JOURNAL OF CHEMICAL RESEARCH 2014 201
DMSO-d6) δ=1.05 (d, 6H, (CH3)2), δ 2.48 (m, 1H, CH), δ7.31 (m, 2H,
ArH), δ 7.72 (d, 1H, ArH), δ7.95 (m, 1H, ArH), δ 8.08 (s, 1H, ArH),
10.10 (bs, 1H, NH).
reproducible results usually slight excesses of iron powder
and of isobutyric acid were used. The yields of optimisation
reactions were determined by gas chromatography with
purified samples as references.
Synthesis of flutamide
Inconclusion,ourmethodissuperiortoothermethodsbecause
3-trifluoronitrobenzene is converted to the corresponding
amide by inexpensive isobutyric acid and iron powder without
any aniline intermediate and without converting the carboxylic
acid into an acyl chloride or anhydride.
Flutamide was synthesised and purified by modification of a literature
procedure.4 3-Trifluoromethylisobutyranilide (58 g, 0.25 mol) was
dissolved in concentrated sulfuric acid (200 mL, 2.2 mol) at 0–5 °C
with efficient agitation (CAUTION: strong acid). A pre-cooled
mixture of 98% sulfuric acid (20 mL, 0.22 mol) and 65% nitric
acid (20 mL, 0.29 mol) (CAUTION: strong acids) was added drop-
wise to the above solution while the temperature was controlled at
0–5 °C. Stirring was continued for 3 h, and the mixture was poured
onto crushed ice (500 g) mixed efficiently with a mechanical stirrer
in a 2 L beaker. The crude product was filtered under suction. The
precipitate obtained was dissolved in 96% ethanol (350 mL) under
reflux and decolourised with charcoal (10 g) by 15 minutes heating
and filtered. The filtrate was cooled and precipitated with drop-wise
addition of distilled water (1.5 L). After 60 min in an ice-cooled bath
the yellow precipitate was filtered off and dried in a good ventilating
hood. The impure product (50 g, 0.18 mol) was twice re-crystallised
from toluene (150 mL) for further purification. The pale yellow needle-
shaped crystals (41 g, 0.15 mol) of flutamide were obtained after gentle
drying under reduced pressure (60% based on the starting material,
3-trifluoroisobutyranilde). The overall yield of three steps was 45%
based on benzotrifluoride. M.p. 111.5–112 °C (lit.4,1 111.5–112 °C and
110–111 °C). IR(KBr) νꢀ=ꢀ3360 (N–H, stretching), 3100–3000 (C–H
aromatic), 1717 (C=O), 1543 (N–H, bending), 1517 and 1347 (N–O),
1243 (C–F). 1H NMR (80 MHz, DMSO-d6) δ=1.02 (d, 6H, (CH3)2), 2.57
(m, 1H, CH(CH3)2), 7.75 (d, 2H, ArH), 8.20 (s, 1H, ArH), 10.27 (bs, 1H,
N–H).
Experimental
1H NMR spectra were recorded on Bruker AC 80 MHz using DMSO-d6
as a solvent. IR (KBr) spectra were recorded on a Shimadzu-IR460
FTIR spectrometer. Melting points were determined by a Buchi B-545
apparatus and the GC analyses were recorded on a VARIAN CP-3800
gas chromatograph.
Synthesis of 1‑nitro‑3‑trifluoromethylbenzene
This step was performed by modification of two literature methods.6,7
A pre-cooled mixture of 98% sulfuric acid (190 mL, 3.5 mol) and 65%
nitric acid (80 mL, 1.15 mol) (CAUTION: strong acids) was added
dropwise to benzotrifluoride (73 g, 0.5 mol) with vigorous stirring
and external cooling to room temperature. The mixture was stirred
for 3 h and then poured onto crushed ice (700 g). Dichloromethane
(250 mL) was added and organic phase was separated and dried with
anhydrous sodium sulfate. After evaporating solvent and residual
crude product under reduced pressure on a boiling water bath, 1-nitro-
3-trifluoromethylbenzene (89.8 g, 0.47 mol) was obtained as a yellow
oil (94% based on benzotrifluoride). It was enough pure for the next
step.
Synthesis of 3‑trifluoromethylisobutyranilide
Iron powder (60 g, 1.07 mol) was added gradually to a mixture of
1-nitro-3-trifluoromethyl benzene (63.5 g, 0.33 mol) and isobutyric
acid (220 mL, 2.42 mol) under reflux conditions in a nitrogen
atmosphere was added over about 15 min. Heating and mixing was
continued for 4 h, and then the mixture was poured into a mixture of
concentrated hydrochloric acid (200 mL) and crushed ice (500 g) and
agitated for 15 minutes. The reaction mixture was extracted with ethyl
acetate (2×500 mL). After evaporating to dryness, the crude product
was dissolved in methanol (1000 mL) and after adding charcoal (10 g),
the mixture was boiled for 10 minutes and filtered while it was hot.
Water (2500 mL) was added to the solution obtained with stirring
and cooling to 0–5 °C. The mixture was kept at 0–5 °C for 2 h. Flaky
cream crystals were obtained. 3-Trifluoromethylisobutyranilide
(62 g, 0.268 mol) was filtered under suction (81% based on the starting
material). M.p. 117–118 °C (lit.4 115–120 °C). IR(KBr) νꢀ=ꢀ663, 892,
Received 11 December 2013; accepted 1 February 2014
Paper 1302330 doi: 10.3184/174751914X13929219796481
Published online: 2 April 2014
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