S. Fardeau et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
9
12H), 2.66 (t, J = 6.6 Hz, 2H), 3.56 (m, 6H), 3.62 (t, J = 6.6 Hz, 2H),
3.81 (s, 2H), 5.04 (s, 6H), 5.12 (s, 6H), 7.13 (m, 6H), 7.22–7.49 (m,
30H), 7.85 (m, 3H), 8.05 (m, 3H); 13C NMR (150 MHz, CDCl3) d
23.0, 31.0, 38.9, 39.4, 40.6, 40.8, 66.5, 70.4, 116.5, 123.0, 124.0,
127.1–128.9, 127.8, 136.1, 146.6, 151.5, 164.6, 168.4; HRMS-ESI
brown powder. Mp: 259 °C; 1H NMR (600 MHz, CDCl3) d 1.12–
1.75 (m, 18H), 2.59 (m, 8H), 2.96 (m, 4H), 3.19 (s, 2H), 3.41 (m,
6H), 3.68 (m, 1H), 5.02 (s, 6H), 5.14 (s, 6H), 7.21 (m, 6H), 7.29–
7.61 (m, 32H), 7.73 (m, 3H), 8.07 (m, 3H), 8.66 (m, 1H); 13C NMR
(150 MHz, CDCl3) d 7.2, 23.3, 25.5, 30.5, 31.7, 36.3, 38.2, 40.4,
45.8, 53.8, 55.3, 59.5, 71.4, 76.8, 102.4, 109.6, 112.3, 115.5, 116.0,
122.7, 124.6, 128.1, 127.1–128.9, 133.3, 135.8, 143.9, 147.1,
152.3, 164.0, 165.3, 170.5, 174.3; HRMS-ESI (m/z): [M+Na]+ calcd
for C95H97FN6NaO14: 1587.6944, found 1587.6749.
(m/z): [M+H]+ calcd for C77H78ClN3O11
:
1256.5403, found
1256.5321.
4.1.9. 5-(2,3-Bis(benzyloxy)benzamido)-2,2-bis(3-(2,3-
bis(benzyloxy)benzamido)propyl) pentyl 4-chlorobutanoate
(14c)
4.1.13. 1-Cyclopropyl-7-(4-(2-(5-(2,3-dihydroxybenzamido)-2,2-
bis(3-(2,3-dihydroxy benzamido)propyl)pentyloxy)-2-
oxoethyl)piperazin-1-yl)-6-fluoro-4-oxo-1,4-dihydro quinoline-
3-carboxylic acid (1a)
According to the same procedure described for 14a, 4-chlorob-
utanoyl chloride was reacted with 4 (330 mg, 0.283 mmol) to
obtain 14c (320 mg, 85%), after purification by column chromatog-
raphy, as a yellow oil. 1H NMR (600 MHz, CDCl3) d 1.17–1.66 (m,
14H), 2.59 (m, 2H), 3.57 (m, 6H), 3.81 (s, 2H), 3.89 (s, 2H), 5.09
(s, 6H), 5.17 (s, 6H), 7.14 (m, 6H), 7.21–7.48 (m, 30H), 7.82 (m,
3H), 7.98 (m, 3H); 13C NMR (150 MHz, CDCl3) d 22.9, 26.4, 28.3,
30.9, 38.9, 40.6, 48.7, 66.5, 70.4, 75.8, 116.5, 123.0, 124.0, 127.1–
128.9, 127.8, 136.1, 146.6, 151.5, 164.6, 169.4; HRMS-ESI (m/z):
[M+Na]+ calcd for C78H80ClNaN3O11: 1292.5379, found 1292.5419.
A suspension of compound 15a (40 mg, 0.026 mmol) and
Pd(OH)2/C (10% wt, 5 mg) in MeOH was stirred under an hydrogen
atmosphere for 4 days at 20 °C. The catalyst was filtered through a
Celite pad and washed with MeOH. The filtrate was concentrated
to give 1a (25 mg, 98%) as a white powder. Mp : 257 °C; 1H NMR
(600 MHz, DMSO-d6) d 1.07–1.41 (m, 16H), 2.21–2.76 (m, 8H),
3.02 (s, 2H), 3.34 (m, 6H), 3.54 (m, 1H), 3.94 (s, 2H), 7.18 (m,
6H), 7.37–7.41 (m, 2H), 7.61 (m, 3H), 7.91 (m, 3H), 8.41 (m, 1H);
13C NMR (150 MHz, DMSO-d6) d 7.5, 23.4, 31.9, 36.4, 38.5, 40.6,
46.0, 53.9, 59.9, 68.4, 102.6, 109.8, 112.6, 115.5, 116.2, 123.8,
124.9, 127.2, 133.6, 144.7, 147.7, 153.0, 164.3, 165.7, 170.8,
4.1.10. 7-(4-(2-(5-(2,3-Bis(benzyloxy)benzamido)-2,2-bis(3-(2,3
bis(benzyloxy)benzamido)propyl)pentyloxy)-2-
oxoethyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-
dihydro quinoline-3-carboxylic acid (15a)
173.2; HRMS-ESI (m/z): [M+Na]+ calcd for C51H57FN6NaO14
:
A mixture of 14a (200 mg, 0.16 mmol), ciprofloxacin (265 mg,
0.8 mmol) and K2CO3 (110 mg, 0.8 mmol) in dry acetonitrile
(5 mL) was refluxed for 3 days. The suspension was filtered and
the solution was evaporated under reduced pressure. The crude
product was purified by silica gel column chromatography (CH2Cl2/
MeOH 90:10) to provide 15a (76 mg, 31%) as a beige powder. Mp:
261 °C; 1H NMR (600 MHz, CDCl3) d 1.17–1.62 (m, 16H), 2.59 (m,
4H), 2.96 (m, 4H), 3.19 (s, 2H), 3.41 (m, 6H), 3.68 (m, 1H), 4.01
(s, 2H), 5.02 (s, 6H), 5.14 (s, 6H), 7.21 (m, 6H), 7.29–7.61 (m,
32H), 7.73 (m, 3H), 8.07 (m, 3H), 8.66 (m, 1H); 13C NMR
(150 MHz, CDCl3) d 7.6, 23.4, 31.8, 36.0, 38.1, 40.3, 45.7, 53.6,
59.6, 68.0, 71.3, 76.7, 102.1, 109.3, 112.2, 115.3, 115.9, 122.8,
124.5, 127.9, 127.1–128.9, 133.2, 135.8, 144.2, 147.5, 152.6,
164.2, 165.3, 170.4, 173.8; HRMS-ESI (m/z): [M+Na]+ calcd for
C93H93FN6NaO14: 1559.6631, found 1559.6849.
1019.3814, found 1019.3846.
4.1.14. 1-Cyclopropyl-7-(4-(3-(5-(2,3-dihydroxybenzamido)-2,2-
bis(3-(2,3-dihydroxy benzamido)propyl)pentyloxy)-3-
oxopropyl)piperazin-1-yl)-6-fluoro-4-oxo-1,4-dihydro
quinoline-3-carboxylic acid (1b)
According to the same procedure described for 1a, 15b (60 mg,
0.038 mmol) gave 1b (36 mg, 97%) as a beige powder. Mp : 254 °C;
1H NMR (600 MHz, DMSO-d6) d 1.24–1.61 (m, 16H), 2.47–2.83 (m,
10H), 3.11 (s, 2H), 3.32 (m, 6H), 3.69 (m, 3H), 7.26 (m, 6H), 7.28–
7.39 (m, 2H), 7.64 (m, 3H), 8.01 (m, 3H), 8.50 (m, 1H); 13C NMR
(150 MHz, DMSO-d6) d 7.7, 23.5, 31.9, 35.9, 37.3, 38.2, 38.3, 40.4,
53.9, 59.8, 102.4, 109.6, 112.5, 115.6, 115.9, 122.9, 124.3, 127.5,
134.6, 144.6, 147.7, 152.8, 163.5, 165.5, 170.7, 175.2; HRMS-ESI
(m/z): [M+Na]+ calcd for C52H59FN6NaO14
: 1033.3971, found
1033.4079.
4.1.11. 7-(4-(3-(5-(2,3-Bis(benzyloxy)benzamido)-2,2-bis(3-(2,3-
bis(benzyloxy)benzamido)propyl)pentyloxy)-3-
oxopropyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-
dihydro quinoline-3-carboxylic acid (15b)
4.1.15. 1-Cyclopropyl-7-(4-(4-(5-(2,3-dihydroxybenzamido)-2,2-
bis(3-(2,3-dihydroxy benzamido)propyl)pentyloxy)-4-
oxobutyl)piperazin-1-yl)-6-fluoro-4-oxo-1,4-dihydro
quinoline-3-carboxylic acid (1c)
According to the same procedure described for 15a, 14b was
reacted with ciprofloxacin (315 mg, 0.95 mmol) to obtain 15b
(80 mg, 26%), after purification by column chromatography, as a
white powder. Mp: 258 °C; 1H NMR (600 MHz, CDCl3) d 1.09–
1.54 (m, 16H), 2.51–2.92 (m, 10H), 3.32 (s, 2H), 3.58 (m, 6H),
3.94 (m, 3H),5.09 (s, 6H), 5.21 (s, 6H), 7.28 (m, 6H), 7.34–7.65
(m, 32H), 7.77 (m, 3H), 8.11 (m, 3H), 8.52 (m, 1H); 13C NMR
(150 MHz, CDCl3) d 7.4, 23.1, 32.5, 35.8, 38.1, 38.8, 38.6, 40.9,
54.0, 60.2, 68.1, 72.1, 76.2, 102.7, 109.7, 112.9, 116.1, 116.4,
122.5, 124.9, 127.2, 126.7–129.5, 133.8, 135.6, 144.4, 146.4,
156.1, 164.1, 165.8, 171.1, 176.3; HRMS-ESI (m/z): [M+H]+ calcd
for C94H96FN6O14: 1551.6969, found 1551.6892.
According to the same procedure described for 1a, 15c (20 mg,
0.013 mmol) gave 1c (13 mg, 99%) as a beige powder. Mp: 261 °C;
1H NMR (600 MHz, DMSO-d6) d 1.11–1.71 (m, 18H), 2.66–2.87 (m,
12H), 3.27 (s, 2H), 3.52 (m, 6H), 3.81 (m, 1H), 7.39 (m, 6H), 7.30–
7.42 (m, 2H), 7.62 (m, 3H), 8.11 (m, 3H), 8.49 (m, 1H); 13C NMR
(150 MHz, DMSO-d6) d 7.6, 23.4, 25.4, 30.9, 31.8, 36.0, 38.1, 40.3,
45.7, 53.6, 55.2, 59.6, 102.1, 109.3, 112.2, 115.3, 115.9, 122.8,
124.5, 126.9, 133.2, 144.2, 147.5, 152.6, 163.8, 165.3, 170.4,
174.3; HRMS-ESI (m/z): [M+Na]+ calcd for C53H61FN6
NaO14:1047.4127, found 1047.4184.
4.1.16. 5-(2,3-Bis(benzyloxy)benzamido)-2,2-bis(3-(2,3-
bis(benzyloxy)benzamido)propyl) pentanoic acid (16)
4.1.12. 7-(4-(4-(5-(2,3-Bis(benzyloxy)benzamido)-2,2-bis(3-(2,3-
bis(benzyloxy)benzamido)propyl)pentyloxy)-4-
To
a solution of KBr (5.5 mg, 0.05 mmol), TBAB (2 mg,
oxobutyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-
dihydro quinoline-3-carboxylic acid (15c)
0.006 mmol) and TEMPO (2.3 mg, 0.015 mmol) in water (2 mL)
was added a solution of 4 (116 mg, 0.1 mmol) in CH2Cl2 (2 mL).
According to the same procedure described for 15a, 14c was
reacted with ciprofloxacin (397 mg, 1.2 mmol) to obtain 15c
(33 mg, 9%), after purification by column chromatography, as a
An aqueous solution of sodium hypochlorite 2.2 N (91 lL,
0.2 mmol) was added and the resulting biphasic mixture was stir-
red vigorously at 0 °C for 2 h. The reaction was quenched to an