studies on clinically important nitrogen and sulphur...

Studies on clinically important nitrogen and sulphur containing heterocyclic compounds

DECEMBER 2013 Page 97

Part 3 In part-III, we have incorporated two medicinally important heterocycles i.e.

quinoline and dihydropyrimidine. It is our ongoing program to search for novel

bio-active molecules.

Introductory features of quinolines

Quinoline (1-azanaphthalene or benzo[b]pyridine) is a stable base. Its derivatives

represent the major class of heterocycles and a number of preparations have

been known for a long time. The quinoline ring system occurs in various natural

products, especially in alkaloids.1-5 The quinoline skeleton is used for many

valuable synthetic agrochemicals and to design many synthetic compounds with

diverse pharmacological activities, dyestuffs6,7 and synthetic building blocks.8,9

In 1959 Rao and Cullen10 disclosed the isolation of an initially un-named dark

brown metabolite of streptomycin floccules that exhibited striking activity against

several animal tumors.11,12 The same crystalline compound was isolated from S.

afrochromogens and S. echinatus. The active agent of all these streptomyces and

actinomyces species is streptonigirin.13 By applying variations on the same

molecular framework,14 two closely related antibiotics, streptonigrone and

lavendamycin were isolated.15 Looking to the literature survey, there are a

number of reports available that covers the isolation, structure determination,

synthesis and biological activity of quinoline alkaloids from plant, microbial and

animal sources,16-22 in which some of the therapeutically active quinoline

alkaloids are cryptolepine as an antimalarial,23-25 buchapine as an anti-HIV,26

semecarpifoline as an antiplatelet and aggregation,27 galipeine as an antimalarial

and cytotoxic28 and aaptamine as cardiac.29

Some synthetic derivatives containing quinoline ring system have been shown

to possess useful pharmacological activities, such as dibucaine hydrochloride

is an anaesthetic, primaquine is an antimalarial agent, apomorphine is

antiperkinosine and oxamniquine is schistosomicidal. Considerable interest

has been created in the chemistry of quinoline due to their wide spectrum of

therapeutic activities like bactericidal,30 anti-HIV,31 antimalarial,32,33 antitumor,34

inhibitors of gastric (H+/K+)-ATPase,35 dihydroorotate dehydrogenase,36 5-

lipoxygenase,37 and leukotriene D4 receptor.38 In fact, introducing chloroquine



into treatment of malaria more than 60 years ago triggered a new era of quickly

developing antimicrobial drugs through nalidixic acid and fluoroquinolones.

Commercially available quinoline based analogues

Synthetic study of quinolines

In the broad field of quinoline, 2-chloro-3-formyl quinoline possesses a prominent

position in the intermediate category as it can be utilized for the synthesis of

many heterocyclic compounds. There has been relentless interest towards the

use of Vilsmeier-Haack reagent in organic synthesis of several nitrogen and



oxygen heterocycles. It is proved to be a mild and efficient method for the

formylation39-41 of reactive aromatic, heteroaromatic and carbonyl compounds.

The utility of this reagent also explores a powerful route for the synthesis of

substituted 2-chloro-3-formyl quinoline. Meth-Cohn et al42 have shown that

treatment of acetanilide (1) with Vilsmeier-Haack reagent using POCl3 allows the

preparation of 2-chloro-3-formyl quinoline (2).

Bose D S and Kumar R K43 have developed an efficient method for the

condensation of 2-aminoaryl ketones (3) with �-methylene ketones (4) in the

presence of catalytic amount of reusable catalyst CeCl3·7H2O (25 mol %) at

ambient temperature to afford the corresponding poly-substituted quinolines (5)

in high yields under mild conditions.

Li-Min W et al44 have proved that ytterbium perfluorooctanoate [Yb(PFO)3], is an

efficient catalyst for Doebner reaction of pyruvic acid (6), aldehydes (8) and

amines (7) under mild conditions in water to afford quinoline-4-carboxylic acid

derivatives (9) with three component one-pot method in good yield. The process is

operationally simple and environmentally benign and the catalyst has readily

been recycled several times with consistent activity.



Suchaud V et al45 have synthesized ethyl 3-hydroxy-2-oxoquinoline-4-

carboxylates (12) from various isatin derivatives (10). Martinez R et al46 have

synthesized polysubstituted quinolines (15) by direct reaction between the

corresponding 2-aminobenzylic alcohol derivative (13) and either a ketone or

alcohol (14) in the presence of a base, without any transition-metal catalyst.

Yang D et al47 have synthesized a rapid and efficient method for the preparation

of various poly-substituted 1H-indeno[1,2-b]quinolines (18) via the Friedlander

condensation of 2-aminoarylaldehyde (16) with a carbonyl compound (17) containing a reactive α-methylene group in the presence of sodium ethoxide

(10 mol %).



Ramakrishnan V T et al48 have synthesized methyl-2-methyl-4-aryl-5-oxo-1H,4H-

5,6,7,8-tetrahydro-quinoline-3-carboxylates (22) by condensation of cyclic 1,3-

diones (21) with aromatic aldehydes (19) and β-aminocrotonate (20) using

thermal and ultrasound irradiation methods.

Kidwai M et al49 have developed a convenient eco-friendly procedure for the

quantitative synthesis of novel quinoline derivatives (25) by simple one pot

reaction of substituted aniline (23) with β-ketoesters (24) at 60 ˚C in ethanol

using recyclable indium chloride as catalyst. The reaction proceeds smoothly

under solvent free conditions with quantitative yield. Garudachari B et al50 have

designed series of quinoline incorporated benzimidazole derivatives (29) from

substituted aniline (26) and p-fluorobenzaldehyde (27) through intermediate 6-

substituted-4-carboxyquinolines (28).



Pharmacological profile of quinolines

Zarghi A et al51 have synthesized a group of 4-carboxyl quinoline (30) derivatives

possessing a methylsulfonyl COX-2 pharmacophore at the para position of the

C-2 phenyl ring as selective COX-2 inhibitors. In vitro COX-1/COX-2 structure

activity relationships were determined by varying the substituents on C-7 and

C-8 quinoline ring. Nandhakumar R et al52 have showed the study of Vilsmeier–

Haack reagent on 4-hydroxy-quinaldines which resulted in a new versatile

intermediate 4-chloro-3-formyl-2-(2-hydroxy-ethene-1-yl)quinolines, which on

further treatment with hydrazine hydrate yielded the desired diazepino quinoline

derivatives (31). Desai et al53 have synthesized new N-[6-(2-chloro(3-quinolyl))-4-

(aryl)pyrimidin-2-yl]-2-morpholin-4-ylacetamides (32) by Vilsmeier-Haack



reaction. Several compounds were found to possess promising antimicrobial

activity.

Desai N C et al54 have synthesized N-(4-((2-chloroquinolin-3-yl)methylene)-5-oxo-

2-phenyl-4,5-dihydro-1H-imidazol-1-yl)-(aryl)amides (33) and studied their

antimicrobial activity. Same group55 has synthesized 1-[2-(2-chloro(3-quinolyl))-5-

(4-nitrophenyl)(1,3,4-oxadiazolin-3-yl)]-3-(aryl)prop-2-en-1-ones (34). Some of

these compounds were found to be good antimicrobial agents.



Paloque L et al56 have synthesized 2-hydroxy-8-nitroquinoline (35) and evaluated

for their in vitro antileishmanial molecule against both Leishmania infantum

promastigotes and the intracellular L. donovani amastigotes. Prasad R et al57

have reported 2-oxo-pyrano[2,3-b]quinoline derivatives (36), and these were

subjected to ammonia treatment to yield the corresponding 2-oxopyrido- [2,3-

b]quinoline derivatives (37). These compounds were tested for antimalarial,

diuretic and antimicrobial activities.

Introductory features of dihydropyrimidines

Pyrimidine is the most important member of all the diazines as this ring system

occurs widely in living organism. Pinner58 was the man who first gave the name

pyrimidine to the unsubstituted parent ring. The chemistry59,60 of pyrimidine has

been widely studied in detail. Derivatives of barbituric acid (38), i.e. oxygenated

pyrimidines are perhaps the most widely used in medicine. For example veronal

(39) is used as hypnotics while sodium pentothal (40) is used as an anaesthetic.

In this connection, great attention has recently been paid to the derivatives of

pyrimidine, including their hydrogenation products. The first investigation into

the synthesis of pyrimidine nucleus appeared more than a hundred years ago

and subsequently several methods for the synthesis of dihydropyrimidine were


DECEMBER 2013 5

reported and their physicochemical properties has been studied (e.g., the Biginelli

reaction).61 Further, the high reactivity and wide range of biological activity

associated with these scaffolds have been demonstrated in the literature. For

example, 2-substituted 5-alkoxycarbonyl-4-aryl-l,4-dihydropyrimidines

(structural analogs of Hantzsch esters) are modulators of the transport of calcium

through membranes.62-64

Several important sulpha drugs are pyrimidine derivatives and namely they are

sulphadiazine (41a), sulphamerazine (41b) and sulphamethiazine (41c). The

antibiotic bacimethrin (42), is a comparatively, simple pyrimidine which has been

synthesized.65

Three pyrimidines are of considerable biological importance because of their

relation to the nucleic acid, these are uracil (43a), thymine (43b) and cytosine

(44). These are known to be concerned principally with the biosynthesis of

complex carbohydrates and lipids. The purine ring system obtained from the

fusion of pyrimidine and imidazole nuclei is very important because certain of its

derivatives, as example adenine (45), are building block of RNA and DNA. Many

substituted pyrimidines and compounds in which pyrimidine ring is a part of a

more complex ring system are very widely distributed. Vitamin B1, B2 and B10 are

pyrimidines. Certain pyrimidine ribosides and deoxyribosides called nucleosides

occur as phosphoric esters. Some coenzymes are nucleotides that play a key role

in metabolic processes. Hence, at present research is focused on the chemistry of

pyrimidines.



Commercially available pyrimidine based analogues



Synthetic study of dihydropyrimidines

Chalcone derivatives66 are important starting materials for the syntheses of

different classes of heterocyclic compounds such as pyrazolines, thiophenes and

pyrimidines etc. Most of these compounds are highly bioactive and are widely

used in pharmaceutics. Since the late 1980s, tremendous interest in the

pyrimidine derivatives has been observed, as evidenced by the growing number of

publications.67,68 Recently, pyrimidine derivatives were found to be associated

with biological activities such as antimalarial,69,70 antibacterial71 and anticancer72

activities. Numerous methods have been reported to prepare pyrimidine

derivatives.73-76

Chandra A et al77 have synthesized the 2-amino-3H-pyrimido[4,5-b]quinolin-4-

ones (48) from t-BuOK-catalyzed cyclization of 2-chloroquinoline-3-carbonitriles

(47) with guanidine hydrochloride. Ramesh B et al78 have reported the synthesis

of novel dihydropyrimidines (50), their dimethylated adducts (51) by three component synthesis between different aldehydes, ethyl cyanoacetate and

thiourea.



Virsodia V et al79 have reported the novel substituted N-phenyl-6-methyl-2-oxo-4-

phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamides (53) as antitubercular

agents derived from substituted acetoacetanilides (52), various aromatic

aldehydes and urea.

Recently, Munawar M A et al80 have reported synthesis and antimicrobial studies

of some quinolinyl pyrimidine derivatives (57). They first synthesized chalcones

(56) by the Claisen-Schmidt condensation reaction between ketone derivatives

(54) and different aldehydes (55) and then quinolinyl chalcones condensed with

urea (or thiourea) in basic media under prolonged refluxing conditions.



De S K and Gibbs R A81 have reported the Sc(III)triflate efficiently catalyzes the

three-component condensation reaction of an aldehyde (58), a β-ketoester (59)

and urea (60) in refluxing acetonitrile to afford the corresponding 3,4-

dihydropyrimidin-2(1H)-ones (61) in excellent yields. The catalyst can be

recovered and reused, making this method friendly and environmentally

acceptable.

Sedova V F et al82 have synthesized 4,6-diaryl-5-nitro-3,4-dihydropyrimidin-

2(1H)-ones (65) using ω-nitro acetophenone (62), aromatic aldehydes (64) and

urea (63) in the presence of iron(III), cobalt(II), nickel(II), and copper(II) salts as

catalyst with moderate to poor yields.

Dandia A et al83 described microwave-enhanced solution-phase Biginelli reactions

employing ethyl acetoacetate (66), thiourea (67) and a wide variety of aromatic

aldehydes (68) as building blocks. Upon irradiation of the individual reaction

mixtures (ethanol, catalytic HCl) in an open glass beaker inside the cavity of a

domestic microwave oven, the reaction time was reduced from 2–24 hours of

conventional heating 80 °C, reflux to 3–11 minutes under microwave activation

(ca. 200-300 W). At the same time the yields of DHPMs (69) obtained were

distinctly improved compared to those reported earlier using conventional

conditions.



Abdel-Mohsen S A84 have synthesized 3-amino-4-imino-5-(8-quinolinol-5-yl)-7-

(p-tolyl)-3,4-dihydropyrrolo[2,3-d]pyrimidine (73) from 2-ethoxymethyleneamino-

4-(8-quinolinol-5-yl)-1-(p-tolyl)-pyrrole-3-carbonitrile (72) in the presence of dry

benzene and hydrazine hydrate. They also reported antibacterial and antifungal

activities of the synthesized compounds.

Pharmacological profile of dihydropyrimidines

There has been considerable interest in the development of different types of

synthesis for the production of pyrimidines. This is because pyrimidines

represent one of the most active classes of compounds, possessing a wide

spectrum of biological activity.85,86 Pyrimidines and their fused ring derivatives

have a broad spectrum of biological activity; best known as heterocyclic core of



the nucleic acid bases. These ring systems are often incorporated into drugs

designed for anticancer,87,88 antiviral,89 antihypertensive,90 analgesic,91

antipyretic,92 anti-inflammatory,93 antipsoriasis94 agents. Nowadays, interest is

also focused on aza-analogs such as dihydropyrimidines (DHPMs) which flaunt a

very similar pharmacological profile to classical dihydropyridine calcium channel

modulators.95-99 Over the past few years several lead-compounds are developed

(i.e. SQ 32,926) that are superior in potency and duration of antihypertensive

activity to classical DHP drugs, and compare favorable with second-generation

analogs such as nifedipine, amlodipine and nicardipine.

Rovnyak G C et al99 have examined a series of novel dihydropyrimidine calcium

channel blockers that contain a basic group attached to either C-5 or N-3 of the

heterocyclic ring (74) and (75). Structure-activity studies show that l-

(phenylmethyl)-4-piperidinylcarbamate moiety at N-3 and sulfur at C-2 are

optimal for vasorelaxant activity in vitro and impart potent and long-acting

antihypertensive activity in vivo. One of these compounds was identified as a

lead, and the individual enantiomers were synthesized. Two key steps of the

synthesis were (1) the efficient separation of the diastereomeric ureido derivatives

and (2) the high-yield transformation of 2-methoxy intermediate to the (p-

methoxybenzyl)thio intermediates. Chirality’s was demonstrated to be a

significant determinant of biological activity, with the DHP receptor recognizing

the enamines ester moiety but not the carbamate moiety. DHPM is equipotent to

nifedipine and amlodipine in vitro. In the spontaneously hypertensive rat, DHPM

is more potent and longer acting than both nifedipine and the long-acting

amlodipine (DHP derivative). DHPM has the potential advantage of being a single

enantiomer.



Pirisino R et al100 have studied 2-phenylpyrazolo-4-ethyl-4,7-dihydro[1,5-

a]pyrimidine-7-one, FPP028 (76), for its analgesic, antipyretic and anti-

inflammatory activities. The anti-inflammatory property of FPP028 was evaluated

by carrageenan-induced paw oedema and cotton pellet-induced granuloma

methods and found to possess activity similar to indomethacin, phenylbutazone

and isoxicam. Similarly FPP028 was shown to possess analgesic and antipyretic

activities comparable to former drugs. Cenicola et al101 evaluated some

imidazolo[1,2-c]pyrimidines (77) for anti-inflammatory, analgesic and antipyretic

activities. Desai et al102 have synthesized some new 4-(4-(4-aminophenyl)-6-(aryl)-

1,6-dihydropyrimidin-2-ylthio)butanenitriles (78) and tested them for

antimicrobial activity.

Nargund L V G et al103 reported the synthesis of few substituted 2-mercapto-3-(N-

alkyl)pyrimido[5,4-c]cinnolin-4-(3H)-ones (79) and screened them for anti-

inflammatory and antimicrobial activities. The compounds showed moderate to

good antimicrobial activity against various Gram-positive and Gram-negative

bacteria. Inhibitory activity of pyrazolo[1,5-a]pyrimidine derivatives (80) against



c-Src kinase for the treatment of acute ischemic stroke was also reported by

Mukaiyama H et al104. One of the synthesized compounds inhibited c-Src

selectively and exhibited satisfactory central nervous system penetration. Desai N

C et al105 have synthesized novel substituted 1,2,3,4-tetrahydropyrimidine

derivatives (81) and evaluated for their in vitro anticancer activity on various cell

lines. Some of the molecules have exhibited significantly potent inhibition on

several cell lines. To find out inter correlation between anticancer activity and

molecular descriptors, QSAR study was carried out. Molecular descriptors used

for the study were Clog P (lipophilic), CMR (steric) and polarity (electronic).

Anticancer activity is expressed in the form of LogGI50+ and activity on different

cell lines was independently correlated with molecular descriptors.



Plausible mechanistic pathway (Section 10-12):

Looking to the literature survey and pharmacological importance of quinoline and

dihydropyrimidine, we have synthesized the following heterocyclic compounds.

Section 10: 3-(6-(2,6-dichloroquinolin-3-yl)-4-(aryl)-1,6-dihydropyrimidin-2-

ylthio)propanenitriles.

Section 11: 3-(6-(2-chloro-6-fluoroquinolin-3-yl)-4-(aryl)-1,6-dihydropyrimidin-

-2-ylthio)propanenitriles.

Section 12: 3-(6-(2-chloro-6-methoxyquinolin-3-yl)-4-(aryl)-1,6-dihydro-

pyrimidin-2-ylthio)propanenitriles.



EXPERIMENTAL PROCEDURE

PREPARATION OF SUBSTITUTED 2-CHLOROQUINOLINE-3-CARB- ALDEHYDES (Ia-c) BY VILSMEIER-HAACK REACTION

Preparation of substituted 2-chloroquinoline-3-carbaldehydes (Ia-c) Dimethylformamide (0.0125 mol) was charged in a three-necked round bottom

flask equipped with a thermometer, a drying tube, mechanical stirrer and cooled

to 0 °C. To it, phosphorous oxychloride (0.035 mol) was added drop wise with

constant stirring at 0-10 °C. To this solution, corresponding substituted

acetanilides (0.1 mol) were added and mixture was refluxed for 3 h at 80 °C.

Reaction mass was cooled to room temperature and poured onto crushed ice.

Solid separated was filtered, washed with water and crystallized from ethyl

acetate. The progress of reaction and purity of compounds Ia-c were checked on TLC

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

(7:3) as an irrigator and plates were visualized with ultraviolet (UV) light, or

iodine vapour. All compounds were prepared by using the same method and their

physical constants are recorded in TABLE A.

TABLE A

Sr.No. -R Molecular Formula

% Yield

M.P. °C

Elemental Analysis

% Carbon % Hydrogen % Nitrogen

Calcd (Found)

Calcd (Found)

Calcd (Found)

Ia -4-Cl C10H5Cl2NO 72 191 53.13 (53.01)

2.23 (2.31)

6.20 (6.31)

Ib -4-F C10H5ClFNO 68 168 57.30 (57.18)

2.40 (2.48)

6.68 (6.77)

Ic -4-OCH3 C11H8ClNO2 73 146 59.61 (59.74)

3.64 (3.57)

6.32 (6.24)



SECTION 10

PREPARATION OF 3-(6-(2,6-DICHLOROQUINOLIN-3-YL)-4-(ARYL)-1,6-DIHYDROPYRIMIDIN-2-YLTHIO)PROPANENITRILES

SYNTHETIC SCHEME 10



PHYSICAL CONSTANTS OF 3-(6-(2,6-DICHLOROQUINOLIN-3-YL)-4-(ARYL)-1,6-DIHYDROPYRIMIDIN-2-YLTHIO)PROPANENITRILES

TABLE 10


% Yield

M.P. °C

Elemental Analysis % Carbon % Hydrogen % Nitrogen

Calcd (Found)

Calcd (Found)

Calcd (Found)

GK10-1 -H C22H16Cl2N4S 61 196 60.14 (60.26)

3.67 (3.58)

12.75 (12.67)

GK10-2 -2-Cl C22H15Cl3N4S 66 181 55.77 (55.87)

3.19 (3.26)

11.82 (11.74)

GK10-3 -3-Cl C22H15Cl3N4S 65 203 55.77 (55.88)

3.19 (3.09)

11.82 (11.90)

GK10-4 -4-Cl C22H15Cl3N4S 69 217 55.77 (55.66)

3.19 (3.11)

11.82 (11.91)

GK10-5 -4-F C22H15Cl2FN4S 60 189 57.78 (57.87)

3.31 (3.24)

12.25 (12.33)

GK10-6 -2-CH3 C23H18Cl2N4S 63 219 60.93 (60.82)

4.00 (4.09)

12.36 (12.44)

GK10-7 -4-CH3 C23H18Cl2N4S 60 244 60.93 (60.83)

4.00 (4.07)

12.36 (12.43)

GK10-8 -3-NO2 C22H15Cl2N5O2S 69 199 54.55 (54.65)

3.12 (3.03)

14.46 (14.37)

GK10-9 -4-NO2 C22H15Cl2N5O2S 70 231 54.55 (54.66)

3.12 (3.05)

14.46 (14.53)

GK10-10 -3-OH C22H16Cl2N4OS 67 241 58.03 (57.91)

3.54 (3.61)

12.30 (12.38)

GK10-11 -4-OH C22H16Cl2N4OS 63 256 58.03 (57.92)

3.54 (3.63)

12.30 (12.39)

GK10-12 -3-OCH3 C23H18Cl2N4OS 59 207 58.85 (58.96)

3.87 (3.78)

11.94 (11.84)

GK10-13 -4-OCH3 C23H18Cl2N4OS 64 234 58.85 (58.97)

3.87 (3.79)

11.94 (11.85)

GK10-14 -4-Br C22H15BrCl2N4S 68 186 50.99 (50.90)

2.92 (2.99)

10.81 (10.90)




3-(2,6-dichloroquinolin-3-yl)-1-phenylprop-2-en-1-one (II)

A mixture of 2,6-dichloroquinoline-3-carbaldehyde Ia (0.01 mol) and

acetophenone (0.01 mol) was stirred in ethanolic potassium hydroxide for 24 h at

room temperature. Product was filtered off, washed with water and crystallized

from ethanol (95%). Yield: 76%; m.p.: 178 °C; Anal. calcd. for C18H11Cl2NO: C-

65.87, H-3.38, N-4.27; Found: C-65.99, H-3.45, N-4.34%.

6-(2,6-dichloroquinolin-3-yl)-4-phenyl-1,6-dihydropyrimidine-2-thiol (III)

A mixture of 3-(2,6-dichloroquinolin-3-yl)-1-phenylprop-2-en-1-one II (0.01 mol)

and thiourea (0.01 mol) in ethanolic potassium hydroxide (1 g in 15 ml) was

heated under reflux for 6 h. The volume of the reaction mixture was reduced to

half of its original volume, diluted with ice cold water, then acidified with dilute

acetic acid and kept overnight. The solid yield thus obtained was filtered and

washed with water and recrystallized from absolute alcohol. Yield: 72%; m.p.:

192 °C; Anal. calcd. for C19H13Cl2N3S: C-59.07, H-3.39, N-10.88; Found: C-58.94,

H-3.46, N-10.96%.

3-(6-(2,6-dichloroquinolin-3-yl)-4-phenyl-1,6-dihydropyrimidin-2-ylthio)- propanenitrile (IV) (GK10-1)

A mixture of compound 6-(2,6-dichloroquinolin-3-yl)-4-phenyl-1,6-

dihydropyrimidine-2-thiol III (0.01 mol) and acrylonitrile (0.02 mol) in 15 mL

pyridine was refluxed for 20 h. Then, reaction mixture was acidified with cold

dilute hydrochloric acid and the solid product was filtered off and crystallized

from methanol. Yield: 61%; m.p.: 196 °C; Anal. calcd. for C22H16Cl2N4S: C-60.14,

H-3.67, N-12.75; Found: C-60.26, H-3.58, N-12.67%.

The progress of reaction and purity of compounds II, III and IV were checked on

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

acetate (7:3) as an irrigator and plates were visualized with ultraviolet (UV) light,

or iodine vapour.



SECTION 11

PREPARATION OF 3-(6-(2-CHLORO-6-FLUOROQUINOLIN-3-YL)-4-(ARYL)-1,6-DIHYDROPYRIMIDIN-2-YLTHIO)PROPANENITRILES

SYNTHETIC SCHEME 11



PHYSICAL CONSTANTS OF 3-(6-(2-CHLORO-6-FLUOROQUINOLIN-3-YL)-4-(ARYL)-1,6-DIHYDROPYRIMIDIN-2-YLTHIO)PROPANENITRILES

TABLE 11


% Yield

M.P. °C


Calcd (Found)

Calcd (Found)

Calcd (Found)

GK11-1 -H C22H16ClFN4S 60 187 62.48 (62.59)

3.81 (3.74)

13.25 (13.17)

GK11-2 -2-Cl C22H15Cl2FN4S 64 199 57.78 (57.66)

3.31 (3.38)

12.25 (12.35)

GK11-3 -3-Cl C22H15Cl2FN4S 62 209 57.78 (57.68)

3.31 (3.37)

12.25 (12.35)

GK11-4 -4-Cl C22H15Cl2FN4S 66 223 57.78 (57.68)

3.31 (3.39)

12.25 (12.34)

GK11-5 -4-F C22H15ClF2N4S 59 191 59.93 (59.80)

3.43 (3.51)

12.71 (12.80)

GK11-6 -2-CH3 C23H18ClFN4S 64 227 63.22 (63.10)

4.15 (4.24)

12.82 (12.72)

GK11-7 -4-CH3 C23H18ClFN4S 66 253 63.22 (63.11)

4.15 (4.23)

12.82 (12.71)

GK11-8 -3-NO2 C22H15ClFN5O2S 65 209 56.47 (56.59)

3.23 (3.13)

14.97 (14.88)

GK11-9 -4-NO2 C22H15ClFN5O2S 67 249 56.47 (56.60)

3.23 (3.14)

14.97 (14.90)

GK11-10 -3-OH C22H16ClFN4OS 63 244 60.20 (60.31)

3.67 (3.73)

12.77 (12.85)

GK11-11 -4-OH C22H16ClFN4OS 67 267 60.20 (60.32)

3.67 (3.74)

12.77 (12.84)

GK11-12 -3-OCH3 C23H18ClFN4OS 62 213 60.99 (60.86)

4.01 (4.10)

12.37 (12.47)

GK11-13 -4-OCH3 C23H18ClFN4OS 64 242 60.99 (60.87)

4.01 (4.09)

12.37 (12.48)

GK11-14 -4-Br C22H15BrClFN4S 68 192 52.66 (52.79)

3.01 (3.10)

11.17 (11.07)




3-(2-chloro-6-fluoroquinolin-3-yl)-1-phenylprop-2-en-1-one (II)

A mixture of 2-chloro-6-fluoroquinoline-3-carbaldehyde Ib (0.01 mol) and



from ethanol (95%). Yield: 75%; m.p.: 158 °C; Anal. calcd. for C18H11ClFNO: C-

69.35, H-3.56, N-4.49; Found: C-69.48, H-3.49, N-4.57%.

6-(2-chloro-6-fluoroquinolin-3-yl)-4-phenyl-1,6-dihydropyrimidine-2-thiol (III)

A mixture of 3-(2-chloro-6-fluoroquinolin-3-yl)-1-phenylprop-2-en-1-one II (0.01

mol) and thiourea (0.01 mol) in ethanolic potassium hydroxide (1 g in 15 ml) was

heated under reflux for 6 h. The volume of the reaction mixture was reduced to

half of its original volume, diluted with ice cold water, then acidified with dilute

acetic acid and kept overnight. The solid yield thus obtained was filtered and

washed with water and recrystallized from absolute alcohol. Yield: 70%; m.p.:

171 °C; Anal. calcd. for C19H13ClFN3S: C-61.70, H-3.54, N-11.36; Found: C-

61.58, H-3.46, N-11.47%.

3-(6-(2-chloro-6-fluoroquinolin-3-yl)-4-phenyl-1,6-dihydropyrimidin-2-ylthio)- propanenitrile (IV) (GK11-1)

A mixture of compound 6-(2-chloro-6-fluoroquinolin-3-yl)-4-phenyl-1,6-




from methanol. Yield: 60%; m.p.: 187 °C; Anal. calcd. for C22H16ClFN4S: C-62.48,

H-3.81, N-13.25; Found: C-62.59, H-3.74, N-13.17%.




or iodine vapour.



SECTION 12

PREPARATION OF 3-(6-(2-CHLORO-6-METHOXYQUINOLIN-3-YL)-4-(ARYL)-1,6-DIHYDROPYRIMIDIN-2-YLTHIO)PROPANENITRILES

SYNTHETIC SCHEME 12



PHYSICAL CONSTANTS OF 3-(6-(2-CHLORO-6-METHOXYQUINOLIN-3-YL)-4-(ARYL)-1,6-DIHYDROPYRIMIDIN-2-YLTHIO)PROPANENITRILES

TABLE 12

Sr.No. -R Molecular

Formula %

Yield M.P. °C


Calcd (Found)

Calcd (Found)

Calcd (Found)

GK12-1 -H C23H19ClN4OS 62 211 63.51 (63.64)

4.40 (4.32)

12.88 (12.78)

GK12-2 -2-Cl C23H18Cl2N4OS 66 192 58.85 (58.71)

3.87 (3.95)

11.94 (12.04)

GK12-3 -3-Cl C23H18Cl2N4OS 64 214 58.85 (58.72)

3.87 (3.94)

11.94 (12.03)

GK12-4 -4-Cl C23H18Cl2N4OS 62 226 58.85 (58.73)

3.87 (3.95)

11.94 (12.05)

GK12-5 -4-F C23H18ClFN4OS 61 197 60.99 (60.88)

4.01 (4.09)

12.37 (12.45)

GK12-6 -2-CH3 C24H21ClN4OS 67 224 64.20 (64.32)

4.71 (4.62)

12.48 (12.37)

GK12-7 -4-CH3 C24H21ClN4OS 62 251 64.20 (64.08)

4.71 (4.80)

12.48 (12.57)

GK12-8 -3-NO2 C23H18ClN5O3S 68 215 57.56 (57.44)

3.78 (3.86)

14.59 (14.70)

GK12-9 -4-NO2 C23H18ClN5O3S 67 258 57.56 (57.43)

3.78 (3.87)

14.59 (14.69)

GK12-10 -3-OH C23H19ClN4O2S 69 241 61.26 (61.38)

4.25 (4.16)

12.42 (12.31)

GK12-11 -4-OH C23H19ClN4O2S 65 271 61.26 (61.39)

4.25 (4.16)

12.42 (12.32)

GK12-12 -3-OCH3 C24H21ClN4O2S 64 218 62.00 (62.14)

4.55 (4.46)

12.05 (11.95)

GK12-13 -4-OCH3 C24H21ClN4O2S 61 254 62.00 (62.12)

4.55 (4.47)

12.05 (11.96)

GK12-14 -4-Br C23H18BrClN4OS 66 199 53.76 (53.88)

3.53 (3.44)

10.90 (10.81)




3-(2-chloro-6-methoxyquinolin-3-yl)-1-phenylprop-2-en-1-one (II)

A mixture of 2-chloro-6-methoxyquinoline-3-carbaldehyde Ic (0.01 mol) and



from ethanol (95%). Yield: 77%; m.p.: 180 °C; Anal. calcd. for C19H14ClNO2: C-

70.48, H-4.36, N-4.36; Found: C-70.59, H-4.28, N-4.45%.

6-(2-chloro-6-methoxyquinolin-3-yl)-4-phenyl-1,6-dihydropyrimidine-2-thiol (III)

A mixture of 3-(2-chloro-6-methoxyquinolin-3-yl)-1-phenylprop-2-en-1-one II (0.01 mol) and thiourea (0.01 mol) in ethanolic potassium hydroxide (1 g in 15

ml) was heated under reflux for 6 h. The volume of the reaction mixture was

reduced to half of its original volume, diluted with ice cold water, then acidified

with dilute acetic acid and kept overnight. The solid yield thus obtained was

filtered and washed with water and recrystallized from absolute alcohol. Yield:

72%; m.p.: 191 °C; Anal. calcd. for C20H16ClN3OS: C-62.90, H-4.22, N-11.00;

Found: C-62.77, H-4.30, N-11.09%.

3-(6-(2-chloro-6-methoxyquinolin-3-yl)-4-phenyl-1,6-dihydropyrimidin-2-ylthio)propanenitrile (IV) (GK12-1)

A mixture of compound 6-(2-chloro-6-methoxyquinolin-3-yl)-4-phenyl-1,6-




from methanol. Yield: 62%; m.p.: 211 °C; Anal. calcd. for C23H19ClN4OS: C-63.51,

H-4.40, N-12.88; Found: C-63.64, H-4.32, N-12.78%.




or iodine vapour.



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