Synthesis of Promising Anti-inflammatory Active 2 ...rspublication.com/ijst/2014/april14/62.pdf ·...

International Journal of Advanced Scientific and Technical Research Issue 4 volume 2, March-April 2014

Available online on http://www.rspublication.com/ijst/index.html ISSN 2249-9954

R S. Publication, [email protected] Page 714

Synthesis of Promising Anti-inflammatory Active 2-

Substituted [4-(4- bromo -3-methy) phenyl]phthalazin-

1(2H)-one Derivatives

M.A.El-Hashash1 and J.M.Morsy

2*

1

Department of Chemistry, Faculty of Science, Ain Shams University, Cairo 11566 ,

Egypt. 2Laboratory of Synthetic Organic Chemistry, Chemistry Department, Faculty of

Education, Roxy 11711 , Cairo, Egypt.

ABSTRACT

The reaction of 4-[(4-bromo-3-methy)phenyl]phthalazin-1(2H)-one with ethyl cyanoacetate,

ethyl chloroacetate and P2S5 afforded N-acyl, N-alkyl and thione derivatives respectively.

Both N-alkyl derivative and thione have been allowed to react with NH2NH2.H2O to yield the

corresponding hydrazide and hydrazino derivatives. Reactions of N-alkyl derivative with

nitrogen nucleophiles namely, benzylamine, picolylamine, 3-N-imidazolylamine, alanine and

sulphur nucleophile namely, o-aminothiophenol and oxygen nucleophile namely, hydroxide

ion have been investigated. The reactions of hydrazino derivative with carbon electrophiles

have also been discussed.

KEYWORDS

Phthalazin-1(2H)-one, picolylamine, 3-(N-imidazolyl)propylamine, 1-(2H)-oxo-

phthalazin-2-yl cinnamic acid, 3,5-dimethylpyrazole, 3-methyl-5-oxo-pyrazoline.

INTRODUCTION

Phthalazin-1(2H)-ones have considerable interest due to their antidiabetic [1], antiallergic

[2], vasorelaxant [3], PDE4 inhibitors [4], VEGF (vascular endothelial growth factor)

receptor tyrosine kinase for the treatment of cancer [5,6], antiasthmatic agents with dual

activity of thromboxane A2 ( TXA2) sythetase inhibition and bronchodialation [7],

herbicidal [8], like activities. A number of established drug molecules like Hydralazine [9,

10], Burdralazine [11, 12], Azelastine [13,14], Ponalrestat [15], and Zopolrestat [16] are

prepared from the corresponding phthalazinones. Several phthalazine derivatives have

been reported to possess antitumor [17-20], antihypertensive [21, 22], anticonvulsant [23,

24], antimicrobial [25] antitrypanosomal [26], and anti-inflammatory activities [27, 28].

NSAIDs are widely used in the treatment of pain and inflammation. Most of the current

non-steroidal anti-inflammatory drugs (NSAIDs) show serious side effects including

gastrointenstinal disorders and kidney damage. Therefore, studies for developing safer

NSAIDs lacking undesired gastrointenstinal and renal side effects of currenly used ones

have been recently of interest for many researchers. Most of the classical NSAIDs exert

their side effects by inhibition of cyclooxygenase (COX-1) enzyme. Since the COX-1

isoform is the constitutive one that is responsible for regulation of physiological processes,




and the COX-2 isoform is discovered to be the enzyme induced by inflammatory stimuli,

selective inhibition of COX-2 provides a rationale for developing potential anti-

inflammatory and analgesic agents that lack the GI liabilities exhibited by currently

marketed NSAIDs and consequently they have an improved safety profile in comparison

to NSAIDs. Although the diarylheterocyclic compounds are mainly studied as new class

of NSAIDs without gastric side effects, many studies have also focused on a different

type of compounds to develop safer NSAIDs [27]. Also in terms of this aspect, many

studies have been focused on pyridazin-3(2H)-ones, which are characterized to possess

good analgesic and anti-inflammatory activities, besides these studies have indicated that

the heterocyclic ring substituents at the six position, and the presence of acetamide side

chain linked to the lactam nitrogen of pyridazinone ring at the two position improve the

analgesic and anti-inflammatory activity along with nil or very low ulcerogenicity [29-33].

In view of the aforementioned facts, it seemed most interesting to synthesize some [4-(4-

bromo-3-methyl) phenyl]-2-substituted phthalazin-1(2H)-one derivatives with the aim to

obtain more precise information about the course of reactions and biological activities.

RESULTS AND DISCUSSION

4-[(4-bromo-3-Methyl)phenyl]phthalazin-1(2H)-one (2) was obtained from the interaction

of 2-[(4-bromo-3-methyl)benzoyl]benzoic acid (1) with hydrazine hydrate in boiling

ethanol according to scheme 1. The IR spectrum of phthalazinone 2 showed band at 1658

cm-1

attributable to ʋ C=O. The 1H NMR spectrum showed a singlet signal at 12.8 ppm

(D2O exchangeable) corresponding to NH.

When compound 2 was submitted to react with ethyl cyanoacetate, ethyl chloroacetate,

and phosphorous pentasulphide, 1(2H)-oxo-phthalazin-2-yl carbonyl acetonitrile, 1(2H)-

oxo-phthalazin-2-yl acetic acid ethyl ester, and 1(2H)-oxo-phthalazin-1-thione 3a-c were

obtained respectively (scheme 1). The structural features of compounds 3 were confirmed

by spectral data. The IR spectrum of 3a exhibits strong absorption band at 2260 cm-1

attributable to ʋ C≡N. The 1H NMR of compound 3b showed a triplet signal at 1.18

ppm assigned for methyl protons of CH3CH2-, a quartet signal at 4.14 ppm assigned for

methylene protons of CH3CH2-, a singlet signal at 4.95 ppm assigned for CH2CO, besides

CH3 and aromatic protons of aryl moiety. Compound 3c showed strong absorption at 1234

cm-1

(ʋ C=S) and lacked any band for ʋ C=O . The 1(2H)-oxo-phthalazin-2-yl acetic acid

ethyl ester 3b was converted to the corresponding hydrazide 3d in high yield via its

reaction with hydrazine hydrate (scheme 1). The 1H NMR of compound 3d showed

signals at 4.26 ppm (s, 2H, NH2, D2O exchangeable), 4.76 ppm (s, 2H, CH2CO), 9.28 (s,

1H, NH, D2O exchangeable) as well as the methyl and aromatic protons of aryl group.

Alkaline hydrolysis of acetic acid ester derivative 3b afforded the corresponding acetic

acid derivative 3e. The IR spectrum of 3e revealed strong absorption band at 1715 cm-1

attributable to ʋ C=O of carboxylic acid. The thione derivative 3c was converted to the

corresponding hydrazino derivative 4 when submitted to react with hydrazine hydrate. The

mass spectrum of 4 showed the prominent ion peaks at m/z 328 (29.91%) and m/z 330

(29.71) corresponding to (M.+) and (M+2

.+) respectively.




N

N

X

Ar

R

a) CNCH2COOC2H5 / Ethanol

b) ClCH2COOC2H5 / dry Acetone / anhydrous K2CO3

c) P2S5 / dry Xylene

(3)

N

N

Ar

NHNH2(4)

(3c)

R Xa) -COCH2CN Ob) -CH2COOC2H5 Oc) -H Sd) -CH2CONHNH2 Oe) -CH2COOH O

(3b)

(3b)

(3d)

aq.NaOH

(3e)

Ar =

Br

CH3

Scheme1

N2H4.H2O / abs.EthanolN2H4.H2O / Ethanol

O

O

O

Br

CH3

anhydrous AlCl3

COOH

O

Ar

(1)

N2H4.H2OEthanol

N

N

O

Ar

H

(2)

The structure of compound 3b was chemically proved via its interaction with

benzaldehyde in the presence of sodium methoxide to yield the the Stobbe product 2-

[1(2H)-oxo-phthalazin-2-yl]cinnamic acid 5 which is characteristic by its solubility in

aqueous sodium bicarbonate solution and its IR spectrum revealed strong absorption bands

at 1667 cm-1

(ʋ C=O) and 1680 cm-1

(ʋ C=O carboxylic acid) (scheme 2).




N

N

Ar

O

CH2COOC2H5

N

N

Ar

O

CCHPh

COOH

C6H5CHO CH3ONa

Methanol

(5)

N

N

Ar

O

CH2COR

6a-e

Ra) C6H5CH2NH

b) C6H4(NH2)S(2)

C)C5H4NCH2(2)NHd)

N

N

CH2CH2CH2NH

e) C5H10N

RNH2

Ethanol

H2N CH

CH3

COOH

PyridineN

N

Ar

O

CH2 CONH CH

CH3

COOH(7)

Scheme 2

3b

Ar =

Br

CH3

The mass spectrum of compound 5 showed characteristic peaks m/z 459 (46.51%) and m/z

461 (46.41%) corresponding to (M.+

) and (M+2.+

) respectively. The reaction possibly takes

place via scheme 3. To support the proposed mechanism, the authors repeated the reaction

in the absences of benzaldehyde under the same conditions. They isolated the unsaponified

ester 3b and this ruled out the Claisen Schmidt condensation followed by saponification.




Q CH2COOC2H5

NaOCH3Q CHCOOC2H5

PhC

O

H

Q

CH CH

C

Ph

OO

OC2H5

Q

CH CH

C

Ph

OHO

OC2H5

H

-H2O

Q

C CH

C

Ph

O

OC2H5

H2O

Q

CH CH

C

Ph

O

ONaOCH3

Q

C CH

C

Ph

O

O

Q

C CH

C

Ph

OO

H2O

Q

CCH

HOOCPh

Scheme 3

Q =N

N

Ar

O

(3b)

(5)

Q

CCH

HOOCPh

In the present work, some phthalazin-1(2H)-one derivatives 6 bearing acetamide side

chain at position-2 of pyridazine moiety have been synthesized. Thus, aminolysis of

compound 3b with aromatic and heteroaromatic amines namely, benzylamine, 2-

aminothiophenol, picolylamine, 3-(N-imidazolyl)-propylamine and piperidine yielded 4-

[(4-bromo-3-methyl)phenyl-1(2H)-oxo-phthalazin-2-yl]-N-arylacetic acid amide 6a-e

respectively (scheme 2). The IR spectra of compounds 6a, 6c, 6d, and 6e exhibit strong

absorption bands in the region 1660-1670 cm-1

attributable to ʋ max of two carbonyl




groups (cyclic amide and acetamide moieties). On the other hand, the IR spectrum of 6b

showed strong absorptions at 1612 and 1665 cm-1

due to ʋ C=O of thioester moiety and

cyclic carboxamide. The lower frequency is corresponding to ʋ C=O of thioester moiety

due to the fact that sulphur is highly electron donor. The IR spectrum of 6b also exhibits

absorption bands at 3263 and 3378 cm-1

attributable to ʋ NH of NH2 group. These results

seem to be reasonable because sulphhydryl group is more nucleophilic than amino group.

Similarly, interaction of ester 3b with alanine in boiling pyridine afforded N-acylalanine

derivative 7 (scheme 2). The IR spectrum of 7 showed strong absorption bands at 1665

and 1677 cm-1

attributable to ʋ max of carbonyl groups.

The hydrazino derivative 4 was used as key starting material for the synthesis of some

interesting heterocyclic compounds. Thus, when compound 4 was allowed to react with

acetylacetone in boiling n-butanol, it yielded 1-[(3, 5-dimethyl)pyrazol-1-yl]-4-[(4-bromo-

3-methyl)phenyl]phthalazin 8 (scheme 4). The 1H NMR spectrum of compound 8 exhibits

signals at 2.41 (s, 3H, Ar-CH3), 2.45 (s, 3H, CH3 of pyrazole moiety at position 5), 2.47 (s,

3H, CH3 of pyrazole moiety at position 3) besides the aromatic signals. Similarly, when

the hydrazine derivative 4 was submitted to react with ethyl acetoacetate in boiling n-

butanol, 1-[(3-methyl-5-oxo-pyrazolin-1-yl]-4-[(4-bromo-3-methyl)phenyl]phthalazin 9

was obtained. IR spectrum of compound 9 exhibits strong absorption bands at 1620 and

1665 cm-1

due to ʋ C=N and ʋ C=O respectively. On the other hand, interaction of

hydrazino compound 4 with benzaldehyde in boiling ethanol gave the benzaldehyde

hydrazone derivative 10 (scheme 4).

N

N

Ar

NHNH2

(4)

N

N

Ar

NN

H3C CH3

(CH3CO)2CH2

n-butanol

(8)

CH3COCH2COOC2H5

n-butanol

N

N

Ar

NN

O CH3

(9)

N

N

Ar

NHN

(10)

CHC6H5

C6H5CHO

Ethanol

Scheme 4

Ar =

Br

CH3



R S. Publication, [email protected] 20

EXPERIMENTAL

All melting points are uncorrected and measured by electro thermal apparatus ( Buchi 535,

Switzerland ) in open capillary tubes. IR spectra expressed in ʋ (cm-1) recorded in KBr

pellets on a PA-9721 IR spectrometer. 1H NMR spectra were recorded in DMSO-D6 as

solvent on a Jeol 270 and / or 500 MHz spectrometer and the chemical shifts were

recorded in values ( ppm ) relative to TMS as internal reference. Mass spectra were

measured on Kratos ( 75 eV ) MS equipment. Elemental analyses were carried out at the

Microanalytical Center, Cairo University, Cairo, Egypt. All reactions were monitored by

TLC.

4-[(4-Bromo-3-methyl)phenyl]phthalazin-1(2H)-one (2)

A solution of 1 (10 mmol) and hydrazine hydrate (15 mmol) in ethanol (30 mL) was

heated under reflux for 3 h. The solid that deposited after cooling was filtered off and

recrystallized from ethanol to give 2.

Compound 2: Yield 87% (colorless crystals), m.p.228-230oC, IR :1658(C=O), 3200 (NH).

1H-NMR : 2.42 (s, 3H, CH3), 7.18- 8.51 (m, 7H, Ar-H), 11.21 (s, 1H, NH, D2O

exchangeable). MS: 315 (M.+

). Anal. calc. for C15H11BrN2O (315.18): C: 57.16, H: 3.52, N:

8.89; found: C: 57.42, H: 3.80, N: 8.64

[4-(4-Bromo-3-methyl)phenyl-1(2H)-oxo-phthalazin-2-yl]carbonylacetonitrile (3a)

To a solution of 2 (10 mmol) in ethanol (30 mL), ethyl cyanoacetate (15 mmol) was added

and the reaction solution was heated at refluxing temperature for 3 h, then left to cool. The

solid that settled down was collected by filtration and recrystallized from toluene to yield

3a.

Compound 3a: Yield 77% (colorless crystals), m.p.159-161oC, IR :1660 (C=O), 2260

(C≡N). 1H-NMR : 2.30 (s, 2H, CH2CO), 2.55 (s, 3H, CH3), 7.36- 8.41 (m, 7H, Ar-H). MS:

382 (M.+

). Anal. calc. for C18H12BrN3O2 (382.23): C: 56.56, H: 3.17, N: 10.99; found: C:

56.91, H: 3.54, N: 11.26.

Ethyl [4- (4-Bromo-3-methyl) phenyl] -1(2H)-oxo-phthalazin-2-yl] acetate (3b)

A mixture of 2 (10 mmol), ethyl chloroacetate (40 mmol) and anhydrous K2CO3 (40 mmol) in

dry acetone (50 mL) was heated under reflux for 24 h. Excess acetone was removed by

distillation and the reaction mixture was diluted by water. The solid that separated out was

filtered off and recrystallized from light petroleum (80-100 oC) to afford 3b.

Compound 3b: Yield 82% (white crystals), m.p.110-112oC, IR :1662 (C=O, cyclic amide),

1742 (C=O ester). 1H-NMR : 1.18 (t, J=11.00 Hz, 3H, CH2CH3), 2.51 (s, 3H, CH3), 4.14 (q,

J=11.00 Hz, 2H, CH2CH3), 4.95 (s, 2H, NCH2CO), 7.50- 8.15 (m, 7H, Ar-H). MS: 382 (M.+

).

Anal. calc. for C19H17BrN2O3 (401.28): C: 56.87, H: 4.28, N: 6.98; found: C: 56.55, H: 4.13,




N: 7. 21.

4- (4-Bromo-3-methyl) phenyl phthalazin--1(2H)-thione 3c

A mixture of 2 (10 mmol) and P2S5 (10 mmol) in dry xylene (50 mL) was heated under reflux

for 1 h then the reaction mixture was filtered while hot and the filtrate was concentrated and

left to cool. The solid that separated down was filtered off and recrystallized from benzene to

give 3c.

Compound 3c: Yield 65% (yellow crystals), m.p.218-220oC, IR :1234 (C=S), 3180 (NH).

1H-NMR : 2.47 (s, 3H, CH3), 7.14 (s, 1H, NH, D2O-exchangeable), 7.33- 7.95 (m, 7H, Ar-

H). Anal. calc. for C15H11BrN2S (331.24): C: 54.39, H: 3.35, N: 8.46, S: 9.68; found: C:

54.71, H: 3.63, N: 8.26, S: 9.66.

[4- (4-Bromo-3-methyl) phenyl -1(2H)-oxo-phthalazin-2-yl] acetic acid hydrazide (3d)

Hydrazine hydrate (10 mmol) was added to a solution of ester 3b (10 mmol) in absolute

ethanol (50 mL).The reaction solution was heated at boiling point under reflux for 3 h then

left to cool. The solid that settled down was filtered off and recrystallized from ethanol to

yield 3d.

Compound 3d: Yield 85% (white crystals), m.p.232-34oC, IR :1650, 1662(C=O), 3200,

3250 (NH). 1H-NMR : 2.45 (s, 3H, CH3), 4.26 (s, 2H, NH2, D2O exchangeable), 4.76 (s, 2H,

CH2CO), 7.25- 8.41 (m, 7H, Ar-H), 9.28 (s, 1H, NH, D2O exchangeable). MS: 387 (M.+

).

Anal. calc. for C17H15BrN4O2 (387.26): C: 52.72, H: 3.91, N: 14.47; found: C: 52.42, H: 3.80,

N: 14.64.

[1(2H)-oxo-4- (4-Bromo-3-methyl) phenyl phthalazin-2-yl] acetic acid (3e)

A mixture of ester 3b (10 mmol) and 10 mL of aqueous sodium hydroxide solution (10 %)

was heated under reflux for 3 h and then left to cool. The reaction mixture was extracted by

ether to get rid of unsaponified material. The aqueous layer was acidified by ice / dilute HCl.

The solid that precipitated was filtered off and crystallized from benzene to afford 3e.

Compound 3e: Yield 62% (brown crystals), m.p.242-44oC, IR :1715 (C=O), 2500- 3200

(chelated OH). 1H-NMR : 2.49 (s, 3H, CH3), 4.81 (s, 2H, NCH2CO), 7.52- 8.10 (m, 7H, Ar-

H), 11.53 (s, 1H, COOH, D2O-exchangeable). MS: 373 (M.+

). Anal. calc. for C17H13BrN2O3

(373.22): C: 54.70, H: 3.52, N: 7.51; found: C: 54.75, H: 3.45, N: 7.62

[4- (4-Bromo-3-methyl) phenyl]-1-hydrazinophthalazine 4

A mixture of thione 3c (10 mmol) and hydrazine hydrate (15 mmol) in absolute ethanol (50

mL) was heated under reflux for 3 h. The solid that separated after concentration and cooling

was filtered off and crystallized from ethanol to give 4.




Compound 4: Yield 65% (pale yellow crystals), m.p.232-34oC, IR : 3300-3370 (NH2), 3200

(NH). 1H-NMR : 2.54 (s, 3H, CH3), 2.87 (s, 2H, NH2, D2O-exchangeable), 4.49 (s, 1H, NH,

D2O-exchangeable), 7.27- 8.31 (m, 7H, Ar-H). MS: 329 (M.+

, 29.91), 331(M+2.+

, 29.71).

Anal. calc. for C15H13BrN4 (329.22): C: 54.72, H: 3.99, N: 17.02; found: C: 54.83, H: 3.85,

N: 17.22.

2-[1(2H)-oxo-4- (4-Bromo-3-methyl) phenyl phthalazin-2-yl] cinnamic acid (5)

A mixture of ester 3b (10 mmol), sodium methoxide (15 mmol; 0.35 g of sodium metal in 30

mL of absolute methanol) and benzaldehyde (10 mmol) was heated under reflux for 3 h, left

to cool, diluted by water and finally extracted by ether to get rid of neutral material. The

aqueous layer was acidified by dilute HCl / ice. The solid that precipitated was filtered off,

washed with cold water , dried and crystallized from benzene to yield 5.

Compound 5: Yield 55% (pale yellow crystals), m.p.267-69oC, IR : 1667 (C=O), 1680

(C=O) 2500-3200 (chelated OH)). 1H-NMR : 2.57 (s, 3H, CH3), 6.40 (s, 1H, olefinic-H),

7.18- 8.16 (m, 12H, Ar-H), 11.25 (s, 1H, COOH, D2O-exchangeable). MS: 461 (M.+

, 46.41),

463 (M+2.+

, 46.51). Anal. calc. for C24H17BrN2O3 (461.33): C: 62.48, H: 3.72, N: 6.07;

found: C: 62.73, H: 3.89, N: 6.35

Reaction of Ethyl [4- (4-Bromo-3-methyl) phenyl-1(2H)-oxo-phthalazin-2-yl] acetate

(3b) with amines (6a-e)

A mixture of ester 3b (10 mmol) and an appropriate aromatic or heteroaromatic amine (15

mmol) in absolute ethanol (40 mL) was heated under reflux for 4 h. After cooling, the

separated solid was collected by filtration, dried and crystallized from the proper solvent to

afford 6a-e.

[4-(4-Bromo-3-methyl)phenyl-1(2H)-oxo-phthalazin-2-yl]-N-benzylacetamide (6a).

Yield 77% (pale brown crystals from ethanol), m.p.196-198oC, IR :1660, 1667 (two C=O),

3180 (NH). 1H-NMR : 2.41 (s, 3H, CH3), 3.70 (s, 2H, NHCH2Ph), 4.79 (s, 2H, NCH2CO),

7.90- 8.30 (m, 12H, Ar-H), 9.10 (s, 1H, NH, D2O exchangeable). MS: 462 (M.+

). Anal. calc.

for C24H20BrN3O2 (462.37): C: 62.34, H: 4.37, N: 9.09; found: C: 62.51, H: 4.73, N: 9.33.

2-Aminophenyl-[4-(4-Bromo-3-methyl)phenyl-1(2H)-oxo-phthalazin-2-yl] thioacetate

(6b).

Yield 65% (pale yellow crystals from toloune), m.p.180-82oC, IR : 1612 (C=O of thioester),

1665 (C=O of cyclic amide) 3263,3378 (NH2)). 1H-NMR : 2.47 (s, 3H, CH3), 3.89 (s, 2H,

NH2, D2O- exchangeable), 4.23 (s, 2H, CH2COS), 6.90- 8.11 (m, 11H, Ar-H), MS: 480 (M.+

,

52.37), 482 (M+2.+

, 52.44). Anal. calc. for C23H18BrN3O2S (480.40): C: 57.50, H: 3.78, N:




8.75; found: C: 57.69, H: 3.91, N: 8.39.

[4-(4-Bromo-3-methyl)phenyl-1(2H) phthalazin-2-yl]-N-picolyl acetic acid amide (6c).


3180 (NH). 1H-NMR : 2.41 (s, 3H, CH3), 4.10 (s, 2H, CH2 of picolyl moiety), 4.90 (s, 2H,

NCH2CO), 7.20- 8.50 (m, 11H, Ar-H and pyridine moiety ), 8.90 (s, 1H, NH, D2O

exchangeable). MS: 463 (M.+

). Anal. calc. for C23H19BrN4O2 (463.36): C: 59.61, H: 4.14, N:

12.09; found: C: 59.81, H: 4.24, N: 12.28.

[4-(4-Bromo-3-methyl)phenyl-1(2H)phthalazin-2-yl]-N-(3-imidazolyl)propyl acetic acid

amide (6d).


3200 (NH). MS: 480 (M.+

). Anal. calc. for C23H22BrN5O2 (480.40): C: 57.50, H: 4.63, N:

14.58; found: C: 57.76, H: 4.48, N: 14.71.

[4-(4-Bromo-3-methyl)phenyl-1(2H)phthalazin-2-yl]-N-piperidinyl acetic acid amide

(6e).

Yield 70% (brown crystals from toluene), m.p.230-32oC, IR :1663, 1670 (two C=O). 1H-

NMR : 1.59 (m, 6H, 3 CH2-piperidine nucleus), 2.53 (s, 3H, CH3), 3.42(m, 4H, 2 CH2-

piperidine nucleus), 4.19 (s, 2H, CH2CO), 7.35- 8.10 (m, 7H, Ar-H). MS: 480 (M.+

). Anal.

calc. for C22H22BrN3O2 (440.37): C: 60.00, H: 5.05, N: 9.54; found: C: 60.33, H: 5.19, N:

9.73.

[4-(4-Bromo-3-methyl)phenyl-1(2H)phthalazin-2-yl]-N-acetoalanine (7).

A mixture of ester 3b (10 mmol) and alanine (15 mmol) in pyridine (20 mL) was heated

under reflux for 2 h. After cooling, the reaction mixture was poured into ice / HCl. The

separated solid was collected by filtration, dried and crystallized from the suitable solvent to

afford compound 7.

Yield 52% (dark brown crystals from ethanol), m.p.236-38oC, IR :1665, 1671 (two C=O).

1H-NMR : 1.49 (d, 3H, CHCH3), 2.52 (s, 3H, CH3-Ar), 4.17 (s, 2H, CH2CO), 4.78 (q, 1H,

CHCH3),7.21- 8.33 (m, 7H, Ar-H), 8.27 (s, 1H, NH, D2O exchangeable), 11.55 (s, 1H,

COOH, D2O-exchangeable). MS: 444 (M.+

). Anal. calc. for C20H18BrN3O4 (444.31): C:

54.06, H: 4.09, N: 9.46; found: C: 54.19, H: 4.28, N: 9.54.

1-[(3,5-Dimethyl)pyrazol-1-yl]-4-(4-bromo-3-methyl)phenyl phthalazine (8).

A solution of hydrazino derivative 4 (10 mmol), acetylacetone (15 mmol) in n-butanol (20

mL) was heated under reflux for 3 h. The solid that separated out after cooling was filtered

off and crystallized from ethanol to give compound 8.




Yield 65% (brown crystals from ethanol), m.p.209-11oC, IR :1620 ( C=N).

1H-NMR : 2.41

(s, 3H, CH3), 2.45 (s, 3H, CH3 of pyrazole moiety at position 5), 2.47(s, 3H, CH3 of pyrazole

moiety at position 3), 7.20- 8.15 (m, 8H, Ar-H and heteroaromatic moieties). MS: 393 (M.+

).

Anal. calc. for C20H17BrN4 (393.31): C: 61.07, H: 4.37, N: 14.25; found: C: 61.34, H: 4.47,

N: 14.39.

1-[(3-methyl-5-oxopyrazolin-1-yl]-4-(4-bromo-3-methyl)phenyl phthalazine (9).

A solution of hydrazino derivative 4 (10 mmol ) and ethyl acetoacetate (15 mmol) in n-

butanol (20 mL) was heated under reflux for 3 h. The solid that separated out after cooling

was filtered off and crystallized from acetic acid to give compound 9.

Yield 67% (brown crystals from acetic acid), m.p.197-99oC, IR :1620 ( C=N), 1665

(C=O). 1H-NMR : 1.22 (s, 3H, CH3-pyrazole), 2.47 (s, 2H, CH2-pyrazole), 2.54 (s, 3H, CH3-

Ar), 7.26- 8.19 (m, 7H, Ar-H). MS: 395 (M.+

). Anal. calc. for C19H15BrN4O (395.28): C:

57.73, H: 3.83, N: 14.18; found: C: 57.81, H: 3.93, N: 14.34

4-(4-bromo-3-methyl)phenyl-1-benzaldehydehydrazone phthalazine (10).

A solution of hydrazino derivative 4 (10 mmol ) and benzaldehyde (15 mmol) in ethanol (30

mL) was heated under reflux for 3 h. The solid that settled down after cooling was filtered

off and crystallized from ethanol to afford compound 10.

Yield 55% ( pale brown crystals from ethanol), m.p.182oC, IR :3180 (NH).

1H-NMR : 2.53

(s, 3H, CH3), 4.63 (s, 1H, NH, D2O- exchangeable), 7.37- 7.98 (m, 12H, Ar-H), 8.21 (s, 1H,

N=CH). MS: 417 (M.+

). Anal. calc. for C22H17BrN4 (417.33): C: 63.31, H: 4.11, N: 13.43;

found: C: 63.52, H: 3.98, N: 13.30.

CONCLUSION

Some 4-[(3-methyl-4-bromo)phenyl]-2-substituted phthalazin-1(2H)-one derivatives have

been synthesized through one pot simple reactions and could be utilized as non-steroidal anti-

inflammatory drugs (NSAIDs) having the analgesic and anti-inflammatory activity with no

serious side effects including gastrointenstinal disorders , kidney damage and nil or very low

ulcerogenicity

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