6322 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 17
Marom et al.
tert-Butyl 2-(2-(2-(4-Hydroxybenzamido)ethoxy)ethoxy)ethyl-
carbamate (2). To a solution of 1 (158 mg, 0.6 mmol) in a
mixture of dry CH2Cl2 (4.0 mL) and dry CH3CN (4.0 mL),
4-hydroxybenzoic acid (124 mg, 0.9 mmol), HBTU (226 mg,
0.72 mmol), HOBt (81 mg, 0.72 mmol), and N,N-diisopropyl-
ethylamine (314 μL, 1.8 mmol) were added at rt under inert
atmosphere and the reaction mixture was stirred for 24 h. After
that time, all volatiles were evaporated and the crude pro-
duct was purified by column chromatography (SiO2; CH3OH/
CH2Cl2, 8:92; Rf 0.46) to give 2 as yellow oil (200 mg, 87%). 1H
NMR (400 MHz, DMSO-d6): δ 1.36 (s, 9H), 3.04 (q, J = 8 Hz,
2H), 3.36 (m, 4H), 3.50 (m, 6H), 3.57 (s, 1H), 6.78 (d, J = 8 Hz,
1H), 7.70 (d, J = 8 Hz, 2H), 8.22 (bs, 1H), 9.93 (s, 1H). 13C
NMR (100 MHz, CDCl3): δ 28.4, 38.7, 39.8, 40.3, 69.9, 70.1,
79.6, 115.5, 125.3, 129.0, 156.2, 160.2, 167.9. IR (film): 3632,
3437, 3203, 2942, 2722, 2521, 1781, 1670, 1618, 1514, 1461, 1391,
1278, 1166, 1030, 922 cm-1. MS (CIþ): m/z 369.0 (MHþ).
UV-vis (CH3CN): λmax 240 nm.
chromatography (SiO2; CH3CN; Rf 0.3) to give 7 as light-yellow
oil (134 mg, 95%). [R]20D þ2.86 (c 0.05, CH3CN). 1H NMR (500
MHz, DMSO-d6): δ 1.46 (s, 3H), 3.24 (q, J = 5 Hz, 2H), 3.38 (q,
J = 5 Hz, 2H), 3.43 (t, J = 5 Hz, 2H), 3.52 (m, 7H), 4.05 (s, 2H),
4.06, 4.29 (ABq, J = 10 Hz 2H), 6.32 (bs, 1H), 6.98 (d, J = 10
Hz, 2H), 7.80 (d, J = 10 Hz, 2H), 8.20 (d, J = 10 Hz, 1H), 8.25
(bs, 1H), 8.36 (m, 2H), 8.58 (d, J = 5 Hz, 1H), 10.66 (s, 1H). 13
C
NMR (125 MHz, DMSO-d6): δ 22.94, 38.16, 38.93, 39.00, 42.48,
68.64, 68.90, 69.47, 73.52, 74.70, 113.98, 118.19, 118.23, 123.00,
126.77, 127.29, 128.87, 141.59, 143.17, 160.59, 165.58, 165.89,
174.40. 19F NMR (376 MHz, CDCl3): δ -60.48. IR (film): 3302,
2875, 1664, 1537, 1419, 1347, 1250, 1145, 1040, 911, 844, 710
cm-1. HRMS (MALDI-TOF): m/z calcd for C26H30ClF3N4-
O9Na, 657.1551; found, 657.1596.
(S)-tert-Butyl-2,20,200-(10-(1-(4-(2-hydroxy-2-methyl-3-(4-nitro-
3-(trifluoromethyl)phenylamino)-3-oxopropoxy)phenyl)-1,12-dioxo-
5,8-dioxa-2,11-diazatridecan-13-yl)-1,4,7,10-tetraazacyclodo-
decane-1,4,7-triyl)triacetate (8). Procedure A. To a mixture of
20 (153 mg, 0.289 mmol) and KHCO3 (40 mg, 0.289 mmol) in
dry DMF (1.0 mL), a solution of 7 (183 mg, 0.289 mmol) in dry
DMF (1.0 mL) was added at rt under inert atmosphere. Then,
the reaction mixture was heated to 90 °C for overnight. After
that time, the solvent was evaporated and the crude product was
purified by column chromatography (SiO2; MeOH:CH2Cl2, 1:9;
Rf 0.3) to give 8 as light-yellow oil (225 mg, 70%). [R]24D þ13.08°
(S)-tert-Butyl-2-(2-(2-(4-(2-hydroxy-2-methyl-3-(4-nitro-3-(tri-
fluoromethyl)phenylamino)-3-oxo-propoxy)benzamido)ethoxy)-
ethoxy)ethylcarbamate (5). To a suspension of 3 (178 mg, 0.615
mmol) and anhydrous K2CO3 (170 mg, 1.230 mmol) in dry
2-butanone (5.0 mL), 2 (244 mg, 0.664 mmol) was added at rt
under inert atmosphere. Then, the reaction mixture was refluxed
for overnight. After that time, 2-butanone was evaporated,
water (20 mL) was added, and the mixture was extracted with
ethyl acetate (3 ꢀ 20 mL). The combined organic fractions were
dried over MgSO4, and the crude product was purified by
column chromatography (SiO2; CH3CN; Rf 0.3) to give 5 as
yellow oil (324 mg, 80%). [R]20D -26.6° (c = 1.7, CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ 1.42 (s, 9H), 1.60 (s, 3H), 3.23 (t,
J = 4.8 Hz, 1H), 3.51 (t, J = 5.2 Hz, 1H), 3.62-3.64 (m, 8H),
4.00, 4.42 (ABq, J = 9.2 Hz 2H), 6.83 (d, J = 8.4 Hz, 2H), 7.70
(d, J = 7.6 Hz, 2H), 7.98 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 8.8 Hz,
2H), 8.13 (bs, 1H), 9.39 (bs, 1H). 13C NMR (100 MHz, CDCl3):
δ 22.9, 28.3, 39.8, 40.3, 70.1, 72.8, 75.6, 79.6, 114.4, 118.3, 118.3,
122.1, 127.0, 127.0, 128.8, 141.8, 143.0, 156.1, 160.6, 167.5,
173.1. 19F NMR (376 MHz, CDCl3): δ -60.5. IR (film): 3372,
2928, 2873, 2077, 1693, 1641, 1515, 1458, 1417, 1353, 1251, 1149,
1042, 910 cm-1. HRMS (MALDI-TOF): m/z calcd for C29H37-
N4O10F3Na, 681.2354; found, 681.2816. UV-vis (CH3CN):
1
(c = 8.9, CHCl3). H NMR (500 MHz, CDCl3): δ 1.43 (ds,
34H), 3.33-3.68 (m, 37H), 4.09 (d, J = 10 Hz, 1H), 4.57 (d, J =
10 Hz, 1H), 6.97 (d, J = 10 Hz, 2H), 7.42 (s, 1H), 7.64 (s, 1H),
7.78 (d, J = 5 Hz, 2H), 7.89 (d, J = 10 Hz, 1H), 8.21 (d, J = 10
Hz, 1H), 8.53 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 22.9, 27.9,
28.0, 29.7, 31.9, 38.9, 39.7, 55.5, 55.7, 56.0, 69.5, 70.0, 70.2, 70.3,
73.4, 81.8, 81.9, 114.8, 118.7, 118.8, 122.8, 126.6, 127.1, 128.9,
142.6, 143.0, 161.2, 167.4, 171.8, 172.4, 174.5. 19F NMR (188
MHz, MeOD): δ -63.53. IR (film): 3421, 2924, 2386, 2298,
1728, 1610, 1535, 1462, 1370, 1313, 1233, 1157, 1039, 848, 762
cm-1. HRMS (MALDI-TOF): m/z calcd for C52H80N8O15F3,
1113.5690; found, 1113.5647.
Procedure B. To a mixture of 3 (100 mg, 0.345 mmol) and
K2CO3 (48 mg, 0.690 mmol) in dry 2-butanone (5 mL), a
solution of 12 (284 mg, 0.345 mmol) in dry 2-butanone (5 mL)
was added at rt under inert atmosphere. Then the reaction
mixture was heated to 80 °C for overnight. After that time,
2-butanone was evaporated, water (15 mL) was added, and the
mixture was extracted with CH2Cl2 (3 ꢀ 15 mL). The combined
organic fractions were dried over MgSO4, and the crude product
was purified by column chromatography to give 8 as yellow oil
(345 mg, 90%).
(S)-2,20,200-(10-(1-(4-(2-Hydroxy-2-methyl-3-(4-nitro-3-(tri-
fluoromethyl)phenylamino)-3-oxopro-poxy)phenyl)-1,12-dioxo-
5,8-dioxa-2,11-diazatridecan-13-yl)-1,4,7,10-tetraazacyclodode-
cane-1,4,7-triyl)triacetic Acid (9). To a solution of 8 (300 mg,
0.270 mmol) in dry CH3CN (10.0 mL), CF3CO2H (10.0 mL)
was added dropwise at 0 °C under inert atmosphere. Then, the
reaction mixture was allowed to warm up to rt and stirred for
overnight. After that time, all volatiles were evaporated and
purification was performed by dissolving in minimum amount
of methanol and triturated with diethyl ether to obtain the pure
λmax 250, 310 nm.
(S)-2-(2-(2-(4-(2-Hydroxy-2-methyl-3-(4-nitro-3-(trifluoro-
methyl)phenylamino)-3-oxopropoxy)-benzamido)ethoxy)ethoxy)-
ethanaminium 2,2,2-trifluoroacetate (6). To a solution of 5 (93.6
mg, 0.412 mmol) in dry CH3CN (2.5 mL), CF3CO2H (2.5 mL)
was added dropwise at 0 °C under inert atmosphere. Then the
reaction mixture was allowed to warm up to rt and stirred for
overnight. After that time, all volatiles were evaporated and
purification was performed by dissolving in minimum amount
of methanol and triturated with diethyl ether to obtain the pure
product 6 as light-yellow precipitate (79.3 mg, 99%). [R]20
D
-1.84° (c = 3.97, acetone). 1H NMR (400 MHz, DMSO-d6): δ
1.46 (s, 3H), 2.95 (m, 2H), 3.57 (m, 10H), 3.58, 4.28 (ABq, J = 8
Hz, 2H), 6.33 (bs, 1H), 6.98 (d, J = 8 Hz, 2H), 7.79 (d, J = 8 Hz,
2H), 8.12 (d, J = 12 Hz, 1H), 8.36 (t, J = 4 Hz, 1H), 8.58 (s, 1H),
10.66 (bs, 1H). 13C NMR (100 MHz, DMSO-d6): δ 22.9, 38.5,
40.1, 66.6, 68.9, 69.3, 69.6, 73.5, 74.7, 114.0, 118.1, 118.2, 123.0,
126.7, 127.3, 128.8, 141.6, 143.1, 160.6, 165.6, 174.4. 19F NMR
(376 MHz, DMSO-d6): δ -59.46, -74.05. IR (film): 3434, 2928,
1684, 1535, 1422, 1352, 1251, 1193, 1142, 1038, 994, 842, 764,
725 cm-1. MS (FABþ): m/z 559.2 (MHþ). HRMS (MALDI-
TOF): m/z calcd for C24H30N4O8F3, 559.2010; found, 559.1997.
(S)-N-(2-(2-(2-(2-Chloroacetamido)ethoxy)ethoxy)ethyl)-4-
(2-hydroxy-2-methyl-3-(4-nitro-3-(trifluoromethyl)phenylamino)-
3-oxopropoxy)benzamide (7). To a solution of 6 (152 mg, 0.272
mmol) in dry CH3CN (5.0 mL), chloroacetic anhydride (46 mg,
0.272 mmol) was added at rt under inert atmosphere. Then, the
reaction mixture was heated to 35 °C for overnight. After
solvent evaporation, the crude product was purified by column
product 9 as light-yellow precipitate solid (229 mg, 90%); mp
1
144.3-145.5 °C. [R]20 -8.3% (c 4.3, MeOH). H NMR (500
D
MHz, CD3OD): δ 1.56 (s, 3H), 3.31-3.64 (m, 39H), 4.10, 4.39
(ABq, J = 10 Hz, 2H), 7.01 (d, J = 10 Hz, 2H), 7.78 (d, J = 10
Hz, 2H), 8.05 (d, J = 10 Hz, 1H), 8.18 (dd, J = 5 Hz, 1H), 8.37 (s,
1H). 13C NMR (125 MHz, CD3OD): δ 23.3, 40.3, 40.8, 56.5, 57.0,
57.1, 70.6, 71.3, 71.4, 75.0, 76.5, 115.6, 119.8, 119.8, 122.5, 124.4,
128.1, 128.3, 130.3, 1440, 144.3, 162.9, 169.8, 175.0, 176.1, 179.4,
179.6. 19F NMR (188 MHz, CD3OD): δ -78.90, -63.51. IR
(KBr):3732, 2752, 2559, 2469, 2419, 2387, 2335, 2295, 2276, 2078,
1640, 1463, 1352, 1317, 1250, 1175, 1138, 1097, 1035, 974, 914,
833, 809, 768, 705, 688, 644, 612 cm-1. HRMS (MALDI-TOF):
m/z calcd for C40H56F3N8O15, 945.3839; found, 945.3877.