JOURNAL OF CHEMICAL RESEARCH 2013 407
Fig. 3 Synthesis of tiaprofenic acid (route 3).
Fig. 4 Novel synthesis of tiaprofenic acid. Reagents and conditions: (a) propanoic anhydride, phosphorus pentoxide, phosphoric
acid, 95–100 °C; (b) PTT, dichloromethane, reflux; (c) ethylene glycol, toluene-p-sulfonic acid, toluene, 120 °C; (d) cuprous oxide,
sodium hydroxide, hydrochloric acid, methanol, 75 °C; (e) benzoyl chloride, zinc oxide, room temperature.
acylation under solvent-free conditions. The synthesis does not
require special conditions such as column chromatographic
purification. It is suitable for industrial production.
room temperature, the reaction mixture was washed with water
100 mL) and brine (100 mL), dried over anhydrous sodium sulfate,
(
and concentrated under reduced pressure to give (4) as pale yellow oil
15,16
−1
(
52.4 g, 99.3%), (lit.
pale yellow oil). IR (cm ): 3104, 2979, 2933,
2
1
893, 1666, 1527, 1471, 1432, 1376, 1353, 1237, 1197, 1140, 1070,
Experimental
1
020, 981, 950, 911, 850, 707, 658; H NMR (300 MHz, DMSO-d )
6
All reagents were purchased from commercial sources and used with-
out further purification. Melting points were determined on a RY-1 hot
stage microscope and are uncorrected. IR spectra were determined as
KBr pellets on a Thermo Nicolet 6700 spectrophotometer. H NMR
spectra was recorded on a Bruker Avance DPX-300 MHz or a 500
δ 1.56–1.58 (m, 3H), 3.83–3.99 (m, 2H), 4.04–4.14 (m, 2H), 4.52–
4.59 (m, 1H), 7.00–7.03 (m, 1H), 7.13–7.14 (m, 1H), 7.46–7.48
1
3
(m, 1H); C NMR (75 MHz, DMSO-d ) δ 20.77, 53.66, 65.60, 65.86,
6
1
125.90, 126.12, 126.82, 136.01, 142.25; MS m/z: 263.0 ([M-H] ,
0%), 265.0 ([M+H] , 20%).
+
+
2
2
-(Thiophen-2-yl) propanoic acid (5): A mixture of compound 4
52.8 g, 0.2 mol), cyclohexane (240 mL) and cuprous oxide (5.28 g,
.06 mol) was heated under reflux for 12 h. After cooling to room
MHz instrument in CDCl . Chemical shifts (δ) are given in part per
3
(
million (ppm) relative to TMS as an internal standard. Mass spectra
0
(
MS) were obtained fromAgilent 1100LC/MS Spectrometry Services.
temperature, the reaction mixture was filtered under reduced pressure.
The filtrate was washed with water (100 mL) and brine (100 mL),
dried over anhydrous sodium sulfate, and concentrated under reduced
pressure. The residue was dissolved in methanol (400 mL) 20% NaOH
solution (160 mL) was added. The mixture was heated under reflux
for 1 h. After cooling to room temperature, the reaction mixture con-
centrated under reduced pressure, and the residue was dissolved in
chloroform (200 mL), washed with concentrated hydrochloric acid
The HRMS spectra were obtained on a Thermo Finnigan spectrome-
ter, model MAT 95XP. All reactions were monitored by TLC on silica
gel GF-254 glass plates (E.Merck).
1
-(Thiophen-2-yl) propan-1-one (2): The mixture of thiophene (1)
(34.1 g, 0.405 mol), propionic anhydride (64.6 g, 0.497 mol), phos-
phoric acid (4 mL) and phosphoric anhydride (0.8 g, 5.633 mmol) was
heated under reflux for 8 h. After cooling to room temperature, cold
water (100 mL) was added, and stirred at room temperature for
(
100 mL), water (50 mL) and brine (50 mL), dried over anhydrous
3
0 min. The mixture was extracted with dichloromethane (3×50 mL).
sodium sulfate, and then concentrated under reduced pressure, to give
The organic layer was washed with 20% NaOH solution (100 mL),
water (100 mL) and brine (100 mL), dried over anhydrous sodium
sulfate, and concentrated under reduced pressure to give (2) as yellow
−1
(5) as a yellow oil (28.4 g, 91.0%). IR (cm ): 3103, 2983, 2937, 1712,
1
5
(
529, 1457, 1379, 1279, 1236, 1081, 1059, 935, 855, 756, 699, 621,
1
02; H NMR (300 MHz, DMSO-d ) δ 1.23–1.44 (m, 3H), 3.92–3.99
8,9
−1
6
oil (54.2 g, 96.8%), (lit. pale yellow oil). IR (cm ): 3091, 2979,
13
m, 1H), 6.94–7.95 (m, 3H), 12.50 (s, 1H); C NMR (75 MHz,
2
7
2
938, 1665, 1518, 1459, 1417, 1356, 1228, 1055, 941, 904, 853, 799,
DMSO-d ) δ 19.44, 40.37, 124.69, 126.68, 128.24, 143.68, 174.56;
6
1
23, 644, 585; H NMR (300 MHz, CDCl ) δ 1.19–1.24 (m, 3H),
–
3
HRMS ([M–H] ): m/z calcd for C H O S: 155.0167; found: 155.0169.
7
7
2
.89–2.96 (m, 2H), 7.09–7.12 (m, 1H), 7.59–7.61 (m, 1H), 7.69–7.71
Tiaprofenic acid (6): Benzoyl chloride (14.05 g, 0.1 mol) was added
dropwise to a mixture of compound 5 (15.6 g, 0.1 mol) and ZnO
powder (1.6 g, 20 mmol). The mixture was stirred at room tempera-
ture, after completion of the reaction as indicated by TLC, the solid
mass was then eluted with dichloromethane (200 mL) and then washed
with saturated sodium bicarbonate (2×200 mL), dried over anhydrous
sodium sulfate, and then concentrated under reduced pressure. The
residue was crystallised from toluene and collected by filtration to
13
(
m, 1H); C NMR (75 MHz, CDCl ) δ 8.27, 32.28, 127.83, 131.39,
3
+
1
32.97,143.89, 193.54; MS m/z: 141.0 ([M+H] , 100%).
-Bromo-1-(thiophen-2-yl) propan-1-one (3): PTT (37.6 g, 0.1 mol)
2
was added to a solution of compound 2 (14 g, 0.1 mol) in dichloro-
methane (150 mL) and the mixture was heated 8under reflux for 12 h.
After cooling to room temperature, the reaction mixture was neu-
tralised with aqueous potassium carbonate solution and extracted with
dichloromethane (3×50 mL). The organic layer was washed with
water (100 mL) and brine (100 mL), dried over anhydrous sodium
sulfate, and concentrated under reduced pressure to give (3) as pale
7
give (6) as white crystal (24.3 g, 93.5% yield); m.p. 96–98 °C, (lit.
–1
1
95–97 °C). IR (cm ): 3106, 1699, 1623, 1446, 1278, 1230, 1079; H
NMR (500 MHz, CDCl ) δ 1.66–1.67 (d, 3H, J = 1.71 Hz), 4.06–4.01
3
14
−1
13
yellow oil (21.1g, 95.9%), (lit. pale yellow oil). IR (cm ): 3103,
(m, 1H), 7.05–7.59 (m, 2H), 7.49–7.84 (m, 5H); C NMR (75 MHz,
2
1
978, 2925, 2862, 1664, 1517, 1441, 1413, 1376, 1355, 1246, 1167,
064, 985, 942, 903, 855, 724, 648, 585, 566, 538; H NMR
CDCl ) δ 18.84, 41.25, 126.35, 128.31, 128.31, 129.00, 129.00,
3
1
132.19, 134.92, 137.72, 142.24, 151.72, 178.14, 188.10; HRMS
+
(
300 MHz, CDCl ) δ 1.84–1.94 (m, 3H), 5.12–5.18 (m, 1H), 7.14–
([M+H] ): m/z calcd for C H O S: 261.0585; found: 261.0587.
14 13
3
3
13
7
.17 (m, 1H), 7.68–7.70 (m, 1H), 7.83–7.85 (m, 1H); C NMR
(
1
75 MHz, CDCl ) δ 20.27, 42.42, 128.23, 133.02, 134.81, 140.76,
3
We are grateful to the National Basic Research Program of
China (No. 2011CB933503) for financial support.
+
+
86.73; MS m/z: 219.0 ([M-H] , 100%), 221.0 ([M+H] , 100%).
-(1-Bromoethyl)-2-(thiophen-2-yl)-1,3-dioxolane (4): A mixture
2
of compound 3 (44.1 g, 0.2 mol), toluene (240 mL), toluene-p-
sulfonic acid (4.4 g, 0.026 mol) was heated under reflux for 1 h.
Ethylene glycol (24.8 g, 0.4 mol)was then added to the mixture, and
the reaction mixture was heated under reflux for 12 h. After cooling to
Received 18 April 2013; accepted 23 May 2013
Paper 1301900 doi: 10.3184/174751913X13709565021526
Published online: 18 July 2013