SYNTHESIS AND BIOLOGICAL EVALUATION OF

NOVEL BIOACTIVE AZETIDINONES SUBSTITUTED

WITH PYRROLE MOIETY

By
ANUPKUMAR N

Dissertation submitted to the

Rajiv Gandhi University of Health Sciences

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Bangalore, Karnataka

In partial fulfillment
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of the requirement for the degree of
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MASTER OF PHARMACY
in
PHARMACEUTICAL CHEMISTRY
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Under the guidance of

Prof. M. NARAYANA BABU

Department of Pharmaceutical Chemistry

M. S. Ramaiah College of Pharmacy
Bangalore-560054
MAY-2010
 Rajiv Gandhi University of Health Sciences
Bangalore, Karnataka

DECLARATION BY THE CANDIDATE

I hereby declare that this dissertation/thesis entitled “SYNTHESIS AND

BIOLOGICAL EVALUATION OF NOVEL BIOACTIVE AZETIDINONES

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SUBSTITUTED WITH PYRROLE MOIETY” is a bonafide and genuine research

work carried out by me under the guidance of Prof. M. Narayana Babu, Department of
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Pharmaceutical Chemistry, M.S. Ramaiah College of Pharmacy, Bangalore.
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Date: Signature of the Candidate

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Place: ANUPKUMAR N
 M. S. Ramaiah College of Pharmacy
Bangalore-560054

CERTIFICATE BY THE GUIDE

This is to certify that the dissertation entitled “SYNTHESIS AND BIOLOGICAL

EVALUATION OF NOVEL BIOACTIVE AZETIDINONES SUBSTITUTED

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WITH PYRROLE MOIETY” is a bonafide research work done by

Mr. Anupkumar N in partial fulfillment of the requirement for the degree of

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Master of Pharmacy in Pharmaceutical Chemistry.
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Date: Prof. M. Narayana Babu

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Dept. of Pharmaceutical Chemistry

Place: M.S.Ramaiah College of Pharmacy
Bangalore-560054
 ENDORSEMENT BY THE HOD/ PRINCIPAL OF THE

INSTITUTION

This is to certify that the dissertation entitled “SYNTHESIS AND BIOLOGICAL

EVALUATION OF NOVEL BIOACTIVE AZETIDINONES SUBSTITUTED

WITH PYRROLE MOIETY” is a bonafide research work done by

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Mr. Anupkumar N under the guidance of Prof. M. Narayana Babu, Department of

Pharmaceutical Chemistry, M.S. Ramaiah College of Pharmacy, Bangalore.

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Prof. C.H.S. Venkataramana Dr. V. Madhavan

Head of Department (in charge) Principal
Dept. of Pharmaceutical Chemistry M.S. Ramaiah College of Pharmacy
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M.S.Ramaiah College of Pharmacy Bangalore-560054

Bangalore-560054

Date: Date:

Place: Place:
 COPYRIGHT

DECLARATION BY THE CANDIDATE

I hereby declare that the Rajiv Gandhi University of Health Sciences, Karnataka shall

have the rights to preserve, use and disseminate the dissertation/thesis in print or

electronic format for academic / research purpose.

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Date: Signature of the Candidate
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Place: ANUPKUMAR N
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© Rajiv Gandhi University of Health Sciences, Karnataka

 ACKNOWLEDGEMENT

It affords me immense pleasure to acknowledge with gratitude, the help and the

guidance rendered to me by a host of people, to whom I owe in a substantial measure

in the successful completion of this project.

I would like to express my gratitude and my sincere thanks to my esteemed Research

Guide Prof. M. Narayana Babu, Department of Pharmaceutical Chemistry, for his

guidance, supervision, support and functional freedom given to me throughout my

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research work.

I deeply owe my honest regards to our Principal of this institution, Dr. V. Madhavan,
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for the facilities provided.

I gratefully wish to express my gratitude to Mrs. Sharon. C. Furtado, lecturer,

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Department of Pharmaceutics, for her help and suggestions for carrying out

antimicrobial activity studies.

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I would like to express my gratitude to Prof. C.H.S.Venkataramana, Dr. Atish

Kumar Sahoo, Associate Professor, Mrs. B. V. Suma, Mrs. Judy Jays, Assistant

Professors, and other teaching staff of our college for their help and suggestions offered

to me during my research work.

My sincere thanks to Indian Institute of Sciences (IISc.), Bangalore, for providing

the 1H NMR reports and to Uwin Global Services, Bangalore, for providing me the Mass

spectral and Elemental analysis reports for my synthesized compounds.

My thanks to M.S.Ramaiah Medical College for providing us the cultures of micro-

organisms.

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 My grateful thanks to Gokula Education Foundation (Medical) Bangalore, the

management of M. S. Ramaiah College of Pharmacy for providing all the facilities for

the project.

My sincere thanks to office staff, Librarian and non-teaching staff of our college

who have always extended their full hearted support.

I express sincere thanks to my colleagues for their help and kind co-operation

during the course of my research work.

Finally, I extend my heartfelt gratitude to my beloved parents and all members of my

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family who are the real source of inspiration, their blessings, wishes and constant
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encouragement which have enabled me to complete this research work successfully.

Despite all this co-operation rendered generously by one and all, I am solely
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responsible for any and all the errors and short comings of this dissertation.
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Date: Signature of the Candidate

Place: Anupkumar N

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 LIST OF ABBREVIATIONS USED

°C Degree centigrade
g Gram
hr Hour
Min Minutes

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IR Infrared
m.p. melting point
mm
ml
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millimeter
milliliter
μg/ml Microgram per milliliter
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mol Mole
Mol. Wt Molecular weight
% Percentage
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RBF Round Bottom Flask

TLC Thin Layer Chromatography
1
H NMR Proton Nuclear Magnetic Resonance
DMF Dimethyl formamide
ppm Parts per million
Std Standard
Compd Compound

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 ABSTRACT

Background and Objectives:

2-azetidinones commonly known as β -lactams are well known heterocyclic compounds

among the organic and medicinal chemists. The activity of the famous antibiotics such

as penicillins, cephalosporins and carbapenems are attributed to the presence of 2-

azetidinone. Some other types of biological activity besides the antibacterial activity

have been reported in compounds containing 2-azetidinone. Such bio-activities include

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antifungal, insecticidal, pesticidal, antitubercular, antimicrobial activity. The β-lactams
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also serve as synthons for many biologically important classes of organic compounds.

The ability to treat bacterial infections with chemotherapeutic agents represents one of
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the most important medical achievements of the last millennium. Unfortunately the

emergence of microorganisms which are resistant to antibacterial agents has been

continued to the present day. Hence, the need for more effective antibacterial drugs is
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ever increasing.

Methodology:

Ethylacetoacetate in presence of Glacial acetic acid, Sodium nitrite and Zinc gives 3,5-

Diethoxy Carbonyl 2,4-Dimethyl Pyrrole [1A] which on reaction with Hydrazine

Hydrate gives 3,5-Dimethyl-1H-Pyrrole 2,4-Dicarbohydrazide [2A]. Hydrazide reacts

with different aldehydes to give corresponding Imines [3A-3H]. These imines on

reaction with Chloroacetyl chloride in presence of Triethylamine give Azetidinones

[4A-4H].

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Interpretation and Conclusion:

All the compounds synthesized were purified by recrystallization and were identified

and characterized by the following methods:

™ Melting point determination:

The melting points of the synthesized compounds were determined by using

Thiel’s melting point apparatus (open capillary tube method) and all the

compounds gave sharp melting points and are uncorrected.

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™ Thin layer chromatography:

Purity of the compounds was ascertained by TLC using appropriate mixtures of

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the following solvents:

Benzene, Acetone and Glacial acetic acid.

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™ Infrared spectroscopy:

The IR spectral analysis was carried out using FTIR (SHIMADZU 8400S)
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making use of diffuse reflectance system.

™ Nuclear Magnetic Resonance spectroscopy:

The 1H NMR spectral analysis of compounds was carried out on amx-400 NMR

spectrometer (Bruker) at Indian Institute of Sciences, Bangalore.

™ Mass spectroscopy:

The mass spectral data of compounds were obtained from Uwin Global

Services, Bangalore (Instrument – SHIMADZU LCMS 2010A).

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 ™ Elemental analysis:

Elemental analysis reports of compounds were obtained to ascertain the

elemental composition and to check the purity of the compounds from Uwin

Global Services, Bangalore. (Instrument-Flash EA112 series Thermo finnigan)

All the newly synthesized compounds have been evaluated for their antimicrobial

activity against gram-positive and gram-negative bacteria and fungi and in vitro anti-

inflammatory activity.

Keywords: Antimicrobial activity, Anti-inflammatory activity.

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 TABLE OF CONTENTS
Section Title Page no.

I Introduction 1-9

II Objectives 10-11

III Review of literature 12-48

IV Methodology 49-116

(A) Chemicals and reagents 49

(B) Analytical techniques 50

(C) Synthesis of proposed compounds 51-74

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(D) Spectra 75-108

(E) Biological Activity

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1. Antimicrobial activity 109-115

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2. Anti-inflammatory activity 116
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V Results 117-139

Physical Data of Synthesized Compounds 117-124

Spectral Data of Synthesized Compounds 125-137

Biological Activity 138-139

VI Computational Studies 140-168

VII Discussion 169-175

VIII Conclusion 176-177

IX Summary 178-179

X Bibliography 180-191

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 LIST OF TABLES

Table No. Tables pages

1 List of Chemicals and reagents 49

2 List of synthesized compounds 52

3 Physical Data of Synthesized Compounds 117-124

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4 Spectral Data of Synthesized Compounds 125-137

(A)IR Spectral Data of compounds (1A,2A,3A-3H,4A-4H) 125-131

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(B) 1H NMR Spectral Data of compounds (4A-4H) 132-134
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(C) Mass Spectral Data of compounds (4A-4H) 135-137

5 Biological activity of compounds (4A-4H) 138-139

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(A) Antimicrobial activity 138

(B) Anti-inflammatory activity 139

6 Computational Studies 149

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 LIST OF FIGURES

Name of Compounds Page

Fig. No.
No.

1 IR spectrum of 3, 5-Diethoxy carbonyl 2, 4-Dimethyl pyrrole [1A] 75

IR spectrum of 3, 5-Dimethyl-1H-pyrrole-2, 4-Dicarbohydrazide [2A]

2 76

IR spectrum of N2, N4-bis (4-hydroxybenzylidene)-3, 5-dimethyl-1H-

3 77

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pyrrole-2, 4-dicarbohydrazide [3A]

IR spectrum of N2, N4-bis (3-ethoxy-4-hydroxybenzylidene)-3, 5-dimethyl-

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4 78
1H- pyrrole-2, 4-dicarbohydrazide [3B]
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IR spectrum of N2, N4-bis (3, 4, 5-trimethoxybenzylidene)-3, 5-dimethyl-
5 79
1H-pyrrole-2, 4-dicarbohydrazide [3C]
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IR spectrum of N2, N4-bis (4-chlorobenzylidene)-3, 5-dimethyl-1H-pyrrole-

6 80
2,4- dicarbohydrazide [3D]

IR spectrum of N2, N4-dibenzylidene-3, 5-dimethyl-1H-pyrrole-2, 4-

7 81
dicarbohydrazide [3E]

IR spectrum of N2, N4-bis (4-nitrobenzylidene)-3, 5-dimethyl-1H-pyrrole-2,

8 82
4- dicarbohydrazide [3F]

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 IR spectrum of N2, N4-bis (2, 4-dichlorobenzylidene)-3, 5-dimethyl-1H-
9 83
pyrrole-2, 4- dicarbohydrazide [3G]

IR spectrum of N2, N4-bis (2, 6-dichlorobenzylidene)-3, 5-dimethyl-1H-

10 84
pyrrole-2,4- dicarbohydrazide [3H]

IR spectrum of N2, N4-bis (3-chloro-2-(4-hydroxyphenyl)-4-oxoazetidin-1-

11 85
yl)-3, 5- dimethyl-1H-pyrrole-2, 4-dicarboxamide [4A]

1
H NMR spectrum of N2, N4-bis (3-chloro-2-(4-hydroxyphenyl)-4-
12 86

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oxoazetidin-1-yl)-3, 5- dimethyl-1H-pyrrole-2, 4-dicarboxamide [4A]

Mass spectrum of N2, N4-bis (3-chloro-2-(4-hydroxyphenyl)-4-oxoazetidin-

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13 87
1-yl)-3, 5- dimethyl-1H-pyrrole-2, 4-dicarboxamide [4A]
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IR spectrum of N2, N4-bis (3-chloro-2-(3-ethoxy-4-hydroxyphenyl)-4-

14 88
oxoazetidin-1-yl)-3, 5-dimethyl-1H-pyrrole-2, 4-dicarboxamide [4B]
PR

1
H NMR spectrum of N2, N4-bis (3-chloro-2-(3-ethoxy-4-hydroxyphenyl)-
15 89
4-oxoazetidin-1-yl)-3, 5-dimethyl-1H- pyrrole-2, 4-dicarboxamide [4B]

Mass spectrum of N2, N4-bis (3-chloro-2-(3-ethoxy-4-hydroxyphenyl)-4-

16 90
oxoazetidin-1-yl)-3, 5-dimethyl-1H- pyrrole-2, 4-dicarboxamide [4B]

IR spectrum of N2, N4-bis (3-chloro-2-oxo-4-(3, 4, 5-trimethoxyphenyl)

17 91
azetidin-1-yl)-3, 5-dimethyl-1H-pyrrole-2, 4-dicarboxamide [4C]

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 1
H NMR spectrum of N2, N4-bis (3-chloro-2-oxo-4-(3, 4, 5-

trimethoxyphenyl) azetidin-1-yl)-3, 5-dimethyl-1H- pyrrole-2, 4-

18 92
dicarboxamide [4C]

Mass spectrum of N2, N4-bis (3-chloro-2-oxo-4-(3, 4, 5-trimethoxyphenyl)

19 93
azetidin-1-yl)-3, 5-dimethyl-1H-pyrrole-2, 4-dicarboxamide [4C]

IR spectrum of N2, N4-bis (3-chloro-2-(4-chlorophenyl)-4-oxoazetidin-1-

20 94
yl)-3, 5- dimethyl-1H-pyrrole-2, 4- dicarboxamide [4D]

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1
H NMR spectrum of N2, N4-bis (3-chloro-2-(4-chlorophenyl)-4-
21 95
oxoazetidin-1-yl)-3, 5- dimethyl-1H-pyrrole-2,4-dicarboxamide [4D]
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Mass spectrum of N2, N4-bis (3-chloro-2-(4-chlorophenyl)-4-oxoazetidin-1-
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22 96
yl)-3, 5- dimethyl-1H-pyrrole-2, 4- dicarboxamide [4D]

IR spectrum of N2, N4-bis (3-chloro-2-oxo-4-phenylazetidin-1-yl)-3, 5-

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23 97
dimethyl-1H- pyrrole-2, 4-dicarboxamide [4E]

1
H NMR spectrum of N2, N4-bis (3-chloro-2-oxo-4-phenylazetidin-1-yl)-3,
24 98
5-dimethyl-1H- pyrrole-2, 4- dicarboxamide [4E]

Mass spectrum of N2, N4-bis (3-chloro-2-oxo-4-phenylazetidin-1-yl)-3, 5-

25 99
dimethyl-1H- pyrrole-2, 4- dicarboxamide [4E]

IR spectrum of N2, N4-bis (3-chloro-2-(4-nitrophenyl)-4-oxoazetidin-1-yl)-

26 100
3, 5- dimethyl-1H-pyrrole-2, 4- Dicarboxamide [4F]

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 1
H NMR spectrum of N2, N4-bis (3-chloro-2-(4-nitrophenyl)-4-oxoazetidin-
27 101
1-yl)-3, 5- dimethyl-1H-pyrrole-2, 4- Dicarboxamide [4F]

Mass spectrum of N2, N4-bis (3-chloro-2-(4-nitrophenyl)-4-oxoazetidin-1-

28 102
yl)-3, 5- dimethyl-1H-pyrrole-2, 4- Dicarboxamide [4F]

IR spectrum of N2, N4-bis (3-chloro-2-(2,4 dichlorophenyl)-4-oxoazetidin-

29 103
1-yl)-3, 5- dimethyl-1H-pyrrole-2, 4- Dicarboxamide [4G]

1
H NMR spectrum N2, N4-bis (3-chloro-2-(2,4 dichlorophenyl)-4-

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30 104
oxoazetidin-1-yl)-3, 5- dimethyl-1H-pyrrole-2, 4- Dicarboxamide [4G]

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Mass spectrum of N2, N4-bis (3-chloro-2-(2, 4 dichlorophenyl)-4-
31 105
oxoazetidin-1-yl)-3, 5- dimethyl-1H-pyrrole-2, 4- Dicarboxamide [4G]
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IR spectrum of N2, N4-bis (3-chloro-2-(2, 6 dichlorophenyl)-4-oxoazetidin-

32 106
1-yl)-3, 5- dimethyl-1H-pyrrole-2, 4- Dicarboxamide [4H]
PR

1
H NMR spectrum of N2, N4-bis (3-chloro-2-(2, 6 dichlorophenyl)-4-
33 107
oxoazetidin-1-yl)-3, 5- dimethyl-1H-pyrrole-2, 4-Dicarboxamide [4H]

Mass spectrum of N2, N4-bis (3-chloro-2-(2, 6 dichlorophenyl)-4-

108
34
oxoazetidin-1-yl)-3, 5- dimethyl-1H-pyrrole-2, 4- Dicarboxamide [4H]

xii
 Introduction

I. INTRODUCTION

Antibiotics are microbial metabolites or synthetic analogs inspired by them that, in small

doses, inhibit the growth and survival of microorganisms without serious toxicity to the

host. Antibiotics are among the most frequently prescribed medications today although

microbial resistance due to evolutionary pressures and misuse threatens their continued

efficacy. In many cases the clinical utility of natural antibiotics has been enhanced

through medicinal chemical manipulation of the original structure leading to broader

antimicrobial spectrum, greater potency, lesser toxicity, more convenient administration,

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etc.
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Antimicrobials can be classified into two groups based upon their effects on target cells.
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Drugs that actually kill microorganisms are termed bactericidal. Drugs that only inhibit

the growth of microorganisms are termed bacteriostatic. The decision to use a

bactericidal or bacteriostatic drug to treat infection depends entirely upon the type of
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infection. For example, bactericidal drugs will only kill cells that are actively growing.

Bacteriostatic drugs in comparison will only inhibit the growth of cells; ultimate

elimination of the organisms is dependent upon host phagocytic activity.1

The β-lactam antibiotics are useful and frequently prescribed antimicrobial agents that

share a common structure and mechanism of action⎯inhibition of synthesis of the

bacterial peptidoglycan cell wall. This class includes penicillins G and V, which are

highly active against susceptible gram-positive cocci; penicillinase-resistant penicillins

Department Of Pharmaceutical Chemistry, MSRCP, Bangalore 1

 Introduction

such as naficillin, which are active against penicillinase-producing Staphylococcus

aureus; ampicillin and other agents with an improved gram-negative spectrum, especially

when combined with a β-lactamase inhibitor; and extended-spectrum penicillins with

activity against Pseudomonas aeruginosa, such as piperacillin.

The β-lactams also include the cephalosporin antibiotics, which are classified by

generation: First-generation agents have excellent gram-positive and modest gram-

negative activity; second-generation agents have somewhat better activity against gram-

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negative organisms and include some agents with anti-anaerobic activity; third-

generation agents have activity against gram-positive organisms and much more activity
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against the Enterobacteriaceae, with a subset active against P. aeruginosa; and fourth-
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generation agents encompass the antimicrobial spectrum of all the third-generation agents

and have increased stability to hydrolysis by inducible chromosomal β-lactamases.

β-Lactamase inhibitors such as clavulanate are used to extend the spectrum of penicillins
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against β-lactamase-producing organisms. Carbapenems, including imipenem and

meropenam, have the broadest antimicrobial spectrum of any antibiotic, whereas the

monobactam aztreonam has a gram-negative spectrum resembling that of the

aminoglycosides.

Bacterial resistance against the β-lactam antibiotics continues to increase at a dramatic

rate. Mechanisms of resistance include not only production of β-lactamases that destroy

Department Of Pharmaceutical Chemistry, MSRCP, Bangalore 2

 Introduction

the antibiotics but also alterations in or acquisition of novel penicillin-binding proteins

and decreased entry and/or active efflux of the antibiotic.

The β-lactam antibiotics can kill susceptible bacteria. Although knowledge of the

mechanism of this action is incomplete, numerous researchers have supplied information

that allows understanding of the basic phenomenon.

The cell walls of bacteria are essential for their normal growth and development.

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Peptidoglycan is a heteropolymeric component of the cell wall that provides rigid

mechanical stability by virtue of its highly cross-linked latticework structure. In gram-

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positive microorganisms, the cell wall is 50 to 100 molecules thick, but it is only 1 or 2
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molecules thick in gram-negative bacteria. The peptidoglycan is composed of glycan

chains, which are linear strands of two alternating amino sugars (N-acetylglucosamine

and N-acetylmuramic acid) that are cross-linked by peptide chains.

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The biosynthesis of the peptidoglycan involves about 30 bacterial enzymes and may be

considered in three stages. The first stage, precursor formation, takes place in the

cytoplasm. The product, uridine diphosphate (UDP)-acetylmuramyl-pentapeptide,

accumulates in cells when subsequent synthetic stages are inhibited. The last reaction in

the synthesis of this compound is the addition of a dipeptide, D-alanyl-D-alanine.

Synthesis of the dipeptide involves prior racemization of L-alanine and condensation

catalyzed by D-alanyl-D-alanine synthetase. D-Cycloserine is a structural analog of D-

alanine and acts as a competitive inhibitor of both the racemase and the synthetase.

Department Of Pharmaceutical Chemistry, MSRCP, Bangalore 3

 Introduction

During reactions of the second stage, UDP-acetylmuramyl-pentapeptide and UDP-

acetylglucosamine are linked (with the release of the uridine nucleotides) to form a long

polymer.

The third and final stage involves completion of the cross-link. This is accomplished by a

transpeptidation reaction that occurs outside the cell membrane. The transpeptidase itself

is membrane-bound. The terminal glycine residue of the pentaglycine bridge is linked to

the fourth residue of the pentapeptide (D-alanine), releasing the fifth residue (also D-

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alanine). It is this last step in peptidoglycan synthesis that is inhibited by the β-lactam

antibiotics and glycopeptide antibiotics such as vancomycin (by a different mechanism

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than the β-lactams. Stereomodels reveal that the conformation of penicillin is very similar
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to that of D-alanyl-D-alanine. The transpeptidase probably is acylated by penicillin; that

is, penicilloyl enzyme apparently is formed, with cleavage of the ⎯ CO⎯N ⎯ bond of

the β-lactam ring.2

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2-azetidinones commonly known as β -lactams are well known heterocyclic compounds

among the organic and medicinal chemists. The activity of the famous antibiotics such as

penicillin, cephalosporins and carbapenems are attributed to the presence of 2-

azetidinone. Some other types of biological activity besides the antibacterial activity have

been reported in compounds containing 2-azetidenone. Such bio-activities include

antifungal, insecticidal, pesticidal, antitubercular, antimicrobial activity. The β-lactams

also serve as synthons for many biologically important classes of organic compounds.

Department Of Pharmaceutical Chemistry, MSRCP, Bangalore 4

 Introduction

2-Azetidinone derivatives possess wide therapeutic activities viz. anticonvulsant,

analgesic and anti-inflammatory, antibacterial, and are effective on central nervous

system as potent neuroleptic agents. Pyrrole is a five membered heterocyclic ring

containing nitrogen which is present in a number of pharmacologically active natural

products and synthetic drugs.

Chemistry of 2-Azetidinones.3

Physical and spectroscopic properties

2-Azetidinone is a solid, m.p., 73- 740C. It is highly soluble in ethanol and chloroform.

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The physical state of other β-lactam varies widely with the degree and nature of the

substituents. The structural data obtained from X-ray studies using sodium benzyl
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penicillin shows that all the four bond angles and bond distances have different values.
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One highly characteristic and useful property of these compounds is the infra-red

absorption spectrum which provides a relative confirmation of the presence of this four-

membered ring system. The carbonyl stretching frequency in an acyclic amide usually
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has a value of about 1665 cm-1 (5.7-5.76 μ) in monocyclic lactams. This implies that the

carbonyl group in β-lactam behaves like an ester carbonyl group.

Synthetic methods

1. Staudinger reaction and related methods:

Staudinger’s ketene–imine reaction is the most common method for the synthesis of

azetidinones. The reaction is carried out thermally or photochemically using acid

chlorides in the presence of triethylamine or a-diazoketones as ketene precursors.

Department Of Pharmaceutical Chemistry, MSRCP, Bangalore 5

 Introduction

CH3
C6H5 CH3
CH3COCl C6H5CH CH3
C6H5CH2NHCH C COOH
TEA C6H5CH2 N C=O
CH3

2. From direct cyclization of amino acids:

A commonly employed method is cyclization of free amino acids using acyl chloride,

phosphorous trichloride or thionyl chloride. No cyclisation of amino acids takes place on

heating, rather it splits into an amine and an acid.

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1,4-Diphenyl β-lactam
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(CH 3 )2 CCOOH CH 3 O
H3C
SOCl2
C 6 H 5 CHNCH 2 C 6 H 5 C6H5 O
N OH
CCH(CH 3 )2
CH(CH 3 )2
O H5C6H2C

H3C
O
H3C
+ (CH3)2CHCOO
N
H5C6 CH2C6H5

1-Benzyl-3, 3-dimethyl-4-phenyl-β-lactam

Department Of Pharmaceutical Chemistry, MSRCP, Bangalore 6

 Introduction

3. Direct combination methods:

An older technique involves the direct combination of two appropriately substituted

components for instance ketenes condense with imines to form β-lactam.

H5 C 6
C6H5
H5C6
H5C6
Ether
C C O + C6H5CH NC6H5
heat N
O
H5C6 H5 C 6

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Chlorosulfonyl isocynate adds similarly with a number of alkenes to lead to the
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corresponding N-chlorosulfonyl-β-lactam. The chlorosulfonyl group can easily be
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removed by treatment with thiophenol in pyridine.

H3C H 3C
H3C
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C CH2 H 3C
Ether H3C C6H5SH
H3C
+ N HN
20 0C Pyridine, -250C
ClO 2SN C O O O
ClO 2S

4,4-dimethylazetidin-2-one

4. From substituted Azetidines:

N-substituted azetidine-2-carboxylic acid can be converted into azetidinone by the

following sequence involving a dicarbanion intermediate. The azetidine carboxylic acid

Department Of Pharmaceutical Chemistry, MSRCP, Bangalore 7

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