Facile synthesis of pyrazolo[3,4-d]pyrimidines and pyrimido[4,5-d] pyrimidin-4-one derivatives

Article abstract of DOI:10.1080/00397910600773726

Pyrazolopyrimidine and pyrimidopyrimidine derivatives have shown a wide range of biological activities such as acting as A₁ adenosine receptors, kinase insert domain receptor (KDR), Rous sarcoma oncogene (Src), epidermal growth factor receptor (EGFR), antiproliferative, dihydrofolate reductase (DHFR), antimicrobial, antifungal, and lipid peroxidation. Because of this wide range of activities, we have synthesized pyrazolo[3,4-d]pyrimidines and pyrimido[4,5-d]pyrimidin-4-one derivatives. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600773726

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Facile Synthesis of
Pyrazolo[3,4‐d]pyrimidines and
Pyrimido[4,5‐d]pyrimidin‐4‐one Derivatives
Sanjay Babu Katiyar a , Arun Kumar a & Prem M. S. Chauhan a
a Medicinal and Process Chemistry Division, Central Drug Research Institute,
Lucknow, India
Published online: 16 Feb 2007.
To cite this article: Sanjay Babu Katiyar , Arun Kumar & Prem M. S. Chauhan (2006) Facile Synthesis of
Pyrazolo[3,4‐d]pyrimidines and Pyrimido[4,5‐d]pyrimidin‐4‐one Derivatives, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:20, 2963-2973, DOI:
10.1080/00397910600773726
To link to this article: http://dx.doi.org/10.1080/00397910600773726
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Synthetic Communicationsw, 36: 2963–2973, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600773726
Facile Synthesis of
Pyrazolo[3,4-d]pyrimidines and
Pyrimido[4,5-d]pyrimidin-4-one Derivatives
Sanjay Babu Katiyar, Arun Kumar, and Prem M. S. Chauhan
Medicinal and Process Chemistry Division, Central Drug
Research Institute, Lucknow, India
Abstract: Pyrazolopyrimidine and pyrimidopyrimidine derivatives have shown a wide
range of biological activities such as acting as A1 adenosine receptors, kinase insert
domain receptor (KDR), Rous sarcoma oncogene (Src), epidermal growth factor
receptor (EGFR), antiproliferative, dihydrofolate reductase (DHFR), antimicrobial,
antifungal, and lipid peroxidation. Because of this wide range of activities, we have
synthesized pyrazolo[3,4-d]pyrimidines and pyrimido[4,5-d]pyrimidin-4-one
derivatives.
Keywords: Pyrazolopyrimidine, pyrimidopyrimidine
INTRODUCTION
Pyrazolo[3,4-d]pyrimidine[1–4] derivatives were found to be selective ligands
with antagonist activity for A1 adenosine receptors (A1AR). They may have
therapeutical use as cognitive enhancers, antidementia drugs (e.g., for Alzhei-
mer’s disease and cerebrovascular dementia), psycostimulants, antidepressant
drugs, and ameliorants of cerebral function.[5] A1AR antagonists have also
demonstrated promising therapeutic potential for renal and cardiac
Received in India March 23, 2006
Address correspondence to Prem M. S. Chauhan, Medicinal and Process Chemistry
Division, Central Drug Research Institute, Lucknow 226001, India. E-mail:
prem_chauhan_2000@yahoo.com
2963

2964
S. B. Katiyar, A. Kumar, and P. M. S. Chauhan
Scheme 1. Reagents and conditions: (I) CS2, NaH, MeI, THF, 08C–r.t.; (II) Ar-
NHNH2, EtOH, reflux; (III) m-CPBA, DCM, r.t.; (IV) NaOH, H2O2. (33%, v/v),
0–r.t.; (V) aromatic aldehydes, PTSA, benzene, reflux.
failure.[6,7] Because of this wide range of activities, we have synthesized the
pyrazolopyrimidine derivatives using thiomethyl ketene acetal as intermediate
and pyrimidopyrimidone derivatives.
Synthesis of pyrazolo[3,4-d]-pyrimidine derivatives 5–16 were carried out
as shown in Scheme 1. 2-(bis-Methylsulfanylmethylene)-malononitrile[8] (1)
was obtained by the reaction of malononitrile with CS2 in the presence of NaH
followed by methylation with methyl iodide at 08C–r.t. Compound 1 was
cyclized with hydrazine hydrate[9,10] in methanol to obtain 5-amino-
4-cyano-3-methylsulfanyl-1-phenyl-1H-pyrazole (2). Compound
2
was
oxidized to the corresponding sulphone 5-amino-4-cyano-3-methanesulfonyl-1-
phenyl-1H-pyrazole-4-carbonitrile[11] (3) in the presence of chloroperbenzoic
acid (m-CPBA). Compound 3 was converted into 5-amino-3-methanesulfonyl-
1-phenyl-1H-pyrazole-4-carboxylic acid amide[12] (4) by means of H2O2 in
the presence of NaOH at 08C–408C. Compound 4 was cyclized[13] with
different aromatic aldehydes in the presence of p-toluenesulfonic acid (PTSA)
to obtain the target products 5–16.
Compound 4-amino-5-cyano-2-methylthiopyrimidine (17) was syn-
thesized by the reaction of S-methyl thiourea hydrogen sulphate and ethox-
ymethylene malonitrile (EMMN) in the presence of diisopropylethylamine
in dry DMF at 08C to r.t.[14] Compound 17 was oxidized with m-chloro-
peroxybenzoic acid to obtain the sulphone (18), which on nucleophilic sub-
stitution with various amines furnished the compounds 19–28.[15]
Compounds 19–28 were benzoylated separately with benzoyl chloride in the
presence of potassium tert. butoxide in dry DMF at 08C–r.t. to obtain
compounds 29–38, which were cyclized in the presence of hydrogen
peroxide/sodium hydroxide and methanol to give the final products 39–48
(Scheme 2).

Synthesis of Pyrazolopyrimidine and Pyrimidopyrimidine
2965
Scheme 2. Reagents and conditions: (I) diisopropylethyl amine, DMF, 08C–r.t.;
(II) 3-chloro peroxybenzoic acid, THF, 08C–r.t.; (III) amines, THF, reflux; (IV) ben-
zoyl chloride, potassium tert. butoxide, DMF, 08C–r.t., (V) NaOH/H2O2, MeOH,
08C–r.t.
EXPERIMENTAL
Melting points were recorded on a capillary melting-point apparatus and are
1
uncorrected. Both H and 13C NMR spectra were recorded on a 200-MHz
Bruker FT-NMR (Avance DPX200) spectrometer using tetramethylsilane as
internal standard, and the chemical shifts are reported in d units. Fast atom
bombardment (FAB) mass spectra were recorded on Jeol SX 102/DA 6000
mass spectrometer using argon/xenon (6 kv, 10 mA) as the FAB gas.
Elemental analyses were carried out on a Carlo-Erba 1108 instrument or Ele-
mentar’s Vario EL III microanalyzer. All chromatographic purification was
performed with silica gel 60 (or 100–200 mesh), whereas all thin-layer
chromatography (TLC) (silica gel) development was performed on silica gel
coated (Merck Kiesel 60 GF-254, 0.2 mm thickness) sheets. All chemicals
were purchased from Aldrich Chemical Ltd. (Milwaukee, WI, USA).
Solvents used for the chemical synthesis acquired from commercial sources
were of analytical grade and were used without further purification unless
otherwise stated.
General Experimental Procedure for the Synthesis of
Compounds 5–16
The solution of compound 4 (1 equiv), appropriate aromatic aldehydes
(1 equiv), and PTSA (1 equiv), in dry benzene was refluxed for 12 h. The
solvent was removed under reduced pressure to get a solid mass, which was
dissolved in CHCl3, washed with water three times, dried over anhyd.
Na2SO4, and crystallized with methanol–ether to afford targeted
compounds 5–16.

2966
S. B. Katiyar, A. Kumar, and P. M. S. Chauhan
Data
6-(3-Bromo-phenyl)-3-methanesulfonyl-1-phenyl-1,5-dihydro-
pyrazolo-[3,4-d]-pyrimidin-4-one (5)
Yield: 73% mp . 2708C; FAB-MS: 446 (M þ 1); IR (KBr): 3428, 3029,
1
2930, 2818, 197, 1588, 1498, 1464, 1394, 1352 cm21; H NMR (200 MHz,
CDCl3): d (ppm) 8.29 (s, 1H, Ar-H), 8.08 (d, 1H, J ¼ 7.92 Hz, Ar-H), 7.98
(d, 2H, J ¼ 7.98 Hz, Ar-H), 7.63 (d, 1H, J ¼ 7.98 Hz, Ar-H), 7.53–7.46
(m, 3H, Ar-H), 7.41–7.35 (m, 1H, Ar-H), 3.53 (s, 3H, SO2CH3); 13C NMR
(50 MHz, DMSO-d6): d (ppm) 172.42, 165.88, 144.65, 139.97, 135.23,
133.90, 130.87, 129.55, 129.96, 127.56, 126.75, 125.25, 123.33, 119.34,
111.42, 41.13. Anal. calcd. for C18H13BrN4O3S: C, 48.55; H, 2.94; N,
12.58. Found: C, 48.23; H, 3.13; N, 12.25%.
3-Methanesulphonyl-6-(4-methoxy-phenyl)-1-phenyl-1,5-dihydro-
pyrazolo-[3,4-d]-pyrimidin-4-one (6)
Yield: 69%; mp . 2708C; FAB-MS: 397 (M þ 1); IR (KBr): 3441, 3065,
2956, 2856, 1698, 1599, 1553, 1498, 1397, 1335 cm21
;
1H NMR
(200 MHz, DMSO-D6): d (ppm) 8.12 (d, 2H, J ¼ 8.80 Hz, Ar-H), 8.01
(d, 2H, J ¼ 7.84 Hz, Ar-H), 7.61–7.40 (m, 3H, Ar-H), 7.04 (d, 2H,
J ¼ 8.80 Hz, Ar-H), 3.78 (s, 3H, OCH3), 3.56 (s, 3H, SO2CH3); 13C NMR
(50 MHz, DMSO-d6): d (ppm) 171.44, 165.89, 162.44, 145.56, 129.67,
128.12, 127.12, 126.45, 125.67, 119.85, 114.23, 110.11, 56.71, 41.53. Anal.
calcd. for C19H16N4O4S: C, 57.57; H, 4.07; N, 14.13. Found: C, 57.73; H,
4.34; N, 14.09%.
6-(2,3-Dimethoxy-phenyl)-3-methanesulfonyl-1-phenyl-1,5-dihydro-
pyrazolo-[3,4-d]-pyrimidin-4-one (7)
Yield: 53%; mp 210–2138C; FAB-MS: 427 (M þ 1); IR (KBr): 3429, 3009,
2962, 2835, 1698, 1594, 1549, 1496, 1467, 1396 cm21
;
1H NMR
(200 MHz, CDCl3): d (ppm) 8.12 (d, 2H, J ¼ 8.74 Hz, Ar-H), 7.96 (dd, 1H,
J ¼ 1.74, 7.84 Hz, Ar-H), 7.60–7.45 (m, 3H, Ar-H), 7.28 (dd, 1H, J ¼ 7.28
& 8.70 Hz, Ar-H), 7.17 (dd, 1H, J ¼ 1.74, 8.18 Hz, Ar-H), 4.03 (s, 3H,
OCH3), 3.96 (s, 3H, OCH3), 3.59 (s, 3H, SO2CH3); 13C NMR (50 MHz,
DMSO-d6): d (ppm) 172.89, 164.98, 147.85, 144.42, 145.67, 140.11,
129.41, 128.74, 126.45, 122.17, 119.89, 119.28, 118.87, 41.15, 116.55,
111.12, 56.89, 56.34. Anal. calcd. for C20H18N4O5S: C, 56.33; H, 4.25; N,
13.14. Found: C, 56.15; H, 4.43; N, 13.24%.

Synthesis of Pyrazolopyrimidine and Pyrimidopyrimidine
2967
6-(2,5-Dimethoxy-phenyl)-3-methanesulphonyl-1-phenyl-1,5-dihydro-
pyazolo-[3,4-d]-pyrimidin-4-one (8)
Yield: 57%; mp 205–2288C; FAB-MS: 427 (M þ 1); IR (KBr): 34029, 3015,
2923, 2836, 1701, 1596, 1553, 1492, 1435, 1398, 1329 cm21 1H NMR
;
(200 MHz, CDCl3): d (ppm) 8.13 (d, 2H, J ¼ 8.26 Hz, Ar-H), 8.02 (d, 1H,
J ¼ 3.02 Hz, Ar-H), 7.59–7.44 (m, 3H, Ar-H), 7.12 (dd, 1H, J ¼ 3.04 &
8.74 Hz, Ar-H), 7.03 (d, 1H, J ¼ 8.74 Hz, Ar-H), 4.07 (s, 3H, OCH3),
3.84 (s, 3H, OCH3), 3.59 (s, 3H, SO2CH3); 13C NMR (50 MHz, DMSO-d6):
d (ppm) 172.75, 165.66, 154.55, 151.91, 145.12, 139.99, 129.33, 127.55,
126.76, 119.56, 118.43, 116.78, 115.67, 112.23, 110.98, 56.84, 56.19,
40.78. Anal. calcd. for C20H18N4O5S: C, 56.33; H, 4.25; N, 13.14. Found:
C, 56.13; H, 4.34; N, 13.35%.
6-(4-Isopropyl-phenyl)-3-methanesulphonyl-1-phenyl-1,5-dihydro-
pyrazolo-[3,4-d]-pyrimidin-4-one (9)
Yield: 55%; mp . 2708C; FAB-MS: 409 (M þ 1); IR (KBr): 3432, 3065,
2962, 2856, 1693, 1595, 1555, 1498, 1396, 1328 cm21
;
1H NMR
(200 MHz, CDCl3): d (ppm) 8.30 (d, 2H, J ¼ 8.34 Hz, Ar-H), 8.14 (d, 2H,
J ¼ 7.66 Hz, Ar-H), 7.62–7.46 (m, 5H, Ar-H), 3.54 (s, 3H, SO2CH3),
3.09–3.02 (m, 1H, CH), 1.35 (s, 3H, CH3), 1.31 (s, 3H, CH3); 13C NMR
(50 MHz, DMSO-d6): d (ppm) 172.42, 165.97, 151.55, 144.43, 139.86,
130.75, 129.12, 128.55, 127.85, 126.49, 125.68, 118.89, 110.11, 40.98,
31.75, 24.54. Anal. calcd. for C21H20N4O3S: C, 61.75; H, 4.94; N, 13.72.
Found: C, 61.82; H, 4.73; N, 13.85%.
3-Methanesulfonyl-1-phenyl-6-(3,4,5-trimethoxy-phenyl)-1,5-dihydro-
pyrazolo-[3,4-d]-pyrimidin-4-one (10)
Yield: 52%; mp . 2708C; FABMS: 457 (M þ 1); IR (KBr): 3443, 3016,
2939, 2836, 1712, 1598, 1495, 1459, 1301 cm21 1H NMR (200 MHz,
;
CDCl3): d (ppm) 8.08 (d, 2H, J ¼ 7.94 Hz, Ar-H), 7.53–7.43 (m, 3H, Ar-
H), 7.39 (s, 2H, Ar-H), 3.89 (s, 6H, OCH3), 3.84 (s, 3H, OCH3), 3.41
(s, 3H, SO2CH3); 13C NMR (50 MHz, DMSO-d6): d (ppm) 171.89, 165.43,
148.76, 144.87, 140.74, 134.68, 129.87, 128.12, 127.74, 126.88, 119.43,
111.23, 105.57, 56.32, 56.77, 41.63. Anal. calcd. for C21H20N4O6S: C,
55.26; H, 4.42; N, 12.27. Found: C, 55.12; H, 4.23; N, 12.45%.
3-Methanesulfonyl-1-phenyl-6-p-tolyl-1,5-dihydro-pyrazolo-[3,4-d]-
pyrimidin-4-one (11)
Yield: 59%; mp . 2708C; FABMS: 381 (M þ 1); IR (KBr): 3434, 3090,
2960, 2865, 1695, 1594, 1479, 1394 1349 cm21 1H NMR (200 MHz,
;
DMSO-d6): d (ppm) 12.96 (bs, 1H, NH), 8.10–8.02 (m, 4H, J ¼ 8.14 Hz,

2968
S. B. Katiyar, A. Kumar, and P. M. S. Chauhan
Ar-H), 7.71–7.49 (m, 3H, Ar-H), 7.43 (d, 2H, J ¼ 8.28 Hz, Ar-H), 3.64
(s, 3H, SO2CH3), 2.42 (s, 3H, CH3); 13C NMR (50 MHz, DMSO-d6): d
(ppm) 172.45, 165.79, 145.34, 141.23, 139.76, 130.45, 129.67, 129.12,
127.87, 126.98, 125.91, 119.34, 111.67, 40.98, 21.96. Anal. calcd. for
C19H16N4O3S: C, 59.99; H, 4.24; N, 14.73. Found: C, 59.45; H, 4.64; N,
14.56%.
6-(4-Dimethylamino-phenyl)-3-methanesulfonyl-1-phenyl-1,5-
dihydro-pyrazolo[3,4-d]pyrimidin-4-one (12)
Yield: 59%; mp . 2708C; FAB-MS: 410 (M þ 1); IR (KBr): 3425, 3093,
2925, 2833, 1690, 1595, 1555, 1453, 1376, 1321 cm21
;
1H NMR
(200 MHz, DMSO-d6): d (ppm) 8.14 (d, 2H, J ¼ 8.16 Hz, Ar-H), 8.00
(d, 2H, J ¼ 7.94 Hz, Ar-H), 7.68–7.52 (m, 3H, Ar-H), 6.84 (d, 2H,
J ¼ 7.96 Hz, Ar-H), 3.60 (s, 3H, SO2CH3), 2.10 (s, 6H, NCH3); 13C NMR
(50 MHz, DMSO-d6): d (ppm) 171.99, 166.23, 145.92, 144.96, 140.24,
129.53, 127.55, 126.80, 126.33, 123.77, 119.25, 113.44, 111.75, 44.76,
44.82, 41.22. Anal. calcd. for C20H19N5O3S: C, 58.67; H, 4.68; N, 17.10.
Found: C, 58.86; H, 4.55; N, 17.25%.
3-Methanesulfonyl-6-(4-methylsulfanyl-phenyl)-1-phenyl-1,5-dihydro-
pyrazolo[3,4-d]pyrimidin-4-one (13)
Yield: 60%; mp . 2708C; FAB-MS: 413 (M þ 1); IR (KBr): 3435, 3095,
2935, 2830, 1691, 1590, 1551, 1463, 1377, 1311 cm21
;
1H NMR
(200 MHz, DMSO-d6): d (ppm) 8.12 (d, 2H, J ¼ 8.26 Hz, Ar-H), 8.04
(d, 2H, J ¼ 8.18 Hz, Ar-H), 7.69–7.48 (m, 3H, Ar-H), 6.80 (d, 2H,
J ¼ 8.16 Hz, Ar-H), 3.63 (s, 3H, SO2CH3), 2.52 (s, 3H, SCH3); 13C NMR
(50 MHz, DMSO-d6): d (ppm) 172.56, 165.66, 145.43, 139.97, 137.33,
129.22, 129.76, 128.12, 127.58, 126.21, 126.79, 119.34, 111.53, 40.98,
21.35. Anal. calcd. for C19H16N4O3S2: C, 55.32; H, 3.91; N, 13.58. Found:
C, 55.52; H, 3.77; N, 13.45%.
6-(4-Fluoro-phenyl)-3-methanesulfonyl-1-phenyl-1,5-dihydro-
pyrazolo[3,4-d]-pyrimidin-4-one (14)
Yield: 61%; mp . 2708C; FAB-MS: 385 (M þ 1); IR (KBr): 3429, 3080,
2974, 2831, 1688, 1597, 1555, 1493, 1391 cm21 1H NMR (200 MHz,
;
DMSO-d6): d (ppm) 13.07 (bs, 1H, NH), 8.26 (d, 2H, J ¼ 8.62 Hz, Ar-H),
8.08 (d, 2H, J ¼ 7.88 Hz, Ar-H), 7.62 (d, 2H, J ¼ 8.60 Hz, Ar-H), 7.57–
7.42 (m, 3H, Ar-H), 3.64 (s, 3H, SO2CH3); 13C NMR (50 MHz, DMSO-d6):
d (ppm) 171.997, 165.57, 163.52, 145.34, 140.14, 129.15, 128.76, 127.23,
127.79, 126.55, 118.92, 115.72, 111.35, 4176. Anal. calcd. for
C18H13FN4O3S: C, 56.24; H, 3.41; N, 14.58. Found: C, 56.83; H, 3.08; N,
14.72%.

Synthesis of Pyrazolopyrimidine and Pyrimidopyrimidine
2969
6-(3,4-Dimethoxy-phenyl)-3-methanesulfonyl-1-phenyl-1,5-dihydro-
pyrazolo-[3,4-d]-pyrimidin-4-one (15)
Yield: 60%; mp . 2708C; FAB-MS: 427 (Mþ1); IR (KBr): 3433, 3107, 2933,
2835, 1706, 1599, 1560, 1498, 1396, 1323 cm21 1H NMR (200 MHz,
;
DMSO-d6): d (ppm) 8.04 (d, 2H, J ¼ 7.80 Hz, Ar-H), 7.83 (d, 1H,
J ¼ 8.64 Hz, Ar-H), 7.77 (d, 1H, J ¼ 1.78 Hz, Ar-H), 7.64–7.45 (m, 3H,
Ar-H), 7.10 (dd, 1H, J ¼ 1.76, 8.62 Hz, Ar-H), 3.82 (s, 3H, OCH3), 3.79
(s, 3H, OCH3), 3.56 (s, 3H, SO2CH3); 13C NMR (50 MHz, DMSO-d6): d
(ppm) 171.79, 166.24, 149.45, 147.75, 145.79, 139.97, 129.66, 127.93,
126.33, 126.95, 119.87, 118.80, 115.64, 112.50, 111.59, 56.32, 56.85,
41.33. Anal. calcd. for C20H18N4O5S: C, 56.33; H, 4.25; N, 13.14. Found:
C, 56.56; H, 4.37; N, 13.08%.
6-(4-Chloro-phenyl)-3-methanesulfonyl-1-phenyl-1,5-dihydro-
pyrazolo[3,4-d]-pyrimidin-4-one (16)
Yield: 59%; mp . 2708C; FAB-MS: 401 (M þ 1); IR (KBr): 3430, 3094,
2965, 2860, 1686, 1592, 1492, 1394 1352 cm21 1H NMR (200 MHz,
;
DMSO-d6): d (ppm) 8.18 (d, 2H, J ¼ 8.62 Hz, Ar-H), 8.06 (d, 2H,
J ¼ 7.44 Hz, Ar-H), 7.69–7.48 (m, 5H, Ar-H), 3.62 (s, 3H, SO2CH3); 13C
NMR (50 MHz, DMSO-d6): d (ppm) 172.55, 165.44, 145.23, 139.76,
135.42, 131.37, 129.55, 129.15, 127.39, 127.68, 126.63, 119.45, 111.79,
41.39. Anal. calcd. for C18H13ClN4O3S: C, 53.93; H, 3.27; N, 13.98. Found:
C, 53.23; H, 3.34; N, 13.85%.
General Experimental Procedure for the Synthesis of
Compounds 39–48
To an ice-cold solution of compounds 29–38 (2.5 mmol) in methanol (20 ml)
and 10% NaOH solution (10 ml), 33% (v/v) H2O2 (10 ml) was added
dropwise. The reaction mixture was stirred at r.t. for 6 h. The methanol was
distilled in vacuum, and the reaction mixture was neutralized with dil. HCl
to pH ¼ 7. The precipited solid was filtered and washed with cold water.
The precipitate was dissolved in chloroform, and the solution was dried
with Na2SO4. Distillation of solvent in vacuum yielded compounds 39–48.
Data
7-Morpholin-4-yl-2-phenyl-3H-pyrimido-[4,5-d]-pyrimidin-4-one (39)
Yield: 59%; mp 230–2358C (dec.); IR (KBr): 3167, 3088, 2957, 2856,
1
1678, 1556 cm21; FAB MS: 310 (Mþ þ 1); H NMR (200 MHz, CDCl3): d

2970
S. B. Katiyar, A. Kumar, and P. M. S. Chauhan
(ppm) 9.16 (s, 1H, Py-H), 8.24 (d, 2H, J ¼ 7.2 Hz, Ar-H), 7.52 (m, 3H, Ar-H),
4.02 (t, 4H, J ¼ 4.43 Hz, N-CH2), 3.77 (t, 4H, 4.54 Hz, O-CH2); 13C NMR
(50 MHz, CDCl3): d (ppm) 184.10, 172.15, 169.55, 164.32, 159.50, 132.98,
129.68, 128.63, 125.78, 110.38, 58.92, 71.40. Anal. calcd. for C16H15N5O2:
C, 62.19; H, 4.88; N, 22.63. Found: C, 61.77; H, 4.96; N, 22.21%.
2-Phenyl-7-piperidin-1-yl-3H-pyrimido-[4,5-d]-pyrimidin-4-one (40)
Yield: 60%; mp . 2508C; IR (KBr): 3319, 3087, 2923, 2859, 1676, 1599,
1
1526 cm21; FAB MS: 308 (Mþ þ 1); H NMR (200 MHz, CDCl3): d (ppm)
9.14 (s, 1H, Py-H), 8.24 (d, 2H, J ¼ 6.46 Hz, Ar-H), 7.52–7.49 (m, 3H, Ar-
H), 4.02 (t, 4H, J ¼ 5.12 Hz, N-CH2), 1.69 (m, 6H, CH2); 13C NMR
(50 MHz, CDCl3): d (ppm) 184.35, 171.94, 169.22, 164.66, 159.77, 133.08,
129.44, 128.15, 125.54, 111.23, 54.74, 25.20, 26.38. Anal. calcd. for
C17H17N5O: C, 66.44; H, 5.57; N, 22.77. Found: C, 66.11; H, 5.59; N, 22.58%.
7-(4-Benzyl-piperazin-1-yl)-2-phenyl-3-pyrimido-[4,5-d]-pyrimidin-4-
one (41)
Yield: 76%; mp . 235–2408C; IR (KBr): 3167, 3085, 2912, 2795, 1683,
1
1593, 1526 cm21; FAB MS: 399 (Mþ þ 1); H NMR (200 MHz, DMSO-
d6): d (ppm) 9.10 (s,1H, Py-H), 8.22 (d, 1H, J ¼ 6.62 Hz, Ar-H), 7.57–7.49
(m, 3H, Ar-H), 7.34–7.27 (m, 5H, Ar-H), 4.03 (t, 4H, J ¼ 4.60 Hz,
N-CH2), 3.55 (s, 2H, N-CH2-Ar), 2.55 (t, 4H, J ¼ 5.56 Hz, N-CH2); 13C
NMR (50 MHz, DMSO-d6): d (ppm) 184.50, 171.80, 169.12, 164.20,
159.60, 144.50, 132.48, 129.80, 129.44, 128.70, 125.92, 118.24, 113.10,
110.39, 59.10, 57.60, 54.50. Anal. calcd. for C23H22N6O: C, 69.33; H, 5.56;
N, 21.09. Found: C, 68.67; H, 5.62; N, 20.24%.
7-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-phenyl-3H-pyrimido-[4,5-
d]-pyrimidin-4-one (42)
Yield: 55%; mp 130–1338C; IR (KBr): 3319, 3086, 2909, 1676, 1594,
1
1525 cm21; FAB MS: 414 (Mþ þ 1); H NMR (200 MHz, CDCl3): d (ppm)
9.07 (s, 1H, Py-H), 8.19 (d, 2H, J ¼ 7.4 Hz, Ar-H), 7.64–7.52 (m, 3H, Ar-
H), 6.97–6.92 (m, 4H, Ar-H), 4.06 (t, 4H, J ¼ 4.74 Hz, N-CH2), 3.82
(s, 3H, O-CH3), 3.02 (t, 4H, J ¼ 5.20 Hz, N-CH2); 13C NMR (50 MHz,
CDCl3): d (ppm) 184.55, 171.54, 169.38, 164.76, 159.32, 146.60, 132.92,
130.10, 129.69, 128.75, 125.32, 121.78, 119.15, 115.23, 114.35, 110.39,
57.92, 57.22, 56.56. Anal. calcd. for C23H22N6O2: C, 66.65; H, 5.35; N,
20.27. Found: C, 66.30; H, 5.45; N, 20.02%.

Synthesis of Pyrazolopyrimidine and Pyrimidopyrimidine
2971
7-(3,4-Dihydro-2H-quinolin-1-yl)-2-phenyl-3H-pyrimido-[4,5-d]-
pyrimidin-4-one (43)
Yield: 50%; mp 215–2178C (dec.); IR (KBr): 3319, 3086, 2924, 1681, 1598,
1
1516, 1422 cm21; FAB MS: 356 (Mþ þ 1); H NMR (200 MHz, CDCl3): d
(ppm) 9.21 (s, 1H, Py-H), 8.25 (d, 2H, J ¼ 6.56 Hz, Ar-H), 7.61–7.51
(m, 3H, Ar-H), 7.21–7.18 (m, 4H, Ar-H), 5.11 (t, 2H, J ¼ 5.78 Hz,
N-CH2), 4.25 (t, 2H, J ¼ 5.76 Hz, Ar-CH2), 2.98 (m, 2H, CH2); 13C NMR
(50 MHz, CDCl3): 184.55, 172.15, 169.28, 164.37, 159.56, 143.35, 132.85,
129.92, 129.14, 128.58, 126.66, 125.65, 122.62, 117.00, 112.46, 110.45,
60.69, 33.91, 29.25. Anal. calcd. for C21H17N5O: C, 69.98; H, 4.82; N,
19.9. Found: C, 69.32; H, 4.61; N, 19.39%.
7-(4-Methyl-piperazin-1-yl)-2-phenyl-3H-pyrimido-[4,5-d]-pyrimidin-
4-one (44)
Yield: 68%; mp 233–2358C (dec.); IR (KBr): 3420, 3170, 3086, 2924, 1681,
1598, 1516, 1422 cm21; FAB MS: 323 (Mþ þ 1); 1H NMR (200 MHz,
CDCl3): d (ppm) 9.19 (s, 1H, Py-H), 8.27 (d, 2H, J ¼ 7.80 Hz, Ar-H),
7.63–7.52 (m, 3H, Ar-H), 4.09 (t, 4H, J ¼ 4.86 Hz, N-CH2), 2.51 (t, 4H,
J ¼ 5.08 Hz, N-CH2), 2.35 (s, 3H, N-CH3); 13C NMR (50 MHz, CDCl3): d
(ppm) 184.55, 172.10, 169.18, 164.35, 159.48, 132.97, 129.92, 128.68,
125.75, 110.38, 57.72, 48.43, 38.70. Anal. calcd. for C17H18N6O: C, 63.34;
H, 5.62; N, 26.06. Found: C, 63.11; H, 5.82; N, 25.87%.
2-Phenyl-7-(4-phenyl-piperazin-1-yl)-3H-pyrimido-[4,5-d]-pyrimidin-
4-one (45)
Yield: 61%; mp 210–2138C; IR (KBr): 3418, 3166, 3084, 2911, 2812, 1679,
1594, 1523 cm21; FAB MS: 385 (Mþ þ 1); 1H NMR (300 MHz, DMSO-d6):
d (ppm) 9.06 (s, 1H, Py-H), 8.16 (d, 2H, J ¼ 7.8 Hz, Ar-H), 7.63–7.52 (m, 3H,
Ar-H), 7.25–6.77 (m, 5H, Ar-H), 4.04 (t, 4H, J ¼ 5.08 Hz, N-CH2), 3.24
(t, 4H, J ¼ 5.08 Hz, N-CH2); 13C NMR (50 MHz, DMSO-d6): d (ppm)
184.53, 171.98, 169.14, 164.25, 159.62, 144.50, 132.45, 129.81, 129.45,
128.75, 125.90, 118.25, 113.12, 110.39, 57.58, 54.52. Anal. calcd. for
C22H20N6O: C, 68.73; H, 5.25; N, 21.87. Found: C, 68.57; H, 5.23; N, 20.86%.
7-Butylamino-2-phenyl-3H-pyrimido-[4,5-d]-pyrimidin-4-one (46)
Yield: 55%; mp 220–2228C; IR (KBr): 3446, 3169, 3083, 2958, 1675,
1592 cm21
;
FAB MS: 296 (Mþ þ 1); 1H NMR (300 MHz,
CDCl3 þ DMSO-d6): d (ppm) 8.97 (s, 1H, Py-H), 8.21 (d, 2H, J ¼ 7.50 Hz,
Ar-H), 7.59–7.49 (m, 3H, Ar-H), 3.47 (t, 2H, J ¼ 6.9 Hz, N-CH2), 1.62–
1.59 (m, 2H, CH2), 1.42–1.39 (m, 2H, CH2), 0.94 (t, 3H, J ¼ 7.2 Hz, CH3);
13C NMR (50 MHz, CDCl3 þ DMSO-d6): d (ppm) 184.73, 172.09, 169.14,

2972
S. B. Katiyar, A. Kumar, and P. M. S. Chauhan
164.35, 159.52, 132.85, 129.91, 128.60, 125.90, 110.34, 51.32, 34.00, 20.55,
13.76. Anal. calcd. for C16H17N5O: C, 65.07; H, 5.80; N, 23.71. Found: C,
65.34; H, 5.96; N, 23.27%.
7-Hexylamino-2-phenyl-3H-pyrimido-[4,5-d]-pyrimidin-4-one (47)
Yield: 58%; mp 218–2208C; IR (KBr): 3344, 3169, 3080, 2956, 1675,
1
1595 cm21; FAB MS: 324 (Mþ þ 1); H NMR (200 MHz, CDCl3): d (ppm)
9.03 (s, 1H, py-H), 8.24 (d, 2H, J ¼ 6.82 Hz, Ar-H), 7.55–7.50 (m, 3H, Ar-
H), 3.49 (t, 2H, N-CH2), 2.02–1.33 (m, 8H, CH2), 0.88 (t, 3H, J ¼ 6.33 Hz,
CH3); 13C NMR (50 MHz, CDCl3): d (ppm) 184.23, 172.35, 169.45,
164.15, 159.44, 131.98, 129.68, 128.73, 125.68, 110.38, 51.66, 31.82,
32.25, 27.40, 23.12, 14.00. Anal. calcd. for C18H21N5O: C, 66.85; H, 6.55;
N, 21.66. Found: C, 66.43; H, 6.77; N, 21.34%.
7-Cyclohexylamino-2-phenyl-3H-pyrimido-[4,5-d]-
pyrimidin-4-one (48)
Yield: 52%; mp 176–1798C; IR (KBr): 3433, 3261, 3089, 1675, 1594,
1
1518 cm21; FAB MS: 322 (Mþ þ 1) H NMR (200 MHz, CDCl3): d (ppm)
9.06 (s, 1H, Py-H), 8.24 (d, 2H, J ¼ 6.93 Hz, Ar-H), 7.58–7.47 (m, 3H, Ar-
H), 4.10 (m, 1H, N-CH), 1.80–1.27 (m, 10H, CH2); 13C NMR (50 MHz,
CDCl3): d (ppm) 184.10, 172.15, 169.55, 164.32, 159.50, 132.98, 129.68,
128.63, 125.78, 110.38, 53.66, 33.32, 27.15, 22.32. Anal. calcd. for
C18H19N5O: C, 67.27; H, 5.96; N, 21.79. Found: C, 66.89; H, 6.13; N, 21.67%.
ACKNOWLEDGMENTS
S. B. K. and A. K. thank the Council of Scientific and Industrial Research
(India) for the award of fellowships. We are also thankful to Sophisticated
Analytical Instrument Facility (SAIF) Division, Central Drug Research
Institute (CDRI), Lucknow, for providing spectroscopic data (CDRI
Communication No. 6858).
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