P. W. Elsinghorst and M. Gu¨tschow
1
(2.59 g, 98%), mp 3201C (decomposition). H NMR (DMSO-d6) d: 13C NMR (DMSO-d6) d: 8.61 (CH2CH3), 10.92 (4-CH3), 13.74
2.49 (s, 3H, 2-CH3), 2.52 (s, 3H, 4-CH3), 6.83 (dd, 1H, 3J (2-CH3), 34.12 (CONHCH2CH2), 47.03 (CH2CH3), 50.37
2
(H,H) = 8.5 Hz, 4J (H,F) = 4.8 Hz, 70-H), 6.92 (ddd, 1H, 3J ðCONHCH2CH2Þ, 106.15 (d, 1C, J (C,F) = 25.3 Hz, C-40), 110.23
4
(H,F) = 9.5 Hz, 3J (H,H) = 8.5 Hz, J (H,H) = 2.5 Hz, 60-H), 7.72 (s, (d, 1C, 3J (C,F) = 8.4 Hz, C-70), 112.62 (d, 1C, 2J (C,F) = 24.3 Hz, C-60),
4
1H, 30-CH-5), 7.74 (dd, 1H, 3J (H,F) = 9.5 Hz, 4J (H,H) = 2.5 Hz, 40-H), 115.11 (d, 1C, 1J (C,C) = 71.3 Hz, J (C,F) = 2.5 Hz, C-30), 119.84
10.88 (s, 1H, NHind), 12.07 (s, 1H, CO2H), 13.84 (s, 1H, NHpyr); 13C (d, 1C, 3J (C,C) = 3.0 Hz, C-3), 124.98 (30-CH-5), 126.04
2
NMR (DMSO-d6) d: 11.59 (4-CH3), 14.62 (2-CH3), 106.32 (d, 1C, J (d, 1C, 1J (C,C) = 68.7 Hz, C-5), 127.26 (d, 1C, 3J (C,F) = 8.7 Hz,
3
(C,F) = 25.5 Hz, C-40), 110.24 (d, 1C, J (C,F) = 8.4 Hz, C-70), 112.85 C-3a0), 130.58 (d, 1C, 2J (C,C) = 4.7 Hz, C-4), 134.78 (d,
2
(d, 1C, J (C,F) = 24.0 Hz, C-60), 114.53 (C-3), 115.83 (d, 1C, 4J 1C, 4J (C,F) = 4.5 Hz, C-7a0), 137.16 (C-2), 158.40 (d, 1C,
(C,F) = 3.0 Hz, C-30), 124.90 (30-CH-5), 126.21 (C-5), 127.15 (d, 1C, 1J (C,F) = 233 Hz, C-50), 165.37 (CONHCH2CH2), 169.72 (d, 1C,
3J (C,F) = 9.4 Hz, C-3a0), 133.58 (C-4), 134.89 (C-7a0), 141.02 (C-2), 2J (C,C) = 2.7 Hz, C-20). LC-MS: purity 99.7%. MS2: ESI1
13
21
13
21
158.42 (d, 1C, 1J (C,F) = 233 Hz, C-50), 166.06 (CO2H), 169.76 (C-20). 400.1 ([C CH27FN4O21H]1, 40%), 327.1 ([C CH27FN4O2–C4H10N]1,
52%), 283.9 ([C CH27FN4O2–C6H15N2]1, 100%); ESIꢁ 398.1
([C CH27FN4O2–H]ꢁ, 100%), 256.1 ([C21 13CH27FN4O2–C7H15N2O]ꢁ, 34%).
13
21
HPLC purity: 97.3%.
13
21
5-((5-Fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-[13C]methyl)-
2,4-dimethyl-1H-pyrrole-3-carboxylic acid (4b)
N - (2 - (Ethylamino)ethyl)-5-((5-fluoro-2-oxo-1,2-dihydro-3H-
indol-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxa-
mide (6a, SU12662)
A solution of 5-fluoro-1,3-dihydro-2H-indol-2-one (1; 3.0 mmol,
0.45 g), 5-[13C]formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid
(3b; 3.0 mmol, 0.59 g), and pyrrolidine (6.0 mmol, 0.5 mL) in
ethanol (20 mL) was reacted as described before to obtain 4b as
a yellow powder (0.86 g, 95%), mp 3161C (decomposition). 1H
NMR (DMSO-d6) d: 2.49 (s, 3H, 2-CH3), 2.52 (s, 3H, 4-CH3), 6.83
A suspension of 5-((5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-
methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (4a; 2.0mmol,
0.60 g), 1-hydroxybenzotriazole (3.0 mmol, 0.40g), 1-(3-dimethyl-
3
4
3
(dd, 1H, J (H,H) = 8.2 Hz, J (H,F) = 4.4 Hz, 70-H), 6.91 (ddd, 1H, J
(H,F) = 9.0 Hz, 3J (H,H) = 9.0 Hz, 4J (H,H) = 2.3 Hz, 60-H), 7.70 (d, 1H,
1J (H,C) = 153 Hz, 30-CH-5), 7.73 (dd, 1H, 3J (H,F) = 9.2 Hz, 4J
(H,H) = 2.2 Hz, 40-H), 10.89 (s, 1H, NHind), 13.82 (s, 1H, NHpyr); 13C
aminopropyl)-3-ethylcarbodiimide
hydrochloride
(4.0 mmol,
0.76 g), and triethylamine (6.0mmol, 0.60 g) in N,N-dimethylform-
amide (20mL) was stirred at room temperature for 2 h. Upon
cooling to ꢁ601C N-ethylethylenediamine (2.4 mmol, 0.22 g) in
N,N-dimethylformamide (1 mL) was added, the solution was stirred
6h at ꢁ601C and warmed to room temperature within 18 h.
Solvent removal provided a crude residue that was subjected to
column chromatography on silica using a mixture of ethyl acetate,
methanol, and triethylamine (8:2:1). Product fractions were
combined, evaporated, dissolved in hydrochloric acid (1.0M,
10 mL), and subsequently filtered. 6a was precipitated as a yellow
powder (0.55 g, 74%) after addition of sodium hydroxide solution
2
NMR (DMSO-d6) d: 11.59 (4-CH3), 14.62 (2-CH3), 106.26 (d, 1C, J
3
(C,F) = 25.3 Hz, C-40), 110.22 (d, 1C, J (C,F) = 8.4 Hz, C-70), 112.78
2
(d, 1C, J (C,F) = 24.0 Hz, C-60), 114.98 (C-3), 115.63 (dd, 1C, 1J
4
(C,C) = 71.7 Hz, J (C,F) = 2.5 Hz, C-30), 124.90 (30-CH-5), 126.24 (d,
1
3
1C, J (C,C) = 68.9 Hz, C-5), 127.18 (d, 1C, J (C,F) = 8.7 Hz, C-3a0),
133.60 (d, 1C, 2J (C,C) = 4.5 Hz, C-4), 134.87 (d, 1C, 4J (C,F) = 4.5 Hz,
1
C-7a0), 140.97 (C-2), 158.41 (d, 1C, J (C,F) = 233 Hz, C-50), 166.25
(CO2H), 169.76 (d, 1C, J (C,C) = 2.5 Hz, C-20). HPLC purity: 97.9%.
2
1
(2.0M, 5 mL), mp 2801C (decomposition). H NMR (DMSO-d6) d:
1.11 (t, 3H, 3J (H,H) = 7.1 Hz, CH2CH3), 2.43 (s, 3H, 2-CH3), 2.45 (s, 3H,
4-CH3), 2.76 (app q, 2H, 3J (H,H)= 7.2 Hz, CH2CH3), 2.85 (app t, 2H,
3J (H,H) =6.5 Hz, CONHCH2CH2), 3.40 (bs, 1H, NH), 3.41 (app q, 2H,
3J (H,H)= 6.1 Hz, CONHCH2CH2), 6.84 (dd, 1H, 3J (H,H) = 8.4 Hz,
4J (H,F)= 4.8Hz, 70-H), 6.91 (ddd, 1H, 3J (H,F) = 9.5 Hz, 3J
N -(2-(Diethylamino)ethyl)-5-((5-fluoro-2-oxo-1,2-dihydro-3H-
indol- 3 -ylidene)-[13C]methyl)-2,4-dimethyl-1H-pyrrole-3-car-
boxamide hydrochloride (5, 13C-SU11248)
A solution of 5-((5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-
[13C]methyl ) - 2,4 - dimethyl -1H - pyrrole - 3 - carboxylic acid (4;
1.0 mmol, 0.30 g), N,N-diethylethylenediamine (1.2 mmol,
0.14 g), 1-hydroxybenzotriazole (1.5 mmol, 0.20 g), 1-(3-dimethyl-
aminopropyl)-3-ethylcarbodiimide hydrochloride (2.0 mmol,
0.38 g), and triethylamine (2.0 mmol, 0.20 g) in anhydrous N,N-
dimethylformamide (10 mL) was stirred at room temperature for
48 h. The reaction mixture was subsequently evaporated in
vacuo and the crude residue subjected to preparative HPLC on
C18-silica using a gradient of methanol–water containing 1.5%
triethylamine. The product fractions were combined, evaporated
in vacuo and lyophilized from hydrochloric acid (0.1 M, 25 mL)
to obtain 5 as an orange powder (0.40 g, 91%), mp 2741C
(decomposition). 1H NMR (DMSO-d6) d: 1.25 (t, 6H, 3J
(H,H) = 7.3 Hz, CH2CH3), 2.45 (s, 3H, 2-CH3), 2.47 (s, 3H, 4-CH3),
3.15 (dq, 4H, 3J (H,H) = 4.8 Hz, 3J (H,H) = 7.3 Hz, CH2CH3), 3.20
4
(H,H) = 8.5 Hz, J (H,H) = 2.5Hz, 60-H), 7.70 (s, 1H, 30-CH-5), 7.71
(t, 1H, 3J (H,H) = 5.7Hz, CONHCH2CH2), 7.74 (dd, 1H, 3J
4
(H,F)= 9.5 Hz, J (H,H)= 2.5 Hz, 40-H), 10.90 (s, 1H, NHind), 13.69
(s, 1H, NHpyr); 13C NMR (DMSO-d6) d: 10.78 (4-CH3), 13.26
ðCH2CH3Þ, 13.58 (2-CH3), 37.40 (CONHCH2CH2), 42.74 (CH2CH3),
2
47.53 ðCONHCH2CH2Þ, 106.07 (d, 1C, J (C,F) = 26.5 Hz, C-40), 110.18
3
2
(d, 1C, J (C,F) = 8.7 Hz, C-70), 112.53 (d, 1C, J (C,F) = 23.8 Hz, C-60),
4
114.86 (d, 1C, J (C,F) = 2.7 Hz, C-30), 120.54 (C-3), 124.99 (30-CH-5),
125.95 (C-5), 127.28 (d, 1C, 3J (C,F) = 9.4 Hz, C-3a0), 130.50 (C-4), 134.69
1
(C-7a0), 136.88 (C-2), 158.38 (d, 1C, J (C,F) = 233 Hz, C-50), 165.12
(CONHCH2CH2), 169.70 (C-20). LC-MS: purity 99.2%. MS2: ESI1 371.1
([C20H23FN4O21H]1, 17%), 325.9 ([C20H23FN4O2–C2H6N]1, 10%), 282.9
([C20H23FN4O2–C4H11N2]1, 100%); ESIꢁ 368.9 ([C20H23FN4O2–H]ꢁ,
100%), 254.9 ([C20H23FN4O2–C5H11N2O]ꢁ, 34%).
3
3
(app q, 2H, J (H,H) = 6.1 Hz, CONHCH2CH2), 3.61 (app q, 2H, J
(H,H) = 6.3 Hz, CONHCH2CH2), 6.84 (dd, 1H, 3J (H,H) = 8.5 Hz, 4J
(H,F) = 4.7 Hz, 70-H), 6.91 (ddd, 1H, 3J (H,F) = 9.5 Hz, 3J
(H,H) = 8.5 Hz, 4J (H,H) = 2.6 Hz, 60-H), 7.70 (d, 1H, 1J
N - (2 - (Ethylamino)ethyl)-5-((5-fluoro-2-oxo-1,2-dihydro-3H-
indol-3-ylidene)-[13C]methyl)-2,4-dimethyl-1H-pyrrole-3-car-
boxamide hydrochloride (6b, 13C-SU12662)
(H,C) = 153 Hz, 30-CH-5), 7.74 (dd, 1H, 3J (H,F) = 9.5 Hz, 4J A suspension of 5-((5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-
3
(H,H) = 2.5 Hz, 40-H), 8.02 (t, 1H, J (H,H) = 5.7 Hz, CONHCH2CH2), [13C]methyl) - 2,4- dimethyl-1H -pyrrole -3 - carboxylic acid (4b;
8.03 (bs, 1H, N1H), 10.92 (s, 1H, NHind), 13.72 (s, 1H, NHpyr); 1.0mmol, 0.30 g), 1-hydroxybenzotriazole (1.5mmol, 0.20g),
J. Label Compd. Radiopharm 2009, 52 360–365
Copyright r 2009 John Wiley & Sons, Ltd.