D. Dou et al. / Bioorg. Med. Chem. 20 (2012) 2111–2118
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ethyl ether (2 Â 25 mL). The pH of the aqueous layer was adjusted
to ꢀ2 with 6 M HCl (ꢀ20 mL) and the acidified solution was ex-
tracted with ethyl acetate (3 Â 100 mL). The combined organic ex-
tracts were dried using anhydrous sodium sulfate, filtered, and
concentrated, leaving a white solid (14.87 g; 85% yield), mp 115–
117 °C. 1H NMR (CDCl3): d 1.39 (s, 9H), 3.71 (d, 2H), 4.73 (s, 2H),
6.90–7.19 (m, 5H), 7.37–7.44 (m, 4H), 8.10 (t, J = 15.8 Hz, 1H).
of 4-(2-aminoethyl)-morpholine (0.185 g; 1.42 mmol) in THF
(5 mL) was added and the solution was stirred at room tempera-
ture overnight. The solvent was removed, leaving a yellow oil
which was taken up in ethyl acetate (40 mL) and washed with
water (2 Â 20 mL) and brine (2 Â 20 mL). The organic layer was
dried over anhydrous sodium sulfate, filtered, and concentrated,
leaving a crude product which was purified by flash chromatogra-
phy (silica gel/ethyl acetate/hexane) to give a light yellow oil
(0.24 g; 38% yield). 1H NMR (CDCl3): d 2.40–2.49 (m, 6H), 3.34–
40 (q, J = 22.7 Hz, 2H), 3.63 (s, 2H), 3.63–3.70 (m, 4H), 4.20 (s,
2H), 6.65 (s, 1H), 6.95 (d, 1H), 7.00 (m, 3H), 7.05–7.18 (m, 2H),
7.30–7.40 (m, 3H). HRMS (ESI) calculated m/z for C21H29N4O5S
[M+H]+ 449.1859; found 449.1854.
3.4.6. (RS)-2-(N-(tert-Butoxycarbonyl)-N-(3-phenoxybenzyl)
sulfamoylamino)propanoic acid 4b
White solid (2.06 g; 71% yield), mp 130–132 °C. 1H NMR
(CDCl3): d 1.40 (d, 3H), 1.43 (s, 9H), 3.83–3.97 (m, 1H), 4.69–4.89
(q, J = 55.4 Hz, 2H), 5.97 (d, 1H), 6.95 (d, 1H), 7.0 (m, 2H), 7.05–
7.15 (m, 2H), 7.28–7.38 (m, 4H).
3.4.14. (RS)-N-(2-Morpholinoethyl)-2-(N-(3-phenoxybenzyl)
sulfamoylamino)propanamide 6b
3.4.7. (RS)-2-(N-(tert-Butoxycarbonyl)-N-(3-phenoxybenzyl)
sulfamoylamino)pentanoic acid 4c
White solid (0.35 g; 34% yield), mp 113–115 °C. 1H NMR
(CDCl3): d 1.39 (d, 3H), 2.36–2.56 (m, 6H), 3.32 (q, J = 18.8 Hz,
2H), 3.65 (t, J = 14.1 Hz, 14H), 3.84–3.93 (m, 1H), 4.20 (d, 2H),
4.95 (s, 1H), 5.05 (s, 1H), 6.55 (s, 1H), 6.95 (d, 1H), 6.99–7.18 (m,
4H), 7.26–7.40 (m,4H). HRMS (ESI) calculated m/z for C22H31N4O5S
[M+H]+ 463.2015; found 463.2014.
White solid (1.44 g; 63% yield), mp 117–119 °C. 1H NMR
(CDCl3): d 0.85–0.95 (t, J = 27.7 Hz, 3H), 1.30–1.50 (m, 2H), 1.42
(s, 3H), 1.53–1.80 (m, 2H), 3.81–3.88 (m, 1H), 4.68–4.89 (q,
J = 64.6 Hz, 2H), 5.84 (d, 1H), 6.92 (d, 1H), 7.0 (d, 2H), 7.12 (m,
2H), 7.25–7.37 (m, 3H).
3.4.8. (RS)-2-(N-(tert-Butoxycarbonyl)-N-(3-phenoxybenzyl)
sulfamoylamino)-4-(methylthio)butanoic acid 4d
White solid (3.11 g; 97% yield), mp 181–183 °C. 1H NMR
(CDCl3): d 1.44 (s, 9H), 1.83–2.00 (m, 2H), 2.05 (s, 3H), 2.57 (t,
J = 18.8 Hz, 2H), 3.98–4.02 (m, 1H), 4.64–4.89 (q, J = 70.3 Hz, 2H),
6.02 (d, 1H), 6.93 (d, 1H), 7.00 (m, 3H), 7.11 (t, J = 18.8 Hz, 2H),
7.25–7.37 (m, 3H).
3.4.15. (RS)-N-(2-Morpholinoethyl)-2-(N-(3-phenoxybenzyl)
sulfamoylamino)pentanamide 6c
Light yellow oil (0.20 g; 25% yield). 1H NMR (CDCl3): d 0.79–1.00
(t, J = 65.6 Hz, 3H), 1.20–1.42 (m, 2H), 1.49–1.72 (m, 2H), 2.20–2.49
(m, 6H), 3.23–3.39 (m, 2H), 3.53–3.71 (m, 4H), 3.70–3.80 (q,
J = 28.1 Hz, 1H), 4.19 (s, 2H), 5.30–5.50 (s, 1H), 5.60–5.80 (s, 1H),
6.79 (s, 1H), 6.82–7.17 (m, 5H), 7.20–7.40 (m, 3H). HRMS (ESI) cal-
culated m/z for C24H35N4O5S [M+H]+ 491.2328; found 491.2290.
3.4.9. 2-(N-(3-Phenoxybenzyl)sulfamoylamino)acetic acid 5a
Compound 4a (1.50 g, 3.44 mmol) was treated with trifluoro-
acetic acid (15 mL) and the reaction mixture was stirred at room
temperature for 30 min. Excess trifluoroacetic acid was removed,
leaving a yellow residue which was treated with diethyl ether
(10 mL). The solvent was removed on the rotary evaporator and
the same process was repeated two more times to remove traces
of acid, leaving a white solid (1.18 g; 100% yield), mp 97–99 °C.
1H NMR (DMSO): d 3.58 (s, 2H), 4.02 (s, 2H), 6.89 (d, 1H), 7.00–
7.19 (m, 4H), 7.21–7.44 (m, 4H).
3.4.16. (RS)-4-(Methylthio)-N-(2-morpholinoethyl)-2-(N-(3-
phenoxybenzyl)sulfamoylamino)butanamide 6d
Colorless oil (0.17 g; 9% yield). 1H NMR (CDCl3): d 1.95–2.03 (q,
J = 28.8 Hz, 2H), 2.09 (s, 3H), 2.35–2.50 (m, 6H), 2.50–2.69 (m, 2H),
3.23–3.43 (m, 2H), 3.64 (t, J = 18.2 Hz, 4H), 4.00–4.08 (q,
J = 28.1 Hz, 1H), 4.19 (d, 2H), 5.00 (t, J = 28.1 Hz, 1H), 5.51 (d, 1H),
6.62 (t, J = 18.2 Hz, 1H), 6.94 (d, 1H), 7.00 (m, 2H), 7.02–7.18 (m,
2H), 7.29–7.38 (m, 3H). HRMS (ESI) calculated m/z for
C
24H35N4O5S2 [M+H]+ 523.2049; found 523.2036.
3.4.10. (RS)-2-(N-(3-Phenoxybenzyl)sulfamoylamino)propanoic
acid 5b
3.4.17. N-(2-Morpholinoethyl)-2-(N-(3-phenoxybenzyl)
sulfamoylamino)acetamide hydrochloride 7a
White solid (1.10 g; 91% yield), mp 130–132 °C. 1H NMR
(CDCl3): d 1.20 (d, 3H), 3.80–3.98 (m, 1H), 4.00 (m, 2H), 6.91 (d,
1H), 7.01 (d, 2H), 7.09–7.20 (m, 2H), 7.30–7.43 (m, 5H).
Compound 6a (0.20 g; 0.45 mmol) was treated with 4 M HCl in
dioxane (10 mL; 40 mmol) and the solution was stirred at room
temperature for 20 min. The solvent was removed, leaving a yellow
oil which was treated with diethyl ether (20 mL) and then concen-
trated again. The residue was treated with a mixture of methylene
chloride (5 mL) and hexane (10 mL) and the solvent was removed,
leaving a yellow solid (0.10 g; 46% yield), mp 140–142 °C. 1H NMR
(DMSO): d 3.10–3.23 (m, 2H), 3.40–3.49 (s, 2H), 3.51–3.69 (m, 6H),
3.88–3.93 (m, 4H), 4.03 (d, 2H), 6.90 (d, 1H), 7.00 (d, 2H), 7.05–7.19
(m, 2H), 7.30–7.43 (m, 3H), 7.55 (t, J = 21.4 Hz, 1H), 8.19 (s, 1H).
HRMS (ESI) calculated m/z for C21H29N4O5S [M+H]+ 449.1859;
found 449.1864.
3.4.11. (RS)-2-(N-(3-Phenoxybenzyl)sulfamoylamino)pentanoic
acid 5c
White solid (0.84 g; 92% yield), mp 78–80 °C. 1H NMR (CDCl3): d
0.93 (t, J = 28.1 Hz, 3H), 1.31–1.50 (m, 2H), 1.52–1.80 (m, 2H),
3.95–4.03 (q, J = 28.1 Hz, 3H), 4.09 (s, 2H), 5.09 (d, 1H), 6.89–7.08
(m, 4H), 7.15 (t, J = 18.2 Hz, 1H), 7.26–7.39 (m, 3H).
3.4.12. (RS)-4-(Methylthio)-2-(N-(3-phenoxybenzyl)
sulfamoylamino)butanoic acid 5d
Light yellow oil (1.62 g; 73% yield). 1H NMR (CDCl3): d1.79–1.95
(m, 2H), 1.21 (s, 3H), 2.43–2.60 (m, 2H), 4.03–4.20 (s, 3H), 5.80 (s,
1H), 6.85 (d, 1H), 6.93–7.12 (m, 4H), 7.21–7.37 (m, 4H).
3.4.18. (RS)-N-(2-Morpholinoethyl)-2-(N-(3-phenoxybenzyl)
sulfamoylamino)propanamide hydrochloride 7b
White solid (0.25 g; 100% yield), mp 166–168 °C. 1H NMR
(DMSO):
d 1.21 (d, 3H), 3.10–3.23 (m, 2H), 3.40–3.49 (q,
3.4.13. N-(2-Morpholinoethyl)-2-(N-(3-phenoxybenzyl)
sulfamoylamino)acetamide 6a
To a solution of compound 5a (0.48 g; 1.42 mmol) in 15 mL dry
THF was added carbonyldiimidazole (0.23 g; 1.42 mmol and the
solution was stirred at room temperature for 20 min. A solution
J = 18.8 Hz, 1H), 3.51–3.69 (m, 6H), 3.88–3.93 (m, 4H), 4.03 (d,
2H), 6.90 (d, 1H), 7.00 (m, 2H), 7.07–7.19 (m, 2H), 7.30–7.43 (m,
3H), 7.55 (t, J = 26.1 Hz, 1H), 8.21 (s, 1H). HRMS (ESI) calculated
m/z for C22H31N4O5S [M+H]+ 463.2015; found 463.2009.