chapter 2 synthesis of novel n-alkyl/aryl-1,4-dihydro...

39

Chapter 2

CHAPTER 2

SYNTHESIS OF NOVEL N-ALKYL/ARYL-1,4-DIHYDRO-4-OXO-3-

QUINOLINE CARBOXYLIC ACIDS/AMIDES

40

Chapter 2

2.1 INTRODUCTION

Since the discovery of the quinolinone antibacterial agent nalidixic

acid in 19621, a large number of its congeners have been synthesized

and extensively evaluated for their structure-activity relationship

studies2. A considerable attention has been paid towards the

structural modifications in quinolones, which led to several new

analogue with dramatic improvement of their antibacterial activity3.

Recent reports on molecular modeling and pharmacological

characterization studies reveals that 4-oxo-1,4-dihydro quinoline-3-

carboxamide derivatives showed an excellent activity towards HSV-1

and HSV-2 viruses of Herpes family, which causes birth defects in

infants and also variety of diseases. And also these carboxamide

compounds have been reported as 5-HT3 antagonists which are used

for neuropsychiatric disorders, recent reports reveals carobaxmides

are potent CB-selective cannabinoid receptor agonist.

Carboxamides showed various mode of action on various active

centers of human body, so these carboxamides are indentified as

important class of biologicalactive compounds. In this chapter our

current interest to synthesize a novel quinolinecarboxylic acids and

corboxamides which are potent antibacterials, antivirals and CB-

selective cannabinoid receptor agonist.

41

Chapter 2

2.2 AN EXPEDITIOUS SYNTHESIS OF NOVEL N-ALKYL/ARYL-

1,4-DIHYDRO-4-OXO-3-QUINOLINE CARBOXYLIC ACIDS

N-alkyl/aryl-1,4-dihydro-4-oxo-3-quinoline carboxylic acids (Fig-2.1)

and its ester derivatives are key building blocks of quinolinone anti-

bacterial agents, which are effective against a variety of

microorganisms, including gram-negative pathogens4. Since

quinolinones are an important class of antibacterial agents, herein, we

wish to report synthesis of N-pyridyl substituted 1,4-dihydro-4-oxo-3-

quinoline carboxylic acids and its derivatives with good yields.

Figure-2.1

N

O O

OR'

R

N

N

N

N

N

N

N

N

2.43 R=

2.44 R=

2.40 R=

2.41 R=

2.42 R=

2.36 R=

2.37 R=

2.29 R=

2.30 R=

2.31 R=

R' = C2H5 R' = H

R' = H

R' = H

R' = H

R' = H

R' = C2H5

R' = C2H5

R' = C2H5

R' = C2H5

42

Chapter 2

2.2.1 Reported methods in literature for the synthesis of

quinoline ring

Quinoline carboxylates were prepared when aniline was reacted in

neat conditions with diethylethoxymethylenemalonate, forming an aryl

aminomethylenemalonate. This was heated in dowtherm A, at 250°C

to form ethyl 1,4-dihydro-4-oxo-3-carboxylate as shown in scheme

2.1, which then precipitates out of solution upon cooling.

NH2

O O

OEtEtO

OEt

O

O

OEt

OEt

NH

NH

O O

OEt

+

Diphenylether-250°C

H2SO4/AC2O

or

100°C

2.4

2.1 2.2 2.3

Scheme 2.1 Synthesis of quinoline carboxylate

There is evidence that the ring closure can be carried out using a

combination of acetic anhydride and concentrated sulphuric acid. A

number of acetoacetate anilines have been cyclised using this

procedure producing 3-substituted-4-quinolones5 as shown in scheme

2.1. An anthranilamide is coupled with a ketone to produce the

intermediate imine (2.7), which is then treated with lithium

43

Chapter 2

diisopropylamide (LDA) in THF, producing a 4-quinolone with 2- and

3-substitution6, as shown in scheme 2.2.

NR

O

NH2

N

O

NR

R2

R3NH

O

R3

R2

O

R2

R3

+Mol.sieves LDA/THF

2.5 2.6 2.7 2.8

Scheme 2.2 Synthesis of quinolones

Nitration of benzoic acid resulted in 2-nitrobenzoic acid which was

converted to corresponding acid chloride using thionyl chloride. The

acid chloride was condensed with β-keto ester to obtain intermediate

diketo ester (2.11). The di keto ester was cyclised under mild

reduction7 conditions using hydrogen and catalytic amount of Pd/C

which resulted in N-hydroxy-2-substituted-4-quinolone as shown in

scheme 2.3.

OH

O

N

O

R3

O

OEt

OH

OH

O

NO2

O

NO2

COR3

O

OEtHNO3/H2SO4

SOCl2/urea

/toluene

Mg, EtOH/toluene

H2/Pd/C

2.9 2.10 2.11

2.12

Scheme 2.3 Synthesis of quinolones

44

Chapter 2

Interestingly, quinolones were synthesized in one step form isatoic

anhydride and ethylacetoacetate with good yields. 2-methyl-3-

ethoxycarbonyl-4(1H)-quinolone8 was prepared using above mentioned

procedure as shown in scheme 2.4.

N

O

O

O

O O

OEt N

O O

OEt

+

2.13 2.14 2.15

Base

Scheme 2.4 Synthesis of quinolone

In another procedure quinolones were synthesized by treating the 4-

chloro-quinolines with tri alkyl phosphates9 as shown in scheme 2.5

O

O

OEt

OEt

NH N

Cl O

OEt

N

O O

OEt

C2H

5

POCl3 Triethylphosphate

Hydrolysis

2.16 2.17 2.18

Scheme-2.5 Synthesis of quinolone

45

Chapter 2

The precursor 2-(2,2,2–trichloro)ethylidine-3-oxo-3-(2-chlorophenyl)

propionate10 of quinolone carboxylates were prepared from clay

catalyzed reactions in high yields as shown in scheme 2.6.

O

Cl

O

OEt

O O

Cl CCl3

OEt

N

O O

OEt

R

H

O

CCl3

O O

Cl NHR

OEt

Montmorillonite/Ac2O

R-NH2

Acetonitrile/reflux

+ 130-140°C

i) NaH/DioxaneRefluxii) KOH/MeOH

2.19 2.20 2.21

2.23 2.22

Scheme 2.6 Synthesis of quinolone

46

Chapter 2

2.3 RESULTS AND DISCUSSION

Herein, we present an expeditious synthesis of novel N-substituted-

1,4-dihydro-4-oxo-3-quinoline carboxylic acids derivatives in five steps

from commercially available 2-bromo benzoic acid (2.24).

Synthesis of ethyl-3-(2-bromophenyl)-2-((dimethylamino)methyl

ene)-3-oxopropanoate

2-bromo benzoic acid (2.24) was converted into corresponding acid

chloride (2.25) in presence of thionyl chloride followed by

condensation with potassium salt of monoethyl malonate (2.26) to

obtain bromobenzoyl β- keto ester (2.27) which was further reacted

with N,N-dimethylformamide dimethyl acetal to give ethyl-3-(2-

bromophenyl)-2-((dimethylamino) methylene)-3-oxopropanoate (2.28)

in about 33% yield. Scheme-2.7

Br

OH

O

O

O

O

Br

O

O

O

Br N

O O

OKOBr

O

Cl+

2.24 2.25 2.26

2.27 2.28

Thionylchloride/ DMF/ DCM

RT0-5°C

MgCl2/ TEA/ ACN

DMF/ DMA

50-55°C

Scheme 2.7 Synthesis of ethyl-3-(2-bromophenyl)-2-((dimethylamino)

methylene)-3-oxopropanoate

47

Chapter 2

In an alternate process, ethyl 3-(dimethylamino) acrylate was

introduced to build quinolinone skeleton as described in scheme 2.8.

Bromobenzoyl chloride (2.25) was reacted with ethyl-3-(dimethyl

amino)acrylate in presence of triethylamine and acetonitrile to give

ethyl-3-(2-bromophenyl)-2-((dimethylamino)methylene)-3-

oxopropanoate (2.28) in about 48% yield.

Br

OH

O O

O

O

Br NBr

O

Cl

2.24 2.25 2.28

Thionylchloride/ DMF/ DCM

RT

Ethyl-3-(dimethylamino)acrylate/ TEA/ ACN

0°C - RT

Scheme 2.8 Synthesis of ethyl-3-(2-bromophenyl)-2-((dimethyl amino)

methylene)-3-oxopropanoate

2.3.1 Synthesis of Ethyl-4-oxo-N-pyridyl-1, 4-dihydroquinoline-3-

carboxylate

In presence of triethylamine or cesium carbonate, ethyl-3-(2-

bromophenyl)-2-((dimethylamino) methylene)-3-oxopropanoate (2.28)

on condensation with 2-aminopyridine, 3-aminopyridine, 4-

aminopyridine undergoes insitu cyclisation to afford ethyl-4-oxo-N-

pyridyl-1,4-dihydroquinoline-3-carboxylate (2.29-2.31) derivatives as

shown in scheme 2.9.

In general the reaction of ethyl-3-(2-bromophenyl)-2-((dimethylamino)

methylene)-3-oxopropanoate (2.28) with various amines will undergo

48

Chapter 2

step wise transfermations. However the reaction with amines like 2-

aminopyridine, 3-aminopyridine, 4-aminopyridine was leading directly

to cyclized quinolones. Generally organic bases like TEA will be used

for these reactions and here the reaction time was found around 12 h.

When we changed the base to Cs2CO3 the reaction time was reduced

to 6 hrs and the yields were also improved to some extent. The results

were shown in table 2.1.

N

O O

O

N

N

O O

O

N

N

O O

O

N

O

Br

O

O

N

2.28

Reflux Y: 60%

Reflux Y: 55%

Reflux Y: 75%

2-AminopyridineCesium carbonate/ TEA/acetonitrile

2.29

2.30

2.31



Scheme 2.9: Synthesis of Ethyl-4-oxo-N-pyridyl-1,4-dihydro quinoline

-3-carboxylate (2.29-2.31)

49

Chapter 2

Table-2.1: Reaction time and yields of Ethyl-4-oxo-1-pyridyl-1, 4-

dihydroquinoline-3-carboxylate (2.30-2.32)

Entry Amine Product Base Time Yield

1 2-aminopyridine 2.29 TEA 12 h 55%

2 2-aminopyridine 2.29 Cs2CO3 6 h 75%





2.3.2 Synthesis of Ethyl-4-oxo-1-alkyl-1,4-dihydroquinoline-3-

carboxylate

N

O O

O

R

O

Br

O

O

N

O

Br

O

O

NH

R

N N

2.28 2.32 R=

2.33 R=

2.36 R=

2.37 R=

Amine/ TEA

Reflux Y: 70-80%

TEA or Cs2CO3 or

Cs2CO3 / CuI

Reflux Y: 65-75%

Scheme 2.10 Synthesis of Ethyl-4-oxo-N-alkyl-1,4-dihydro quinoline-

3-carboxylate

50

Chapter 2

Ethyl-3-(2-bromophenyl)-2-((dimethylamino)methylene)-3-oxopropano

ate (2.28) when treated with 4-phenylbutan-2-amine, 4-(aminomethyl)

pyridine, 2-aminothiazole and 1-amino-4-methyl piperazine in the

presence of bases such as triethylamine or cesium carbonate obtained

an intermediate ethyl-3-(2-bromophenyl)-2-(( N-alkyl/aryamino)methyl

ene)-3-oxo propanoate (2.32-2.35) the yields were shown in the table

2.2.

Table-2.2: Reaction time and yields of Ethyl-3-(2-bromophenyl)-2-

(alkyl amino) methylene)-3-oxopropanoate (2.32-2.35)

Entry Amine Product Base Time Yield

1 4-phenylbutan-2-amine 2.32 TEA 5 h 80%

2 4-phenylbutan-2-amine 2.32 Cs2CO3 2 h 90%

3

4(aminomethyl)

pyridine

2.33 TEA 4 h 75%

4

4(aminomethyl)

pyridine

2.33 Cs2CO3 2 h 90%

5 2-aminothiazole 2.34 TEA No rexn

6 2-aminothiazole 2.34 Cs2CO3 5 h 50%

7

1-amino-4 -

methylpiperazine 2.35 TEA 12 h 70%

8

1-amino-4-

methylpiperazine 2.35 Cs2CO3 2 h 75%

51

Chapter 2

The open forms (2.32-2.33) were then converted to quinolinone ester

(2.36 and 2.37) by further treatment with cesium carbonate and

catalytic amount of copper iodide as shown scheme 2.10. Whereas the

open forms (2.34 and 2.35) did not cyclize even after using stronger

bases like NaH and tBuOK, the results are tabulated in table 2.2 and

2.3.

N

O O

O

R

O

Br

O

O

N

O

Br

O

O

N

R

S

N

NN CH3

S

N

NN CH3

2.28 2.34 R=

2.35 R=

2.38 R=

2.39 R=

Amine/ TEA

Reflux Y: 50-70%

TEA or Cs2CO3 or

Cs2CO3 / CuI

NaH

Reflux X

Scheme 2.11 Synthesis of Ethyl-3-(2-bromophenyl)-2-(thiazolo/

methylpyrazino amino) methylene)-3-oxopropanoate

Table-2.3: Synthesis of Ethyl-4-oxo-1-alkyl-1,4-dihydroquinoline-3-

carboxylate (2.36 and 2.39)

Entry

Starting

material Product Base/cat Time Yield

1 2.32 2.36 TEA/CuI No rexn

2 2.32 2.36 Cs2CO3/CuI 6 h 85%

3 2.33 2.37 TEA/ CuI 24 h 40%

52

Chapter 2

4 2.33 2.37 Cs2CO3/ CuI 6 h 73%

5 2.34 2.38 Cs2CO3/ CuI No rexn

6 2.34 2.38 NaH No rexn

7 2.35 2.39 TEA/ CuI No rexn

8 2.35 2.39 Cs2CO3/ CuI No rexn

2.3.3 Synthesis of 4-oxo-N-substituted-1,4-dihydroquinoline-3-

carboxylic acids

Compounds (2.29-2.31 and 2.36-2.37) were hydrolyzed in presence

of aqueous NaOH to obtain the respective N-alkyl/ary-1,4-dihydro-4-

oxo-3-quinoline carboxylic acid (2.40-2.44) in about 55-75 % yields as

shown in table 2.4.

N

O O

O

RN

O O

OH

R

N

N

N

N

N

N

N

N

20% NaOH solution

2.36 R=

2.37 R=

2.29 R=

2.30 R=

2.31 R=

2.43 R=

2.44 R=

2.40 R=

2.41 R=

2.42 R=

RefluxY: 70-80%

Scheme 2.12 Synthesis of 4-oxo-N-substituted-1,4-dihydroquinoline-

3-carboxylic acids

53

Chapter 2

Table-2.4 Yield of 4-oxo-1-1,4-dihydroquinoline-3-carboxylic acid

(2.40-2.46)

Table-2.5 Synthesised quinolone (2.29-2.31 and 2.36-2.46)

N

O O

OR1

R

Entry Starting material Product Yield

1 2.29 2.40 75%

2 2.30 2.41 55%

3 2.31 2.42 60%

4 2.36 2.43 75%

5 2.37 2.44 65%

Entry Product R R1 Yield

1 2.29 N

C2H5 75%

2 2.30 N

C2H5 55%

3 2.31 N

C2H5 60%

54

Chapter 2

2.4 Conclusion

In conclusion, a novel N-alkyl/ary-1,4-dihydro-4-oxo-3-quinoline

carboxylic acids were synthesized with an efficient synthetic route.

The purpose of this investigation was to evaluate new and high

potential quinolone class of antibacterials. The method we adopted in

this chapter is economically viable and operationally simple in

comparison to those reported for the synthesis of substituted

quinolone carboxylic acids.

4 2.36

C2H5 75%

5 2.37 N

C2H5 65%

6 2.40 N

H 75%

7 2.41 N

H 55%

8 2.42 N

H 60%

9 2.43

H 75%

10 2.44 N

H 65%

55

Chapter 2

2.5 EXPERMENTAL SECTION

2.5.1 Synthesis of Ethyl 3-(2-bromophenyl)-2-((dimethylamino)

methylene)-3-oxo propanoate (2.28)

O

Br

O

O

N

2.28

Procedure-1

A mixture of bromobenzoic acid (2.24) (5 g, 0.025 mol),

dimethylformamide (0.5 ml) and thionyl chloride (32 g, 0.270 mol) in

dichloromethane (50 ml) was stirred at room temperature for 3h.

Resulting mixture was evaporated under reduced pressure and dry

tetrahydrofuran (20 ml) was added (solution A). A mixture of

potassium salt of malonic acid ethyl ester (12.82 g, 0.075 mol),

triethylamine (7.6 g, 0.075 mol) in tetrahydrofuran (50 ml) was cooled

to 0-10°C and magnesium chloride (3.4 g, 0.035 mol) was added at

same temperature. The resulting mixture was stirred at room

temperature for 7-8h. A solution of freshly prepared bromobenzoyl

chloride (2.25) (solution A) was added dropwise maintaining the

temperature at 0°C and reaction mixture was stirred overnight at

room temperature. After completion of reaction, the reaction mass was

quenched with 1N hydrochloric acid at 20°C and the product was

56

Chapter 2

extracted with ethyl acetate. The organic layer was washed with

saturated sodium bicarbonate solution, and brine solution. The

organic layer was dried over anhydrous sodium sulfate and then

organic layer was evaporated under reduced pressure to get ethyl 3-(2-

bromophenyl)-3-oxopropanoate (2.27) as viscous syrup (3.74 g, 55%

yield).

A mixture of ethyl 3-(2-bromophenyl)-3-oxopropanoate (2.27) (3.5 g,

0.012 mol) and N,N-dimethylformamide dimethyl acetal (1.84 g, 0.015

mol) was stirred at room temperature under nitrogen. The resulting

mixture was stirred at 50°C under nitrogen atmosphere for 1h. After

completion of the reaction, reaction mixture was concentrated under

reduced pressure to get viscous material which was purified by

column chromatography using ethyl acetate and hexane 25:75, to get

pure ethyl-3-(2-bromophenyl)-2-[(dimethylamino)methylene]-3-

oxopropanoate (2.28) (2.5 g, 60% yield) as viscous syrup.

Procedure-2

A mixture of bromobenzoic acid (2.24) (5 g, 0.025 mol), DMF (0.5 ml)

and thionyl chloride (32 g, 0.270 mol) in dichloromethane (50 ml) was

stirred at room temperature for 3h. Resulting mixture was evaporated

under reduced pressure and dry acetonitrile (20 ml) was added

(solution A). A mixture of ethyl 3-(dimethylamino)acrylate (4.94 g,

0.034 mol), triethylamine (9.3 g, 0.092 mol) in acetonitrile (50 ml) was

cooled to 0-10°C and freshly prepared bromobenzoyl chloride (2.25)

(solution A) was added drop wise at 0-10°C. Reaction mixture was

57

Chapter 2

stirred overnight at room temperature and then evaporated under

reduced pressure. The residue was dissolved in ethyl acetate and

washed with water and brine. The organic layer was dried over sodium

sulphate and concentrated under reduced pressure. The residue was

purified by column chromatography using ethyl acetate and hexane

(25:75) as eluent to afford ethyl -3-(2-bromophenyl)-2-[(dimethyl

amino) methylene]-3-oxopropanoate (2.28) (4 g, 48% yield) as viscous

syrup.

Ethyl-3-(2-bromophenyl)-2-[(dimethylamino)methylene]-3-oxo

propaneate (2.28)

1H-NMR (300MHz, DMSO-d6): δ 0.76 (t, J = 7.1 Hz, 3H), 2.83 (s, 3H),

3.30 (s, 3H), 3.71-3.79 (q, J = 7.1 Hz, 2H), 7.10-7.30 (m, 3H), 7.55 (m,

1H ), 7.69 (s, 1H)

ESI-MS m/z. 328 (M+H)+

2.5.2 General procedure for ethyl 4-oxo-1-(2-, 3- or 4-pyridyl)-1, 4-

dihydro quinoline -3-carboxylate (2.29-2.31)

N

O O

O

R

In a round bottom flask compound 2.28 (1 g, 0.003 mol) in

acetonitrile (10 mL) was stirred at room temperature. Selected amine

(0.003 mol) and triethylamine or cesium carbonate (0.015 mol) were

added, resulting mixture was stirred for 3h at reflux and reaction

58

Chapter 2

mixture was evaporated under reduced pressure. The residue was

dissolved in ethyl acetate and washed with water, and brine. The

organic layer was dried over sodium sulfate and concentrated. The

residue was purified by column chromatography using

dichloromethane: methanol (98:2) as eluent to afford the

corresponding compound (2.29-2.31) as a solid.

Ethyl-4-oxo-1-(2-pyridyl)-1,4-dihydroquinoline-3-carboxylate

(2.29)

N

O O

O

N

2.29

Mp: 158-161°C.

IR (KBr): 3370, 3186, 2978, 1726, 1693, 1626, 1553 and 1482 cm-1.

1H-NMR (300MHz, DMSO-d6): δ 1.23 (t, J = 7.2 Hz, 3H), 4.21 (q, J =

7.2 Hz, 2H), 7.14 (d, J = 8.7 Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H ), 7.62-

7.70 (m, 2H ), 7.82 (d, J = 7.8 Hz, 1H), 8.17 (td, J = 7.8 Hz, 1.8, 1H),

8.28 (dd, J = 8.1 Hz, 1.2 Hz, 1H), 8.64 (s, 1H), 8.72 (d, J = 4.2 Hz, 1H).

ESI-MS m/z: 333 (M+K)+ , 317 (M+Na)+ and 295 (M+H)+.


(2.30)

59

Chapter 2

N

O O

O

N

2.30

Mp: 212-217°C.

IR (KBr): 3446, 3046, 1725, 1693, 1633, 1554 and 1479 cm-1.


7.2 Hz, 2H), 6.93 (d, J = 8.4 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H ), 7.62-

7.71 (m, 2H), 8.15 (d, J = 8.1 Hz, 1H), 8.27 (dd, J = 8.1 Hz, 1.2 Hz,

1H), 8.52 (s, 1H), 8.83 (dd, J = 4.5 Hz, 1.2 Hz, 1H), 8.86 (d, J = 2.4 Hz,

1H).

ESI-MS m/z. 295 (M+H)+.


(2.31)

N

O O

O

N

2.31

Mp: 240-241°C.

IR (KBr): 3425, 3056, 1724, 1629, 1555 and 1477 cm-1; 1H-NMR

(300MHz, DMSO-d6): δ 1.24 (t, J = 7.1 Hz, 3H), 4.17-4.20 (q, J = 7.1

Hz, 2H), 7.05 (d, J = 8.4 Hz, 1H), 7.5 (t, J = 7.1 Hz, 1H ), 7.65 (t, J =

60

Chapter 2

7.1 Hz, 1H), 7.74 (d, J = 7.8 Hz, 2H), 8.27 (d, J = 8.0 Hz, 1H), 8.49 (s,

1H), 8.88 (m, 2H).

ESI-MS m/z. 295 (M+H)+.

2.5.3 General procedure for ethyl 3-(2-bromophenyl)-2-(4-

phenylbutyl-2-amino / 4-pyridinemethylamino)-3-oxo

propanoate (2.32-2.35)

O

Br

O

O

NH

R

A stirred solution of 3-(2-bromophenyl)-2-[(dimethylamino)methylene]-

3-oxopropanoate (2.28) (1g 0.003 mol), selected amine (0.003 mol)

and base (cesium carbonate or triethylamine) (0.006 mol) in

acetonitrile (10 ml) was refluxed for 5-6h. After completion of reaction,

the reaction mixture was concentrated under reduced pressure. The

residue obtained was purified by column chromatography using ethyl

acetate and hexane as an eluent to afford corresponding compound

(2.32 – 2.35) as viscous syrup.

Ethyl-3-(2-bromophenyl)-2-[(4-phenylbutyl-2-amino)methylene]-3-

oxopropanoate (2.32)

O

Br

O

O

NH

2.32

61

Chapter 2

1H-NMR (300MHz, DMSO-d6): δ 0.78 (t, J = 7.2 Hz, 3H), 1.29 (d, J =

6.6 Hz, 3H), 1.88 (m, 2H), 2.58 (m, 2H), 3.77 (q, J = 7.2 Hz, 2H), 7.13-

7.54 (m, 8H), 8.16 (m, 1H), 10.83 (m, 1H).

Ethyl-3-(2-bromophenyl)-2-[( 4-pyridinmethyl amino)methylene]-3-

oxopropanoate (2.33)

O

Br

O

O

NH

N

2.33


7.2 Hz, 2H), 4.71 (d, J = 6.3 Hz, 2H), 7.17-7.36 (m, 5H), 7.53 (dd, J =

7.8 Hz, 1.2 Hz, 1H), 8.28 (m, 1H), 8.55 (m, 2H), 11.04 (m, 1H).

Ethyl-3-(2-bromophenyl)-2-[(thiazolamino)methylene]-3-oxo

propanoate (2.34)

O

Br

O

O

NH

SN

2.34


7.0 Hz, 2H), 7.03 (m, 1H), 7.20-7.54 (m, 6H), 8.89 (m, 1H), 12.83 (m,

1H).

Ethyl-3-(2-bromophenyl)-2-[(4-methylpiperazinamino)methylene]-

3-oxopropanoate (2.35)

62

Chapter 2

O

Br

O

O

NH

N

N

2.35

1H-NMR (300MHz, DMSO-d6): δ 0.82 (t, J = 7.1 Hz, 3H), 2.16 (s, 3H),

2.46 (bs, 4H), 2.95 (bs, 4H), 7.11-7.34 (m, 3H), 7.50 (m, 1H), 8.13 (m,

1H), 11.23 (m, 1H).

2.5.4 General procedure for ethyl 4-oxo-1-(1-methyl-3-

phenylpropyl / 4-pyridinemethyl)-1,4-dihydroquinoline-3-

carboxylate (2.36-2.37)

N

O O

O

R

A mixture of compound (2.32 and 2.33) (0.002 mol), cesium

carbonate (0.0075 mol) and catalytic amount of copper iodide (0.25

mmol) was refluxed for 4h in acetonitrile. After completion of the

reaction resulting mixture was filtered and filtrate was concentrated

under reduced pressure. The residue obtained was purified by column

chromatography using dichloromethane: methanol (99:1) as an eluent

to afford the corresponding compound (2.36-2.37).

63

Chapter 2

Ethyl 4-oxo-1-(1-methyl-3-phenylpropyl)-1, 4-dihydroquinoline-3-

carboxylate (2.36)

N

O O

O

2.36

Compound was isolated as liquid

IR (KBr): 3455, 3061, 1726, 1689, 1630, 1553 and 1488 cm-1.

1H-NMR (300MHz, DMSO-d6): δ 1.26 (t, J = 7.2 Hz, 3H), 1.52 (d, J =

6.3 Hz, 3H), 2.18 (m, 2H), 2.55 (m, 2H), 4.20 (q, J = 7.2 Hz, 2H), 4.93

(d, J = 6.4 Hz, 1H), 7.11-7.25 (m, 5H), 7.45 (t, J = 7.2 Hz, 1H), 7.73

(td, J = 8.1 Hz, 1.5 Hz, 1H), 7.81 (d, J = 9.0 Hz, 1H), 8.26 (dd, J = 8.1

Hz, 1.5 Hz, 1H), 8.59 (s, 1H).

ESI-MS m/z. 350 (M+H)+.

Ethyl 4-oxo-1-(4-pyridinemethyl)-1, 4-dihydroquinoline-3-carboxyl

ate (2.37)

N

O O

O

N

2.37

Compound was isolated as solid

Mp: 178-182°C; IR (KBr): 3426, 3048, 1720, 1679, 1644, 1555 and

1489 cm-1.

64

Chapter 2


7.2 Hz, 2H), 5.72 (s, 2H), 7.15 (d, J = 6.0 Hz, 2H), 7.39-7.47 (m, 2H ),

7.64 (t, J = 7.8 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.50 (d, J = 4.5 Hz,

2H), 8.90 (s, 1H).

ESI-MS m/z: 331 (M+Na)+ and 309 (M+H)+

2.5.5 General procedure for 4-oxo-1-( 2-, 3- or 4-pyridyl / 1-

methyl-3-phenylpropyl / 4-pyridinemethyl)-1, 4-

dihydroquinoline-3-carboxylic acid (2.40-2.44)

N

O O

OH

R

A mixture of product (2.29-2.31, 2.37-2.38) (0.003 mol) in 10%

aqueous sodium hydroxide solution (10 vol.) was refluxed for 3h. After

cooling, resulting mixture was neutralized with hydrochloric acid and

then extracted with ethyl acetate. The organic layer was dried over

sodium sulfate and concentrated under reduced pressure. Crude

product was washed with dichloromethane and methanol (1:1)

mixture to afford the corresponding compound (2.40-2.44) as solids.

65

Chapter 2

4-oxo-1-(2-pyridyl)-1, 4-dihydroquinoline-3-carboxylic acid (2.40)

N

O O

OH

N

2.40

Compound was isolated as a sodium salt

Mp: 265-266°C; IR (KBr): 3442, 3049, 1731, 1613, 1551, 1512 and

1477 cm-1.

1H-NMR (300MHz, D2O): δ 7.14 (d, J = 8.7 Hz, 1H), 7.44 (t, J = 7.8 Hz,

1H), 7.57-7.63 (m, 2H), 8.11 (td, J = 7.8 Hz, 1.5 Hz, 1H), 8.24 (d, J =

7.2 Hz, 1H), 8.41 (s, 1H), 8.54 (d, J = 3.6 Hz, 1H).

13C NMR (75MHz, D2O): δ 117.5, 118.5, 122.3, 125.4, 125.7, 125.8,

126.3, 132.9, 139.4, 141.2, 145.5, 149.5, 151.8, 168.4, 172.3, 177.4.

ESI-MS m/z: 289 (M+Na)+ and 267 (M+H)+.

Anal. Calcd (%) for C15H10N2O3: C, 67.67; H, 3.79; N, 10.52. Found.

(%): C, 67.58; H, 3.81; N, 10.53.


N

O O

OH

N

2.41

66

Chapter 2


Mp: 262-263°C.

IR (KBr): 3445, 3028, 1730, 1617, 1549, 1506 and 1474 cm-1; 1H-

NMR (300MHz, D2O): δ 7.05 (d, J = 8.7 Hz, 1H), 7.42 (t, J = 7.8 Hz,

1H ), 7.55 (t, J = 8.4 Hz, 1H ), 7.60-7.64 (m, 1H), 7.95 (d, J = 8.4 Hz,

1H), 8.22 (d, J = 8.1 Hz, 1H), 8.31 (s, 1H), 8.61 (d, J = 2.4 Hz, 1H),

8.64 (d, J = 5.1 Hz, 1H).

13C NMR (75MHz, D2O): δ 120.1, 120.9, 127.9, 128.4, 129.0, 135.5,

139.0, 140.0, 142.8, 149.3, 149.8, 152.6, 170.9, 174.7, 179.7, 183.9;



(%): C, 67.68; H, 3.71; N, 10.50.


N

O O

OH

N

2.42


Mp: 276-280°C.

IR (KBr): 3411, 3030, 1739, 1612, 1550, 1507 and 1466 cm-1; 1H-

NMR (300MHz, D2O): δ 7.18 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 7.8 Hz,

67

Chapter 2

1H), 7.56 (m, 3H), 8.25 (d, J = 8.1 Hz, 1H), 8.33 (s, 1H), 8.71 (d, J =

5.7 Hz, 2H).

13C NMR (75MHz, D2O): δ 117.6, 118.9, 122.7, 125.5, 125.9, 126.5,

133.0, 139.4, 145.7, 148.6, 151.2, 168.3, 172.3, 177.2.



(%): C, 67.62; H, 3.65; N, 10.49.

4-oxo-1-(1-methyl-3-phenylpropyl)-1,4-dihydroquinoline-3-

carboxylic acid (2.43)

N

O O

OH

2.43

Mp: 107-110°C; IR (KBr): 3425, 3027, 2933, 1717, 1615, 1547, 1515

and 1469 cm-1; 1H-NMR (300MHz, DMSO-d6): δ 1.59 (d, J = 6.6 Hz,

3H), 2.26 (m, 2H), 2.6-2.8 (m, 2H), 5.1-5.2 (m, 1H), 7.07-7.20 (m, 5H),

7.65 (t, J = 7.5 Hz, 1H), 7.92 (t, J = 7.2 Hz, 1H), 8.08 (d, J = 8.7 Hz,

1H), 8.40 (d, J = 7.2 Hz, 1H), 8.86 (s, 1H), 15.2 (acid protan); 13C

NMR(75MHz, DMSO-d6): δ 20.2, 31.8, 37.1, 46.1, 56.0, 94.9, 108.3,

117.7, 126.0, 126.3, 126.5, 126.6, 128.5, 128.6, 134.6, 140.3, 140.9,

144.9, 166.3, 177.8; ESI-MS m/z. 322 (M+H)+, 344 (M+Na)+ and 360

(M+K)+.

68

Chapter 2

Anal. Calcd (%) for C20H19NO3: C, 74.75; H, 5.96; N, 4.36. Found. (%):

C, 74.68; H, 5.92; N, 4.38.

4-oxo-1-(4-pyridinemethyl)-1,4-dihydroquinoline-3-carboxylic acid

(2.44)

N

O O

OH

N

2.44


Mp: 264-268°C; IR (KBr): 3442, 3045, 1721, 1614, 1547, 1517 and

1474 cm-1; 1H-NMR (300MHz, D2O): δ 5.53 (s, 2H), 7.07 (d, J = 5.7 Hz,

2H), 7.31-7.39 (m, 2H ), 7.50 (t, J = 7.8 Hz, 1H), 8.20 (d, J = 7.8 Hz,

1H), 8.28 (d, J = 6.0 Hz, 2H), 8.46 (s, 1H); 13C NMR (75MHz, D2O): δ

116.7, 118.0, 121.5, 125.0, 126.1, 127.2, 132.8, 138.6, 145.5, 145.6,

148.2, 148.9, 168.4, 172.2, 176.8; ESI-MS m/z. 281 (M+H)+, 303

(M+Na)+ and 319 (M+K)+.

Anal. Calcd (%) for C16H12N2O3: C, 68.56, H, 4.32; N, 9.99. Found. (%):

C, 68.41, H, 4.32; N, 9.93.

69

Chapter 2

2.6 N-PYRIDYL-1, 4-DIHYDRO-4-OXO-3-QUINOLINE CARBOX-

-AMIDS AS POTENTIAL ANTI VIRAL AND CB2 CANNABINOID

RECEPTOR AGONISTS

2.6.1 Introduction on Quinolone-3-carboxamides as potential

antiviral agents.

Acquired immunodeficiency syndrome (AIDS) caused by the human

immunodeficiency virus (HIV) remains a health threat of global

significance. Although the highly active anti-retroviral therapy

(HAART) effectively reduced the mortality rate and prolonged the life

expectancy in developing and developed countries, it has not

eradicated HIV-1 from the infected tissues. Since viral replication

remains active in cellular reservoirs, the long-term use of the

combined therapy is mandatory but in a restricted way due to the

increased prevalence of HIV-1 resistant strains, metabolic disorders,

and complex administration. Therefore, the search for new anti

retroviral agents are crucial, and compounds that inhibits different

steps of HIV-1.

6-chloro-1,4-dihydro-4-oxo-1-(Dribofuranosyl)quinoline-3-carboxylic

acid (2.45) and the corresponding amides (2.46)11 has shown to

inhibit HIV-1 replication in vitro in both acutely and chronically.

Interestingly, this quinolone class of compounds presents an

extremely low cytotoxic effect compared to AZT.

70

Chapter 2

N

OO

Cl

O

OH OH

OH

OH

2.45

Quinolone derivatives are a class of potential drugs that may

contribute to the control of the latent HIV-1 reservoir. Literature

precedence shows that quinolone carboxamides (2.47)12 show

significant improved anti viral activity on Nipah Virus (NiV), which

belongs to the family of Henipa-virus which caused respiratory

diseases in pigs and in pig-farmers in Malaysia, Singapore,

Bangladesh and in India in 1998. These carboxamides also showed an

excellent activity towards HSV-1 and HSV-2 viruses of Herpes family,

which causes birth defects in infants and variety of diseases in

immuno compromised patients such as retinitis and pneumonia and

chickenpox.

NH

N

OO

Cl

OOH

NH

N

OO

Cl

Cl

F

N

N

O

EtO

2.46 2.47

71

Chapter 2

2.6.2 Quinolone-3-carboxamides as potential CB1 agonists.

Pharmacological point of view, a few compounds such as some

biarylpyrazoles (e.g., SR-144528), 1,2-dihydro quinoline-3-

carboxamide13, 1,8-naphthyridines14, and triaryl bis-sulfones15 are

selective for the CB2 cannabinoid receptor subtype. Recent reports

on molecular modeling and pharmacological characterization studies

reveal that 4-oxo-1, 4-dihydro quinoline-3-carboxamide derivatives

(Figrue-2.2) are active as potent CB2-selective receptor ligands16.

Figure-2.2

N

O O

NH

R

R''

The cannabinoid receptors are a class of cell membrane receptors

under the G-protein coupled receptor super family. Cannabinoid

receptors are activated by ligands, which are lipid compounds known

collectively as cannabinoids. There are two sub types, termed CB1 and

CB2. They differ in sequence, tissue localisation, and to some extent

signal transduction mechanism.

The cannabinoid CB1 receptor is being extensively studied due to its

implications both in the therapeutic and psychoactive effects of

cannabinoids in the central nervous system. Selective cannabinoid

72

Chapter 2

CB1 receptor antagonists are currently under investigation for the

treatment of obesity and the associated metabolic syndrome17.

The cannabinoid CB2 receptors are mainly expressed on T cells of the

immune system, on macrophages, B cells, and in hematopoietic cells.

They also have a function in keratinocytes. The endocannabinoid

system through CB2 signaling plays a key role in the maintenance of

bone mass. CB2 is expressed in osteoblasts, osteocytes, and

osteoclasts. CB2 agonists enhance endocortical osteoblast number and

activity while restraining trabecular osteoclastogenesis. Another

important effect is that CB2 agonists attenuates ovariectomy-induced

bone loss while increasing cortical thickness. These findings suggest

CB2 offers a potential molecular target for the diagnosis and

treatment of osteoporosis. It was very recently shown that low doses of

9-THC (tetrahydrocannabinol) could reduce atherosclerosis in mice

by acting at the CB2 cannabinoid receptor. Cannabinoid agonists that

selectively target CB2 cannabinoid receptors should be devoid of

psychoactive effects and also CB2 cannabinoid receptors participate in

the control of peripheralpain18, inflammation, cough, and cancer

proliferation17. It also has an antifibrogenic role in the liver. Moreover,

the recent discovery of the presence of the CB2 cannabinoid receptors

in the brain microglial cells20 gave a rationale for prevention of

Alzheimer’s disease pathology by cannabinoid agents. Indeed, it was

recently shown that CB2 cannabinoid receptor agonists might provide

neuroprotection by blockade of microglial activation21.

73

Chapter 2

2.6.3 Biological active Quinolone-3-carboxamides

Wyeth has reported synthesis of quinolone-3-carboxamides such as

(Endo)-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-1,4-dihydro-1-ethyl

-4-oxoquinoline-3-carboxamide by using 1-ethyl-1,4-dihydro-4-oxo-

quinolone carboxylic acid, (endo)-3-amino-9-methyl-9-aza bicycle

[3.3.1] nonane dihydrochloride, Isobutyl chloroformate, Triethylamine

in dichloromethane as a solvent (scheme-2.13)22. These compounds

have been reported as 5-HT3 antagonists which is used for

neuropsychiatric disorders

N

OH

OO

O Cl

O

N

NH2

NH

N

OO

N

+ +

2.48 2.49 2.50 2.51

TEA/DCM

Scheme-2.13 Synthesis of 5-HT3 Active quinolone corbaxamides

Upjohn Pharmacia has patented the work on the synthesis of 1-

(Allyloxy)-N-(4-chlorobenzyl)-4-oxo-1,4-dihydro-3-quinoline

carboxamide by using reagents 1,1'-carbonyldiimidazole in DMF as a

solvent (scheme-2.14).23 these compounds reported as antiviral agents

which were active on against viruses of the herpes family .

74

Chapter 2

N

OH

OO

O

NH

N

OO

O

NH2

Cl

N

N

NN

O

+ +

2.52 2.53 2.54 2.55

DMF

Scheme-2.14 Synthesis of antiviral quinolone corbaxamides

Eric et. al24 reported the preparation of various 1, 4-dihydro-4-oxo-3-

quinolinecarboxamid analogues under library synthesis by using

polystyrene-HOBt resin and bromo trispyrrolidinophosphonium

hexafluorophosphate in dimethylformamide at 20°C (scheme-2.15)

with optimum yields and these library of compounds were tested

against CB cannabinoid receptor agonists and the results have shown

that these class of compounds are active.

N

OH

OO

NH

N

OONH

2

+

2.56 2.57 2.58

Polystyrene-HOBtDMF

Scheme-2.15 Synthesis of Cannabinoid agonist quinolone

carboxamides

75

Chapter 2

In similar fashion Eric et al synthesized various potent CB-selective

cannabinoid receptor ligands using PyBRoP (Bromo-tris-pyrrolidino-

phosphonium hexafluorophosphate) as reagent for the synthesis of

1, 4-dihydro-4-oxo-3-quinolinecarboxamid (scheme-2.16).25

N

OH

OO

NH

N

OONH

2

+

2.56 2.59 2.60

PyBRoP

Scheme 2.16 Synthesis of quinolone carboxamides

1, 4-dihydro-4-oxo-3-quinolinecarboxamids were prepared with Et3N,

ethyl chlorocarbonate in CHCl3 at -10°C to-5°C (scheme-2.17).26

NH

OH

OO

NH

NH

OO N N

N

N

NH2

+

2.61 2.62 2.63

TEA/DCM

Scheme-2.17 Synthesis of quinolone carboxamides

76

Chapter 2

1, 4-dihydro-4-oxo-3-quinolinecarboxamid was synthesized by neat

reaction at 120 °C.27 Same reaction was reported in the presence of

pyridine at 125°C (scheme-3.6).28

NH

O

OO

NH

NH

OO

NH2

+

2.64 2.65 2.66

Neat Rexn

Scheme-2.18 Synthesis of quinolone corbaxamides

77

Chapter 2

2.7 RESULTS AND DISCUSSION

The recent interesting results in multiple therapeutic activities above

motivated us to synthesize new analogues of quinolone class of

carboxamides which are active on HIV-1, NiV, HSV-1, HSV-2 and

cannabinoid CB1 receptor agonist. A general and high yielding and

scaleable synthetic route for the preparation of novel N-pyridyl- 1, 4-

dihydro-4-oxo-3-quinolinecarboxamide derivatives (Figure-2.3) in

presence of N, N, N’, N’ tetramethyl-O-(7-azobenzotriazol-1-yl)uronium

hexafluorophosphate (HATU) and diisopropyl ethyl amine was well

demonstrated in this chapter and showed in general scheme-2.19.

Figure-2.3

N

O O

NH

R

R''

2.70-2.82

R = 2-, 3- or 4-Pyridyl / 1-Methyl-3-phenylpropyl / 4-Pyridinemethyl

R' = 1-Phenylethyl / 2-Methylphenyl / 4-Pyridinemethyl

78

Chapter 2

N

O O

OH

RN

O O

NH

R

R'

R-Amine/HATU/diisopropylethyl amine/ DMF/DCM

Scheme 2.19 General scheme for the synthesis of 1,4-

dihydroquinoline-3-carboxamides

The synthesis of N-alkyl/ary-1,4-dihydro-4-oxo-3-quinoline carboxylic

acid (2.40-2.44) were reported in the part 1 of this chapter. These

carboxylic acids were coupled with variety of amines like 4-

(aminomethyl) pyridine (primary amines), phenylethylamine

(secondary amine) and 2-methyl-anilines (aromatic amine). The

coupling agent used in this process was N,N,N’,N’-tetramethyl-O-(7-

azobenzotriazol-1-yl)uronium hexafluoro phosphate (HATU) in mixture

of solvents such as dimethylformamide and dichloromethane which

resulted amides (2.70-2.82) (Table-2.6) in high purity with yields

ranging from 50-75%. The reaction yields have been improved in the

case of HATU reaction when we have changed the base from TEA to

DIPEA.

Initial reactions carried out with coupling agents such as EDC and

HOBt in DCM and DMF mixture resulted only 30-40% of product,

mostly the starting material remained unchanged in the reaction even

after 24 hrs.

79

Chapter 2

2.7.1 Synthesis of 4-oxo-1-(2-pyridyl)-1,4-dihydro quinoline-3-

carboxamide (2.70-2.71)

N

O O

OH

N

NH2

CH3

NH

N

O O

N

NH

N

O O

N

N

NH2

NH2

CH3

No product

2.40

2.67 2.68 2.69


2.70 2.71

Scheme-2.20 Synthesis of 4-oxo-1-(2-pyridyl)-1,4-dihydro quinoline-

3-carboxamide

4-oxo-1-(2-pyridyl)-1,4-dihydro quinoline-3-carboxylicacid (2.40)

treated with phenylethylamine (2.67) in the presence of HATU and

diisopropyl ethyl amine resulted in 4-oxo-N-(1-phenylethyl)-1-(2-

pyridyl)-1,4-dihydroquinoline-3-carbox amide (2.70). Similarly 2-

methylphenyl amine (2.68) resulted 4-oxo-1-(2-pyridyl)-N-(2-

methylphenyl)-1,4-dihydro quinoline-3-carboxamide (2.71). Whereas

80

Chapter 2

4-methylamino pyridine (2.69) did not reacted with acid 2.40 in same

conditions and both the starting materials were remains unchanged

even after 48 hrs. (scheme 2.20).



N

O O

OH

N

NH

N

O O

N

NH

N

O O

N

NH

N

O O

N

N

NH2

CH3

N

NH2

NH2

CH3

2.67 2.68 2.69


2.41

2.72 2.73 2.74


3-carboxamide

4-oxo-N-(1-phenylethyl)-1-(3-pyridyl)-1, 4-dihydro quinoline-3-carbox

amide (2.72), 4-oxo-1-(3-pyridyl) N-(2-methyl phenyl)-1, 4-

dihydroquinoline-3-carbox amide (2.73) and 4-oxo-1-(3-pyridyl)-N-(4-

81

Chapter 2

pyridine methyl)-1, 4-dihydroquinoline-3-carbox amide (2.74) were

prepared from 4-oxo-1-(3-pyridyl)-1, 4-dihydroquinoline-3-carboxylic

acid (2.41) using above reaction conditions with corresponding

amines such as phenylethylamine (2.67), 2-methylphenylamine

(2.68) and 4-methylamino pyridine (2.69) respectively (scheme

2.21)and yeilds are tabulated in table -2.6.



N

O O

OH

N

NH

N

O O

N

NH

N

O O

N

NH

N

O O

N

N

NH2

CH3

NH2

CH3

N

NH2

2.67 2.68 2.69


2.42

2.75 2.76 2.77


3-carboxamide

82

Chapter 2

4-oxo-1-(4-pyridyl)-1, 4-dihydroquinoline-3-carboxylic acid (2.42) was

treated with amines such as phenyl ethylamine, 2-methylphenylamine

and 4-methylamine pyridine to obtain amides such as 4-oxo-N-(1-

phenylethyl)-1-(4-pyridyl)-1, 4-dihydroquinoline-3-carbox amide

(2.75), 4-oxo-1-(4-pyridyl) N-(2-methylphenyl)-1, 4-dihydroquinoline-

3-carbox amide (2.76) and 4-oxo-1-(4-pyridyl)-N-(4-pyridinemethyl)-1,

4-dihydroquino line-3-carbox amide (2.77) as shown in scheme-2.22.

2.7.4 Synthesis of 4-oxo-1-(1-methyl-3-phenyl propyl)-1,4-dihydro

quinoline-3-carboxamide (2.78-2.79)

N

O O

OH

N

O O

NH

N

O O

NH

NH2

CH3

NH2

CH3

N

NH2

No product

2.67 2.68 2.69


2.43

2.78 2.79

Scheme 2.23 Synthesis of 4-oxo-1-(1-methyl-3-phenyl propyl)-1,4-

dihydro quinoline-3-carboxamide

83

Chapter 2

4-oxo-1-(1-methyl-3-phenylpropyl)-N-(1-phenylethyl)-1,4-dihydro

quinoline-3-carboxamide (2.78) and 4-oxo-1-(1-methyl-3-phenyl

propyl) N-(2-methylphenyl)-1, 4-dihydro quinoline-3-carboxamide

(2.79) were prepared from 4-oxo-1-(1-methyl-3-phenylpropyl)-1, 4-

dihydroquinoline-3-carboxylic acid (2.43). The acid 2.43 was tretaed

with phenyl ethylamine and 2-methyl phenylamine to obtain the

corresponding compounds 2.78 and 2.79 . Whereas 2.73 did not

reacted with 4-methylamine pyridine in presence on both coupling

reagents such as EDC-HOBt and HATU and starting materials were

remained unchanged (scheme-2.23).

2.7.5 Synthesis of 4-oxo-1-(4-pyridinemethyl)-1,4-di hydro

quinoline-3-carboxamide (2.80-2.82)

4-oxo-N-(1-phenylethyl)-1-(4-pyridinemethyl)-1, 4-di hydroquinoline-

3-carboxamide (2.79), 4-oxo-1-(4-pyridinemethyl)- N-(2-methyl

phenyl)-1, 4-dihydroquinoline-3-carboxamide (2.81) and 4-oxo-N, 1-

bis(4- pyridinemethyl)-1, 4-dihydroquinoline-3-carboxamide (2.82)

were synthesized from 4-oxo-1-(4-pyridinemethyl)-1, 4-

dihydroquinoline-3-carboxylic acid (2.44) which was condensed with

phenyl ethylamine, 2-methyl phenylamine and 4(amino methyl)

pyridinein using HATU and diisopropyl ethyl amine in mixture of

dichloromethane and dimethylformide to obtain corresponding

compounds as shown in scheme- 2.24.

84

Chapter 2

N

O O

OH

N

N

O O

NH

N

N

O O

NH

N

N

O O

NH

N

N

NH2

CH3

NH2

CH3

N

NH2

2.67 2.68 2.69


2.44

2.80 2.81 2.82

Scheme-2.24 Synthesis of 4-oxo-1-(4-pyridinemethyl)-1,4-di hydro

quinoline-3-carboxamide

Table-2.6 Synthesis of 4-oxo-N-(pyridyl)-1-(aryl)-1, 4-

dihydroquinoline-3-carboxamide (2.70-2.82)

N

O O

NHR1

R

2.70-2.82

85

Chapter 2

Entry Product R R1 Yield

1 2.70 N

CH3

55

2 2.71 N

CH3

55

3 2.72 N

CH3

65

4 2.73 N

CH3

75

5 2.74 N

N

68

6 2.75 N

CH3

45

7 2.76 N

CH3

65

8 2.77 N

N

53

9 2.78

CH3

50

86

Chapter 2

2.8 CONCLUSION

In conclusion, In this chapter we have demonstrated an efficient

synthesis for the preparation of various novel 4-oxo-N-(pyridyl)-1,4-

dihydroquinoline-3-carboxamides (2.70-2.82) with 50-70% yield.

These carboxamides are prepared as potential new candidates for anti

viral and cannabinoid CB2 receptor agonists.

10 2.79

CH3

60

11 2.80 N

CH3

46

12 2.81 N

CH3

60

13 2.82 N

N

69

87

Chapter 2

2.9 EXPERIMENTAL SECTION

General procedure for 4-oxo-1-(pyridyl)-1, 4-dihydroquinoline-3-


A stirred solution of 1,4-dihydro-4-oxo-1-(alkyl/aryl)quinoline-3-

carboxylic acid (2.40-2.44) (0.0037 mol), selected amine (0.00563

mol), diisopropylethyl amine (0.0075 mol) and N, N, N’, N’ tetramethyl-

O-(7-azo benzotriazol-1-yl)uronium hexafluorophosphate (HATU)

(0.00563 mol) in a mixture of dimethyl formamide (1 ml) and

dichloromethane (10 ml) was stirred at 25-30°C for 2-3 h. After

completion of reaction, the reaction mixture was quenched with water

and extracted with ethylacetate. Organic layer was concentrated

under reduced pressure. The residue obtained was purified by column

chromatography using 2% methanol in dichloromethane as an eluent

to afford the corresponding pure 4-oxo-1-(pyridyl)-1,4-

dihydroquinoline-3-carboxamide (2.70-2.82).

4-oxo-N-(1-phenylethyl)-1-(2-pyridyl)-1,4-dihydroquinoline-3-

carbox amide (2.70)


NH

N

O O

N

2.70

88

Chapter 2

Mp: 134-137°C.

IR (KBr): 3434, 3057, 2979, 1663, 1604 and 1545 cm-1.

1H NMR (300MHz, CDCl3 ): δ 1.63 (d, J = 7.5 Hz, 3H), 5.34 (m, 1H),

7.20 – 7.63 (m, 10H), 8.01 ( td, J = 7.8 Hz, 1.2 Hz, 1H), 8.54 ( dd, J =

7.8 Hz, 1.2 Hz, 1H), 8.72 ( dd, J = 4.8 Hz, 1.2 Hz, 1H), 8.93, ( s, 1H)

and 10.42 (d, J = 7.5 Hz, NH).

13C NMR (75MHz, CDCl3 ): δ 23.2, 48.4, 111.6, 118.3, 122.4, 123.9,

125.8, 126.0, 126.3, 126.6, 127.2, 128.8, 129.0, 133.5, 139.6, 140.8,

144.5, 147.0, 150.4, 152.6, 163.1, 176.5.


4-oxo-1-(2-pyridyl)-N-(2-methylphenyl)-1,4-dihydroquinoline-3-

carbox amide (2.71)


NH

N

O O

N

2.71

Mp: 145-148°C.

IR (KBr): 3454, 3047, 2958, 1726, 1677, 1606 and 1547 cm-1.

1H NMR (DMSO-d6, 300MHz): δ 2.41 (s, 3H), 7.01 (m, 1H), 7.18 (t, J =

7.8 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.60 (m,

1H), 7.73 (m, 2H), 7.88 (d, J = 7.8 Hz, 1H), 8.21 (td, J = 7.8 Hz, 2.1 Hz,

89

Chapter 2

1H), 8.29 (d, J = 7.5 Hz, 1H), 8.46 (dd, J = 8.1 Hz, 1.2 Hz, 1H), 8.76

(m, 1H), 8.9 (s, 1H) and 12.21 (br, NH).

13C NMR (75MHz, DMSO-d6): δ 18.3, 111.8, 118.4, 121.0, 122.5,

124.0, 125.9, 126.3, 126.5, 126.6, 126.7, 127.4, 130.6, 133.8, 137.4,

139.6, 140.8, 147.6, 150.5, 152.5, 162.2, 176.7.


4-oxo-N-(1-phenylethyl)-1-(3-pyridyl)-1, 4-dihydroquinoline-3-

carbox amide (2.72)


NH

N

O O

N

2.72

Mp: 170-172°C.

IR (KBr): 3450, 3054, 2969, 1666, 1604 and 1538 cm-1.

1H-NMR (300MHz, DMSO-d6): δ 1.48 (d, J = 6.9 Hz, 3H), 5.16 (m, 1H),

7.02 (d, J = 8.1 Hz, 1H), 7.32 (m, 1H), 7.36 (m, 3H), 7.55 (td, J = 8.1

Hz, 0.6 Hz, 1H), 7.70 (m, 2H), 8.16 (d, J = 8.4 Hz, 1H), 8.39 (dd, J =

8.1 Hz, 1.2 Hz, 1H), 8.61 (s, 1H), 8.82 (dd, J = 4.8 Hz, 1.5 Hz, 1H),

8.86 (d, J = 2.1 Hz, 1H) and 10.37 (d, J=7.8, NH).

13C NMR (75MHz, DMSO-d6): δ 23.2, 80.4, 111.7, 118.4, 125.2, 125.8,

126.3, 126.4, 126.8, 127.2, 128.8, 133.7, 136.0, 137.6, 140.8, 144.6,

148.3, 148.7, 151.3, 163.1, 176.5.

90

Chapter 2

ESI-MS m/z: 392 (M+Na)+ and 370 (M+H) +

4-oxo-1-(3-pyridyl) N-(2-methylphenyl)-1, 4-dihydroquinoline-3-

carbox amide (2.73)


NH

N

O O

N

2.73

Mp: 211-212°C.

IR (KBr): 3459, 3039, 1675, 1605 and 1548 cm-1.

1H-NMR (300MHz, DMSO-d6): δ 2.42 (s, 3H), 7.02 (td, J = 7.5 Hz, 1.2

Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.60 (td, J =

7.5 Hz, 0.9, 1H), 7.75 (m, 2H), 8.22 (m, 1H), 8.28 (d, J = 7.2 Hz, 1H),

8.48 (dd, J = 8.1 Hz, 1.5 Hz, 1H), 8.79 (s, 1H), 8.85 (dd, J = 4.8 Hz, 1.5

Hz, 1H), 8.92 (d, J = 2.1 Hz, 1H) and 12.16 (s, NH).

13C NMR (75MHz, DMSO-d6): δ 18.3, 111.8, 118.5, 121.0, 123.9,

125.3, 126.1, 126.5, 126.6, 126.7, 127.4, 130.6, 133.9, 136.1, 137.4,

137.5, 140.9, 148.7, 148.8, 151.4, 162.3, 176.7


4-oxo-1-(3-pyridyl)-N-(4-pyridinemethyl)-1, 4-dihydroquinoline-3-

carbox amide (2.74)


91

Chapter 2

NH

N

O O

N

N

2.74

Mp: 193-197°C.

IR (KBr):3447, 3039, 1662, 1603 and 1541 cm-1.

1H-NMR (300MHz, DMSO-d6): δ 4.61 (d, J = 6.0 Hz, 2H), 7.04 (d, J =

8.4 Hz, 1H), 7.30 (d, J = 5.7 Hz, 2H), 7.56 (t, J = 7.8 Hz, 1H), 7.72 (m,

2H), 8.16 (m, 1H), 8.41 (dd, J = 8.1 Hz, 0.6 Hz, 1H), 8.48 (d, J = 4.5

Hz, 2H), 8.65 (s, 1H), 8.83 (dd, J = 4.8 Hz, 1.5 Hz, 1H), 8.87 (d, J = 2.1

Hz, 1H) and 10.36 (t, J = 6.0 Hz, NH).

13C NMR (75MHz, DMSO-d6): δ 41.6, 111.6, 118.4, 122.5, 125.2,

125.9, 126.4, 126.8, 133.7, 136.1, 137.5, 140.9, 148.4, 148.7, 148.8,

149.9, 151.3, 164.5, 176.3.

ESI-MS m/z: 357 (M+H)+

4-oxo-N-(1-phenylethyl)-1-(4-pyridyl)-1, 4-dihydroquinoline-3-

carbox amide (2.75)


NH

N

O O

N

2.75

92

Chapter 2

Mp: 190-195°C.

IR (KBr): 3422, 3056, 2963, 1667, 1607 and 1547 cm-1.


7.16 (d, J = 8.4 Hz, 1H), 7.26 (m, 1H), 7.35 (m, 4H), 7.57 (m, 1H), 7.72

(m, 1H), 7.73 (m, 2H), 8.38 (dd, J = 8.1 Hz, 1.5 Hz, 1H), 8.59 (s, 1H),

8.89 (dd, J = 4.5 Hz, 1.5 Hz, 2H) and 10.33 (d, J = 7.8 Hz, NH).

13C NMR (75MHz, DMSO-d6): δ 23.0, 48.5, 112.0, 117.9, 122.5, 125.7,

126.1, 126.5, 126.9, 127.0, 128.6, 133.3, 139.7, 144.5, 147.2, 147.8,

152.3, 163.1, 176.5.


4-oxo-1-(4-pyridyl) N-(2-methylphenyl)-1, 4-dihydroquinoline-3-

carbox amide (2.76)


NH

N

O O

N

2.76

Mp: 208-210°C.

IR (KBr): 3455, 3041, 2921, 1678, 1608 and 1541 cm-1.

1H-NMR (300MHz, DMSO-d6): δ 2.42 (s, 3H), 7.01 (td, J = 7.5 Hz, 0.9

Hz, 1H), 7.18 (t, J = 8.1 Hz, 2H), 7.26 (d, J = 7.2 Hz, 1H), 7.60 (td, J =

8.1 Hz, 0.9 Hz, 1H), 7.77 (m, 1H), 7.81 (dd, J = 4.5 Hz, 1.5 Hz, 2H),

93

Chapter 2

8.28 (d, J = 7.5 Hz, 1H), 8.46 (dd, J = 8.1 Hz, 1.2 Hz, 1H), 8.77 (s, 1H),

8.93 (dd, J = 4.5 Hz, 1.5 Hz, 2H) and 12.11 (br, NH).

13C NMR (75MHz, DMSO-d6): δ 18.3, 112.0, 118.4, 121.0, 122.7,

123.9, 126.2, 126.6, 126.7, 127.4, 130.6, 133.9, 137.4, 139.9, 147.9,

148.0, 152.4, 162.2, 176.7.


4-oxo-1-(4-pyridyl)-N-(4-pyridinemethyl)-1, 4-dihydroquinoline-3-

carbox amide (2.77)


NH

N

O O

N

N

2.77

Mp: 195-198°C.

IR (KBr): 3445, 3056, 2921, 1660, 1605 and 1544 cm-1.

1H-NMR (300MHz, DMSO-d6): δ 4.60 (d, J = 6.0 Hz, 2H), 7.17 (d, J =

8.4 Hz, 1H), 7.30 (dd, J = 4.5 Hz, 1.5, 2H), 7.58 (td, J = 7.8 Hz, 0.9 Hz,

1H), 7.73 (m, 1H), 7.76 (dd, J = 4.5 Hz, 1.5 Hz, 2H), 8.40 (dd, J = 8.1

Hz, 1.5 Hz, 1H), 8.48 (dd, J = 4.5 Hz, 1.5 Hz, 2H), 8.63 (s, 1H), 8.88

(dd, J = 4.5 Hz, 1.5 Hz, 2H) and 10.32 (t, J = 6.0 Hz, NH).

13C NMR (75MHz, DMSO-d6): δ 41.6, 111.7, 118.3, 122.5, 122.7,

126.0, 126.4, 126.8, 133.7, 139.8, 147.6, 147.9, 148.8, 149.9, 152.4,

164.4, 176.3.

94

Chapter 2


4-oxo-1-(1-methyl-3-phenylpropyl)-N-(1-phenylethyl)-1, 4-dihydro

quinoline-3-carboxamide (2.78)

Compound was isolated as viscous syrup

N

O O

NH

2.78

IR (KBr): 3450, 2929, 1660, 1603 and 1543 cm-1.

1H NMR (300MHz, CDCl3 ): δ 1.61 (d, J = 6.8 Hz, 3H), 1.63 (d, J = 6.7

Hz, 3H), 2.21 (m, 1H), 2.33 (m, 1H), 2.65 (m, 2H), 4.71 (m, 1H,) 5.31

(m, 1H), 7.00-7.63 (m, 12H), 8.56 (d, J = 8.2 Hz, 1H), 8.91 (d, J = 3.0

Hz, 1H) and 10.54 (d, J = 7.5 Hz, NH).

13C NMR (75MHz, CDCl3 ): δ 20.2, 22.9, 31.9, 37.2, 48.9, 53.8, 112.0,

114.9, 124.7, 126.0, 126.4, 126.8, 127.4, 128.2, 128.4, 128.5, 139.5,

142.9, 144.2, 164.1, 176.2.

ESI-MS m/z: 425 (M+H)+.

4-oxo-1-(1-methyl-3-phenylpropyl) N-(2-methylphenyl)-1, 4-

dihydro quinoline-3-carboxamide (2.79)

Compound was isolated as viscous syrup

95

Chapter 2

N

O O

NH

2.79

IR (KBr): 3452, 2926, 1676, 1605 and 1543 cm-1.

1H-NMR (300MHz, DMSO-d6): δ 1.59 (d, J = 6.2, 3H), 2.25 (m, 2H),

2.39 (s, 3H), 2.62 (m, 2H), 5.11 (m, 1H), 7.02 (td, J = 7.4 Hz, 1.2, 1H),

7.10-7.22 (m, 7H), 7.56 (t, J = 7.4 Hz, 1H), 7.83 (m, 1H), 7.98 (d, J =

9.0 Hz, 1H), 8.34 (m, 1H), 8.45 (dd, J = 7.5 Hz, 1.5 Hz, 1H), 8.96 (s,

1H) and 12.25 (br, NH).

13C NMR (75MHz, DMSO-d6): δ 18.4, 20.3, 31.8, 37.3, 55.2, 111.5,

117.0, 120.9, 123.7, 125.6, 126.3, 126.6, 126.9, 127.3, 127.4, 128.5,

128.6, 130.6, 133.6, 137.6, 139.9, 140.9, 143.8, 162.7, 175.8; ESI-

MS m/z: 433 (M+Na)+ and 411 (M+H)+.

4-oxo-N-(1-phenylethyl)-1-(4-pyridinemethyl)-1,4-dihydro

quinoline-3-carboxamide (2.80)


N

O O

NH

N

2.80

Mp: 217-219°C.

96

Chapter 2

IR (KBr): 3434, 3043, 2961, 1668, 1609 and 1561 cm-1.


5.83 (s, 2H), 7.14 (d, J = 6.0 Hz, 2H), 7.24 (m, 1H), 7.38 (m, 4H), 7.50

(t, J = 7.8 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.71 (m, 1H), 8.34 (dd, J =

8.0 Hz, 1.5, 1H), 8.48 (d, J = 6.0 Hz, 2H), 9.05 (s, 1H) and 10.43 (d, J

= 7.8 Hz, NH).

13C NMR (75MHz, DMSO-d6): δ 116.7, 118.0, 121.5, 125.0, 126.1,

127.2, 132.8, 138.6, 145.5, 145.6, 148.2, 148.9, 168.4, 172.2, 176.8;

ESI-MS m/z: 384 (M+H)+

4-oxo-1-(4-pyridinemethyl)- N-(2-methylphenyl)-1, 4-

dihydroquinoline-3-carboxamide (2.81)

N

O O

NH

N

2.81

Mp: 230-233°C.

IR (KBr):3449, 3037, 2977, 1668, 1608 and 1534 cm-1.

1H-NMR (300MHz, DMSO-d6): δ 2.41 (s, 3H), 5.92 (s, 2H), 7.00 (td, J =

7.5 Hz, 0.9, 1H), 7.20 (m, 3H), 7.25 (d, J = 7.5 Hz, 1H), 7.53 (t, J = 7.1

Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.75 (m, 1H), 8.32 (d, J = 8.0 Hz,

1H), 8.44 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 8.50 (d, J = 4.5 Hz, 2H), 9.23 (s,

1H) and 12.24 (br, NH).

97

Chapter 2

13C NMR (75MHz, DMSO-d6): δ 18.4, 55.3, 111.8, 118.1, 121.0, 121.7,

123.7, 125.9, 126.7, 126.8, 127.3, 127.5, 130.6, 133.7, 137.6, 139.4,

145.4, 150.0, 150.4, 162.6, 176.5.


4-oxo-N,1-bis(4-pyridinemethyl)-1,4-dihydroquinoline-3-carbox

amide (2.82)

N

O O

NH

N

N

2.82

Mp: 246-249°C.

IR (KBr):3434, 3044, 2924, 1663, 1602 and 1562 cm-1.

1H NMR (300MHz, CDCl3 ): δ 4.72 (d, J = 6.0 Hz, 2H), 5.48 (s, 2H),

7.05 (d, J = 6.0 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 6.0 Hz,

2H), 7.50 (td, J = 7.8 Hz, 0.6 Hz, 1H), 7.64 (m, 1H), 8.57 (m, 3H), 8.62

(dd, J = 4.8 Hz, 1.8 Hz, 2H), 8.92 (s, 1H) and 10.53 (t, J = 6.0 Hz, NH).

13C NMR (75MHz, CDCl3 ): δ 42.0, 56.3, 112.0, 116.2, 120.6, 122.1,

125.5, 127.5, 127.9, 133.2, 138.9, 143.1, 147.7, 148.5, 149.8, 150.7,

165.0, 176.8.


98

Chapter 2

2.10 SPECTRAL DATA (1H NMR, 13C NMR, MASS and IR)

2.10.1 (Spectrum 1, compound 2.28) 1H NMR Spectrum

(300MHz, DMSO-d6)

2.10.2 (Spectrum 2, compound 2.28) MASS Spectrum

99

Chapter 2


(300MHz, DMSO-d6)


100

Chapter 2

2.10.5 (Spectrum 5, compound 2.30) IR Spectrum (KBr)


(300MHz, DMSO-d6)

101

Chapter 2


(300MHz, DMSO-d6)


102

Chapter 2


(300MHz, DMSO-d6)


(300MHz, DMSO-d6)

103

Chapter 2



104

Chapter 2


(300MHz, DMSO-d6)


105

Chapter 2



(300MHz, D2O)

106

Chapter 2

2.10.17 (Spectrum 17, compound 2.41) 13C NMR Spectrum

(75MHz, D2O)


107

Chapter 2



(300MHz, DMSO-d6)

108

Chapter 2


(75MHz, DMSO-d6)


109

Chapter 2



(300MHz, D2O)

110

Chapter 2


(75MHz, D2O)


111

Chapter 2



(300MHz, DMSO-d6)

112

Chapter 2


(75MHz, DMSO-d6)


113

Chapter 2



(300MHz, DMSO-d6)

114

Chapter 2


(75MHz, DMSO-d6)


115

Chapter 2



(300MHz, DMSO-d6)

116

Chapter 2


(75MHz, DMSO-d6)


117

Chapter 2



(300MHz, CDCl3)

118

Chapter 2


(75MHz, CDCl3)


119

Chapter 2



(300MHz, DMSO-d6)

120

Chapter 2


(75MHz, DMSO-d6)


121

Chapter 2


122

Chapter 2

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chapter 2 synthesis of novel n-alkyl/aryl-1,4-dihydro...

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