Indian journal of Chemistry Vol. 39B, March 2000, pp. 2 10 - 214

Pyridopyrimidines : Part IX - Synthesis and antibacterial activity of 2,..methylthio-

6-phenylazo-5 ,7-dimethylpyrido[2,3-d]pyrimidin-4(3H)-ones

Chaitanya G Dave* & Manish C Shukla Organic Syntheses Laboratory, M. G. Science Institute, Navrangpura, Ahmedabad 380 009, India

Received 6 November 1998; accepted (revised) 9 November 1 999.

2-Amino-3-carbethoxy-5-phenylazo-4,6-dimethylpyridine 2, obtained by diazo coupling of 2-arnino-3-carbethoxy-4,6-dimethyl-pyridine 1 and phenyl diazonium chloride, has been reacted with various aryl isothiocyanates 3 to get N1-substituted N2 -[3-carbethoxy-5-phenylazo-4,6-dimehyl-2-pyridyl]thioureas 4. Cyclization of pyridyl thioureas 4 using two different reaction conditions affords 3-substituted 2-thioxo-6-phenylazo-5-,7-dimethylpyrido[2,3-d]pyrimidin-4(3H)­ones 5, which are S-methylated by dimethyl sulfate under alkaline condition to yielct the title 2-methylthio-6-phenylazo-5,7-dimethylpyrido[2,3-d]pyrimidines 6. All the newly synthesized compounds 4, 5 and 6 have been screened for their antibacterial activity.

Pyridopyrimidines, the bioisosters of wellknown quinazolones have been reported to possess a variety of pharmacological properties '-3. Pyridopyrimidi­nethiones with analgesics, antipyratic, antiinflamma­tory and CNS depressant activities have been pat­ented4• Recently-, pyridopyrimidinones have been re­ported to possess PQtent inhibitory activity towards calcium-independent phosphodiesterase enzyme5. In continuation of our endeavour to search for bioactive pyrido[2,3-dJpyrimidones,6-9 synthesis of 3-substitu­ted-2-thioxo-6-pheny lazo-5, 7 -dimethy Ipyrido[2,3-dJ­pyrimidin-4(3H)-ones 5 and their reactions with di­methyl sulphate were undertaken.

The . required starting compound 2-amino-3-carbethoxy-4,6-dimethyl-5-pheny lazopyridine 2 was prepared by the diazo coupling of phenyl diazonium chloride with 2-amino-3-carbethoxy-4,6-dimethyl­pyridine 1 in concentrated hydrochloric acid under diazotization condition and condensed with various aryl isothiocyanates 3 in ethanol ·at reflux temperature to yield the uncyclic N'-substituted-N2 -[3-carbethoxy-5-phenylazo-4,6-dimethyl-2-pyridyl]thioureas 4. The cyclization of 4 was studied employing two different cyclization conditions and the yields obtained via both the methods were compared. When thioureas 4 were cyclized thermally by heating in an oil-bath at 190-200 °c with stirring, 3-substituted-2-thioxo-6-phenyl­azo-5,7 -dimethy Ipyrido[2,3-dJpyrimidin-4(3H)-ones 5 were obtained in good to excellent yields (60-80%, Method-A), while cyclization in refluxing pyridine provided the identical compounds 5, but in lower yields (37�50%, Method-B) because after several

hours the conversion was not complete and starting material was recovered (TLC). 3-Substitu�ed-2-thioxo-6-phenylazo-5,7-dimethylpyrido[2,3-dJpyrimi­din-4(3H)-ones 5 were reacted with dimethyl sulfate in alcoholic sodium hydroxide solution at 60-70 °c under stirring to obtain 3-substituted-2-methylthio-6-phenylazo-5,7-dimethylpyrido[2,3-dJpyrimidin-4(3H)-ones 6 (Scheme I).

PhN=Nrr,CH3

0 N-R " I )

H3C N N�

SCH3

6

R= Ph,4-CH3Ph,4-OCH)fh,4CIPh

Scheme I

.,

f

-+

DAVE et al. : PYRIDOPYRIMIDINES : SYNTHESIS AND ANTmACfERIAL ACTIVITY 21 1

The absorption bands due to N-H stretching vibra­tions (3485-3370 cm-I) and C=O ( 1 7 1 0 cm-I ) were observed in the IR (KBr) spectrum of 2. Characteriza­tion of N=N stretching vibration. in aromatic azo com­pounds is difficult because of the interference of C=C ring vibrations, but La Fevre et allO have reported the consistent appearance of N=N stretching vibration in the region 1 585- 1 569 cm-I for azo functionality in aromatic azo compounds and in the case of 2 the char­acteristic band was found at 1 576 cm-I . The IH NMR (CDCh) spectrum of 2 displayed two singlet integrat­ing each for 3H at 0 2.33 and 2.44 indicating the pres­ence of two methyl groups. The triplet at 0 1 .39 inte­grating for 3H (J=6.0 Hz) and the quartet at 0 4.35 (J= 6.0 Hz) integrating for 2H were suggestive of methyl and methylene protons respectively present in the car­bethoxy group. The amino protons resonated as a broad singlet integrating for 2H at 0 5.55.

For compounds 4, the IR bands near 1 540- 1 350 and 930 cm-I for NH-C=S functionality were found in agreement with those reported earlier for the same6. The IH NMR (CDCh) spectra of 4 showed 2 x NH protons in downfield region giving two broad singlets each integrating for 1 H in the region 0 1 1 .50- 1 2.55 together with a multiplet near 0 7. 1 0-7.80 due to Ar­H. The triplet (3H) and quartet (2H) at 0 1 .30- 1 .40 (J=6.4-6.5 Hz) and 0 4.30-4.40 (J=6.4-6.5 Hz) respec­tively were assigned to ethyl protons of carbethoxy group. The S-methylation of 5 was confirme9 by the absence of N-H and C=S stretching vibrations and an additional singlet at 0 2.70-2.8 1 integrating for 3H in the IR and IH NMR spectra of 6 respectively.

assay was carried out by the agar plate diffusion methodl l • l: against different bacterial cultures com­prising E. coli, E. entericus, P. aeruginosa, S. typhi, S. aureous and B. subtilis. Different bacterial cultures were streakered across the ditch filled with the each compound (4, 5 and 6, 1 mL at the concentration of 1 % solution in DMSO) and the compound was al­lowed to diffuse in the nutrient agar plate. Antibiotic ampicillin was used as +ve control and the solubilizing DMSO was used as -ve control. The results were re­corded as relative zone of inhibition observed around the ditch with reference to -ve control (Table I).

Experimental Section

General. Melting points were determined on an electrothermal apparatus (capillary method) and are uncorrected. UV (methylene chloride) spectra were recorded on a Beckman Du-64 spectrophotometer. IR spectra were recorded on a Buck scientific spectrophotometer using potassium bromide technique. IH NMR spectra were recorded on a Varian 400 MHz spectrometer using TMS as internal standard (chemical shifts, 0 ppm). TLC analysis were performed using silica gel G and the spots visualized by exposure to iodine vapours.

Synthesis of 2-amino-3-carbethoxy-S-phenylazo-4,6-dimethylpyridine 2. To the cold solution (0-5 0c) of 2-amino-3-carbethoxy-4,6-dimethylpyridine13 1 ( 1 .96 g, 0.01 mole) in concentrated hydrochloric acid ( 1 2 N, 5 mL) was added drop wise a freshly prepared phenyl diazonium chloride ( 1 .44 g, 0.01 mole) over a period of 1 0 min with constant stirring. The reaction mixture was further stirred for 3 hr at the same tem-

-4, Antibacterial activity. The antibacterial activity perature and neutralized with sodium bicarbonate so-

Table I - Antibacterial activity data of compounds 4,5 and 6 Zone of inhibition in mm after 48 hr. Compd R E. coli E. entericus P. aeruginosa S. typhi S. aureous B. subtilis

4a CJIs 1 5.0 10.0 1 5.0 9.0 10.0 9.0 4b 4-CH3C6� 10.0 9.0 1 3.0 1 3 .0 10.0 4c 4-OCH3C� 14.5 1 1 .5 10.5 12.5 1 5.5 12.0 4d 4-CIC� 9.0 9.5 9.5 9.0 9.0 5a CJIs 9.5 6.5 12.5 13.5 9.5 5b 4-CH3C� 10.5 5.5 12.5 10.0

i 5c 4-OCH3C� 10.0 1 1 .0 1 1 .5 10.0 10.0 5d 4-CIC6� 1 1 .0 12.0 1 3.5 12.0 1 1 .0 6a CJIs 10.0 10.0 14.5 12.5 10.0 6b 4-CH3� 1 1 .5 1 1 .5 9.5 1 1 .0 1 1 .5 6c 4-OCH3C� 10.5 6.5 9.5 10.0 10.0 10.5 6d 4-CIC� 1 1 .0 10.0 12.0 1 1 .0 15.5 1 1 .0

Ampicillin 15.0 1 1 .0 12.0 10.5 0.5 DMSO

212 INDIAN 1. CHEM. SEC B, MARCH 2000

lution(50% w/v) to pH 8 under cooling to get the solid. The reaction mixture was then allowed to attain the room temperature and stirred for 30 min. The solid obtained was filtered, washed with water, dried and crystallized from ethanol. Yield 66%, mp 100 DC; UV (CH2Ch) Amax (log E): 345 (3 .878), 295 (3.887); IR (KBr): 3445, 3390 (NH2), 1 665 (C=O), 1 600, 1 590 (C=C, C=N ring), 1 576 (N=N) em-I ; IH NMR (CDCh): 0 1 .39 (3H, t, CH3, J=6.0 Hz), 2.33 (3H, s, CH3), 2.44 (3H, s, CH3), 4.35 (2H, q, CH2, J=6.0 Hz), 5.55 ( 1 H, s, NH2), 7.46-7.60 (5H, m,. Ar-H) : Anal. Calcd for CI6HI8N402 : C, 64.40; H, 6.04; N, 1 8 .79%. Found: C, 64.4 1 ; H, 6.08; N, 1 8 .88%.

Synthesis of N1-substituted-N2 -[3-carbethoxy-S­phenylazo-4,6-dimethyl-2-pyridyl]-thioureas 4 a-d: Gelrleral procedure. A mixture of 2-amino-3-carbethoxy-5-phenylazo-4,6-dimethylpyridine 2 (2.98 g, 0.0 1 mole) and aryl isothiocyanates (0.01 mole) was refIuxed on a steam-bath for a period of 8 hr. The reaction mixture was allowed to cool, poured onto the crushed ice (25 g), and the solid separated was fil­tered, washed with water, dried and crystallized from ethanol.

Jli -PhenyJ-N2 -[3-carbethoxy-S-phenylazo-4,6-di­methyl-2-pyridyl]thiourea 4a: Yield 93%, mp 50 DC; UV (CH2Ch) Amax (log E) : 330 (4.064), 295 (4. 1 26); IR (KBr): 3400 (NH), 1 682 (C=O), 1 6 10, 1550 (C=C, C=N ring), 1 575 (N=N), 1 5 1 2, 1 500 (NHC=S), 1 1 95 (C::S) em-I ; IH NMR (CDCh): 0 1 .30 (3H, t, CH3, J=6.5 Hz), 2.33 (3H, s, CH3), 2.58 (3H, s, CH3), 4.30(2H, q, CH2, J=6.5 Hz), 7 .00-7.65 ( l OH, m, Ar­H), 1 1 .5 1 ( l H, s, NH), 1 2.5 1 ( 1 H, s, NH). Anal. Calcd for C23H23N502S: C, 68. 1 5 ; H, 5 .68; N, 17 .28%. Found: C, 68.42; H, 5.9 1 ; N, 1 7 .47%.

N1-(4-Methylphenyl)-N2 -[3-carbethoxy-S-phenyl­azo-4,6-dimethyl-2-pyridyl]thiourea 4b: Yield 70%, mp 48 DC; UV (CH2Ch) Amax (log E): 467 (2.554), 295 (4.056); IR (KBr): 3220 (NH), 1 662 (C=O), 1 600, 1550 (C=C, C=N ring), 1 572 (N=N), 1 500, 1 440 (NHC=S), 1 200 (C=S) em-I ; 'H NMR(CDCh): 0 1 .37 (3H, t, CH3, J=6.5 Hz), 2.33 (3H, s, CH3), 2.58 (3H, s, CH3), 2.70 (3H, s, CH3), 4.40 (2H; q, CH2, J=6.5 Hz), 6.95-7.60 (9H, m, Ar-H), 1 1 .50 ( lH, s, NH), 12.52 ( l H, s, NH). Anal. Calcd for C24H25N502S: C, 64.40; H, 5.63; N, 1 5 .64%. Found: C, 64.77; H, 5 .2 1 ; N, 1 5 .39%.

N1_( 4-Methoxyphenyl)-N2 -[3-carbethoxy-S-phenyl­azo-4,6-dimethyl-2-pyridyl]thiourea 4c: Yield 79%, mp 49 DC; UV (CH2Ch) Amax (log E): 467 (2.554), 295 (4.056); IR (KBr): 3240 (NH), 1 680 (C=O), 1 608,

1 560 (C=C, C=N ring), 1 580 (N=N), 1506, 1473 (NHC=S), 1 204 (C=S) em-I ; I H NMR (CDCh): 0 1 .39 (3H, t, CH3, J=6.4 Hz), 2.40 (3H, s, CH3), 2.60 (3H, s, CH3), 3.85 (3H, s, OCH3), 4.38 (2H, q, CH2, J=6.4 Hz), 7 . 1 6-7.75 (9H, m, Ar-H), 1 1 .53 ( 1 H, s, NH), 1 2.54 ( l H, s, NH). Anal . Calcd for C24H25N503S C, 62. 1 8 ; H, 5 .44; N, 1 5 . 1 1 %. Found: C, 62.43; H, 5 . 19; N, 1 5 .42% .

N1_( 4-Chlorophenyl)-N2 -[3-carbethoxy-S-phenyl­azo-4,6-dimethyl-2-pyridyl]thiourea 4d: Yield 79%, mp 58 DC; UV (CH2Ch) Amax (log E): 467 (2.687), 295 (4. 1 59); IR (KBr): 3250 (NH), 1 665 (C=O), 1 608, 1 550 (C=C, C=N ring), 1 580 (N=N), 1 508, 1488 (NHC=S), 1 200 (C=S) em-I ; I H NMR (CDCh): 0 1 .40 (3H, t, CH3, J=6.4 Hz), 2.44(3H, s, CH3), 2.65 (3H, s, CH3), 4.40 (2H, q, CH2, J=6.4 Hz), 7.20-7.80 (9H, m, Ar-H) , 1 1 .55 ( lH, s, NH), 1 2.55 ( l H, s, NH). Anal. Calcd for C23H22ClN502S: C, 59.02; H, 4.73 ; N, 14.96% . Found: C, 59.38; H, 5 .0 1 ; N, 14.73%.

3-Substituted -2-thioxo-6-phenylazo-S, 7 -dimethyl­pyrido[2,3-d]pyrimidin-4-(3H)-ones 5 a-d: General procedure. Method-A. NI -Substituted-N

2 -[3-carb­

ethoxy-5-phenylazo-4,6-dimethyl-2-pyridyl]thioureas 4 (3.0 g) were heated in an oil-bath with constant stir­ring till the mobile phase was obtained. The tempera­ture was then allowed to increase slowly upto 1 90-200 DC with stirring until the solidification occurred. The content was cooled, treated with ice water(50 mL) followed by aqueous Na2C03 solution( l O mL, 10% w/v), filtered, washed with water, dried and crystal­lized from DMF.

Method-B. NI-Substituted-N2 -[3-carbethoxy-5-

phenylazo-4,6-dimethyl-2-pyridyl]thioureas 4 ( 1 .0 g) in pyridine( l O mL) were heated under reflux for 24 hr. The reaction mixture was allowed to cool, added to the crushed ice (25 g), filtered, washed with water, dried and crystallized from DMF.

2-Thioxo-3- phenyl-6- phenylazo-S, 7 -dimethyl­pyrido[2,3-d]pyrimidin-4(3H)-ones Sa: Yield 60% (Method-A), 40% ( Method-B); mp 253-55 DC (Method-A), 253-55 DC (Method B); UV (CH2Ch) Amax (log E): 326 (4.074), 295 (4.078); IR (KBr): 3250 (NH), 1 690 (C=O), 1 590, 1 550 (C=C, C=N ring), 1 573 (N=N), 1 396 (NHC=S), 1 200 (C=S) em-I ; 'H NMR (DMSO-d6): 0 2.30 (3H, s, CH3), 2.60 (3H, s, CH3), 7 .06-7.60 ( l 1 H, m, Ar-H). Anal. Calcd for C2IH17N50S: C, 65.09; H, 4.42; N, 1 8.07%. Found: C, 64.78; H, 4. 19 ; N, 1 8 .32%.

2-Thioxo-3- (4- methylphenyl)-6-phenylazo-S, 7-dimethylpyrido[2,3-d]pyrimidin-4(3H)-ones Sb:

,

DAVE et ai. : PYRIDOPYRIMIDINES : SYNTHESIS AND ANTIBACTERIAL ACTIVITY 213

Yield 65% (Method-A), 43% (Method-B); mp 235-37 DC (Method-A), 235-37 DC (Method-B); UV (CH2Ch) Amax(log E): 325 (4.083), 295 (4.075); IR (KEr): 3 1 80(NH), 1 676 (C=O), 1 604, 1 560 (C=C, C=N ring), 1 572(N=N), 1 395(NHC=S), 1 204 (C=S) cm-I ; IH NMR (DMSO-d6): 0 2.32 ( 3H, s, CH3), 2.55 (3H, s, CH3), 2.69 (3H, s, CH3), 7.05-7.70 ( l OH, m, Ar-H). Anal. Calcd for CZ2HI9N50S: C, 65.8 1 ; H, 4.76; N, 17.44%. Found: C, 64.50; H, 4.93; N, 1 7 .73%.

2-Thioxo-3-( 4-methoxyphenyl)-6-phenylazo-5, 7-dimethylpyrido[2,3-d]pyrimidin-4(3H)-ones 5c: Yield 80% (Method-A), 43% (Method-B); mp 251 -53 DC (Method-A), 25 1 -53 DC (Method-B); UV (CH2Ch) Amax(log E): 327 (4. 1 08), 295 (4. 1 09); IR (KEr): 3270 (NH), 1 700 (C=O), 1 620, 1 550 (C=C, C=N ring), 1 572 (N=N), 1 4 1 6 (NHC=S), 1 2 12 (C=S) cm-I ; IH NMR (DMSO-d6): 0 2.35 (3H, s, CH3), 2.60 (3H, s, CH3), 3.90 (3H, s, OCH3), 7 . 1 0-7.70 ( 1 OH, m, Ar­H). Anal. Calcd for C22H19N502S: C, 63.28; H, 4.58; N, 1 6.77%. Found: C, 63.00; H, 4.79; N, 1 6.48 %.

2-Thioxo-3-( <khlorophenyl-6-phenyIazo-5,7-dime­thylpyrido[2,3-d]pyrimidin-4(3H)-ones 5d: Yield 70% (Method-A), 40% (Method-B); mp 278-80 DC (Method-A), 278-80 DC (Method-B); UV (CH2Ch) Amax (log E): 328 (4. 1 1 4), 295 (4. 1 4); IR (KEr): 3 1 50 (NH), 1 686 (C=O), 1 608, 1 550 (C=C, C=N ring), 1 565 (N=N), 1 406(NHC=S), 1 208 (C=S) cm-I ; IH NMR (DMDO-d6): 0 2.40 (3H, s, CH3), 2.64 (3H, s, CH3), 7. 1 5-7.70 ( l 1 H, m, Ar-H). Anal. Calcd for C2 IHI6CIN50S: C, 59.77; H, 3 .82; N, 1 6.60%. Found: C, 60.07; H, 4 . 1 5 ; N, 16.28%.

Synthesis of 3-substituted-2-S-Methylthio-6-phenyl-. azo-5, 7-dimethylpyrido[2, 3-d]-pyrimidin-4-(3H)­

ones 6a-d: General procedure. A mixture of 3-substituted-2-thioxo-6-pheny lazo-5, 7 -dimethy lpyrido­[2,3-dJpyrimidin-4(3H)-ones 6 (0.01 mole) and alco­holic NaOH solution (0.04 g in 20 mL ethanol) was heated at 60-70 DC to get the clear solution. To this was added dimethyl sulphate(O.Ol mole, 1 .26 g) dropwise with constant stirring over a period of 20 min. After the completion of addition, the reaction mixture was further stirred at the same temperature for 1 .5 hr. It was then allowed to attain the room tempera­ture, and the solid separated was filtered, washed with water, dried and crystallized from n-propanol.

2-S-Methylthio-3-phenyl-6-phenylazo-5,7 -dime­thylpyrido[2, 3-d]pyrimidin-4(3H)-ones 6a: Yield 75%, mp 2 1 8-20 DC; UV (CH2Ch) Amax (log E): 520 (2.587), 295 (4. 107); IR (KEr): 1 686 (C=O), 1 608, 1 550 (C=C, C=N ring), 1 586 (N=N), 1 390 (CH-

alkyl), 872 (SCH3) cm-I ; IH NMR (CDCh): 0 2.3 1 (3H, s, CH3), 2.52 (3H, s, CH3), 2.77 (3H, s, SCH3), 6.95-7.60 ( l OH, m, Ar-H). Anal. Calcd for C22H19N50S: C, 59.77; H, 3.82; N, 16 .60%. Found: C, 60.07; H, 4. 1 5 ; N, 1 6.28%.

2-S-Methylthio-3-(4-methylphenyl)-6-phenylazo-5, 7 -dimethylpyrido[2, 3-d]-pyrimidin-4(3H)-ones

6b: Yield 83%, mp 1 68-70 DC; UV (CH2Ch) Amax (log E): 556 (2.678), 295 (4.092); IR (KEr): 1 680 (C=O), 1 608, 1 550 (C=C, C=N ring), 1 5 86 (N=N), 1 390 (CH-alkyl), 872 (SCH3) cm-I ; IH NMR (CDCh): o 2.32 (3H, s, CH3), 2.55 (3H, s, CH3), 2.65 (3H, s, CH3), 2.80 (3H, s, SCH3), 7.05-7.60 (9H, m, Ar-H). Anal. Calcd for C23H21N50S: .C, 66.48; H, 5 .09; N, 1 6.85%. Found: C, 66. 1 9; H, 5 .45; N, 1 6.53%.

2-S-Methylthio -3-(4- methQxyphenyl)-6-phenyl­azo-5,7 -dimethylpyrido[2,3-d]-pyrimidin-4(3HJ­ones 6c: Yield 70%, mp 227-29 Dc;:; UV (CHl�h) Amax (log E): 523 (2.6 1 6), 295 (4. 1 27); IR (KEr): 1 684 (C=O), 1 604, 1 560 (C=C, C=N ring), 1 578 (N=N), 1 392 (CH-alkyl), 828 (SCH3) cm-I ; IH NMR (CDCh): 0 2.35 (3H, s, CH3), 2.60 (3H, s, CH3), 2.85 (3H, s, SCH3), 3 .95 (3H, s, OCH3), 7 . 1 0-7.60 (9H, m, Ar-H). Anal. Calcd for C23H21N502S : C, 64.0 1 ; H, 4.95; N, 1 6.23%. Found: C, 64.47; H, 5 .3 1 ; N, 1 6.07%.

2-S-MethyIthio-3-(4-chlorophenyl)-6-phenylazo-5, 7 -dimethylpyrido[2, 3-d]-pyrimidin-4(3H)-ones

6d: Yield 88%, mp 248-50 DC; UV (CH2Ch) Amax (log E): 505 (2.7 1 1), 295 (4. 1 2 1) ; IR (KEr): 1 684 (C=O), 1 608, 1 550 (C=C, C=N ring), 1 586 (N=N), 1 370 (CH-a1kyl), 852 (SCH3) cm-I ; IH NMR (CDCh): o 2.4 1 (3H, s, CH3), 2.65 (3H, s, CH3), 2.8 1 (3H, s, SCH3), 7 .05-7.80 (9H, m, Ar-H). Anal. Calcd for C22HIsCIN50S: C, 60.6 1 ; H, 4. 1 6; N, 1 6.06%. Found: C, 60.79; H, 3.93; N, 1 6.39%.

Acknowledgment

We wish to thank Regional Sophisticated Instru­mentation Centre, Central Drug Research Institute, Lucknow for NMR and mass spectra.

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214 INDIAN J. CHEM. SEC B, MARCH 2000

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