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MedChemComm
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DOI: 10.1039/C6MD00306K
ARTICLE
Journal Name
as a light yellow solid, mp: 115.9-118.1 °C; Rf: 0.27 (ethyl acetate); DMSO-d6): δ 0.42-0.72 (4H, m), 2.69-2.81 (1H, m), 4.63 (2H, d, J =
IR (vmax (neat)): 3208, 3124, 2987, 2947, 2882, 1719, 1674, 1563, 5.3 Hz), 5.28 (1H, d, J = 10.6 Hz), 5.33 (1H, d, J = 17.1 Hz), 5.94-6.06
1347, 1226, 1194, 1167, 1147, 1115, 1024, 999, 985, 945 cm–1 1H (1H, m), 7.46 (1H, s), 8.85 (1H, s), 12.82 (1H, bs) ppm, (COOH peak
;
NMR (300 MHz, DMSO-d6): δ 1.26 (3H, t, J = 7.1 Hz), 4.25 (2H, q, J = not observed); 13C NMR (75 MHz, DMSO-d6): δ 5.7, 22.7, 75.1, 115.7
7.1 Hz), 4.65 (2H, d, J = 5.3 Hz), 5.23 (1H, d, J = 10.6 Hz), 5.34 (1H, d, (q, JCF = 286.5 Hz), 118.0, 122.3, 123.7, 127.0, 133.7, 148.2, 153.4 (q,
J = 17.2 Hz), 5.92-6.06 (1H, m), 7.49 (1H, s), 11.90 (1H, s), 13.77 (1H, JCF = 39.2 Hz), 163.1, 163.2, 164.5 ppm; 19F NMR (282 MHz, DMSO-
bs) ppm; 13C NMR (75 MHz, DMSO-d6): δ 13.7, 61.4, 75.4, 115.3 (q, d6): δ –74.0 ppm; LRMS (+ESI) m/z: 450 ([M+2Na-H]+ 100%), 428
JCF = 287.2 Hz), 117.8, 117.8, 122.8, 129.7, 133.9, 142.9, 146.5, ([M+Na]+ 86%), HRMS (+ESI) Calcd for C15H14F3N3O5S [M+Na]+:
154.0 (q, JCF = 38.4 Hz), 162.0, 163.2 ppm; 19F NMR (282 MHz, 428.0499, found: 428.0502.
DMSO-d6): δ –74.3 ppm; LRMS (+ESI) m/z: 417 ([M+Na]+ 100%), 439
([M+2Na–H]+ 67%), HRMS (+ESI) calcd for C14H13F3N2O6S [M+Na]+:
4-(1-((Allyloxy)imino)-2-(cyclopropylamino)-2-oxoethyl)-N-(4-
fluorophenyl)-2-(2,2,2-trilfluroracetamido)thiophene-3-
carboxamide 10
417.0339, found: 417.0340.
Ethyl
4-(1-((allyloxy)imino)-2-(cylopropylamino)-2-oxoethyl)-2-
(2,2,2-trifluoroacetamido)thiophene-3-carboxylate 8
The acid
oxytripyrrolidinophosphonium hexafluorophosphate (3.59 g, 6.91
(20.0 g, 50.7 mmol) and benzotriazol-1-yl- mmol) were dissolved in N,N-dimethylformamide (10 mL) and the
9
(2.00 g, 4.93 mmol) and benzotriazol-1-yl-
The acid
7
oxytripyrrolidinophosphonium hexafluorophosphate (36.9 g, 70.9 solution cooled to 0 °C. To this was added, dropwise, 4-fluoroaniline
mmol) were dissolved in N,N-dimethylformamide (300 mL) and the (655 μL, 6.91 mmol), then N,N-diisopropylethylamine (1.72 mL, 9.86
solution cooled to
0 °C. To this was added, dropwise, mmol) and the mixture warmed to room temperature and stirred
cyclopropylamine (4.92 mL, 70.9 mmol), then N,N- for 16 h. The reaction mixture was diluted with water (20 mL) and
diisopropylethylamine (13.6 mL, 75.8 mmol) and the mixture extracted with ethyl acetate (3 x 20 mL). The combined organic
warmed to room temperature and stirred for 16 h. The reaction phases were washed with water (4 x 30 mL) and brine (30 mL) and
mixture was diluted with water (400 mL) and extracted with ethyl dried over anhydrous magnesium sulfate. The solvent was removed
acetate (3 x 250 mL). The combined organic components were under reduced pressure and the crude solid purified by flash
washed with water (4 x 200 mL) and brine (200 mL), dried over column chromatography, using ethyl acetate, hexane 0:1 to 1:1 as
anhydrous magnesium sulfate and the solvent removed under an eluent to afford the product as an off-white solid which was
reduced pressure. The crude residue was purified by flash column recrystallised from dichloromethane, hexane to yield the title
chromatography, using ethyl acetate, dichloromethane 0:1 to 1:4 as compound 10 (1.39 g, 55%) as a white crystalline solid, mp: 198.0-
an eluent, to afford the amide 8 (20.3 g, 92%) as an off-white solid, 199.2 °C; Rf: 0.57 (4:1 ethyl acetate, hexane); IR (vmax (neat)): 3271,
mp: 163.8-166.1 °C; Rf: 0.46 (2:3 ethyl acetate, hexane); IR (vmax 3221, 3158, 3115, 3086, 3015, 2903, 1716, 1684, 1557, 1525, 1506,
1
(neat)): 3308, 3219, 3123, 3009, 2986, 2923, 2867, 1726, 1675, 1256, 1225, 1210, 1186, 1167, 1118, 1003, 991, 922, 739 cm–1; H
1632, 1555, 1316, 1243, 1229, 1192, 1172, 1146, 1120, 1028, 940, NMR (300 MHz, DMSO-d6): δ 0.52-0.75 (4H, m), 2.78-2.81 (1H, m),
919, 791 cm–1 1H NMR (300 MHz, DMSO-d6): δ 0.70-0.45 (4H, m), 4.67 (2H, d, J = 5.4 Hz), 5.28 (1H, d, J = 10.5 Hz), 5.34 (1H, d, J = 17.4
;
1.25 (3H, t, J = 7.0 Hz), 2.73-2.77 (1H, m), 4.22 (2H, q, J = 7.0 Hz), Hz), 5.93-6.05 (1H, m), 7.17-7.24 (2H, m), 7.54 (1H, s), 7.65-7.71
4.60 (2H, d, J = 5.3 Hz), 5.23 (1H, d, J = 10.5 Hz), 5.31 (1H, d, J = 17.4 (2H, m), 8.98 (1H, s), 10.78 (1H, s), 13.01 (1H, bs) ppm; 13C NMR (75
Hz), 5.92-6.06 (1H, m), 7.40 (1H, s), 8.40 (1H, d, J = 3.9 Hz), 11.88 MHz, DMSO-d6): δ 5.7, 22.7, 75.1, 115.5 (q, JCF = 287.1 Hz), 115.6 (d,
(1H, bs) ppm; 13C NMR (75 MHz, DMSO-d6): δ 5.8, 13.7, 22.4, 61.2, JCF = 22.8 Hz), 117.9, 121.6 (d, JCF = 7.8 Hz), 124.0, 124.1 , 124.2,
75.2, 115.2 (q, JCF = 289.3 Hz), 117.7, 119.7, 122.9, 130.3, 133.9, 127.5, 133.8, 134.2, 149.7, 154.1 (q, JCF = 38.0 Hz), 158.4 (d, JCF
=
141.1, 148.6, 154.2 (q, JCF = 39.4 Hz), 161.6, 163.2 ppm; 19F NMR 241.1 Hz), 160.4, 164.8 ppm; 19F NMR (282 MHz, DMSO-d6): δ –
(282 MHz, DMSO-d6): δ –74.1 ppm; LRMS (+ESI) m/z: 456 ([M+Na]+ 74.1, –117.9 ppm; LRMS (–ESI) m/z: 497 ([M–H]– 100%), 995 ([2M–
100%), 889 ([M+2Na]+, 11%), HRMS (+ESI) calcd for C17H18F3N3O5S H]– 3%), HRMS (+ESI) calcd for C21H18F4N4O4S [M+Na]+: 521.0877,
[M+Na]+: 456.0812, found: 456.0813.
found: 521.0879.
4-(1-((Allyloxy)imino)-2-(cyclopropylamino)-2-oxoethyl)-2-(2,2,2-
trifluoroacetamido)thiophene-3-carboxylic acid 9
4-(1-((Allyloxy)imino-2-(cyclopropylamino)-2-oxoethyl)-2-amino-
N-(4-fluorophenyl)thiophene-3-carboxamide 12
To
a solution of 8 (18.0 g, 41.5 mmol) in a mixture of A solution of 10 (500 mg, 1.00 mmol) and triethylammonium
tetrahydrofuran, methanol and water (2:2:1, 540 mL) was added formate (442 μL, 3.00 mmol) in a 4:1 methanol water mixture (5
lithium hydroxide monohydrate (5.23 g, 125 mmol) and the mixture mL) was heated at reflux for 24 h. The solvent was removed under
stirred for 16 h. The organic solvent was removed under reduced reduced pressure and the residue diluted with ethyl acetate (25
pressure and the remaining aqueous component acidified to pH = 3 mL), washed with water (2 x 20 mL), dried over anhydrous
with 6 M hydrochloric acid (aq). The resulting precipitate was magnesium sulfate and the solvent removed. The crude product
collected by filtration, washed with water (10 mL), ethanol (5 mL) was purified by flash column chromatography, using ethyl acetate,
and diethyl ether (2 x 25 mL) and dried in vacuo to obtain the acid 9 hexane 0:1 to 3:2 as an eluent, to afford an off-white solid, which
(14.9 g, 88%) as an off-white powder, mp: 161.5 °C was recrystallised from dichloromethane, hexane, to yield 12 (270
(decomposition); Rf: 0 (2:3 ethyl acetate, hexane); IR (vmax (neat)): mg, 68%) as a white crystalline solid, mp: 194.8-195.9 °C; Rf: 0.52
3226, 3092, 3009, 2874, 2564, 1739, 1702, 1594, 1535, 1263, 1207, (4:1 ethyl acetate, hexane); IR (vmax (neat)): 3466, 3306, 3253, 3203,
1194, 1159, 1121, 1015, 995, 929, 743 cm–1
;
1H NMR (300 MHz, 3151, 3119, 3050, 3013, 2903, 2859, 2923, 1678, 1643, 1556, 1504,
6 | J. Name., 2012, 00, 1-3
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