Convenient synthesis of?novel 4-substitutedamino-5-trifluoromethyl-2,7-disubstituted pyrido[2,3-d] pyrimidines and?their?antibacterial activity

Article abstract of DOI:10.1016/j.ejmech.2006.03.028

Novel pyrido[2,3-d]pyrimidines 4 have been synthesised starting from 2-amino-4-trifluoromethyl-6-substituted nicotinonitriles 1 via imine formation, selective amination followed by Dimroth rearrangement. Compound 4 were screened against Gram +ve and -ve b

Full text of DOI:10.1016/j.ejmech.2006.03.028

European Journal of Medicinal Chemistry 41 (2006) 1011–1016
http://france.elsevier.com/direct/ejmech
Preliminary communication
Convenient synthesis of novel 4-substitutedamino-5-trifluoromethyl–
2,7-disubstituted pyrido[2,3-d] pyrimidines and their antibacterial activity
☆
S. Ravi Kanth a, G. Venkat Reddy a, K. Hara Kishore b, P. Shanthan Rao a
B. Narsaiah a,*, U. Surya Narayana Murthy b
a Fluoroorganics Division, Indian Institute of Chemical Technology, Hyderabad, India
b Biology Division (Bioinformatics), Indian Institute of Chemical Technology, Hyderabad, India
Received 1 July 2005; revised and accepted 27 March 2006
Available online 12 June 2006
Abstract
Novel pyrido[2,3-d]pyrimidines 4 have been synthesised starting from 2-amino-4-trifluoromethyl-6-substituted nicotinonitriles 1 via imine
formation, selective amination followed by Dimroth rearrangement. Compound 4 were screened against Gram +ve and –ve bacteria in vitro.
Compounds 4h and 4d showed significant activity against all species of Gram positive bacteria and moderate activity against Gram negative
bacteria. N-2,4 difluorophenyl compounds 4l and 4m were the least active among all the compounds. All the compounds were inactive against
Pseudomonas aeruginosa at the maximum concentration of 200 μg ml–1.
© 2006 Elsevier SAS. All rights reserved.
Keywords: Pyrido[2,3-d]pyrimidines; Imino-ether; Dimroth rearrangement; Aminolysis; Antibacterial; Ciprofloxacin
1. Introduction
cycles, we report here a convenient synthesis of 4-substituted
amino-5-trifluoromethyl-2,7-disubstituted pyrido[2,3-d]pyrimi-
dines 4, starting from 2-amino-4-trifluoromethyl-6-substituted
nicotinonitriles 1 via imine formation, selective amination fol-
lowed by Dimroth rearrangement and their in vitro antibacterial
activity.
The pyrido [2,3-d] pyrimidine ring system is present in a
number of biologically active organic compounds which in-
cludes antitumour [1], antibacterial [2] and anticonvulsant
agents [3]. Pyrido[2,3-d] pyrimidines also have antipyretic
[4], analgesic [5] and CNS depressant activity [6]. More speci-
fically pyrido [2,3-d] pyrimidines were considered as inhibitors
of Pneumocystis carinii (pc), Toxoplasma gondii (tg) of tumour
cell lines in culture [7] and some have anticytokinin activity
[8]. The activity is mainly due to inhibition of dihydrofolate
reductase (DHFR) [9,10].
The synthesis of pyrido[2,3-d] pyrimidines is mainly by two
ways i.e. annulation of pyrimidine ring over pyridine or vice
versa [11]. The wide range of activity profile of pyrido[2,3-d]
pyrimidines given insight to probe into synthesis of novel ana-
logues and to study their antibacterial activity. Moreover tri-
fluoromethyl substituted compounds are supposed to have en-
hanced activity due to high lipid solubility. Thus in
continuation of our efforts [12] to synthesise novel hetero-
2. Chemistry
The 2-amino-4-trifluoromethyl-6-substituted nicotinonitriles
[13] 1 were reacted with triethylorthoformate/triethylorthoace-
tate in presence of catalytic amount of acetic acid at 140 °C
gave iminoethers 2 in sufficiently good yields. The rate of re-
action and yields of products formed are found to be indepen-
dent of substituents used in pyridine ring. The geometry of the
iminoethers 2 has not been determined due to limited data on
these compounds [14,15]. The reaction is schematically drawn
in Scheme 1.
The compounds 2 were further reacted with aliphatic/aro-
matic primary amines and obtained 4-substituted amino-5-tri-
fluoromethyl-2,7-disubstituted pyrido [2,3-d] pyrimidines, 4 in
high yields. In case of aliphatic amines, the reaction was car-
ried out at room temperature in aqueous medium as the rate of
reaction being fast and with aromatic amines the reaction was
☆
IICT communication number 050701.
* Corresponding author.
E-mail address: narsaiah@iict.res.in (B. Narsaiah).
0223-5234/$ - see front matter © 2006 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.03.028

1012
S. Ravi Kanth et al. / European Journal of Medicinal Chemistry 41 (2006) 1011–1016
Scheme 1.
carried out at 110 °C. The yields of the products with aliphatic
amines is comparatively higher than with aromatic amines. The
sequence of reactions is mainly selective aminolysis of com-
pounds 2, followed by the spontaneous cyclisation to less
stable intermediate 3 which further undergoes Dimroth rearran-
gement [16–18] to give the more stable isomer 4 (Scheme 2).
More specifically nicotinonitriles 2 on reaction with ethyla-
mine/ammonia solution resulted an intermediate product 3
which was converted into 4 by refluxing in ethanolic amine
solution. However other amines gave the stable isomer 4 di-
rectly at room temperature.
ceum (MTCC 2656) were selected and obtained from the In-
stitute of Microbial Technology, Chandigarh. Cultures of test
organisms were maintained on nutrient agar slants and were
subcultured in Petri dishes prior to testing. The media used
was nutrient agar, nutrient broth procured from Himedia La-
boratories, Mumbai.
The minimum inhibitory concentration (MIC) was deter-
mined by broth dilution method [19].
4. Results and discussion
Compounds 4a, b, d, e, f, h, i and 4k–o were screened for
their in vitro antibacterial activity. The antibacterial activity
were tested against Gram positive (B. subtilis, B. sphaericus,
S. aureus) and Gram negative (P. aeruginosa, K. aerogenes,
C. violaceum) bacteria. Compounds 4d and 4h showed signifi-
cant activity against all species of Gram positive bacteria and
moderate activity against Gram negative bacteria. Enhanced
3. In vitro antibacterial assays
Six bacterial test organisms such as Bacillus subtilis (MTCC
441), Staphylococcus aureus (MTCC 96), and Pseudomonas
aeruginosa (MTCC 741), Klebsiella aerogenes (MTCC 39),
Bacillus sphaericus (MTCC 511), Chromobacterium viola-
Scheme 2.

S. Ravi Kanth et al. / European Journal of Medicinal Chemistry 41 (2006) 1011–1016
1013
activity was observed as in the case of 4h by replacing H with
CH3 on C-2 and NH2. Compound 4b having methyl on C-2
and NH2 exhibited activity against B. sphaericus and moderate
activity against all other tested microorganisms. Compounds 4e
and 4k were active against B. subtilis. The N-phenyl com-
pound 4i exhibited activity against B. subtilis. The N-m-CF3-
phenyl analogue 4n showed significant to moderate activity
against all the tested microorganisms whereas the N-2,4-di-
fluorophenyl compounds 4l and 4m were the least active
among the screened compounds. All the compounds were in-
active against P. aeruginosa at the maximum concentration of
200 μg ml–1. In conclusion the 4-amino and N-methyl amino
compounds 4d and 4h were the most active among the
screened compounds. In case of N-phenyl and N-substituted
phenyl compounds, N-m-CF3 substituted compound 4n
showed significant activity. The MIC values of the compounds
were compared with commercial antibiotic (ciprofloxacin). The
details of compounds and their activity against various micro-
organisms tabulated in Table 1.
triethylorthoacetate (8 ml) along with catalytic amount of
acetic acid and heated at 140 °C for 6 h. The resulting dark
brown solution was allowed to cool to room temperature and
evaporated in vacuo to give a brown coloured solid residue. To
the residue n-hexane was added and separated solid is filtered,
washed with n-hexane. The crude product was dried and pur-
ified through column using 60–120 mesh silica gel and the
desired product was eluted using 10% CHCl3 in hexane solvent
mixture.
5.1.1. Ethyl N-[3-cyano-6-phenyl-4-(trifluoromethyl)-2-
pyridyl]iminoformate (2a)
Yield 90%; m.p. 116 °C; IR (KBr): 2250 (CN), 1640 (N–
C), 1230 (C–O) cm−1. 1H NMR (200 MHz, CDCl3): δ 1.4 (3H,
t, J = 8.2 Hz, CH3), 4.5 (2H, quartet, J = 9.6 Hz, CH2), 7.5
(3H, m, Ar-H), 7.8 (1H, s, H-C(5), Ar-H), 8.1(2H, m, Ar-H),
8.7 (1H, s, CH); EIMS, m/z: 319 (M+), 290 (M – 29). Anal.
Calcd. for C16H12F3N3O: C, 60.18; H, 3.78; N, 13.16. Found:
C, 60.25; H, 3.86; N, 13.23.
5. Experimental
5.1.2. 1-Ethyl N-1-[3-cyano-6-phenyl-4-(trifluoromethyl)-2-
pyridyl]ethanimidate (2b)
Melting points were recorded on Casia-siamia (VMP-AM)
melting point apparatus and are uncorrected. IR spectra were
recorded on a Perkin–Elmer FT-IR 240-C spectro photometer
Yield 85%; m.p. 93 °C; IR (KBr): 2246 (CN), 1644 (N–C),
1
1232 (C–O) cm−1. H NMR (300 MHz, CDCl3): δ 1.4 (3H, t,
1
using KBr optics. H NMR spectra were recorded on Gemini
J = 8.2 Hz, OCH2CH3), 2.1 (3H, s), 4.4 (2H, quartet,
J = 9.6 Hz, CH2), 7.5 (3H, m, Ar-H), 7.7 (1H, s, (C)-5 Ar-
H), 8.1(2H, m, Ar-H); EIMS, m/z: 333 (M+), 304 (M – 29).
Anal. Calcd. for C17H14F3N3O: C, 61.26; H, 4.23; N, 12.60.
Found: C, 61.18; H, 4.32; N, 12.55.
varian 200 MHz, Bruker AV 300 MHz and Unity 400 MHz
spectro meter in CDCl3 using TMS as an internal standard.
Electron impact (EI) and chemical ionisation mass spectra were
recorded on a VG 7070 H instrument at 70 ev. All reactions
were monitored by thin layer chromatography (TLC) on pre-
coated silica gel 60 F254 (mesh); Spots were visualised with
UV light. Merck silica gel (100–200 mesh) was used for chro-
matography. CHN analyses were recorded on a Vario EL ana-
lyser.
5.1.3. Ethyl N-[3-cyano-6-(4-methylphenyl)-4-
(trifluoromethyl)-2-pyridyl]iminoformate (2c)
Yield 88%; m.p. 152 °C; IR (KBr): 2252 (CN), 1642 (N–
1
C), 1226 (C–O) cm−1. H NMR(300 MHz, CDCl3): δ 1.5 (3H,
t, J = 8.2 Hz, OCH2CH3), 2.4 (3H, s, CH3), 4.6 (2H, quartet,
J = 9.6 Hz, CH2), 7.3 (2H, m, Ar-H), 7.8 (1H, s, H- C-(5), Ar-
H), 7.9 (2H, d, J = 14 Hz, Ar-H), 8.65 (1H, s, CH); EIMS, m/z:
333 (M+), 290 (M – 29). Anal. Calcd. for C17H14F3N3O: C,
61.26; H, 4.23; N, 12.60. Found: C, 60.18; H, 4.31; N, 12.55.
5.1. Ethyl-3-cyano-6-substituted-4-(trifluoromethyl)pyridin-2-
ylimidoformate/ethanamidoate (2): general procedure
The 2-amino-4-trifluoromethyl-6-substituted nicotinonitriles
1 (11.4 mmol) was taken in excess of triethylorthoformate/
Table 1
MIC (in μg ml–1) values of novel 4-substituted amino-5-trifluoromethyl-2,7-disubstituted pyrido[2,3-d]pyrimidines
Compounds
Microorganisms
Gram positive
Gram negative
K. aerogenes
50
B. subtilis
25
B. sphaericus
S. aureus
25
P. aeruginosa
–
C. violaceum
25
4a
25
4b
4d
4e
4f
4h
4i
4k
4l
25
3.25
3.25
25
12.5
3.25
25
25
6.25
25
50
1.25
25
–
–
–
–
–
–
–
–
50
25
25
12.5
25
50
25
25
25
12.5
50
25
25
25
12.5
25
6.25
12.5
25
1.25
6.25
12.5
25
25
25
25
25
4m
25
25
50
–
25
50
4n
4o
50
25
6.25
25
12.5
50
–
–
12.5
25
50
25
Ciprofloxacin
0.78
0.78
0.39
0.78
0.78
0.39

1014
S. Ravi Kanth et al. / European Journal of Medicinal Chemistry 41 (2006) 1011–1016
5.1.4. Ethyl N-[6-(4-chlorophenyl)-3-cyano-4-
(trifluoromethyl)-2-pyridyl]iminoformate (2d)
8.8 (1H, s, CH). EIMS, m/z: 290 (M+), 221 (M+ – 69). Anal.
Calcd. for C14H9F3N4: C, 57.93; H, 3.12; N, 19.30. Found: C,
57.88; H, 3.22; N, 19.42.
Yield 80%; m.p. 160 °C; IR (KBr): 2248 (CN), 1645 (N–
C), 1232 (C–O) cm−1. 1H NMR(300 MHz, CDCl3): δ 1.5 (3H,
t, J = 8.2 Hz,), 4.6 (2H, quartet, J = 9.6 Hz, CH2), 7.5 (2H, d,
Ar-H), 7.8 (1H, s, H- C-(5), Ar-H), 8.0 (2H, d, J = 14 Hz, Ar-
H), 8.7 (1H, s, CH); EIMS, m/z: 353 (M+), (40%), 355 (M+ +
2), (14%). Anal. Calcd. for C16H11F3N3OCl: C, 54.32; H, 3.13;
N, 11.87. Found: C, 54.27; H, 3.22; N, 11.75.
5.3.2. 2-Methyl-7-phenyl-5-(trifluoromethyl)pyrido[2,3-d]
pyrimidin-4-amine (4b)
Yield 82%; m.p. 230 °C; IR (KBr): 3355, 3440 (NH2), 1354
1
(C–N) cm−1. H NMR (200 MHz, CDCl3): δ 2.6 (3H, s), 6.1
(2H, br, s, NH2), 7.5–7.6 (3H, m, Ar-H), 8.2 (1H, s, Ar-H),
8.3–8.4 (2H, m, Ar-H). EIMS, m/z: 304 (M+). Anal. Calcd. for
C15H11F3N4: C, 59.21; H, 3.64; N, 18.41. Found: C, 57.15; H,
3.55; N, 18.53.
5.2. 3-Substituted-2-methyl-7-phenyl-5-(trifluoromethyl)pyrido
[2,3-d]pyrimidin-4(3H)-imine (3): general procedure
Compound 2 (0.5 g, 1.57 mmol) was dissolved in ethanolic
solution (10 ml) of ammonia/ethylamine (5 ml), and was stir-
red at room temperature for 3 h, during which time solid sepa-
rated out from the solution. Ethanol was removed under va-
cuum. The crude product residue was purified by column
using 60–120 mesh silica gel and the desired product was
eluted with 10% CHCl3 in hexane mixture.
5.3.3. 7-(4-Methylphenyl)-5-(trifluoromethyl)pyrido[2,3-d]
pyrimidin-4-amine (4c)
Yield 78%; m.p. 242 °C; IR (KBr): 3350, 3400 (NH2), 1350
1
(C–N) cm−1. H NMR (200 MHz, CDCl3): δ 2.5 (3H, s), 5.5
(2H, br, s, NH2), 7.3–7.4 (2H, m, Ar-H), 8.2–8.3 (2H + 1H),
m, Ar-H), 8.8 (1H, s, CH). EIMS, m/z: 304 (M+). Anal. Calcd.
for C15H11F3N4: C, 59.21; H, 3.64; N, 18.41. Found: C, 59.33;
H, 3.72; N, 18.38.
5.2.1. 2-Methyl-7-phenyl-5-(trifluoromethyl)pyrido[2,3-d]
pyrimidin-4(3H)-imine (3a)
Yield 76%; m.p. 248 °C; IR (KBr): 3450 (N–H), 1645
5.3.4. 7-(4-Chlorophenyl)-5-(trifluoromethyl)pyrido[2,3-d]
pyrimidin-4-amine (4d)
1
(C=N), 1354 (N–C) cm−1. H NMR (300 MHz, CDCl3): δ
2.6 (3H, s, CH3), 6.6 (1H, br, s, NH), 7.5–7.6 (3H, m, Ar-H),
8.15 (1H, s, Ar-H), 8.2–8.3 (2H, m, Ar-H). EIMS, m/z: 304
(M+). Anal. Calcd. for C15H11F3N4: C, 59.21; H, 3.64; N,
18.41. Found: C, 57.15; H, 3.55; N, 18.53.
Yield 70%; m.p. 252 °C; IR (KBr): 3350, 3445 (NH2), 1350
1
(C–N) cm−1. H NMR (200 MHz, CDCl3): δ 5.5 (2H, brs,
NH2), 7.3–7.4 (2H, m, Ar-H), 8.2–8.3 ((2H + 1H), m, Ar-H),
8.8 (1H, s, CH). EIMS, m/z: 324 (M+), (50%), 326 (M+ + 2),
(17%). Anal. Calcd. for C14H8F3N4Cl: C, 51.78; H, 2.48; N,
17.25. Found: C, 51.65; H, 2.55; N, 17.38.
5.2.2. 3-Ethyl-2-methyl-7-phenyl-5-(trifluoromethyl)pyrido
[2,3-d]pyrimidin-4(3H)-imine (3b)
Yield 81%; m.p. 82 °C; IR (KBr): 3456 (N–H), 1655
5.3.5. N-ethyl-7-phenyl-5-(trifluoromethyl)pyrido[2,3-d]
pyrimidin-4-amine (4e)
1
(C=N), 1350 (N–C) cm−1. H NMR (200 MHz, CDCl3): δ
1.45 (3H, t, NCH2CH3), 2.65 (3H, s, CH3), 4.2 (2H, qt,
CH2), 7.45–7.55 (3H, m, Ar-H), 7.95 (1H, s, Ar-H), 8.15–8.2
(2H, m, Ar-H). EIMS, m/z: 332 (M+). Anal. Calcd. for
C17H15F3N4: C, 61.44; H, 4.54; N, 16.85. Found: C, 61.52;
H, 4.61; N, 16.96.
Yield 80%; m.p. 88 °C; IR (KBr): 3450 (N–H), 1360 (C–N)
cm−1. 1H NMR (200 MHz, CDCl3): δ 1.3 (3H, t, CH3), 3.6–3.7
(2H, m, CH2), 6.1 (1H, br, s, NH2), 7.4–7.5 (3H, m, Ar-H), 8.1
(1H, s, Ar-H), 8.2–8.3 (2H, m, Ar-H), 8.7 (1H, s, CH). EIMS,
m/z: 318 (M+). Anal. Calcd. for C16H13F3N4: C, 60.37; H,
4.11; N, 17.60. Found: C, 60.44; H, 4.25; N, 17.52.
5.3. 2,7-Disubstituted-5-(trifluoromethyl)pyrido[2,3-d]
pyrimidin-4-amine (4): general procedure
5.3.6. N-methyl-7-phenyl-5-(trifluoromethyl)pyrido[2,3-d]
pyrimidin-4-amine (4f)
Compound 2 (0.8 g, 2.5 mmol) was dissolved in ethanolic
solution of the corresponding amine (10 ml, and was stirred at
room temperature for 3 h, during which time solid separated
out from the solution. In case of substituted anilines, the reac-
tion was carried out at 110 °C for 6 h. Ethanol or aniline was
removed under vacuum. The crude product residue was puri-
fied by column using 60–120 mesh silica gel and the desired
product was eluted with 20% CHCl3 in hexane mixture.
Yield 86%; m.p. 150 °C; IR (KBr): 3452 (N–H), 1360 (C–
N) cm−1. 1H NMR (300 MHz, CDCl3): δ 3.2 (3H, d, CH3), 6.2
(1H, br, s, NH), 7.5–7.6 (3H, m, Ar-H), 8.1 (1H, s, Ar-H), 8.2–
8.3 (2H, m, Ar-H), 8.8 (1H, s, CH). EIMS, m/z: 304 (M+).
Anal. Calcd. for C15H11F3N4: C, 59.21; H, 3.64; N, 18.41.
Found: C, 59.33; H, 3.55; N, 18.38.
5.3.7. N-ethyl-2-methyl-7-phenyl-5-(trifluoromethyl)pyrido
[2,3-d]pyrimidin-4-amine (4g)
Yield 78%; m.p. 97 °C; IR (KBr): 3456 (N–H), 1365 (C–N)
cm−1. 1H NMR (200 MHz, CDCl3): δ 1.4 (3H, t, NHCH2CH3),
2.7 (3H, s, CH3), 3.7–3.8 (2H, m, CH2), 6.1 (1H, br, s, NH),
7.5–7.6 (3H, m, Ar-H), 8.1 (1H, s, Ar-H), 8.3–8.4 (2H, m, Ar-
5.3.1. 7-Phenyl-5-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-
amine (4a)
Yield 85%; m.p. 222 °C; IR (KBr): 3350, 3400 (NH2), 1350
1
(C–N) cm−1. H NMR (200 MHz, CDCl3): δ 6.3 (2H, br, s,
NH2), 7.4–7.6 (3H, m, Ar-H), 8.2–8.4 (2H + 1H, m, Ar-H),

S. Ravi Kanth et al. / European Journal of Medicinal Chemistry 41 (2006) 1011–1016
1015
H). EIMS, m/z: 332 (M+). Anal. Calcd. for C17H15F3N4: C,
LSIMS, m/z: 431 (M+ + 1); Anal. Calcd. for C20H11N4F5: C,
61.44; H, 4.54; N, 16.85. Found: C, 61.52; H, 4.61; N, 16.96.
59.70; H, 2.75; N, 13.92. Found: C, 59.66; H, 2.62; N, 13.88.
5.3.14. 2-Methyl-7-phenyl-5-(trifluoromethyl)-N-[3-
5.3.8. N-methyl-2-methyl-7-phenyl-5-(trifluoromethyl)pyrido
[2,3-d]pyrimidin-4-amine (4h)
trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-4-amine (4n)
Yield: 82%; m.p. 129 °C; IR (KBr) n: 3370 (N–H), 1348
Yield 84%; m.p. 124 °C; IR (KBr): 3458 (N–H), 1362 (C–
1
(C–N), 1152 (C–F) cm−1; H NMR (400 MHz, CDCl3) δ: 2.7
1
N) cm−1. H NMR(300 MHz, CDCl3): δ 2.7 (3H, s, CH3), 3.2
(3H, s, CH3), 7.3–7.5 (5H, m, Ar-H), 7.8–7.9 (1H + 1H, m, Ar-
H), 8.1 (1H, s, Ar-H), 8.3 (2H, m, Ar-H); LSIMS, m/z: 449
(M+ + 1); Anal. Calcd. for C22H14N4F6: C, 58.93; H, 3.14; N,
12.49. Found: C, 58.85; H, 3.22; N, 12.56.
(3H, d, NHCH3), 6.2 (1H, br, s, NH), 7.5–7.6 (3H, m, Ar-H),
8.1 (1H, s, Ar-H), 8.2–8.3 (2H, m, Ar-H). EIMS, m/z: 319
(M+). Anal. Calcd. for C16H13F3N4: C, 60.37; H, 4.11; N,
17.60. Found: C, 60.44; H, 4.25; N, 17.52.
5.3.15. 7-Phenyl-5-(trifluoromethyl)-N-[3-(trifluoromethyl)
phenyl]pyrido[2,3-d]pyrimidin-4-amine (4o)
5.3.9. 2-Methyl-N,7-diphenyl-5-(trifluoromethyl)pyrido[2,3-d]
pyrimidin-4-amine (4i)
Yield: 80%; m.p. 176 °C; IR (KBr) n: 3550 (N–H), 1350
Yield 78%; m.p. 136 °C; IR (KBr): 3450 (N–H), 1360 (C–
N) cm−1. 1H NMR(200 MHz, CDCl3): δ 2.7 (3H, s, CH3), 7.45
(2H, t, J = 13 Hz, Ar-H) 7.5–7.6 (3H, m, Ar-H), 7.7 (3H, m,
Ar-H), 7.8 (1H, br, s, NH), 8.2 (1H, s, Ar-H), 8.3 (2H, m, Ar-
H). EIMS, m/z: 380 (M+). Anal. Calcd. for C21H15F3N4: C,
66.37; H, 3.97; N, 14.72. Found: C, 66.44; H, 3.88; N, 14.66.
1
(C–N), 1100 (C–F) cm−1; H NMR (400 MHz, CDCl3) δ: 7.5
(1H, d, J = 17.5 Hz, Ar-H); 7.6 (4H, m, Ar-H), 7.85 (1H, d,
J = 17.5 Hz, Ar-H), 8.1 (1H, s, Ar-H), 8.3–8.4 (3H, m, Ar-H),
8.9 (1H, s, CH); LSIMS, m/z: 435 (M+ + 1); Anal. Calcd. for
C21H12F6N4: C, 58.07; H, 2.78; N, 12.89. Found: C, 58.15; H,
2.65; N, 12.77.
5.3.10. N-cyclopropyl-7-phenyl-5-(trifluoromethyl)pyrido[2,3-
d]pyrimidin-4-amine (4j)
Acknowledgements
Yield 75%; m.p. 87 °C; IR (KBr): 3445 (N–H), 1360 (C–N)
1
Authors are thankful to Dr. J.S. Yadav, Director, IICT, Hy-
derabad, Shri S. Narayan Reddy, Head, Fluoroorganics Divi-
sion, IICT for their constant encouragement and S.R.K. is
grateful to CSIR, New Delhi for grant of senior research fel-
lowship.
cm−1. H NMR(200 MHz, CDCl3): δ 0.6 (2H, d, J = 2.5 Hz,
CH2), 0.9 (2H, d, J = 5.2 Hz, CH2), 3.1 (1H, m, CH), 6.2(1H,
br, s, NH), 7.5–7.6 (3H, m, Ar-H), 8.1–8.3 (3H, m, Ar-H), 8.7
(1H, s, CH). EIMS, m/z: 330 (M+). Anal. Calcd. for
C17H13F3N4: C, 61.81; H, 3.96; N, 16.96. Found: C, 61.72;
H, 3.88; N, 16.84.
References
5.3.11. N-cyclopropyl-2-methyl-7-phenyl-5-(trifluoromethyl)
pyrido[2,3-d]pyrimidin-4-amine (4k)
[1] a) R. Piper James et al., US patent (1989) US 4, 725, 687; C.A. 109:
129064x. b) K.A. Watanabe et al., PCT, Int. Appl. WO 90, 00, 172,
C.A. 113: 40343x. c) J.R. Piper et al., US patent (1989) US 5, 077 404,
C.A. 116: 128965z.
[2] a) Masuda, Satoru et al. Jpn. Kokai. Tokkyo Koho JP 03, 106, 880. C.A.
15: 183361d. b) Tamura et al. Jpn. Kokai. Tokkyo Koho JP 61, 249, 983,
C.A. 106: 213979.
[3] J. Ram, D.A. Vanden Berghe, A.J.J. Vlietinck, Heterocycl. Chem. 28
(1988) 217.
[4] J.R. Piper, G.S. Mc Calab, J.A. Montgomery, R.L. Kishiuk, Y. Gamount,
F.M. Sirotnak, J. Med. Chem. 29 (1986) 1080–1087.
Yield: 85%; m.p. 96 °C; IR (KBr) n: 3345 (N–H), 1345 (C–
N), 1154 (C–F) cm−1; 1H NMR (400 MHz, CDCl3) δ: 2.7 (3H,
s, CH3), 0.7 (2H, d, J = 2.2 Hz, CH2), 0.9 (2H, d, J = 5.3 Hz,
CH2), 3.1 (1H, m, CH), 6.2 (1H, br, s, NH), 7.6 (3H, m, Ar-H),
8.1 (1H, s, Ar-H), 8.2–8.3 (2H, m, Ar-H); LSIMS, m/z: 344
(M+), 329 (M+ – CH3); Anal. Calcd. for C18H15N4F3: C,
62.78; H, 4.39; N, 16.27. Found: C, 62.65; H, 4.44; N, 16.33.
[5] R.K. Robins, G.H.J. Hitchings, Am. Chem. Soc. 80 (1958) 3449.
[6] M.F. Hasan, A.M. Madkour, I. Saleem, J.M.A. Rahman, E.A.z. Mo-
hammed, Heterocycles 38 (1994) 57.
[7] Lowe, John Adams Austrian At. 388378 (1989) 378, Chem. Abstr. 112
(1990) 21008.
[8] G. Kouichiro, Y. Kurimoto, N. Kitamura, Eur pat. Appl. EP 243,311,
Chem. Abstr. 108 (1988) 75422.
[9] A. Gangjee, O.O. Adair, S.F. Queener, J. Med. Chem. 46 (2003) 5074–
5082.
5.3.12. N-(2,4-difluorophenyl)-2-methyl-7-phenyl-5-
(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-amine (4l)
Yield: 80%; mp.: 140 °C; IR (KBr) n: 3360 (N–H), 1350
1
(C–N), 1150 (C–F) cm−1; H NMR (400 MHz, CDCl3) δ: 2.6
(3H, s, CH3), 6.95 (2H, m, Ar-H), 7.55 (3H, m, Ar-H), 8.2
(1H, s, Ar-H), 8.3 (2H, m, Ar-H), 8.55 (1H, m, Ar-H); LSIMS,
m/z: 417 (M+ + 1); Anal. Calcd. for C21H13 F5N4: C, 60.58; H,
3.14; N, 13.45. Found: C, 60.66; H, 3.22; N, 13.52.
[10] H. Iwamura, S. Murakami, K. Koshimizu, S. Matsabura, J. Med. Chem.
28 (1985) 577–583.
[11] A.R. Kataritzky, Charles, E.F.V. Rees, Scriven, Comprehensive Hetero-
cyclic Chemistry—II 7 (1996) 591–603.
5.3.13. N-(2,4-difluorophenyl)-7-phenyl-5-(trifluoromethyl)
pyrido[2,3-d]pyrimidin-4-amine (4m)
Yield: 76%; m.p. 152 °C; IR (KBr) n: 3385 (N–H), 1346
(C–N), 1156 (C–F) cm−1; 1H NMR (400 MHz, CDCl3) δ: 7.05
(2H, m, Ar-H), 7.55–7.6 (3H, m, Ar-H), 8.15 (1H, s, Ar-H),
8.3 (2H, m, Ar-H), 8.55 (1H, m, Ar-H); 8.85 (1H, s, CH);
[12] (a) S. Ravikanth, G. Venkat Reddy, D. Maitraie, V.V.V.N.S. Rama Rao,
P. Shanthan Rao, B. Narsaiah, Synthetic Communication. 34 (2004)
4463–4469. (b) D. Maitraie, G. Venkat Reddy, V.V.V.N.S. Rama Rao,
S. Ravikanth, P. Shanthan Rao, B. Narsaiah, J. of Fluorine Chem. 118
(2002), 73–79. (c) G. Venkat Reddy, D. Maitraie, V.V.V.N.S. Rama
Rao, S. Ravi Kanth, B. Narsaiah, P. Shanthan Rao, J. of Fluorine

1016
S. Ravi Kanth et al. / European Journal of Medicinal Chemistry 41 (2006) 1011–1016
Chem. 124 (2003), 203–209. (d) D. Maitraie, G. Venkat Reddy, V.V.V. [16] D.J. Brown, Kazuharu, Lenega, JCS Perkin Trans 1 21 (1975) 2182–
N.S. Rama Rao, S. Ravikanth, B. Narsaiah, P. Shanthan Rao, K. Raviku-
mar, B. Sridhar, Tetrahedron 61 (2005) 3999.
[13] B. Narsaiah, A. Siva Prasad, R.V. Venkataratnam, J. Fluorine Chem. 67
(1994) 87.
2285.
[17] E.C. Taylor, R.V.J. Ravindranathan, Org. Chem. 27 (1962) 2622.
[18] D.J. Brown, in “Mechanisms of molecular Migrations’’ ed. by S. Thya-
garajan, Interscience, New York 1 (1968) 209.
[19] NCCLS, Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria, which Grows Aerobically, fifth ed, Approved Standard M7-
A5, NCCLS, Villanova, PA, 2000.
[14] W. Ried, J. Laoutidis, Synthesic neuartiger Triazoloanellierter, Liebigs
Ann. Chem. (1988) 1107–1109 8–Azapurine.
[15] A.P. Harris, W. Penderghast, J. Hetero. Chem. 33 (1998) 319–322.