part - ii studies on compounds consisting thiazole and 2...

Part - II

Studies on Compounds Consisting

Thiazole and 2-Azetidinone

Heterocycles

PART 2 STUDIES ON THIAZOLE & 2-AZETIDINONES

Page 89

SYNTHESIS, CHARACTERIZATION AND ANTIMICROBIAL SCREENING OF SOME BIO-ACTIVE HETEROCYCLIC COMPOUNDS

Introduction to thiazole

Thiazoles are one of the most intensively investigated classes of aromatic

five-membered heterocycles. It was first described by Hantzsch and Weber in

1887.1 This five membered ring system containing sulfur and nitrogen heteroatoms

at positions-1 and -3, respectively is involved in many of the natural products.

For example, the thiazolium ring present in vitamin B1 (1) serves as an electron

sink, and its coenzyme form is important for the decarboxylation of α-keto acids.2

Thiazole and its derivatives are very useful compounds in various fields of

chemistry including medicine and agriculture. In addition, thiazoles are also

synthetic intermediates and common substructures in numerous biologically

active compounds such as various derivatives of penicillins (2) and antibacterial

thiazoles.3 Reduced thiazoles serve in the study of polypeptides and proteins and

occur as structural units in compounds of biological importance.4

The properties of thiazole are similar to those of oxazole and the nitrogen atom

with unshared pair of electron is basic in nature. Among the different aromatic

heterocycles, thiazoles occupy a prominent position in the drug discovery process5

and this ring structure is found in several marketed drugs which are given below

with their pharmaceutical activity. It can also be used in a scaffold hopping

strategy6 or as an amide isostere7 during the course of probing structure activity

relationships for lead optimization. As a result, thiazoles are frequently included

in the design or are used as a core structure for the synthesis of chemical libraries.8

Thus the thiazole nucleus has been much studied in the field of organic and

medicinal chemistry.


Page 90


Figure 1: Clinically used thiazoles

Structure of thiazole

The structure of thiazole is considered as the resonance hybrid of the following

resonating structures. However, some additional resonating structures are also

possible with the involvement of d-orbitals of sulfur (Figure 2).

The π-bond orders calculated by molecular orbital methods have indicated

thiazole molecule to be aromatic with some dienic character. Localization energies

have predicted decreasing order of the electrophilic reactivities as: 5 > 2 > 4 and

the nucleophilic reactivities follow the order: 2 > 5 > 4. Three hydrogen atoms in

thiazole are predicted to have the order of acidity as: H2 >> H5 > H4.

Geometrical structure9

The geometrical structure of thiazole was first approached10 by the combination of

bond angles deduced from a correlation between 13C, 1H NMR coupling constants

and interorbital and internuclear bond angles, C-H bond length deduced from a

correlation between the same coupling constants and C-H bond length,11 and C-C,

C-N and C-S bond length obtained from bond orders calculated with the HMO


Page 91


method.12 More recently, a complete determination of the geometrical parameters of

molecule was performed by microwave spectrometric study of thiazole and eight

isotopically labeled isomers13 (Fig. 3). The structure obtained for thiazole is

surprisingly close to an average of the structure of thiophene14 and 1,3,4-thiadiazole15

(Fig. 4). From a comparison of the molecular structures of thiazole, thiophene,

thiadiazole and pyridine,16 it appears that around C4, the bond angles of thiazole C4-H

with bond adjacent C4-N and C4-C5 bonds show a difference of 5.4° that compared to

a difference in C2-H of pyridine of 4.2°, is interpreted by Nygaard L13 as resulting

from an attraction of H4 by the electron lone pair of nitrogen.

Figure 3. Molecular structure of thiazole; bond length in Ǻ (left), bond angle in

degree (right)

Figure 4. Molecular structure of thiophene and 1,3,4-thiadiazole; bond length in Ǻ (left),

bond angle in degree (right)

From the direction of the quadrupole axis of nitrogen it is concluded that its lone

pair is symmetrically placed outside the ring, along the bisector of angle C2-N-C4.12

Synthesis of thiazole

In view of the importance of thiazoles and their derivatives, several methods for

the synthesis of thiazole derivatives were developed by Hantzsch, Tchernic,

Cook-Heilborn, Gabriel and other groups.17 Recently, thiazole derivatives were

synthesized by using catalyst such as ammonium-12-molybdophosphate,18

cyclodextrin,19 iodine20a and silica chloride20b in organic solvents at elevated


Page 92


temperature and solvents such as 1-methyl-2-pyrrolidinone,21 and with the use of

microwave.22 Several methods for the synthesis of thiazole compounds are available,

which can be classified into the partial structures illustrated in figure 5. The first of

these structures (Figure 5) is by far the most useful and versatile of all the thiazole

synthesis. By a judicious choice of reactants it allows alkyl, aryl, aralkyl or heterocyclic

substituents to be placed in any one of the 2-, 3-, 4- or 5-positions of the ring. This

method, better known by the name of the German chemist Hantzsch who originated

it in 1887, involves the condensation of a compound bearing the two heteroatoms on

the same carbon with a compound bearing one halogen and one carbonyl function on

two neighbouring carbons. A great variety of compounds may serve as nucleophilic

reagent in this reaction, such as thioamide, thiourea, ammonium thiocarbamate or

dithiocarbamate and their derivatives.23

Figure 5. Various types of ring closures for thiazoles.


Page 93


(I) Synthesis from α-halocarbonyl compounds (Type Ia): Hantzsch’s synthesis.

First described in 1887 by Hantzsch, the cyclization of -halo carbonyl compounds

by a great variety of reactants bearing the N-C-S fragment of the ring is still the

most widely used method of synthesis of thiazoles.

Hantzsch’s synthesis mechanism

1. Reactions with thioamides

A. Chloroacetaldehyde and derivatives

Thiazole (5) itself can be obtained by condensing chloroacetaldehyde (3) and

thioformamide (4).24, 25

B. Condensation with higher thioamides (2,4-Disubstituted and 2,4,5-

trisubstituted thiazoles)

The reaction of a thioamide

with -halocarbonyl

compounds (6) has been

applied extensively, and

many thiazoles (7) with

alkyl, aryl, arylalkyl or

heteroaryl functional groups at 2-, 4- or 5-positions have been reported.

XR3

R2 ONH2

R1S S

N

R1R3

+

R1, R2 = Alkyl, aryl, arylakyl substituents, R3 = H

6 7

R2


Page 94


C. Condensation of -haloketone with dithioamide (2,4-Disubstituted

thiazoles)

The cyclization of two moles of -haloketone with dithioamide (8) resulted in

1,4-bis(4-phenyl-2-thiazolyl)benzene (9) in high yield.26

2. Reaction with N-substituted thioamides (Thiazolium salts)

Thiazolium salts can be obtained successfully by a modification of the Hantzsch’s

thiazole synthesis. This method is particularly valuable for those thiazolium

compounds in which the substituent on the ring nitrogen cannot be introduced by

direct alkylation, for example, aryl or heteroaryl thiazolium salts.

N-Monosubstituted thioamides (10) have been cyclized with -halocarbonyl

compounds to give thiazolium salt (11) in excellent yields.27-31

3. Reactions with thiourea

Of all the methods described for the synthesis of thiazole compounds, the most

efficient involves the condensation of equimolar parts of thiourea and

–haloketones or aldehydes to yield the corresponding 2-aminothiazoles (12a) or

their 2-imino-Δ-4-thiazoline tautomers (12b) with no by-products.

R1 O

XR2

NH2

NH2S S

N

R2

R1

NH2 S

NH

R2

R1

NH

12a 12bR1, R2 = Different substituents

+


Page 95


4. Reactions with N-substituted thiourea

A. N-monosubstituted thioureas

The cyclization of N-substituted thioureas (13) with halocarbonyl compounds

gives 2-monosubstituted aminothiazoles32 (14).

R2 O

XR3

NH2

NHR1S S

N

R3

R2

NHR1

14

R1, R2, R3 = Different substituents

+

13

B. N,N-disubstituted thioureas

The N,N-disubstituted thioureas (15) condensed with -halocarbonyl compounds

to give 2-disubstituted aminothiazoles (16) but in lower yields33- 36 (30 to 70%).

5. Reaction with salts and esters of thiocarbamic acid: 2-hydroxy thiazoles

and derivatives

This method, initiated by Marchesini,36,37 in 1893 consists of the condensation of an

-halocarbonyl compound with ammonium thiocarbamate (17) to give

2-hydroxythiazole derivatives (18).

R2 O

XR3

NH2

OR1S S

N

R3

R2

OR1

18R1 = HR2, R3 = Different substituentsX = Different halogen substituents

+

17


6


(II) Thiazoles from rearrangement of the -thiocyanatoketones (Type Ib)

1. Acid or alkaline hydrolysis

The cyclization of

-thiocyanatoketones (19) in

aqueous acid, concentrated

sulfuric acid in acetic acid

and water or alkaline

solution leads to 2-hydroxy

thiazoles (20) after dilution in water. These reactions can be carried out for several

hours at room temperature or by heating for 1 or 2 hrs on a steam bath.38-42

2. Action of labile sulfur

Thioacids (22) react with -thiocyanatoacetophenone (21) to produce 2-mercapto-

4-phenyl thiazole (23).

Ph O

S S

NPh

SH

2321

C

N+

SH

OR+ RCOOH

22

R = Different substituents

3. Action of labile nitrogen

-Thiocyanatoketones (24) also react with ammonium chloride or alkyl amine to

give 2-aminothiazoles or their N-substituted derivatives (25).43

(III) Thiazoles from -aminonitriles (Cook-Heilbron’s synthesis) (Type-II)

This type of synthesis, which was investigated by Cook, Heilbron44 and

Takahashi45,46 gives 5-aminothiazoles variously substituted in the 2-position by

R1

SR2 S

N

R2

R1

OH

20

R1, R2 = Alkyl, phenyl

19

C

NH3O

O


Page 97


reacting with an aminonitrile with salts and esters of dithioacids, carbon

disulfide, carbon oxysulfide and isothiocyanates under exceptionally mild

conditions.

1. Carbon disulfide: 2-mercapto-5-aminothiazole derivatives

Carbon disulfide readily reacts with -aminonitriles (26) giving 2-mercapto-5-

amino thiazoles47,48 (27),

which can be converted

to 5-amino thiazoles

unsubstituted in the

2-position.

2. Salts and esters of dithioacids: 5-aminothiazole derivatives and related

condensations

By condensing the salts or the esters of either dithioformic (29) or dithiophenacetic

acids with -aminonitriles (28), 5-aminothiazoles (30) were obtained in fairly good

yields.49 These reactions were carried out in aqueous ethereal solution at room

temperature.

N

NH2R2

+SH

R1S

NH

N S

R2

R1 S

N

R1H2N

R2

302928

R1 = H, -CH2C6H5 R2 = -C6H5, -COOEt, -COOC6H5

(IV) Thiazoles from acylaminocarbonyl compounds and phosphorus

pentasulfide and related condensation (Gabriel’s synthesis) (Type III)

This reaction was first described by Gabriel50 in 1910, when reacted an

acylaminoketone (31) with an equimolecular amount of phosphorus pentasulfide

to yield 2-phenyl-5-alkyl-thiazole (32). The reaction is similar to the preparation of

other five-membered oxygen and sulfur containing rings from 1,4-dicarbonyl

compounds.

N

NH2R

+S

S S

N

SHH2N

R

2726

R = H, iPr, n-hexyl, n-heptyl, -CO2Et, -C6H5


Page 98


S

NR2

R1

32

HeatR3

O

NHR2

OR1

31

R3

OH

N

HOR1

R2

P2S5

R3

R1 = -C6H5, R2 = H, R3 = alkyl

(V) Thiazoles from nitriles and -mercaptoketones: 2,4-disubstituted and

2,4,5- trisubstituted derivatives

Besides -halocarbonyl compounds, -mercaptoketones and acids are also used for

the preparation of thiazoles from nitriles and aldehyde oximes.

1. 2,4,5-Trisubstituted thiazoles from -mercaptoketones and nitriles

Miyatake and Yashikawa prepared several 2,4,5-trisubstituted thiazoles (35) in

fairly low yield (16 to 40%) by the action of -mercaptoketones (33) on nitriles (34).

Asinger and Thiel51 used an aldehyde and ammonia instead of nitrile.

R3

OR2

+S

N

R1R3

R2

3533

R1, R2, R3 = Different substituents

SH

N

R1

HCl

34

2. 2,4-Diaminothiazole derivatives from -halonitriles and thiourea

-Halonitrile (36) can replace -halogenocarbonyl compounds in the Hantzsch’s

synthesis.52-54 Thus the reaction of thiourea with an -halonitrile in boiling alcohol

gives 2,4-diaminothiazole (37).


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(VI) Thiazoles from vinyl bromide

Thiazoles bearing a variety of substituents such as aliphatic, aromatic, heterocyclic,

or alkenyl groups can be prepared by intramolecular nucleophilic substitution

reaction of N-(2-bromoprop-2-enyl)thioamides (38).55 This vinylic substitution

method would provide unique synthetic route for a variety of heterocycles.

(VII) Synthesis of 2,4-disubstituted-5-acetoxythiazoles.

From the commercially available methyl benzoate derivatives (39) and with

racemic phenylglycine, a variety of 2,4- disubstituted-5-acetoxythiazoles (40) were

prepared in good to moderate yields using the following protocol.56 Because of the

high thermal stability of the thiazole nucleus, the polymers incorporating thiazole

ring system have also been synthesized.

Biological importance of thiazoles

Thiazole derivatives find now a wide variety of applications ranging from

bacteriostatics, antibiotics, CNS regulants to high selling diuretics.57−61 Thiazole

system has found broad application in drug development for the treatment of

inflammation,62 hypertension63 and HIV infections.64 Aminothiazoles are known to

be ligands of estrogen receptors65 as well as a novel class of adenosine receptor

Br

HN R1

S

CH21.5 equi. K2CO3

DMF, 800CS

N

Me R1

R1 = Aliphatic, aromatic, heterocyclic or alkenyl groups

38


Page 100


antagonists.66 Other analogues are used as fungicides, inhibiting in vivo growth of

Xanthomonas, as an ingredient of herbicdes or as schistosomicidal and

anthelmintic drugs.67

HI El-Subbagh et al.68 synthesized a series

of 2,4-disubstituted thiazole derivatives

bearing N-n-butyl or N-cyclohexyl

thioureido synthon at position-2 and

N-substituted thiosemicarbazone moiety

at position-4 and tested for antitumor

activity. All of the tested compounds

showed antineoplastic activity at concentrations less than 100 µM. Compounds

(41a), (41b), (41c) and (41d) are the most active members of this series, showing

broad spectrum antitumor activity with Gl50 (mean-graph midpoint) of 17.8, 8.5,

9.5 and 7.4 µM respectively. Both the moieties -NHCOC6H5 and –NHCSNHC6H11

could replace each other without loss of antitumor activity.

Zablotskaya A et al.69

synthesized trimethylsilyl ethers

of various hydroxyl-containing

thiazole derivatives. All the

compounds investigated possess

antihypoxic properties and

prolong the life of mice under

conditions of hypoxia by

20-78%. The silylated and

unsilylated compounds in the

majority of cases display

antihypoxic activity of the same order. The most active antihypoxic agents were

the piperidine-containing thiazoles N-(4-phenyl-5-tetradecyl-2-thiazolyl)-2-

(4-hydroxypiperidino)-acetamide (42) and N-(5-tetradecyl-4-phenyl-2-thiazolyl)-2-

(4-trimethylsilyloxy piperidino)acetamide (43), prolonging the life of mice by 78%

41a; R = n-C4H9, R1 = -COC6H541b; R = n-C6H11, R1 = -COC6H541c; R = n-C6H11, R1 = -CSNHC2H541d; R = -C6H11, R1 = -CSNHC6H11

41a-dS

N

NHNH R1

N

H

S

N

R

H

O

S

N

NH

O

N OHC14H29

S

N

NH

O

N OSiMe3C14H29

42

43


Page 101


and 70% respectively. The strongest anticonvulsive action was also possessed by

the piperidine-containing thiazole (42) and its trimethylsilyl ether (43).

Sherif A F R et al.70 synthesized series of thiazolylantipyrine and

thiadiazolylantipyrine out of which compounds belonging to the

thiazolylantipyrine series exhibited better antibacterial potencies than members of

the thiadiazolylantipyrine one. Among these, compounds (44), (45a) and (45b) are

considered to be the most active antimicrobial members identified in this study

with a broad spectrum of antibacterial activity against both Gram positive and

Gram negative bacteria. Finally, compound (45a) could be identified as the most

biologically active member within this study with an interesting dual

anti-inflammatory, analgesic and antibacterial profile.

Dae-Kee K et al.71 synthesized a series of 5-(pyridin-2-yl)thiazoles containing a

meta- or para-carbonitrile or carboxamide-substituted phenylmethylamino moiety

at the 2-position of the thiazole

ring and was evaluated for activin

receptor-like kinase 5 (ALK5)

inhibitory activity in cell-based

luciferase reporter assays. The

structure–activity relationships in

this series of compounds have

been established and discussed. The most potent compound in this series,

3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)thiazol-2-ylamino)methyl)benzamide

N

N

S

N

N

NH

CH3

CONH2

46

NN

ON

H

CH3

H3C

O

SN

S

R

HN

NH

S

R1

45a; R = R1 = -C6H545b; R = -C6H5, R1 = 4-ClC6H4

NN

H3CCH3

ON

H

O

N

S

H2N

COOEt

CN

C6H544 45a,b


Page 102


(46), inhibited transforming growth factor-β (TGF-β)-induced (ALK5) activity, 96%

and 78% at 0.1 µM in luciferase reporter assays using HaCaT cells transiently

transfected with p3TP-luc reporter construct, ARE-luciferase reporter construct,

and SBEluciferase reporter construct, respectively.

Rajan S G et al.72 synthesized and designed a series of 2-(2,4-disubstituted-thiazole-

5-yl)-3-aryl-3H-quinazoline-4-one derivatives.

Synthesized molecules were evaluated for

their inhibitory activity towards transcription

factors, nuclear factor-kB (NF-kB) and

activating factor (AP-1) mediated

transcriptional activation in a cell line based

in vitro assay as well as for their anti-

inflammatory activity in vivo model of acute

inflammation. Two of the compounds (47c)

and (47e) turned out to be the most promising

dual inhibitors of NF-kB and AP-1 mediated

transcriptional activation with an IC50 of 3.3 µM for both. Compounds (47d) (IC50¼

5.5 µM) and (47f) (IC50¼ 5.5 µM) emerged as selective inhibitors of NF-kB mediated

transcriptional activation and (47a) (IC50¼ 5.5 µM) and (47b) (IC50¼ 5.5 µM) were

found to be more selective inhibitor of AP-1 mediated transcriptional activity.

Johan D O et al.73 synthesized a

novel series of Aurora kinase

inhibitors containing thiazole

moiety. Key SAR as well as

crucial binding elements have

been described. Further, they

have shown that the more

advanced analogues have potent activities in cell-based assays and induce

phenotypes consistent with Aurora kinase inhibition. Moreover, these profiles

translate into efficient target modulation (pHH3) in vivo. In particular, analogue


Page 103


(48) (SNS-314) is a potent and selective Aurora kinase inhibitor that displays

significant activity in pre-clinical in vivo models. The compound is currently in

clinical trials in patients with advanced solid tumors.

The synthesis and the biological (antioxidant and antiviral) activities of novel

hydroxycinnamic acid amides of a thiazole containing TFA.valine-4-carboxylic

acid ethyl ester were reported

by Stankova I et al.74 The

amides have been synthesized

from p-coumaric, ferulic and

sinapic acids with the

corresponding TFA.valine-

thiazole-4-carboxylic acid

ethyl ester using the coupling

reagent N-ethyl-N’-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)

and 4-(dimethylamino)pyridine (DMAP) as a catalyst. The antioxidant properties

of the newly synthesized amides, p-coumaroyl-2-valyl-thiazole-4 carboxylic acid

ethyl ester (49a), feruloyl-2-valyl-thiazole-4 carboxylic acidethyl ester (49b) and

sinapoyl-2-valyl-thiazole-4 carboxylic acid ethyl ester (49c) have been studied for

antioxidative activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH) test. The newly

synthesized compounds have been tested against the replication in vitro of

influenza virus A (H3N2) and human herpes virus 1 and 2 (HSV-1 and HSV-2).

Hussein I E et al.75 synthesized ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo

[3,2-a][1,3]diazepin-3-carboxylate HIE-124 (50) which is a member of a new

generation of ultra-short acting hypnotics. HIE-124 (50) exhibited potent in vivo

activity with a rapid onset of action and a short

duration of action, with no acute tolerance or

noticeable side effects. The metabolic profile of (50) is

also performed. HIE-124 (50) has the potential use as

a preanesthetic medication, anesthesia inducer and

could be used with thiopental sodium to maintain anesthesia for longer duration.


Page 104


Four membered heterocycles76

Four-membered heterocycles are the heterocyclic analogs of cyclobutane and are

considered to be derived by replacing a –CH2 (methylene group) by a heteroatoms

(N, O or S). The four-membered saturated heterocycles containing nitrogen,

oxygen and sulfur are known as azetidines, oxetanes and thietanes respectively.

Four-membered heterocyclic rings are less strained, and hence more stable than

the three-membered rings and therefore, the ring cleavage is less likely. Moreover,

four-membered heterocycles are more difficult to synthesize by direct

intermolecular cyclization than the three-membered heterocycles because ring

forming ability falls off with the chain length.

Introduction to azetidinones

β-Lactam heterocycles are considered as an important contribution of science to

humanity.77 Natural and synthetic azetidinone derivatives occupy a central

place among medicinally important compounds due to their diverse and

interesting antibiotic activity.78 Even though they have a long history of

development starting from the discovery of penicillin in 1928, the quest for new

synthetic methods and refinement of those already known remains appealing to

synthesize novel biologically active azetidinone derivatives. The utility of

azetidinones as synthons for various biologically active compounds, as well as

their recognition as medicinally active compounds has given impetus to these

studies.

The discovery of penicillin structure that contains β-lactam system led

extensive investigations to obtain β-lactam antibiotics with a wider spectrum of

activities and greater resistance to enzymatic cleavage. β-lactam antibiotics

contain two basic structural units; penam (51) and cepham (52), and include

two powerful antibiotics; penicillins (53) and cephalosporins (54). After the

spectacular world-wide recognition and tremendous success of the penicillins,

the best known family of β-lactams are termed as cephalosporins, wherein the

β-lactam ring is strategically fused to a 6-membered dihydrothiazine ring

system.


Page 105


N

S

ON

S

O

N

S

N

S

O CH2OCOCH3

COOH

HN

HN

COOH

CH3

CH3

51 52

53 54

R

OO

R

O

After the discovery of antibacterial activity of penicillin, thousands of compounds

containing β-lactam ring have been either isolated from natural sources or

synthesized by chemical means. Following are the structures of several β-lactam

antibiotics that have been applied clinically.

Structural features of azetidinone

Azetidinones79,80 are the carbonyl derivatives of azetidines containing carbonyl

group at the position-2 and the naming protocol closely follows that for lactones,

the cyclic esters. Lactams are named systematically as “azacycloalkanones”. These

are also known as 2-azetidinones or more commonly β-lactams.


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α-Lactam β-Lactam γ-Lactam δ-Lactam

X-Ray crystallographic studies81 of a number of monocyclic azetidin-2-ones

indicate that the ring is essentially planar with the nitrogen atom slightly out of the

mean plane of its substituents except where steric factors enforce greater

deviations from the planarity. The >C=O distance of 1.38 Å is rather greater than

that of a ‘normal’ amide (1.32 Å); this has been attributed to ring strain and to

inhibition of normal amide resonance by interaction with the N-aryl substituents.

Infrared absorption spectrum of monocyclic β-lactams (absorption at 1735-1765

cm-1 as compared to that of unstrained amides at 1660 cm-1) reflects the behaviour

of carbonyl group as an ester linkage which accounts for its higher reactivity in the

ring (making carbonyl carbon more electrophilic than in acyclic amides). In

penicillins and cephalosporins, the fusion of β-lactam with heterocyclic ring has

the effect of shifting the amide carbonyl absorption to 1770-1780 cm-1 suggesting

increased electrophilicity and, in turn, more reactivity of carbonyl group. The

increased reactivity of carbonyl group which has been considered to be associated

with the antibiotic activity in penicillin and cephalosporin is attributed to the fact

that the ring fusion does not allow the amide nitrogen (bridgehead nitrogen) to

achieve the planarity, since sp2-hybridized nitrogen imposes greatly increased

angle strain on the system.

Synthetic route for azetidinones

1. Cyclization of β,γ-unsaturated hydroxamates

The bromine induced cyclization of o-acyl-β,γ-hydroxamates (55) provides β-lactams

(57) via the formation of bromonium ion intermediate (56). The presence of a phenyl

group at the γ-position fails to provide β-lactams because the regioselectivity of

opening of the bromonium ion intermediate (56) is reversed due to the formation

of stabilized benzylic carbonium ion.82


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NH

OCOCH2C6H5

R

O

Br2/K2CO3/H2O

CH3CNO

N

OCOCH2C6H5

Br R

5655

NO

57

R = Alkyl, -CH=CH2

OCOCH2C6H5

R

Br

2. Cyclization of β-halo amides

N-substituted β-halo amides (58) are cyclized in the presence of a base to β-lactams

(60) via an intermediate (59).83-85

3. Intramolecular cyclization of β–amino acids

Intramolecular cyclization of β–amino acids in the presence of certain reagents

including acyl chloride, phosphorus trichloride and thionyl chloride provides

β–lactams.86-92 However, β-aminopropionic acids are not cyclized to β–lactams on

heating, but undergo elimination reaction providing amines and acids.

NC6H5 CH2C6H5

H3C O

H3CCH3COCl

NH

OH

O

CH2C6H5C6H5

H3C

H3C

C6H5HN CH2

C6H5

COOH PCl3N

C6H5 C6H5

O

OH

N

O

CH2C6H5

H3C

H3C

C6H5

O

CH(CH3)2

SOCl2N

C6H5 CH2C6H5

H3C O

H3C+

CH3

COOH

CH3

H


Page 108


4. Cyclization of amino esters

The reaction of β-amino esters with Grignard reagents (61) leads to the formation

of azetidinones (63) via the formation of N-anion (62).86-88

Singh G S et al.93 synthesized 2-azetidinones (66) by the reaction of

N-salicylideneamines (65) and (2.2 equivalent) α-diazocarbonyl compounds (64).

Ph N2

OPh

+OH

NR

OCOCHAr2

NR

Ar

Ar O

Ar = -C6H5, p-CH3C6H5R = Different aryl substituents

Reflux,6-8 hrs

Dry benzene

64 65 66

Alcaide B et al.94 have reported

β-lactams as versatile building blocks

for the stereoselective synthesis of non-

β-lactam products. They have reported

that lithium aluminium hydride in

diethyl ether under reflux for 7-16 hrs

converted 1,4,4-trisubstituted β-lactams

(67a-c) into azetidines (68a-c) in 63-82% yield.95

Couty F et al.96 have reported a straightforward synthesis of 3-substituted

azetidinic amino acids. The given synthetic scheme envisioned to access (71) is

based on an anionic intramolecular alkylation of amino chloride (70), which was

prepared from the corresponding β-amino alcohol (69), bearing an electron

N NO R1

R3R2 R2

R3

R1

(67a-c) (68a-c)

68a; R1 = R2 = -CH3, R3 = i-Pr68b; R1 = -CH3, R2 = -CH2CH3, R3 = t-Bu68c; R1 = R2 = -CH2CH3, R3 = t-Bu

LiAlH4, Et2O

Reflux, 7-16 hrs


Page 109


withdrawing group on the nitrogen atom, which was able to stabilize an adjacent

carbanion.

N Bn

R

HO N Bn

EWG

69

R = -C6H5EWG = -CN, -CO2t-Bu

R

ClIntramolecular SN2

Base

EWG

N

R

GWE BnN

R

HOOC H

DeprotectionEWG = CO2tBu

70 71

Chlorination

Deshmukh A S et al.97 have synthesized monocyclic 1,3-disubstituted-4-

(2-nitrophenyl)azetidin-2-ones (72a) by [2+2] cycloaddition reaction

(Staudinger reaction) of ketenes, generated in situ from substituted acetyl

chlorides using tertiary amines and imines derived from reaction of

2-nitrobenzaldehyde with various amines. The cycloaddition reaction was highly

stereoselective and gave cis β-lactams (J = 5-6 Hz for cis β-lactam ring protons) in

good to moderate yields.

NO2

CHOR NH2

NR

NO2 NO2

NOR

R1HH

72a

a) b)

R -C6H5, 4-OCH3C6H4, 4-CH3C6H4R1 = -OCOCH3, -OC6H5, -OCH3, -OCH2C6H5a) = anhyd. MgSO4, rt, 15 hrs, CH2Cl2b) = R1CH2COCl, Et3N, CH2Cl2, 0°C to rt, 18 hrs

+

Desai N C et al.98 have synthesized N-(3-chloro-2-oxo-4-arylazetidin-1-yl)-2-

(4-chlorophenyl)acetamides (74) from compound (73) in the presence of

2-chloroacetylchloride, triethylamine and 1,4-dioxane as solvent. They also have

ClNH

O

NAr ClCH2COCl

(C2H5)3N1,4-Dioxan

NHO

N

Cl

Ar

O

Cl

73 74

Ar = Different aromatic substituents


Page 110


reported the QSAR studies along with antibacterial activity of the synthesized

compounds.

Ring modifications99

Cyclopropanone (75) by ring expansion and pyrollidine (77) by ring contraction

(by Wolff Rearrangement) have been reported to be transformed into respective

azetidinone derivatives (76 & 78).

Biological importance of 2-azetidinones

2-Azetidinone (β-lactam) skeleton is well established as the key pharmacophore of

β-lactam antibiotics, the most widely employed class of antibacterial agents.100

Being recognized as a potentially useful structural motif, azetidines have since

then been included in many studies aimed at the development of new drugs, as

diverse as antibacterial,101 anticonvulsant,102 antitumor,103 antipsychotic,104

antiasthmatic,105 antihypertensive agents,106 immunostimulants,107 cocaine

antagonists108 and muscarine agonists109 in the treatment of Alzheimer’s disease.

They also function as enzyme inhibitors and are effective on the central nervous

system. 110-112

One of these functionalized azetidines that has reached the stage of clinical trials,


Page 111


is ABT-594 (79).113 This surprisingly simple

molecule is a powerful analgesic agent, about 30-

100 times more potent than morphine in animal

models, and does not seem to cause severe side

effects associated with the use of morphine, such as

the development of a dependency.

Srivastava S K et al.114 have synthesized a

series of compounds from carbazole, which

on condensation with chloroacetyl chloride

in the presence of triethylamine afforded

azetidinones (80). Some of the compounds

exhibited promising antibacterial,

antifungal, anti-inflammatory and anticonvulsant activities.

Mahadevan K M etal.115 have synthesized series of compounds containing

azetidinone skeleton incorporated with quinoline which showed promising

activity against P. aerugenosa,

S. aureus, A. niger and

C. albicans. The compounds

(81a) and (81b) showed

promising activity against

P. aerugenosa and (81c), (81e)

and (81d) against S. aureus.

The compounds (81a) and

(81e) against A. niger and (81a)

and (81c) against C. albicans

exhibited significant activity.

Goel R K et al.116 have evaluated some azetidin-2-one derivatives for their central

nervous system (CNS) modulating activities. The compounds were chosen from a

series (82a-o) which were previously synthesized and evaluated for hypolipidemic

O

HN

O

N

O Cl

81a; R = R2 = R3 = H, R1 = -CH381b; R = R1 = R3 = H, R2 = -OCH381c; R = R1 = R3 = H, R2 = -Cl81d; R = R3 = H, R1 = R2 = -OCH381e; R = H, R1 = R2 = R3 = -OCH3

NCl

R

R1

R2

R3

81a-e


Page 112


and antihyperglycemic activity based on the predictions

made by the computer software, Prediction of Activity

Spectra for Substances (PASS).117 Compounds were selected

for particular CNS modulating activity as (82a) for

antianxiety; (82b), (82n) and (82j) for nootropic activity

and compound (82c) anti-catatonic and antidyskinetic

activities. Finally, it was concluded that azetidinones possess considerable CNS

activity and can be further explored to find additional CNS active compounds.

Ji J et al.118 have reported an efficient synthesis

of (1R,5S)-6-(5-cyano-3-pyridinyl)-3,6-diaza-

bicyclo [3.2.0]heptane (A-366833) (83), a novel

potent selective neuronal nicotinic receptor

(NNR) agonist. A-366833 was found to be a

selective α4β2 agonist with broad-spectrum

analgesic activity and an improved safety profile relative to ABT-594 (79).119

Giuliana C et al.120 synthesized, via

intramolecular hydroxyl-epoxides’ring opening,

novel classes of spiro-β-lactams: among them

compound (84) showed an encouragin gacyl-

CoA:cholesterol acyl-transferase inhibitory

activity. The (S) configuration at C4 of the lactam

seemed to be fundamental for enzymatic inhibition.

Shrenik K S et al.121 have stereospecifically

synthesized monocyclic β-lactam inhibitors of

human leukocyte Elastase. They reported

synthesis of four stereoisomers of 3-ethy1-

4-[(4-carboxyphenyl)oxy]-l-[[(phenylmethyl)

amino]carbonyl]-2-azetidinone starting from

either D or L aspartic acid out of which the trans (3R.4R) isomer (85), prepared from

N

O

O

HN Ph

COOH

O

85


Page 113


L-aspartic acid had the most inhibitory activity against human leukocyte elastase

(HLE). This monocyclic β-lactam was very resistant to hydrolysis and was found

to be orally bioavailable in marmosets.

Sch 48461 (86) is a trans azetidinone that was recently identified as a potent

cholesterol absorption inhibitor (CAI) in the cholesterol-fed hamster121a and

monkey models.121b Initial studies by Burner et al.122,123 demonstrated that both

trans and cis azetidinones had CAI activity. Subsequent work at Schering led to the

discovery of the spirocyclic azetidinone (87), which also displayed potent CAI

activity.122,124 The reduced conformational flexibility of (88), and similar

compounds, then served as a model to help define the likely binding conformation

of the C-3 phenylpropyl sidechain.123 The C-3 side chain of azetidinones related to

Sch 48461 was modified by introducing a hydroxyl group at the 1' position and

eight stereoisomeric 1' hydroxylated azetidinones. This led to the discovery of the

cis azetidinone 2c, which had improved CAI activity relative to its deshydroxy

analog. This represents the first example where a cis azetidinone displayed greater

activity than the corresponding trans isomer.

N

O

OCH3

NPh

O

OCH3

86 (SCH 48461)

N

O

OCH3

Ph

87

88

OH

Ph

OCH3 OCH3


Page 114


As part of interest in heterocycles, we have explored the possibility for developing

pharmaceutically important molecules. Due to this reasons it is worth to

incorporate medicinally important heterocycles like quinoline, thiazole and

azetidinone in part-II.

Section 7 : 3-Chloro-4-(2-chloroquinolin-3-yl)-1-(4-arylthiazol-2ylamino)

azetidin-2-ones.

Section 8 : 3-Chloro-4-(2-chloro-8-methylquinolin-3-yl)-1-(4-arylthiazol-2-

ylamino)azetidin-2-ones.

Section 9 : 3-Chloro-4-(2-chloro-6-methylquinolin-3-yl)-1-(4-arylthiazol-2-


Section 10 : 3-Chloro-4-(2-chloro-6-methoxyquinolin-3-yl)-1-(4-arylthiazol-2-


Section 11 : 3-Chloro-4-(2-chloro-6-ethoxyquinolin-3-yl)-1-(4-arylthiazol-2-


Section 12 : 3-Chloro-4-(2,6-dichloroquinolin-3-yl)-1-(4-arylthiazol-2-ylamino)

azetidin-2-ones.

EXPERIMENTAL

Page 115


EXPERIMENTAL PROCEDURE

Synthesis of 2-bromo-1-(aryl)ethan-1-ones

Acetophenone (0.01 mole) was added to 60 ml of methanol in 500 ml four necked

flask, well equipped with additional funnel, condenser, thermometer pocket and

mechanical stirrer. The flask was immersed in an ice bath and anhydrous

aluminium chloride (0.005 mole) was added to it. The temperature was maintained

between 0-5°C for 2 hrs, with stirring. A solution of bromine (0.01 mole) in 30 ml of

methanol was added drop wise to the reaction mass. The reaction mixture was

further stirred for 4 hrs at the same temperature and then for 1 hr at room temp.

The solvent was removed under reduced pressure. The residue obtained was

shaken well with hexane, filtered and recrystallized from benzene. Product was

obtained in 85% yield. m.p.: 48-50ºC.

The progress of the reaction and the purity of the compounds was checked on TLC

[Aluminium sheet silica gel 60 F245 (E. Merck)] plates using ethyl acetate:n-hexane

(1:9) as an irrigator and the plates were developed in an iodine chamber.

SECTION 7 EXPERIMENTAL

Page 116


SYNTHESIS OF 3-CHLORO-4-(2-CHLOROQUINOLIN-3-YL)-1-

(4-ARYLTHIAZOL-2-YLAMINO)AZETIDIN-2-ONES


Page 117


PHYSICAL CONSTANTS OF 3-CHLORO-4-(2-CHLOROQUINOLIN-3-YL)-1-


v TABLE-7

Sr. No. -R Molecular Formula

Yield (%)

M.P. (°C)

Elemental Analysis % Carbon % Hydrogen % Nitrogen

Req Obs Req Obs Req Obs JH7-1 -H C21H14Cl2N4OS 68 244 57.15 57.10 3.20 3.17 12.69 12.60

JH7-2 -4-CH3 C22H16Cl2N4OS 65 233 58.03 57.90 3.54 3.40 12.30 12.21

JH7-3 -4-OCH3 C22H16Cl2N4O2S 62 212 56.06 56.00 3.42 3.31 11.89 11.79

JH7-4 -2-Cl C21H13Cl3N4OS 70 235 53.01 52.97 2.75 2.71 11.78 11.72

JH7-5 -4-Cl C21H13Cl3N4OS 58 216 53.01 52.94 2.75 2.70 11.78 11.73

JH7-6 -4-Br C21H13BrCl2N4OS 60 219 48.48 48.44 2.52 2.47 10.77 10.68

JH7-7 -4-F C21H13Cl2FN4OS 62 211 54.91 54.90 2.85 2.79 12.20 12.11

JH7-8 -4-NO2 C21H13Cl2N5O3S 60 250 51.86 51.66 2.69 2.49 14.40 14.25


Page 118



Synthesis of 2-((2-chloroquinolin-3-yl)methylene)hydrazinecarbothioamide (III)

The solution of compound (IIa) (0.01 mole) in methanol and thiosemicarbazide

(0.01 mole) was refluxed for 1 hr. The mixture was allowed to attain room

temperature and poured onto crushed ice with stirring. The separated solid was

filtered, washed twice with water and recrystallized using methanol. Yield: 90%;

m.p.: 160°C; Elemental anal. obs. C, 49.25%; H, 3.15%; N, 21.02%. Calcd. for

C11H9ClN4S: C, 49.91%; H, 3.43%; N, 21.16%.

Synthesis of N-((2-chloroquinolin-3-yl)methylene)-4-p-tolylthiazol-2-amine (IV)

The solution of compound (III) (0.01 mole) in methanol and 2-bromo-1-p-

tolylethanone (0.01 mole) was refluxed for 30 minutes. The mixture was then

cooled down to room temperature. The separated solid was filtered, air dried and

recrystallized from chloroform. Yield: 92%; m.p.: 195°C; Elemental anal. obs.

C, 65.85%; H, 3.35%; N, 11.24%. Calcd. for C20H15ClN4S: C, 66.02 %; H, 3.88%;

N, 11.55%.

Synthesis of 3-chloro-4-(2-chloroquinolin-3-yl)-1-(4-p-tolylthiazol-2-ylamino)

azetidin-2-one (JH7-2) (V)

To a stirred solution of compound (IV) (0.01 mol) and Et3N (0.01 mol) in

1,4-dioxan, ClCOCH2Cl (0.01 mol) was added drop wise at 0-5˚C. The mixture was

refluxed for about 48 hrs. After the reaction was completed, reaction mixture was

filtered. The solid obtained on removal of solvent from filtrate was recrystallized

from methanol. Yield: 65%, m.p.: 233°C; Elemental anal. obs.: C, 57.90%; H, 3.40%;

N, 12.21%. Calcd. for C22H16Cl2N4OS: C, 58.03%; H, 3.54%; N, 12.30%.

The progress of the reaction and the purity of the compounds (III), (IV) and (V)

were checked similarly on TLC [Aluminium sheet silica gel 60 F245 (E. Merck)]

plates using ethyl acetate:n-hexane (2:8) as an irrigator and the plates were

developed in an iodine chamber. All other compounds of this series were prepared

by using the same method and their physical data are recorded in Table-7.


Page 119


SYNTHESIS OF 3-CHLORO-4-(2-CHLORO-8-METHYLQUINOLIN-3-YL)-1-



Page 120


PHYSICAL CONSTANTS OF 3-CHLORO-4-(2-CHLORO-8-

METHYLQUINOLIN-3-YL)-1-(4-ARYLTHIAZOL-2-YLAMINO)

AZETIDIN-2-ONES

v TABLE-8


Yield (%)

M.P. (°C)



JH8-2 -4-CH3 C23H18Cl2N4OS 70 248 58.85 58.70 3.87 3.40 11.94 11.81

JH8-3 -4-OCH3 C23H18Cl2N4O2S 70 233 56.91 56.60 3.74 3.66 11.54 11.33

JH8-4 -2-Cl C22H15Cl3N4OS 75 219 53.95 53.67 3.09 3.02 11.44 11.32

JH8-5 -4-Cl C22H15Cl3N4OS 62 226 53.95 53.70 3.09 2.99 11.44 11.40

JH8-6 -4-Br C22H15BrCl2N4OS 65 243 49.46 49.13 2.83 2.69 10.49 10.32

JH8-7 -4-F C22H15Cl2FN4OS 60 239 55.82 55.55 3.19 3.11 11.84 11.77

JH8-8 -4-NO2 C22H15Cl2N5O3S 68 241 52.81 52.69 3.02 2.87 14.00 13.90


Page 121



Synthesis of 2-((2-chloro-8-methylquinolin-3-yl)methylene)hydrazinecarbothio

amide (III)

The solution of compound (IIb) (0.01 mole) in methanol and thiosemicarbazide





C12H11ClN4S: C, 51.70%; H, 3.98%; N, 20.10%.

Synthesis of N-((2-chloro-8-methylquinolin-3-yl)methylene)-4-p-tolylthiazol-2-amine

(IV)

The solution of compound (III) (0.01 mole) in methanol and 2-bromo-1-p-tolylethanone

(0.01 mole) was refluxed for 30 minutes. The mixture was then cooled down to room

temperature. The separated solid was filtered, air dried and recrystallized from

chloroform. Yield: 92%; m.p.: 190°C; Elemental anal. obs. C, 66.40%; H, 4.12%;

N, 11.01%. Calcd. for C21H17ClN4S: C, 66.75%; H, 4.27%; N, 11.12%.

Synthesis of 3-chloro-4-(2-chloro-8-methylquinolin-3-yl)-1-(4-p-tolylthiazol-2-

ylamino) azetidin-2-one (JH8-2) (V)





from methanol. Yield: 70%; m.p.: 248°C; Elemental anal. obs. C, 58.70%; H, 3.40%;








Page 122


SYNTHESIS OF 3-CHLORO-4-(2-CHLORO-6-METHYLQUINOLIN-3-YL)-1-


N

CHO

Cl

N Cl

N

HN NH2

S+

COCH2Br

Reflux,30 min

N

N

HN

S

N

Cl

1,4-Dioxan,Reflux,48 hrs

N Cl

HN

S

N

Stirring, 50oC,1 hr

N

R

IIc

III

VR = Different substituents

ROCl

R

Methanol,H2NNHCSNH2

IV

H3C

H3C

H3C

H3C

TEA,ClCOCH2Cl

Methanol

B


Page 123


PHYSICAL CONSTANTS OF 3-CHLORO-4-(2-CHLORO-6-METHYL

QUINOLIN-3-YL)-1-(4-ARYLTHIAZOL-2-YLAMINO)AZETIDIN-2-ONES

v TABLE-9


Yield (%)

M.P. (°C)



JH9-2 -4-CH3 C23H18Cl2N4OS 63 217 58.85 58.77 3.87 3.66 11.94 11.60

JH9-3 -4-OCH3 C23H18Cl2N4O2S 65 243 56.91 56.79 3.74 3.5O 11.54 11.40

JH9-4 -2-Cl C22H15Cl3N4OS 60 236 53.95 53.80 3.09 2.96 11.44 11.23

JH9-5 -4-Cl C22H15Cl3N4OS 59 211 53.95 53.78 3.09 2.97 11.44 11.33

JH9-6 -4-Br C22H15BrCl2N4OS 61 215 49.46 49.30 2.83 2.70 10.49 10.39

JH9-7 -4-F C22H15Cl2FN4OS 62 204 55.82 55.56 3.19 3.05 11.84 11.70

JH9-8 -4-NO2 C22H15Cl2N5O3S 68 246 52.81 52.69 3.02 2.87 14.00 13.90


Page 124



Synthesis of 2-((2-chloro-6-methylquinolin-3-yl)methylene)hydrazinecarbo

thioamide (III)

The solution of compound (IIc) (0.01 mole) in methanol and thiosemicarbazide





C12H11ClN4S: C, 51.70%; H, 3.98%; N, 20.10%.

Synthesis of N-((2-chloro-6-methylquinolin-3-yl)methylene)-4-p-tolylthiazol-2-

amine (IV)

The mixture of compound (III) (0.01 mole) in methanol and 2-bromo-1-p-tolylethanone




N, 11.01%. Calcd. for C21H17ClN4S: C, 66.75%; H, 4.27%; N, 11.12%.

Synthesis of 3-chloro-4-(2-chloro-6-methylquinolin-3-yl)-1-(4-p-tolylthiazol-2-

ylamino)azetidin-2-one (JH9-2) (V)













Page 125


SYNTHESIS OF 3-CHLORO-4-(2-CHLORO-6-METHOXYQUINOLIN-3-YL)-1-


N

CHO

Cl

N Cl

N

HN NH2

S+

COCH2Br

Reflux,30 min

N

N

HN

S

N

Cl

1,4-Dioxan,Reflux,48 hrs

N Cl

HN

S

N

Stirring, 50oC,1 hr

N

R

IId

III

VR = Different substituents

ROCl

R

Methanol,H2NNHCSNH2

IV

H3CO

H3CO

H3CO

H3CO

TEA,ClCOCH2Cl

Methanol

B


Page 126


PHYSICAL CONSTANTS OF 3-CHLORO-4-(2-CHLORO-6-METHOXY


v TABLE-10


Yield (%)

M.P. (°C)


Req Obs Req Obs Req Obs JH10-1 -H C22H16Cl2N4O2S 65 218 56.06 57.89 3.42 3.22 11.89 11.72

JH10-2 -4-CH3 C23H18Cl2N4O2S 68 220 56.91 56.55 3.74 3.50 11.54 11.34

JH10-3 -4-OCH3 C23H18Cl2N4O3S 64 222 55.10 55.01 3.62 3.52 11.17 11.04

JH10-4 -2-Cl C22H15Cl3N4O2S 58 230 52.24 52.03 2.99 2.77 11.08 10.97

JH10-5 -4-Cl C22H15Cl3N4O2S 59 234 52.24 52.11 2.99 2.79 11.08 10.96

JH10-6 -4-Br C22H15BrCl2N4O2S 56 219 48.02 47.78 2.75 2.62 10.18 10.02

JH10-7 -4-F C22H15Cl2FN4O2S 60 226 54.00 57.66 3.09 2.79 11.45 11.30

JH10-8 -4-NO2 C22H15Cl2N5O4S 61 245 51.17 51.04 2.93 2.75 13.56 13.34


Page 127



Synthesis of 2-((2-chloro-6-methoxyquinolin-3-yl)methylene)hydrazinecarbothio

amide (III)

The solution of compound (IId) (0.01 mole) in methanol and thiosemicarbazide





C12H11ClN4OS: C, 48.90%; H, 3.76%; N, 19.01%.

Synthesis of N-((2-chloro-6-methoxyquinolin-3-yl)methylene)-4-p-tolylthiazol-2-

amine (IV)

The solution of compound (III) (0.01 mole) in methanol and 2-bromo-1-p-tolylethanone




N, 10.37%. Calcd. for C21H17ClN4OS: C, 64.03%; H, 4.09%; N, 10.67%.

Synthesis of 3-chloro-4-(2-chloro-6-methoxyquinolin-3-yl)-1-(4-p-tolylthiazol-2-


To a stirred solution of compound (IV) (0.01 mol) and Et3N (0.01 mol) in 1,4-dioxan,

ClCOCH2Cl (0.01 mol) was added drop wise at 0-5˚C. The mixture was heated


filtered. The solid obtained on removal of solvent from filtrate was recrystallized from

methanol. Yield: 65%; m.p.: 220°C; Elemental anal. Obs. C, 56.55%; H, 3.50%;

N, 11.34%. Calcd. for C23H18Cl2N4O2S: C, 56.91%; H, 3.74%; N, 11.54%.







Page 128


SYNTHESIS OF 3-CHLORO-4-(2-CHLORO-6-ETHOXYQUINOLIN-3-YL)-1-



Page 129


PHYSICAL CONSTANTS OF 3-CHLORO-4-(2-CHLORO-6-ETHOXY


v TABLE-11


Yield (%)

M.P. (°C)


Req Obs Req Obs Req Obs JH11-1 -H C23H18Cl2N4O2S 67 175 56.91 56.70 3.74 3.56 11.54 11.34

JH11-2 -4-CH3 C24H20Cl2N4O2S 66 232 57.72 57.60 4.04 3.87 11.22 11.05

JH11-3 -4-OCH3 C24H20Cl2N4O3S 59 211 55.93 55.66 3.91 3.88 10.87 10.65

JH11-4 -2-Cl C23H17Cl3N4O2S 60 237 53.14 53.00 3.30 3.11 10.78 10.64

JH11-5 -4-Cl C23H17Cl3N4O2S 60 189 53.14 53.02 3.30 3.15 10.78 10.66

JH11-6 -4-Br C23H17BrCl2N4O2S 58 155 48.96 48.76 3.04 2.88 09.93 09.77

JH11-7 -4-F C23H17Cl2FN4O2S 57 203 54.88 54.63 3.40 3.20 11.13 11.02

JH11-8 -4-NO2 C23H17Cl2N5O4S 61 215 52.08 54.96 3.23 3.10 13.20 13.07


Page 130



Synthesis of 2-((2-chloro-6-ethoxyquinolin-3-yl)methylene)hydrazinecarbothio

amide (III)

The solution of compound (IIe) (0.01 mole) in methanol and thiosemicarbazide





C13H13ClN4OS: C, 50.57%; H, 4.24%; N, 18.14%.

Synthesis of N-((2-chloro-6-ethoxyquinolin-3-yl)methylene)-4-p-tolylthiazol

-2-amine (IV)

The mixture of compound (III) (0.01 mole) in methanol and 2-bromo-1-p-tolylethanone




N, 10.20%. Calcd. for C22H19ClN4OS: C, 64.78%; H, 4.45%; N, 10.30%.

Synthesis of 3-chloro-4-(2-chloro-6-ethoxyquinolin-3-yl)-1-(4-p-tolylthiazol-2-


To a stirred solution of compound (IV) (0.01 mol) and Et3N (0.01 mol) in 1,4-dioxan,

ClCOCH2Cl (0.01 mol) was added drop wise at 0-5˚C. The mixture was heated


filtered. The solid obtained on removal of solvent from filtrate was recrystallized from

methanol. Yield: 66%; m.p.: 232°C; Elemental anal. obs. C, 57.60%; H, 3.87%;

N, 11.05%. Calcd. for C24H20Cl2N4O2S: C, 57.72%; H, 4.04%; N, 11.22%.







Page 131


SYNTHESIS OF 3-CHLORO-4-(2,6-DICHLOROQUINOLIN-3-YL)-1-



Page 132


PHYSICAL CONSTANTS OF 3-CHLORO-4-(2,6-DICHLOROQUINOLIN-3-YL)

-1-(4-ARYLTHIAZOL-2-YLAMINO)AZETIDIN-2-ONES

v TABLE-12


Yield (%)

M.P. (°C)



JH12-2 -4-CH3 C22H15Cl3N4OS 64 229 53.95 53.78 3.09 2.87 11.44 11.23

JH12-3 -4-OCH3 C22H15Cl3N4O2S 59 226 52.24 52.11 2.99 2.69 11.08 10.89

JH12-4 -2-Cl C21H12Cl4N4OS 60 234 49.43 49.32 2.37 2.22 10.98 10.78

JH12-5 -4-Cl C21H12Cl4N4OS 66 236 49.43 49.29 2.37 2.23 10.98 10.87

JH12-6 -4-Br C21H12BrCl3N4OS 63 237 45.47 45.23 2.18 2.04 10.10 10.00

JH12-7 -4-F C21H12Cl3FN4OS 58 240 51.08 54.88 2.45 2.33 11.35 11.22

JH12-8 -4-NO2 C21H12Cl3N5O3S 69 243 48.43 48.31 2.32 2.21 13.45 13.30


Page 133



Synthesis of 2-((2,6-dichloroquinolin-3-yl)methylene)hydrazinecarbothioamide (III)

The solution of compound (IIf) (0.01 mole) in methanol and thiosemicarbazide





C11H8Cl2N4S: C, 44.16%; H, 2.70%; N, 18.73%.

Synthesis of N-((2,6-dichloroquinolin-3-yl)methylene)-4-p-tolylthiazol-2-amine (IV)

The mixture of compound (III) (0.01 mole) in methanol and 2-bromo-1-p-

tolylethanone (0.01 mole) was refluxed for 30 minutes. The mixture was then

cooled down to room temperature. The separated solid was filtered, air dried and

recrystallized from chloroform. Yield: 92%; m.p.: 199°C; Elemental anal. obs.

C, 60.11%; H, 3.17%; N, 10.30%. Calcd. for C20H13Cl2N3S: C, 60.31%; H, 3.29%;

N, 10.55%.

Synthesis of 3-chloro-4-(2,6-dichloroquinolin-3-yl)-1-(4-p-tolylthiazol-2-ylamino)

azetidin-2-one (JH12-2) (V)












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