Arch. Pharm. Chem. Life Sci. 2009, 342, 94–99
Antimycobacterial 1,2,4-Triazolo[1,5-a]pyrimidines
97
through a research and development contract with the U.S. 4-Substituted-7-oxo-2-(trifluoromethyl)-4,7-dihydro-1,2,4-
National Institute of Allergy and Infectious Diseases.
triazolo[5,1-a]pyrimidine-6- carboxylic acid ethyl ester
6a–e
The authors have declared no conflict of interest.
A solution of compound 3 (2.76g, 0.01mol) in dry DMF (25 mL)
was treated with sodium hydride (0.4 g, 0.0167 mol) and stirred
at room temperature for 10 minutes. Alkyl or aralkyl halides
5a–e (0.03 mol) were added and stirring was continued over-
night. The reaction mixture was poured over ice-water (100 mL),
the resulting precipitate was filtered, washed with water and air
dried. The product was recrystallized from methanol / water.
Experimental
Chemistry
Melting points were determined on an electrothermal melting
point apparatus and are uncorrected. 1H-NMR spectra were
determined on EM-360 (60 MHz; Varian Inc., Palo Alto, CA, USA)
in DMSO-d6 using tetramethylsilane (TMS) as the internal stand-
ard and chemical shifts values are given in d ppm. IR spectra
were recorded on 470-Shimadzu infrared spectrophotometer
(Shimadzu, Tokyo, Japan) as KBr discs. Elemental microanalysis
was performed by the Microanalysis Unit of the Faculty of Sci-
ence, Assiut University. Product purity was checked by TLC (Kie-
selgel 60 F254). Yields given are those of the crude products.
4-Methyl-7-oxo-2-(trifluoromethyl)-4,7-dihydro-1,2,4-
triazolo[5,1-a]pyrimidine-6-carboxylic acid ethyl ester 6a
Yield: 75%; m.p.: 2258C; IR (KBr) m [cm– 1] 3235, 1749, 1571, 1184,
1
1144; H-NMR (DMSO-d6) d [ppm]: 8.3 (s, 1H, C-H5), 4.3 (q, 2H,
CH2CH3), 4.0 (s, 3H, N-CH3), 1.3 (t, 3H, CH2CH3). Anal. Calcd for
C10H9F3N4O3: C, 41.4; H, 3.1; N, 19.3. Found: C, 41.55; H, 3.3; N,
18.9.
4-Ethyl-7-oxo-2-(trifluoromethyl)-4,7-dihydro-1,2,4-
5-Amino-3-trifluoromethyl-1,2,4-triazole 1
triazolo[5,1-a]pyrimidine-6-carboxylic acid ethyl ester 6b
Yield: 70%; m.p.: 168-1708C; IR (KBr) m [cm– 1]: 1758, 1679, 1559,
5-Amino-3-trifluoromethyl-1,2,4-triazole was prepared in 92%
yield following the reported procedures [20]: Trifluoroacetic
acid (15.05 mL, 0.202 mol) was added to aminoguanidine bicar-
bonate (25 g, 0.184 mol) followed by mixing for 30 minutes at
room temperature. Toluene (200 mL) was added thereto, and the
mixture was stirred under reflux for 15 h while distilling water
off formed by the reaction using a Dean–Stark trap. The reac-
tion mixture was left to stand overnight. Precipitated white crys-
tals were collected by filtration and used directly in the next
step without further purification.
1
1181; H-NMR (DMSO-d6) d [ppm]: 9.0 (s, 1H, C-H5), 4.3 (m, 4H, 2
CH2CH3), 1.4 (m, 6H, 2 CH2CH3). Anal. Calcd. for C11H11F3N4O3: C,
43.4; H, 3.6; N, 18.4. Found: C, 43.3; H, 4.0; N, 18.2.
4-Allyl-7-oxo-2-(trifluoromethyl)-4,7-dihydro-1,2,4-
triazolo[5,1-a]pyrimidine-6-carboxylic acid ethyl ester 6c
Yield: 54%; m.p.: 143–1458C; IR (KBr) m [cm– 1]: 1757, 1567, 1222;
1H-NMR (DMSO-d6) d [ppm]: 9.1 (s, 1H, C-H5), 6.3 (m, 1H, CH=CH2),
5.5 (m, 2H, CH=CH2), 4.9 (m, 2H, N-CH2), 4.3 (q, 2H, CH2CH3), 1.4 (t,
3H, CH2CH3). Anal. Calcd. for C12H11F3N4O3: C, 45.6; H, 3.5; N, 17.7.
Found: C, 45.9; H, 3.4; N, 17.3.
7-Oxo-2-(trifluoromethyl)-4,7-dihydro-1,2,4-triazolo[5,1-
a]pyrimidine-6-carboxylic acid ethyl ester 3
To a stirred solution of 5-amino-3-trifluoromethyl-1,2,4-triazole
1(0.373 g, 0.0025 mol) in 5 mL glacial acetic acid, diethyl ethoxy-
methylene malonate (DEEM) 2 (0.86 g, 0.004 mol) was added
dropwise. The reaction mixture was refluxed for 3 h and refri-
gerated overnight. The precipitated solid was filtered off,
washed with ethyl acetate, and dried. The crude product was
crystallized from acetic acid. Yield: 0.48 g, 70%; m.p.: 280–
2818C; IR (KBr) m [cm– 1]: 3485, 3135, 1734, 1618, 1578, 1180, 781;
1H-NMR (DMSO-d6) d [ppm]: 9.3 (brs, 1H, NH, exchangeable with
D2O), 8.4 (s, 1H, C-H5), 4.1 (q, 2H, CH2CH3), 1.1 (t, 3H, CH2CH3).
Anal. Calcd. for C9H7F3N4O3: C, 39.1; H, 2.5; N, 20.3. Found: C,
39.4; H, 2.4; N, 20.0.
4-p-Bromobenzyl-7-oxo-2-(trifluoromethyl)-4,7-dihydro-7-
oxo-1,2,4-triazolo[5,1-a] pyrimidine-6-carboxylic acid
ethyl ester 6d
Yield: 83%; m.p.: 161-1628C; IR (KBr) m [cm– 1]: 1755, 1692, 1585,
1
983, 559, 522; H-NMR (DMSO-d6) d [ppm]: 9.4 (s, 1H, C-H5), 7.8
(dd, 4H, Ar-H), 5.6 (d, 2H, N-CH2-Ar), 4.2 (q, 2H, CH2CH3), 1.2 (t, 3H,
CH2CH3). Anal. Calcd. for C16H12BrF3N4O3: C, 43.2; H, 2.7; N, 12.3.
Found: C, 43.4; H, 2.5; N, 12.3.
4-p-Nitrobenzyl-7-oxo-2-(trifluoromethyl)-4,7-dihydro-
1,2,4-triazolo[5,1-a]pyrimidine-6-carboxylic acid ethyl
ester 6e
7-Oxo-2-(trifluoromethyl)-4,7-dihydro-1,2,4-triazolo[5,1-
Yield: 90%; m.p.: 180–1828C; IR (KBr) m [cm– 1]: 1747, 1556, 1513,
1337, 1180, 845; 1H-NMR (DMSO-d6) d [ppm]: 9.5 (s, 1H, C-H5), 8.0
(dd, 4H, Ar-H), 5.8 (d, 2H, N-CH2-Ar), 4.3 (q, 2H, CH2CH3), 1.3 (t, 3H,
CH2CH3). Anal. Calcd for C16H12F3N5O3: C, 46.7; H, 2.9; N, 17.0.
Found: C, 46.4; H, 2.7; N, 17.1.
a]pyrimidine-6- carboxylic acid 4
The ethyl ester 3 (0.01 mol) was dissolved in a solution of sodium
hydroxide (0.8g, 0.02 mol) in water (15 mL). The reaction mix-
ture was heated under reflux for 3 h. After cooling, the reaction
mixture was filtered and acidified by dropwise addition of 4 M
HCl. The carboxylic acid precipitated was collected by filtration,
washed with water, air dried and recrystallized from the metha-
nol / water. Yield: 82%; m.p.: 238–2408C; IR (KBr) m [cm– 1]: 3490,
4-Substituted-7-oxo-2-(trifluoromethyl)-4,7-dihydro-1,2,4-
triazolo[5,1-a]pyrimidine-6-carboxylic acid 7a–e
The corresponding ethyl esters 6a–e (0.01 mol) were dissolved
in a solution of sodium hydroxide (0.8 g, 0.02 mol) in water
(15 mL). The reaction mixture was heated under reflux for 3 h.
After cooling, the reaction mixture was filtered and acidified by
1
3140, 1729, 1667, 1622, 1572, 1279, 783; H-NMR (DMSO-d6) d
[ppm]: 9.0 (s, 1H, C-H5), 6.9 (brs, 1H, NH, D2O exchangeable).
Anal. Calcd for C7H3F3N4O3: C, 33.9; H, 1.2; N, 22.6. Found: C,
33.7; H, 1.4; N, 22.2.
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