INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/2187/14/14_chapter 5.pdf · H 3...
Transcript of INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/2187/14/14_chapter 5.pdf · H 3...
139
14. Verma A. R, Krishna P,
Polymorphism and Polytypism in Crystal, 1966, 15.
15. Sherman B. C, WO
01/036409, 2001.
16. Aktiebolag A, Anders G, Ake K, WO
1997/022603, 1997.
17. http://www.technoforce.net/design/agited_dryers.htm.
18. Midler M, Paul E. L, Whittington E. F, Futran M, Liu P. D, Hsu J, Pan
S. H, US 5,314,506,
1994.
CHAPTER-V
140
SYNTHESIS AND CHARACTERIZATION OF NOVEL
BENZIMIDAZOLE DERIVATIVES
5.1 Introduction
Benzimidazole 1 is one of the prominent nitrogen heterocycles in view of
its immense pharmacological importance. Several benzimidazole derivatives are
successfully commercialized as potent Active Pharmaceutical Ingredients
(APIs).
N
NS
1
X
Y
Benzimidazole moiety 1 assumed enormous significance as a
pharmacophore with its presence in various active pharmaceutical ingredients.
Several benzimidazole derivatives find application as promising drugs in
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different therapeutic categories as Anthelmintics,1-3 Anti thrombotics,4 Anti
psychotics,5 Analgesics,6-7 Anti hypertensives,8 Fungicides,9 Anti fungals,10 Anti
histamines,11-12 Anti emetics,13 Anti hyperthyroidals,14 Anti ulcerative,15 Anti
biotics,16 Anti cancer agents,17 MCP-I antagonists,18 Hypoglycemic agents,19
Agonists,20 Anti inflammatory agents,21 Anti tumor compounds,22 Anti virals,23
Anti microbials,24 Anti HIV agents,25 Anti allergics26 and Anti phytovirucides27
Table: 5.1: Various active pharmaceutical compounds.
S.
No
Drug Name Pharmacological
Activity
Structure Reference
2
Albendazole
Anthelmintic N
HN
SH3C
NH
O
H3CO
28
3
Dabigatran
Anti
thrombotics
N
N
NH
H2N
HN
N
O
COOH
NH3C
29
4
Droperidol
Anti psychotics
NH
NO
N
O
F
30
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5
Benzitramide
Analgesic CN
NN
N
CH3
OO
31
6
Candesartan
Anti
hypertensive N
N O CH3
NN
N
HN
COOH
32
7
Chlormidazole
Anti fungal and
Abtibiotic
N
NCH3
Cl
33
8
Enviroxime
Anti histamine
C N
N
NH2
SN
CH3
H3CO
O
HO
34
9
Domperidone
Anti emetics
NH
NN
O
N NH
O
Cl
35
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10
Rabeprazole
Anti ulcer NH
N
N
O
H3CO
36
11
Bendamustine
Anti cancer
N
N
CH3
COOH
N
Cl
Cl
37
12
Bendazac
Anti
inflammatory N
N
OCOOH
38
13
Imiquimod
Anti viral
N
NN
NH2
H3C CH3
39
The synthesis of a new class of antibacterial and antifungal agents
against especially gram-positive drug resistant bacteria and some fungi are
need, since these types of microorganisms are responsible for some infections
in the acute and long-term care units in hospitals.40 Well known azole
derivatives, having a gem-phenyl-1H-imidazol-1-ylmethyl) moiety 14 which is
thought to be largely responsible for imparting of antifungal activity, such as
clotrimazole, miconazole 15. Structure-Activity Relationship (SAR) studies
revealed that imidazole and phenyl rings, which are also pharmacophoric
portion of all these molecules, can be replaced by the furan41 and triazole42-43
respectively. On the other hand, recently highly potent antifungal44 and
antibacterial45 activities of the benzimidazoles have been reported.
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These encouraging results prompted Ozden et al., to replace phenyl and
imidazole ring of the miconazole 15 type structure to furan and benzimidazole,
respectively, with the aim of finding new agents with higher antifungal and/or
antibacterial activity.
In this study, a series of novel furyl and benzimidazole substituted
benzyl ethers are synthesized and evaluated for antibacterial and antifungal
activities against Gram-positive Staphylococcus aureus, Methicillin-resistant
Staphylococcus aureus (MRSA), Gram-negative Escherichia coli bacteria,
Candida krusei by the diffusion method.44-45 The Compound 16 and 17 are
exhibited the most potent anti-bacterial activity with lowest minimum
inhibitory concentration (MIC) values of 3.12 µg/mL against Staphylococcus
aureus and Methicillin-resistant Staphylococcus aureus (MRSA), respectively.
N
N
NN
O
Cl
Cl
Cl
Cl
14
15
O
N
NO
Cl
O
N
NO
Cl
Cl
16
17
Cl
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Benzimidazoles have been exhibit a large number of biological activities.
Similarly, benzimidazole-2-thiol and its derivatives have also been reported to
have potent biological activities, such as proton pump inhibitors,46 antiulcer
activity47 inhibitors of H+/K+ ATPase.48
Kumar et. al., synthesized 2-(substituted benzylsulfanyl)-1H-
benzimidazoles.49 The compounds are tested for antimicrobial activity and the
two compounds exhibited moderate activity against Bacillus subtilis,
Escherichia coli, Micrococcus luteus, Pseudomonas aeruginosa, Candida albicans
and Aspergillus niger in a preliminary screening. From the activity studies it
can be inferred that compounds containing the halogens on the phenyl ring at
2-position showed good to moderate activity against both the bacteria and
fungal stains tested. The compound 18 having both bromo and iodo
substituents showed promising activity against both bacteria and fungus.
Further, the presence of methyl group along with bromo in 19 also showed
good activity. However, compound with a nitro substituent in 20 did not show
much activity except against the fungal stain P. aeruginosa.
N
HN
S
N
HN
S
18 19
N
HN
S
O2N
20
Br
I
Br CH3
Significantly, the benzimidazole moiety is a constituent part of Vitamin-B12
core structure.51 Like albendazole 21, mebendazole 22 and thiabendazole 23
are widely used as antihelmintic drugs.52 Similarly, 2-substituted
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benzimidazoles and their derivatives have been found to be potent biologically
active compounds as well.53 The activity and structural diversity exhibited by
compounds containing the benzimidazole moiety has led to the discovery and
development of novel and useful bioactive benzimidazole libraries.54
NH
N
N
HN
NH
N
S
NH
NH
O
21
22
23
S
N
H3C
OCH3
O
OCH3
O
Mashelkar et. al., have been synthesized a series of 23 novel class of N-
substituted-2-(benzo[d]isoxazol-3-ylmethyl)-1H-benzimidazoles.55 Some
compounds exhibited promising anti-bacterial activity against Salmonella
typhimurium, however poor activity against Staphylococcus aureus. Out of these
compounds the compound 24 was found to have high activity even at 1ug/mL
compared to Cephalexin against Staphylococcus aureus. The biological activity
against for potential anti-asthamatic effect and against for potential anti-
diabetic effects was disappointing.
N
N
24
R
ON
Benzimidazole derivatives have been found to posse wide range of
biological activities. In view of the biological and pharmacological importance of
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both pyridine and benzimidazole moieties, it was thought worthwhile to
synthesize new benzimidazole derivatives coupled with both pyridine and
benzimidazole moiety.
5.2 Present work
In this connection, we have been interested in the synthesis of molecules
having sulphur containing benzimidazoles by condensing with biphenyl
tetrazole derivatives and bisbenzimidazole derivatives of sartan molecules.
Our attempts to telescope the three series of benzimidazole derivatives
containing both pyridine and benzimidazole moieties. These compounds are
classified into three categories.
I. N-alkylated benzimidazole derivatives.
II. S-alkylated benzimidazole derivatives.
III. N, S-alkylated benzimidazole derivatives.
I. N-Alkylated benzimidazole derivatives
Condensation of 2-n-propyl-4-methyl-6-(1-methyl benzimidazole-2-
yl)benzimidazole (25) with 2-chloromethyl-4-(methoxy)-3,5-dimethyl pyridine
(26a) in the presence of aqueous sodium hydroxide at 50 oC for 15 h to give a
product which is characterized as 4'-[[(2-n-propyl-4-methyl-6-(1-
methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-4-(methoxy)-3,5-dimethyl
pyridine 27a on the basis of its spectral data. Thus, the compound 27a showed
its IR spectrum disappearance of N-H and characteristic absorption assignable
to the N-alkylation of benzimidazole (Fig. 5.1). In 1H-NMR spectrum (Fig. 5.3),
methylene group protons show the signal at δ 5.59 as a singlet. Further
confirms its assigned structure in the positive mode mass spectrum (Fig. 5.2)
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showed M+1 peak at m/z 454. The reaction extended to different substituted
pyridine derivatives and synthesized compounds 27b-d as shown in the
Scheme 5.1.
Scheme: 5.1
N
NN
N CH3
N
R1
R2R3
CH3
CH3
N
NNH
N CH3
CH3
CH3Aq. NaOH
25
27
b =
c =
d =
R1 R2 R3
CH3 OCH3CH3
OCH3 OCH3H
CH3 OCH2CF3H
CH3 OCH2CH2CH2OCH3H
a =
N
R3
R2
R1
Cl
26
II. S-Alkylated benzimidazole derivatives
Reaction of 2-mercapto-1H-benzimidazole (28) with 4'-bromo methyl-
biphenyl-2-tetrazole (29) in aqueous sodium hydroxide at ambient temperature
to give a product 2-[2'-(1-triphenyl-methyl-1H-tetrazol-5-yl)-biphenyl-4-
ylmethylsulfinyl]-1H-benzimidazole 30.
Oxidation of 30 with m-CPBA in the presence of chloroform to give compound
31. The compound 31 is deprotected with aqueous hydrochloric acid in the
presence of methanol to give compound 2-[2'-(1H-tetrazol-5-yl)-biphenyl-4-
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ylmethanesulfinyl]-1H-benzimidazole 32 (Scheme 5.2) which was
characterized based on its spectral data. Thus, its IR spectrum showed the
characteristic absorption at 3421 cm-1 assignable to the tautomeric N-H, peak
at 1019 cm-1 to S=O assignable stretching (Fig. 5.4). In 1H-NMR spectrum
showed the up field region signals due to methylene protons adjacent to
sulphoxide show two doublets at δ 4.68, dd, 1H; δ 4.49, dd, 1H having J value
of δ 13.2 Hz (Fig. 5.6). In the positive mode mass spectrum of 32 M+1 peak at
m/z 401 corresponds to the molecular weight, 400 (Fig. 5.5) and thus further
confirms its assigned structure.
Scheme: 5.2
NH
NS
NN
N
N
CPh
PhPh
31
NH
NS
NHN
N
N
32
HCl/MeOH
OO
NH
NBr
N
NN
N+
Aq. NaOH
NH
NS
NN
N
N
CPh
PhPh
28
29
30
SH
m-CPBA
C
Ph
Ph
Ph
III. N and S-Alkylated benzimidazole derivatives
The other series N and S-alkylated benzimidazoles are prepared as, the
compound (30) is reacted with 2-chloromethyl-4-(methoxy)-3,5-dimethyl
pyridine (26a) in the presence of aqueous sodium hydroxide at ambient
temperature to give compound 33a. The compound 33a is treated with
aqueous hydrochloric acid in the presence of methanol to give a product which
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was characterized as 1-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-2-[2'-(1H-
tetrazol-5-yl)-biphenyl-4-ylmethyl sulfinyl]-1H-benzimidazole 34a based on its
spectral data. Thus, the compound 34a showed its IR spectrum characteristic
absorption at 3435 cm-1 assignable to the N-H group of the tetrazole (Fig. 5.7).
In 1H NMR spectrum the down field region was characterized by the presence
of signals due to aromatic proton adjacent to the nitrogen of the pyridine
(δ7.96, s, 1H), up field region signals are due to methyl protons δ 2.24, s, 3H; δ
2.13, s, 3H, methoxy protons δ 3.71, s, 3H, methylene protons δ 5.38, s, 2H; δ
4.49, s, 2H (Fig. 5.9). In the positive mode mass spectrum of 34a M+1 peak at
m/z 534 further confirms its assigned structure (Fig. 5.8). In similar way
synthesized different substituted derivatives as shown in the Scheme-5.3.
Scheme: 5.3
NH
NS
NN
N
N
CPh
PhPh
N
R3
R2
R1
Cl
N
NS
NN
N
N
CPh
PhPh
30
N
R1
R2R3
33
26
N
NS
NHN
N
N
N
R1
R2R3
34
HCl/MeOH
b =
c =
d =
R1 R2 R3
CH3 OCH3 CH3
OCH3 OCH3 H
CH3 OCH2CF3 H
CH3 OCH2CH2CH2OCH3 H
a =
NaOH/H2O
In conclusion, we have successfully synthesized three different
substituted benzimidazoles, such as N-alkylated, S-alkylated and N and S
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alkylated and characterized their structures based on IR, NMR and Mass
spectral data.
5.3 Experimental section
5.3.1 Preparation of compound 27a-d
General procedure:
To a clear solution of sodium hydroxide (15 g 0.37 mol) in water (75 ml)
and acetone (500 ml), added compound 25 (25 g, 0.082 mol) and compound
26a-d (0.082 mol). The reaction mass was heated to 50 oC for 15 h and the
reaction mixture concentrated. Water (100 mL) and acetone (50 mL) were
added then stirred for solid separation at ambient temperature, the separated
solid was filtered and dried. Yield: 85-90 %.
4'-[[(2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-
methyl]-4-(methoxy)-3,5-dimethyl pyridine (27a): Yield: 88%, M.R: 182-
184 oC.
FT-IR (cm-1): 3061 (Ar-H), 2963 (C-H), 1588, 1568 (C=C, C=N), 1459 (C-H),
1079 (C-O), 834, 734 (Ar-H).
1H NMR δ ppm: 0.95 (t, J = 7.2 Hz, 3H, CH3), 1.75 (m, 2H, CH2), 2.14 (s, 3H,
CH3), 2.32 (s, 3H, CH3), 2.62 (s, 3H, CH3), 2.76 (t, J = 7.2 Hz, 2H, CH2), 3.73 (s,
3H, CH3), 3.80 (s, 3H, CH3), 5.59 (s, 2H, CH2), 7.23 (m, 2H, Ar-H), 7.41 (s, 1H,
Ar-H), 7.57 (s, 1H, Ar-H), 7.58 (m, 2H, Ar-H), 7.97 (s, 1H, Ar-H).
Mass: 454 (M++H).
4'-[[(2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol -1-
yl]-methyl]-3,4-dimethoxy pyridine (27b):
Yield: 90%, M.R: 173-175 oC.
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FT-IR (cm-1): 3048 (Ar-H), 2964 (C-H), 1583, 1527 (C=C, C=N), 1451 (C-H),
1071 (C-O), 823, 745 (C-H).
1H NMR δ ppm: 0.98 (t, J = 7.6 Hz, 3H, CH3), 1.79 (m, 2H, CH2), 2.59 (s, 3H,
CH3), 2.91 (t, J = 7.2 Hz, 2H, CH2), 3.77 (s, 3H , CH3), 3.83 (s, 3H, CH3), 3.87
(s, 3H, CH3), 5.57 (s, 1H, CH2), 7.05 (d, J = 5.6 Hz, 1H, Ar-H), 7.25 (m, 2H, Ar-
H), 7.44 (s, 1H, Ar-H), 7.57 (d, J = 7.2 Hz, 1H, Ar-H), 7.64 (d, J = 7.6 Hz, 1H,
Ar-H), 7.68 (s, 1H, Ar-H), 8.07 (d, J = 5.6 Hz, 1H, Ar-H).
Mass: 456 (M++H).
4'-[[(2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-
methyl]- 4-trifluoroethoxy pyridine (27c):
Yield: 87%. M.R: 109-111 oC.
FT-IR (cm-1): 3056 (Ar-H), 2963 (C-H), 1579, 1527 (C=C, C=N), 1458 (C-H),
1166 (C-O), 834, 744 (C-H).
1H NMR δ ppm: 0.94 (t, J = 6.8 Hz, 3H, CH3), 1.75 (m, 2H, CH2), 2.31 (s, 3H,
CH3), 2.62 (s, 3H, CH3), 2.76 (t, J = 7.6 Hz, 2H, CH2), 3.81 (s, 3H, CH3), 4.89 (q,
J = 8.6 Hz, 17.2 Hz, 2H, CH2), 5.66 (s, 2H, CH2), 7.03 (d, J = 6.0 Hz, 1H, Ar-H),
7.23 (m, 2H, Ar-H), 7.42 (s, 1H, Ar-H), 7.58 (m, 2H, Ar-H), 7.60 (s, 1H, Ar-H),
8.10 (d, J = 5.2 Hz, 1H, Ar-H).
Mass: 508 (M++H).
4'-[[(2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol -1-
yl]-methyl]- 4-methoxypropoxy pyridine (27d):
Yield: 85%. M.R: 148-151 oC.
FT-IR (cm-1): 3038 (Ar-H), 2960 (C-H), 1579, 1524 (C=C, C=N), 1459 (C-H),
1090 (C-O), 832, 730 (C-H).
153
1H NMR δ ppm: 0.95 (t, J = 7.2 Hz, 3H, CH3), 1.75 (m, 2H, CH2), 1.97 (m, 2H,
CH2), 2.27 (s, 3H, CH3), 2.62 (s, 3H, CH3), 2.77 (t, J = 7.6 Hz, 2H, CH2), 3.24 (s,
3H, CH3), 3.48 (t, J = 6.0 Hz, 2H, CH2), 3.80 (s, 3H, CH3), 4.09 (t, J = 6.0 Hz,
2H, CH2), 5.60 (s, 2H, CH2), 6.88 (d, J = 5.2 Hz, 1H, Ar-H), 7.23 (m, 2H, Ar-H),
7.41 (s, 1H, Ar-H), 7.55 (d, J = 7.2 Hz, 1H, Ar-H), 7.58 (s, 1H, Ar-H), 7.61 (d, J
= 7.2 Hz, 1H, Ar-H), 8.03 (d, J = 6.0 Hz, 1H, Ar-H).
Mass: 498 (M++H).
5.3.2 Preparation of 2-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethane
sulfinyl]-1H-benzimidazole (32):
To a clear solution of sodium hydroxide (30 g, 0.75 mol) in water (150
mL) and acetone (1000 mL), added 2-mercapto-1H-benzimidazole 28 (14 g,
0.093 mol) and 1-bromomethyl biphenyl tetrazole 29 (50 g, 0.089 mol) at room
temperature. The reaction mass was stirred for 15 h at ambient temperature
and concentrated the reaction mixture followed by isolation of the product 30
in water (200 mL). Yield 48 g (85%).
To a clear solution of compound 30 (20 g, 0.031 mol) in dichloromethane (100
mL), added a mixture of m-CPBA (11 g, 0.063 mol) in dichloromethane (100
mL) at 5-10 oC. The reaction mixture was stirred for 1h and filtered the
separated byproduct (m-chlorobenzoic acid) and washed the organic layer with
5 % aqueous sodium hydroxide solution (2X100 mL). The dichloromethane
layer was concentrated and isolated the product in acetone (20 mL) to give
compound 31. Yield: 75 %. To a clear solution of compound 31 (10 g, 0.015
mol) in methanol (80 mL), added 36 % HCl solution (20 mL) at 10-15 oC. The
reaction was stirred for 1h and filtered the separated byproduct. The organic
154
layer was concentrated and added water (200 mL). The separated solid stirred
and filtered, Yield: 65 %.
FT-IR (cm-1): 3421 (N-H), 3058 (C-H), 2964 (C-H), 1604, 1586 (C=C, C=N),
1476 (C-H), 1105 (C-O), 1019 (S=O), 748 (C-H).
1H NMR δ ppm: 4.49 (d, J = 13.2 Hz, 1H, CH2), 4.68 (d, J = 13.2 Hz, 1H, CH2),
7.03 (d, J = 8.4 Hz, 1H, Ar-H), 7.16 (d, J = 8.4 Hz, 1H, Ar-H), 7.35 (m, 4H, Ar-
H), 7.51 (d, J = 8 Hz, 1H, Ar-H), 7.57 (d, J = 6.4 Hz, 1H, Ar-H), 7.64 (m, 4H, Ar-
H).
Mass: 312 (M++H).
5.3.3 Synthesis of compounds 34a-d
General procedure:
To a clear solution of sodium hydroxide (24 g, 0.6 mol) in water (120 mL)
and acetone (800 mL) added compound 30 (40 g, 0.063 mol) and compound
26 (0.063 mol) at room temperature. The reaction mixture was stirred for 15h
and the reaction mixture was concentrated followed by isolation of the product
34 in water (160 mL).
To a solution of compound 34 (25 g) and methanol (200 mL) added 36 %
HCl solution (50 mL) at 10-15 oC and stirred for 1h. The separated byproduct
(trityl chloride) was filtered and to the filtrate added water (500 mL), the
separated solid was filtered and dried.
1-(4-Methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-2-[2'-(1H-tetrazol-5-yl)-
biphenyl-4-ylmethylsulfinyl]-1H-benzimidazole (34a):
Yield: 64%. M.R: 178-180 oC.
FT-IR (cm-1): 3435 (N-H), 3050 (C-H), 2960 (C-H), 1638, 1580 (C=C, C=N),
1460 (C-H), 1071 (C-O), 760, 744 (C-H).
155
1H NMR δ ppm: 2.13 (s, 3H, CH3), 2.24 (s, 3H, CH3), 3.71 (s, 3H, CH3), 4.49 (s,
2H, CH2), 5.38 (s, 2H, CH2), 7.02 (d, J = 7.6 Hz, 1H, Ar-H), 7.12 (m, 4H, Ar-H),
7.18 (d, J = 8 Hz, 1H, Ar-H), 7.31 (m, 4H, Ar-H), 7.52 (d, J = 6.8 Hz, 1H, Ar-H),
7.59 (d, J = 8 Hz, 1H, Ar-H), 7.96 (s, 1H, Ar-H).
Mass: 534 (M++H).
1-(3,4-Dimethoxy-pyridin-2-ylmethyl)-2-[2'-(1H-tetrazol-5-yl)-biphenyl-4-
ylmethylsulfinyl]-1H-benzimidazole (34b):
Yield: 60%. M.R: 206-208 oC.
FT-IR (cm-1): 3392 (N-H), 3058 (C-H), 2974 (C-H), 1637, 1585 (C=C, C=N),
1459 (C-H), 1070 (C-O), 762, 748 (C-H).
1H NMR δ ppm: 3.73 (s, 3H, CH3), 3.86 (s, 3H, CH3), 4.53 (s, 2H, CH2), 5.41 (s,
2H, CH2), 7.03 (d, J = 5.6 Hz, 1H, Ar-H), 7.15 (m, 4H, Ar-H), 7.29 (m, 6H, Ar-
H), 7.52 (d, J = 5.2 Hz, 1H, Ar-H), 7.57 (d, J = 6.8Hz, 1H, Ar-H), 8.03 (d, J =
5.6 Hz, 1H, Ar-H).
Mass: 536 (M++H).
1-[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethyl]-2-[2'-(1H-
tetrazol-5-yl)-biphenyl-4-ylmethylsulfinyl]-1H-benzimidazole (34c):
Yield: 65%. M.R: 189-191 oC.
FT-IR (cm-1): 3421 (N-H), 3053 (C-H), 2970 (C-H), 1630, 1583 (C=C, C=N),
1477 (C-H), 1169 (C-O), 760, 745 (C-H).
1H NMR δ ppm: 2.25 (s, 3H, CH3), 4.63 (s, 2H, CH2), 4.93 (q, J = 8.4 Hz, 16.8
Hz, 2H, CH2), 5.59 (s, 2H, CH2), 7.03 (d, J = 8 Hz, 1H, Ar-H), 7.12 (d, J = 6 Hz,
1H, Ar-H), 7.26 (m, 4H, Ar-H), 7.33 (d, J = 8.4 Hz, 1H, Ar-H), 7.56 (m, 6H, Ar-
H), 8.16 (d, J = 6 Hz, 1H, Ar-H).
Mass: 588 (M++H).
156
1-[4-(3-Methoxy-propoxy)-3-methyl-pyridin-2-ylmethyl]-2-[2'-(1H-tetrazol-
5-yl)-biphenyl-4-ylmethylsulfinyl]-1H-benzimidazole(34d): Yield: 61%.
M.R: 151-153 oC.
FT-IR (cm-1): 3421 (N-H), 3058 (C-H), 2929 (C-H), 1630, 1582 (C=C, C=N),
1478 (C-H), 1087 (C-O), 760, 743 (C-H).
1H NMR δ ppm: 1.96 (m, 2H, CH2),.2.19 (s, 3H, CH3), 3.24 (s, 3H, CH3), 3.48 (t,
J = 6.4 Hz, 2H, CH2), 4.08 (t, J = 6.4 Hz, 2H, CH2), 4.54 (s, 2H, CH2), 5.40 (s,
2H, CH2), 6.88 (d, J = 5.6 Hz, 1H, Ar-H), 7.01 (d, J = 8.4 Hz, 1H, Ar-H), 7.11
(m, 4H, Ar-H), 7.32 (d, J = 8 Hz, 1H, Ar-H), 7.56 (m, 6H, Ar-H), 8.03 (d, J = 5.6
Hz, 1H, Ar-H).
Mass: 578 (M++H).
157
5.4 References:
1. a) White K, Bull
environ contam. Toxicol., 5, 1970, 67.
b) Kouba US
3649530, 1970.
2. Raeymackersl A. H. M,
Arzeneimittel Forsch., 27, 1977, 593.
3. a] Theodorides V. J,
Experientia., 32, 1976, 702.
b] Pene P,
Am. J. Trop-Med-Hyg., 31, 1982, 263.
4. Uwe R, Iris K, Norbert H, Henning P, Herbert N, Jean S,
Marie, WO
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CONCLUSIONS
163
In conclusion our studies during this thesis work have contributed to the
existing knowledge of heterocyclic chemistry in the following aspects.
1. In rabeprazole an improved process is developed to get all the known
and unknown impurities within the limits.
2. In rabeprazole and omeprazole the known impurities and novel
impurities are detected, synthesized and characterized.
3. In rabeprazole two novel polymorphs are prepared and characterized.
In omeprazole the stable omeprazole form-B and amorphous form of
omeprazole magnesium was prepared with a novel technique by using
agitated thin film dryer.
4. Nine novel derivatives of benzimidazoles are synthesized and
characterized.
LIST OF PUBLICATIONS
164
1. Pingili Ramchandra Reddy, Vurimidi Himabindu, Lilakar
Jaydeepkumar, G. Madhusudan Reddy, J. Vijay Kumar Reddy, Ghanta
Mahesh Reddy*. An Improved and Cost Viable Process for the Production of
Rabeprazole Sodium Substantially Free from the Impurities: Organic Process
Research and Development., 13, 2009, (896-899).
2. Pingili Ramchandra Reddy, M. Reddy Jambula, M. Reddy Ganta, M.
Reddy Ghanta, E. Sajja, V. Sundaram, V. B. Bhaskar. Identification and
Synthesis of Potential Impurities of Rabeprazole Sodium. Die Pharmazie., 60,
2005, (814-818).
3. Pingili Ramchandra Reddy, Vurimidi Himabindu, Lilakar
Jaydeepkumar, Boluggdu Vijaya Bhaskar, Ghanta Mahesh Reddy* Preparation
of Amorphous Form of Anti Ulcer Drugs: Rasayan Journal of Chemistry., 1(1),
2008, (166-170).
4. Pingili Ramchandra Reddy, Vurimidi Himabindu, G. Madhusudan
Reddy, Ghanta Mahesh Reddy* Synthesis and Characterization of
Benzimidazole Derivatives. Synthetic communications., Accepted.
5. Ganta Madhusudan Reddy, B. Vijaya Bhaskar, P. Pratap Reddy, P.
Sudhakar, J. Moses Babu, K. Vyas, Pingili Ramchadnra Reddy, K. Mukkanti.
Identification and Characterization of Potential Impurities of Rabeprazole
Sodium. Journal of pharmaceutical and biomedical analysis., 60, 2005, (814-
818).