Sodium Late Current Blockers
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 3863
HPLC Chiralpak AD (Daicel) eluting with hexane/ethanol, 97:3
(1 mL/min, UV, 220 nm), tR ) 8.6 min, 94.3% dr; MS (ESI) m/z
) 404 [MH+]. Anal. (C22H29NS2O2 ·C4H4O4) C, H, N.
3,4-Dihydro-N-[(2S)-3-[(2-methoxyphenyl)thio]-2-methylcar-
bonyloxypropyl]-2H-(3R)-1,5-benzoxathiepin-3-amine (22). A
solution of 3,4-dihydro-N-[(2S)-3-[(2-methoxyphenyl)thio]-2-me-
thylcarbonyloxypropyl]-2H-(3R)-1,5-benzoxathiepin-3-tert-butoxy-
carbonylamine (1.9 g, 3.65 mmol) in dichloromethane (10 mL) was
treated with a 4 N aqueous solution of hydrogen chloride (20 mL).
The reaction mixture was stirred overnight at room temperature
and then slowly poured into a 1 N aqueous solution of sodium
hydroxide and extracted with dichloromethane. The combined
organic layer was washed with water and brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The compound of the title was
purified by flash column chromatography (silica gel, cyclohexane/
ethylacetate, 70:30). Crystallization of 22 as a maleate salt gave a
white powder: mp ) 130 °C; IR (KBr) ν 2955, 2834, 1745, 1578,
General Method for Ring-Opening of Epoxides 13 by 3-Amino-
1,5-benzoxathiepine. To a solution of compound 13 (1 equiv) and
3-amino-1,5-benzoxathiepine (1 equiv) in 2-propanol (10 mL/mmol)
was added sodium carbonate (5 equiv). The mixture was heated at
reflux until completion of the reaction and then cooled to room
temperature. The solvent was removed under reduced pressure and
then the residue taken up in dichloromethane and washed with water
and brine, dried over Na2SO4, filtered, and concentrated in vacuo.
The free base was purified by flash column chromatography.
3,4-Dihydro-N-[3-[(2-methoxyphenyl)thio]-2-hydroxypropyl]-
2H-(3R)-1,5-benzoxathiepin-3-amine (18ab). Crystallization of
18ab as maleate salt gave a white powder: mp ) 128 °C; IR (KBr)
ν 3349, 3067, 1577, 1473 cm-1; 1H NMR (DMSO-d6) δ 2.98-3.09
(m, 3H), 3.26 (d, J ) 4.4 Hz, 2H), 3.33 (m, 1H), 3.83 (s, 3H), 3.87
(s, 1H), 3.99 (m, 1H), 4.26 (d, J ) 13.2 Hz, 0.5H), 4.32 (d, J )
13.2 Hz, 0.5H), 4.44 (m, 1H), 5.85 (s, 1H), 6.03 (s, 3H), 6.95-7.02
(m, 2H), 7.06-7.11 (m, 2H), 7.19-7.26 (m, 2H), 7.32 (d, J ) 7.6
Hz, 1H), 7.40-7.43 (m, 1H); [R]2D5 +29° (c 0.48, CH3OH); HPLC
Chiralcel OD (Daicel) eluting with hexane/ethanol, 80:20 (1 mL/
min, UV, 220 nm), tR ) 15.6 min, 50.5% and tR ) 19.3 min, 49.2%;
HPLC purity: 99.7% (Xbridge C8, 5 µM, acetonitrile-water-
KH2PO4, 300:700:6.8 g, pH 4). Anal. (C19H23NO3S2 ·C4H4O4) C,
H, N.
1
1473 cm-1; H NMR (DMSO-d6) δ 1.95 (s, 3H), 3.15-3.31 (m,
5H), 3.39 (d, J ) 12.1 Hz, 1H), 3.74 (s, 1Η), 3.82 (s, 3H), 4.28 (d,
J ) 12.8 Hz, 1H), 4.37 (d, J ) 12.6 Hz, 1H), 5.15 (m, 1H), 6.07
(s, 2H), 6.94-7.08 (m, 4H), 7.21-7.26 (m, 2H), 7.39 (d, J ) 7.5
Hz, 2H); 13C NMR (DMSO-d6) δ 20.8, 31.7, 32.1, 46.8, 55.6, 57.4,
69.3, 71.0, 111.0, 120.9, 121.9, 122.9, 124.0, 126.5, 127.3, 128.7,
128.8, 131.5, 134.9 (2C), 156.7, 159.2, 167.0 (2C), 169.9; [R]D25
+19.8° (c 0.26, CH3OH); HPLC Chiralpak AD (Daicel) eluting
with heptane/ethanol, 80:20 (1 mL/min, UV, 220 nm), tR ) 11.3
min, 99.4% dr; MS (ESI) m/z
(C21H25NO4S2 ·C4H4O4) C, H, N.
)
420 [MH+]. Anal.
3,4-Dihydro-N-[(2S)-3-[(2-methoxyphenyl)thio]-2-phenylcar-
bonyloxypropyl]-2H-(3R)-1,5-benzoxathiepin-3-amine (23). 3,4-
Dihydro-N-[(2S)-3-[(2-methoxyphenyl)thio]-2-phenylcarbonylox-
y p r o p y l ] - 2 H - ( 3 R ) - 1 , 5 - b e n z o x a t h i e p i n - 3 - t e r t -
butoxycarbonylamine (1.47 g, 2.4 mmol) was treated as described
for product 22.The compound of the title was purified by flash
column chromatography (silica gel, dichloromethane/ethylacetate,
93:7). Crystallization of 23 as a maleate salt gave a white powder:
mp ) 172 °C; IR (KBr) ν 3057, 2985, 2935, 1731, 1575, 1451
3,4-Dihydro-N-[3-[(2-methoxyphenyl)thio]-2-hydroxypropyl]-
2H-(3S)-1,5-benzoxathiepin-3-amine (18cd). Crystallization of
18cd as a maleate salt gave a white powder: mp ) 126 °C; IR
1
(KBr) ν 3397, 3006, 1618, 1572 cm-1; H NMR (DMSO-d6) δ
2.98-3.09 (m, 3H), 3.26 (d, J ) 4.8 Hz, 2H), 3.27-3.39 (m, 2H),
3.83 (s, 3H), 3.87 (s, 1H), 3.99 (m, 1H), 4.26 (d, J ) 12.4 Hz,
0.5H), 4.32 (d, J ) 12.4 Hz, 0.5H), 4.46 (m, 1H), 5.85 (s, 1H),
6.03 (s, 3H), 6.97-7.02 (m, 2H), 7.06-7.11 (m, 2H), 7.19-7.26
(m, 2H), 7.32 (d, J ) 7.5 Hz, 1H), 7.40-7.42 (m, 1H); [R]2D5 -26.2°
(c 0.31, CH3OH); HPLC Chiralcel OD (Daicel) eluting with
heptane/ethanol, 80:20 (1 mL/min, UV, 220 nm), tR 14.6 min,
48.8% and tR 18.1 min, 48.7%; HPLC purity: 99.9% (Xbridge C8,
1
cm-1; H NMR (DMSO-d6) δ 3.24 (m, 2H), 3.28-3.44 (m, 2H),
3.55 (m, 2H), 3.78 (s, 3H), 3.86 (s, 1H), 4.35 (d, J ) 12.4 Hz,
1H), 4.44 (d, J ) 12.3 Hz, 1H), 5.46 (m, 1H), 6.08 (s, 2H),
6.93-6.96 (m, 2H), 7.05-7.07 (m, 2H), 7.17-7.24 (m, 2H), 7.39
(d, J ) 7.6 Hz, 1H), 7.44 (d, J ) 7.3 Hz, 1H), 7.51 (t, J ) 7.6 Hz,
2H), 7.67 (t, J ) 7.5 Hz, 1H), 7.94 (d, J ) 7.5 Hz, 2H); 13C NMR
(DMSO-d6) δ 31.6, 32.5, 46.9, 55.6, 57.5, 70.0, 70.8, 111.0, 120.9,
121.8, 122.8, 124.0, 126.4, 127.4, 128.5, 128.7, 128.8, 129.4, 129.5,
131.5, 133.4, 134.7 (2C), 156.7, 159.1, 165.2, 167.1 (2C); [R]D25
+55.1° (c 0.46, CH3OH); HPLC Chiralpak AD (Daicel) eluting
with heptane/ethanol, 80:20 (1 mL/min, UV, 220 nm), tR ) 11.4
5µM,acetonitrile-water-KH2PO4,300:700:6.8g,pH4).Anal.(C19H23
-
NO3S2 ·C4H4O4) C, H, N.
3,4-Dihydro-N-[(2S)-3-[(2-methoxyphenyl)thio]-2-hydroxypro-
pyl]-2H-(3R)-1,5-benzoxathiepin-3-amine (18a). Crystallization
of 18a as a maleate salt gave a white powder: mp ) 138 °C; IR
1
(KBr) ν 3416, 2920, 1577, 1473 cm-1; H NMR (DMSO-d6) δ
3.02-3.09 (m, 3H), 3.28 (m, 2H), 3.36 (d, J ) 12.7 Hz, 1H), 3.83
(s, 3H), 3.90 (s, 1H), 4.01 (m, 1H), 4.34 (d, J ) 12.6 Hz, 1H),
4.50 (dd, J ) 13.6, 2.8 Hz, 1H), 5.09 (s, 1H), 6.06 (s, 2H),
6.97-7.10 (m, 4H), 7.19-7.25 (m, 2H), 7.32 (d, J ) 7.4 Hz, 1H),
7.39 (d, J ) 7.6 Hz, 1H); 13C NMR (DMSO-d6) δ 31.1, 35.4, 48.8,
55.6, 56.8, 65.5, 70.4, 110.9, 120.9, 121.0, 123.7, 124.2, 126.3,
126.8, 127.7, 128.9, 131.7, 137.7 (2C), 156.3, 159.2, 167.2 (2C);
[R]2D5 -60.3° (c 0.74, CH3OH); HPLC Chiralcel OD (Daicel) eluting
with hexane/ethanol, 80:20 (1 mL/min, UV, 220 nm), tR ) 15.8
min, 99.9% dr; MS (ESI) m/z
(C26H27NO4S2 ·C4H4O4) C, H, N.
)
482 [MH+]. Anal.
3,4-Dihydro-N-[3-[(2-methoxyphenyl)thio]-2-methylenepro-
pyl]-2H-(3R)-1,5-benzoxathiepin-3-amine (24). A suspension of
(R)-3-amino-1,5-benzoxathiepine (0.41 g, 2.26 mmol) and 15 (0.42
g, 1.81 mmol) and sodium carbonate (0.19 g, 1.81 mmol) in ethanol
(5 mL) was heated at 100-110 °C for 24 h. The reaction mixture
was cooled to room temperature, and then the solvent was
evaporated off. The residue was taken up in dichloromethane and
washed with water and brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The title compound was purified by flash
column chromatography (silica gel, dichloromethane/methanol, 98:
2). Crystallization of 24 as an oxalate salt gave a white powder:
mp ) 155 °C; IR (KBr) ν 3003, 2834, 1708, 1654, 1475 cm-1; 1H
NMR (DMSO-d6) δ 3.18-3.28 (m, 2H), 3.61 (m, 1H), 3.64-3.71
(m, 4H), 3.82 (s, 3H), 4.30 (dd, J ) 12.8, 3.7 Hz, 1H), 4.37 (d, J
) 11.2 Hz, 1H), 5.12 (s, 1Η), 5.20 (s, 1H), 6.91 (t, J ) 7.4 Hz,
1H), 6.97-7.06 (m, 3H), 7.19-7.24 (m, 2H), 7.28 (d, J ) 6.8 Hz,
1H), 7.36 (d, J ) 6.8 Hz, 1H); 13C NMR (DMSO-d6) δ 32.0, 34.9,
47.3, 55.6, 56.5, 71.5, 110.9, 118.3, 120.8, 121.8, 123.0, 123.9,
126.6, 127.3, 128.6, 129.3, 131.4, 138.1, 156.9, 159.2, 163.7 (2C);
[R]2D5 +27.5° (c 0.43, CH3OH); HPLC Chiralpak AD (Daicel)
eluting with heptane/ethanol/diethylamine, 95:5:0.1 (1 mL/min, UV,
220 nm), tR ) 22.5 min, 95.2% dr; MS (ESI) m/z ) 374 [MH+].
Anal. (C20H23NO2S2 ·C2H2O4) C, H, N.
min, 97% dr; MS (ESI) m/z
(C19H23NO3S2 ·C4H4O4) C, H, N.
)
378 [MH+]. Anal.
3,4-Dihydro-N-[(2R)-3-[(2-methoxyphenyl)thio]-2-hydrox-
ypropyl]-2H-(3R)-1,5-benzoxathiepin-3-amine (18b). Crystal-
lization of 18b as a maleate salt gave a white powder: mp ) 136
°C; IR (KBr) ν 3503, 2925, 1625, 1572, 1458 cm-1 1H NMR
;
(DMSO-d6) δ 2.99-3.09 (m, 3H), 3.27 (d, J ) 4.9 Hz, 2H), 3.38
(d, J ) 12.5 Hz, 1H), 3.83 (s, 3H), 3.83 (s, 1H), 4.02 (m, 1H),
4.28 (d, J ) 13.2 Hz, 1H), 4.45 (dd, J ) 13.6, 3.3 Hz, 1H), 5.90
(s, 1H), 6.06 (s, 2H), 6.97-7.11 (m, 4H), 7.21-7.22 (m, 2H), 7.33
(d, J ) 7.6 Hz, 1H), 7.43 (d, J ) 7.6 Hz, 1H); 13C NMR (DMSO-
d6) δ 31.2, 35.3, 48.9, 55.6, 56.8, 65.4, 70.4; 110.9, 121.0, 122.0,
123.8, 124.3, 126.7, 126.8, 127.6, 129.0, 131.6, 135.6 (2C), 156.3,
159.4, 167.2 (2C); [R]2D5 -3.2° (c 0.43, CH3OH); HPLC Chiralcel
OD (Daicel) eluting with hexane/ethanol, 80:20 (1 mL/min, UV,
220 nm), tR ) 20.0 min, 94.5% dr; MS (ESI) m/z ) 378 [MH+].
Anal. (C19H23NO3S2 ·C4H4O4) C, H, N.