett.
998, 829.
4. Akira, N.; Yoshitaka, M. Eur. Pat. Appl. No. 0208,252; Chem. Abstr.
987, 106, 138448r.
5. Keiji, K.; Katsuaki, O.; Tatsuhiko, K.; Hiroshi, S.; Akira, N. Chem.
Pharm. Bull. 1990, 38, 2853.
1
1
6. Senn-Bilfinger, J.; Schaefer, H.; Figala, V.; Klemm, K.; Rainer, G.;
Riedal, G.; Schudt, Ch.; Simon, W.A. Ger. Offen. DE 3240248,
1
981; Chem. Abstr. 1983, 100, P7023k.
1
4
1
7. 2d is reported as light brown oil.
1
8. Akira, N.; Yoshitaka, M. Eur. Pat. Appl. No. 0208,452; Chem. Abstr.
987, 106, 138448r.
1
Received in the UK September 20, 2000