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

141

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

142

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

143

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.

144

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

145

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

146

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

147

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)

148

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-

149

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

150

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

151

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.

152


1071 (C-O), 823, 745 (C-H).


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.


1166 (C-O), 834, 744 (C-H).


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.


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.


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.


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.


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.


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

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environ contam. Toxicol., 5, 1970, 67.

b) Kouba US

3649530, 1970.

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7. a) Heenger,

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b) Hoffmann K, Binningen, Hunger A, Kebrle J, Roosi A, US

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158

9. Clemons G. P, Sister H. D, Pestic,

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10. Herrling S, Keller H, Muckter H, US

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11. Jerchel D,

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Ther. Res., 29, 1981, 24.

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JPN Kokal Tokkyo KoHo., JP 09,77,765, 1997.

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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).

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