W. Xin et al. / European Journal of Medicinal Chemistry xxx (xxxx) xxx
7
1H), 1.96 (d, J ¼ 7.7 Hz, 2H), 1.16 (t, J ¼ 7.1 Hz, 3H). 13C NMR
1H), 1.06e0.95 (m, 1H), 0.85e0.69 (m, 6H). 13C NMR (101 MHz,
DMSO‑d6) 168.54, 167.03, 153.48, 143.54, 132.52, 131.39, 129.56,
(101 MHz, DMSO‑d6)
d
172.56, 166.36, 153.47, 140.75, 140.26, 132.47,
d
131.37, 128.32, 123.20, 118.55, 116.22, 112.80, 68.08, 60.39, 54.24,
123.22, 119.24, 116.23, 112.84, 68.01, 57.40, 36.58, 24.19, 14.97, 11.63.
Mp: 259e260 ꢂC. HRMS: [MþH]þ calcd [C20H23BrClN3O5S þ H]þ
532.0308, found 532.0319. HPLC: Gradient A, 100.0% purity,
10.8 min.
29.72, 26.89, 14.52. Mp: 115e117 ꢂC. HRMS: [MþNa]þ calcd
[C21H23BrClN3O7S
þ
Na]þ 598.0027, found 598.0025. HPLC:
Gradient B, 97.7% purity, 10.0 min.
5.1.12. (S)-Tert-butyl(5-amino-1-(4-(2-(40-bromo-20-
chlorophenoxy)acetamido) phenylsulfonamido)-1,5-dioxopentan-2-
yl)carbamate (13)
Compound 13 (141 mg, 30.4% yield) was prepared from 5
(300 mg, 0.71 mmol) and (S)-5-amino-2-((tert-butoxycarbonyl)
amino)-5- oxopentanoic acid (264 mg, 1.07 mmol) following the
general procedure. The residue was dissolved in DCM and washed
with 0.5 M NaOH solution (20 mL). The aqueous phase was acidified
and filtered to give a white solid. The solid was recrystallized from
DCM/MeOH/hexane to give 13 as a white solid. 1H NMR (400 MHz,
5.1.16. 2-(40-Bromo-20-chlorophenoxy)-N-(4’-(((N-carbobenzoxyl-
L-leucyl)amino)sulfonyl)phenyl)acetamide (17)
Compound 17 (173 mg, quantitative yield) was prepared from 5
(100 mg, 0.24 mmol) and L-Cbz-leucine (126 mg, 0.48 mmol)
following the general procedure. The crude product was purified by
column chromatography to give 17 as a white solid. 1H NMR
(400 MHz, DMSO‑d6)
d
12.23 (s, 1H), 10.61 (s, 1H), 7.85 (d, J ¼ 8.8 Hz,
2H), 7.79 (d, J ¼ 9.2 Hz, 2H), 7.70 (d, J ¼ 2.4 Hz, 1H), 7.47 (dd, J ¼ 8.9,
2.4 Hz, 1H), 7.34e7.29 (m, 5H), 7.05 (d, J ¼ 8.9 Hz, 1H), 4.97 (s, 2H),
4.91 (s, 2H), 4.03 (s, 1H), 1.60e1.49 (m, 1H), 1.39e1.29 (m, 2H), 0.81
DMSO‑d6)
d
12.12 (s, 1H), 10.63 (s, 1H), 7.86 (d, J ¼ 8.3 Hz, 2H), 7.80
(dd, J ¼ 8.5, 6.8 Hz, 6H). 13C NMR (101 MHz, DMSO‑d6)
d 166.90,
(d, J ¼ 8.4 Hz, 2H), 7.71 (d, J ¼ 2.3 Hz, 1H), 7.48 (dd, J ¼ 8.7, 2.2 Hz,
1H), 7.24 (s, 1H), 7.08e7.02 (m, 2H), 6.77 (s, 1H), 4.92 (s, 2H),
3.91e3.79 (m, 1H), 2.12e1.93 (m, 2H), 1.80e1.65 (m, 1H), 1.64e1.51
156.37, 153.48, 137.33, 132.51, 131.41, 129.25, 128.79, 128.23, 123.25,
119.22, 116.29, 112.88, 68.07, 65.95, 53.91, 24.67, 23.42, 21.51. Mp:
71e72 ꢂC. HRMS: [MþNa]þ calcd [C28H29BrClN3O7S
þ
Na]þ
(m, 1H), 1.33 (s, 9H). 13C NMR (101 MHz, DMSO‑d6)
d
173.89, 166.85,
688.0496, found 688.0499. HPLC: Gradient A, 97.3% purity, 17.3 min.
153.48, 132.51, 131.42, 129.10, 123.24, 119.11, 116.28, 112.87,þ78.70,
68.09, 55.06, 31.84, 28.59. Mp: 171e172 ꢂC. HRMS: [MþNa] calcd
5.1.17. 2-(40-Bromo-20-chlorophenoxy)-N-(4’-(((N-tert-
[C24H28BrClN4O8S
Gradient A, 100.0% purity, 13.2 min.
þ
Na]þ 669.0398, found 669.0383. HPLC:
butoxycarbonyl-L- leucyl)amino)sulfonyl)phenyl)acetamide (18)
Compound 18 (382 mg, quantitative yield) was prepared from 5
(252 mg, 0.6 mmol) and L-Boc-leucine (278 mg, 1.2 mmol)
following the general procedure. The crude product was purified
with column chromatography to give 18 as a white solid. 1H NMR
5.1.13. 2-(40-Bromo-20-chlorophenoxy)-N-(4’-((
sulfonyl)phenyl)acetamide (14)
L-glutaminylamino)
Compound 13 (97 mg, 0.15 mmol) was treated with HCl gas in
(300 MHz, CDCl3)
d
9.60 (s, 1H), 8.80 (s, 1H), 8.05 (d, J ¼ 8.7 Hz, 2H),
DCM to give 14 as a white solid (69 mg, 78.7% yield). 1H NMR
7.78 (d, J ¼ 8.8 Hz, 2H), 7.60 (d, J ¼ 2.3 Hz, 1H), 7.41 (dd, J ¼ 8.7,
2.2 Hz, 1H), 6.86 (d, J ¼ 8.7 Hz, 1H), 4.74 (s, 1H), 4.66 (s, 2H),
4.08e3.94 (m, 1H), 1.69e1.58 (m, 1H), 1.44 (s, 9H), 0.88 (dd, J ¼ 10.9,
(400 MHz, DMSO‑d6)
d
10.76 (s, 1H), 8.22 (s, 3H), 7.91 (d, J ¼ 8.8 Hz,
2H), 7.82 (d, J ¼ 8.5 Hz, 2H), 7.70 (d, J ¼ 2.3 Hz, 1H), 7.48 (dd, J ¼ 8.6,
2.3 Hz, 2H), 7.07 (d, J ¼ 8.9 Hz, 1H), 6.98 (s, 1H), 4.93 (s, 2H), 3.80 (s,
1H), 2.15 (t, J ¼ 7.7 Hz, 2H), 1.94e1.85 (m, 2H). 13C NMR (101 MHz,
6.1 Hz, 6H). 13C NMR (101 MHz, DMSO‑d6)
d 166.92, 155.80, 153.46,
132.52, 131.40, 129.25, 123.25, 119.19, 116.27, 112.89, 78.70, 68.09,
53.53, 28.58, 24.68, 23.33, 21.64. Mp: 85e86 ꢂC. HRMS: [MþNa]þ
calcd [C25H31BrClN3O7S þ Na]þ 654.0653, found 654.0655. HPLC:
Gradient A, 96.2% purity, 17.1 min.
DMSO‑d6)
d 177.52, 173.52, 167.04, 153.48, 143.58, 133.50, 132.53,
131.41, 129.58, 123.22, 119.41, 116.24, 112.86, 68.01, 56.08, 52.97,
30.69.
Mp:
165e166
ꢂC.
HRMS:
[MþH]þ
calcd
[C19H20BrClN4O6S þ H]þ 547.0053, found 547.0046. HPLC: Gradient
A, 97.3% purity, 8.4 min.
5.1.18. 2-(40-Bromo-20-chlorophenoxy)-N-(4’-((
sulfonyl)phenyl)acetamide (19)
L-leucylamino)
5.1.14. 2-(40-Bromo-20-chlorophenoxy)-N-(4’-(((N-tert-
Compound 18 (193 mg, 0.30 mmol) was treated with HCl gas in
butoxycarbonyl- L-isoleucyl)amino)sulfonyl)phenyl)acetamide (15)
Compound 15 (369 mg, 97.1% yield) was prepared from 5
(249 mg, 0.59 mmol) and L-Boc-isoleucine (278 mg, 1.18 mmol)
following the general procedure. The crude product was purified
with column chromatography to give 15 as a white solid. 1H NMR
DCM to give 19 as a white solid (139 mg, 80.6% yield). 1H NMR
(400 MHz, DMSO‑d6)
d 12.85 (s, 1H), 10.88 (s, 1H), 8.23 (s, 3H), 7.90
(d, J ¼ 8.9 Hz, 2H), 7.83 (d, J ¼ 8.8 Hz, 2H), 7.70 (d, J ¼ 2.4 Hz, 1H),
7.47 (dd, J ¼ 8.9, 2.4 Hz, 1H), 7.06 (d, J ¼ 8.9 Hz, 1H), 4.94 (s, 2H), 3.79
(s, 1H), 1.57 (dt, J ¼ 12.6, 6.4 Hz, 1H), 1.49 (t, J ¼ 6.8 Hz, 2H), 0.82 (dd,
(400 MHz, CDCl3)
d
9.29 (s, 1H), 8.81 (s, 1H), 8.06 (d, J ¼ 8.7 Hz, 2H),
J ¼ 6.2, 2.0 Hz, 6H). 13C NMR (101 MHz, DMSO‑d6)
d 169.46, 167.06,
7.79 (d, J ¼ 8.8 Hz, 2H), 7.61 (d, J ¼ 2.3 Hz, 1H), 7.41 (dd, J ¼ 8.7,
2.3 Hz, 1H), 6.86 (d, J ¼ 8.8 Hz, 1H), 4.87 (d, J ¼ 7.6 Hz, 1H), 4.66 (s,
2H), 3.88 (s, 1H), 1.64e1.59 (m, 2H), 1.43 (s, 9H), 1.16e1.02 (m, 1H),
153.48, 143.67, 133.40, 132.52, 131.39, 129.58, 123.22, 119.37, 116.23,
112.84, 68.01, 51.83, 23.87, 23.10, 22.04. Mp: 263e264 ꢂC. HRMS:
[MþH]þ calcd [C20H23BrClN3O5S þ H]þ 532.0308, found 532.0314.
HPLC: Gradient A, 100.0% purity, 10.9 min.
0.95e0.80 (m, 6H). 13C NMR (101 MHz, DMSO‑d6)
d 171.93, 166.94,
155.90, 153.47, 143.38, 133.72, 132.52, 131.40, 129.39, 123.25, 119.14,
116.28, 112.89, 78.78, 68.09, 59.30, 36.21, 28.58, 24.72, 15.40, 11.08.
Mp: 187e188 ꢂC. HRMS: [MþNa]þ calcd [C25H31BrClN3O7S þ Na]þ
654.0653, found 654.0667. HPLC: Gradient A, 95.2% purity, 17.0 min.
5.1.19. General procedure for the synthesis of 22a-g
Anhydrous K2CO3 (1.1 eq) was added to a solution of 20a-g (1.0
eq.) and ethyl 2-bromoacetate (1.0 eq.) in DMF. After stirring
overnight at 70 ꢂC, the mixture was poured into water and
extracted with ethyl acetate. The organic layers were combined,
washed with brine, dried over anhydrous Na2SO4, and concentrated
to obtain 21a-g as a colorless oil without further purification.
1 M NaOH was added dropwise to a solution of 21a-g in dioxane
at 0 ꢂC. After stirring at r.t. for 1 h, the dioxane was evaporated and
the residue was washed with ethyl acetate. Then the water layer
was acidified with 1 M HCl to pH ¼ 3 and extracted with ethyl ac-
etate. The combined organic layer was washed with brine (50 mL),
5.1.15. 2-(40-Bromo-20-chlorophenoxy)-N-(4’-((
sulfonyl)phenyl)acetamide (16)
L-isoleucylamino)
Compound 15 (170 mg, 0.27 mmol) was treated with HCl gas in
DCM to give 16 as a white solid (148 mg, 96.8% yield). 1H NMR
(400 MHz, DMSO‑d6)
d 12.81 (s, 1H), 10.92e10.83 (m, 1H), 8.22 (s,
3H), 7.90 (d, J ¼ 8.8 Hz, 2H), 7.83 (d, J ¼ 8.6 Hz, 2H), 7.70 (d,
J ¼ 2.3 Hz, 1H), 7.47 (dd, J ¼ 8.8, 2.3 Hz, 1H), 7.06 (d, J ¼ 8.9 Hz, 1H),
4.99e4.88 (m, 2H), 3.67 (s, 1H), 1.83e1.78 (m, 1H), 1.26e1.18 (m,
Please cite this article as: W. Xin et al., Design and synthesis of
a-phenoxy-N-sulfonylphenyl acetamides as Trypanosoma brucei Leucyl-tRNA