Na+/ H+ Antiporter Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19 3743
7.42 (m, 5H), 7.56 (s, 1H), 8.36 (s, 1H); IR (KBr) 1719, 1315,
1136, 1105 cm-1. Anal. (C18H18O5S‚0.25H2O) C, H, S.
Meth od K. 5-(Meth ylsu lfon yl)-2-m eth yl-4-p r op ion yl-
ben zoic Acid Meth yl Ester (23a ). Epoxide 22a (19.5 g, 68.6
mmol) and BF3‚Et2O (50 mL, 398 mmol) were heated under
reflux in CH2Cl2 (300 mL) for 5 h. The solvent was evaporated,
and the residue was purified by silica gel chromatography
(petroleum ether f Et2O) to give 23a (11.6 g, 59%) as white
crystals on trituration with (i-Pr)2O: mp 141-142 °C; NMR δ
1.09 (t, J ) 7.2, 3H), 2.64 (s, 3H), 2.93 (q, J ) 7.1, 2H), 3.27 (s,
3H), 3.90 (s, 3H), 7.71 (s, 1H), 8.33 (s, 1H); IR (KBr) 1729,
1710, 1304, 1256, 1143 cm-1. Anal. (C13H16O5S) C, H, S.
5-(Meth ylsu lfon yl)-2-m eth yl-4-(p h en yla cetyl)ben zoic
a cid m eth yl ester (23b) was prepared as above from epoxide
22b in 54% yield: mp 133-134 °C (Et2O); NMR δ 2.66 (s, 3H),
3.27 (s, 3H), 3.91 (s, 3H), 4.32 (s, 2H), 7.26-7.38 (m, 5H), 7.84
(s, 1H), 8.36 (s, 1H); IR (KBr) 1729, 1718, 1299, 1254, 1137
cm-1. Anal. (C18H18O5S) C, H, S.
Meth od L. 4-Acetyl-2-m eth yl-5-(m eth ylsu lfon yl)ben -
zoic Acid Meth yl Ester (23c). To a solution of 4-bromo-2-
methyl-5-(methylsulfonyl)benzoic acid methyl ester4 (2d , 12.9
g, 41.7 mmol) in THF (324 mL) were added (1-ethoxyvinyl)-
tributylstannane (15 mL, 44.4 mmol), dried LiCl (5.52 g, 130
mmol), and Pd(PPh3)4 (1.01 g, 0.874 mmol). Under an argon
atmosphere, the suspension was heated at reflux for 48 h while
two additional portions of (1-ethoxyvinyl)tributylstannane (2
× 15 mL, 88.8 mmol) were added. The reaction mixture was
diluted with Et2O (750 mL) and consecutively washed with
H2O, NH4OH (5%), and brine. The organic layer was dried
and concentrated, yielding 4-(1-ethoxyvinyl)-2-methyl-5-(me-
thylsulfonyl)benzoic acid methyl ester as a semisolid residue.
The crude enol ether thus obtained (12.5 g) was stirred in
THF (100 mL) and HCl (2 N, 30 mL) at room temperature for
48 h. After dilution with Et2O (150 mL), the mixture was
washed with a saturated NaHCO3 solution and H2O, and the
organic phase was dried and evaporated to produce the title
compound 23c (10.5 g, 93% overall yield) upon crystallization
from MeOH: mp 114-115 °C; NMR δ 2.59 (s, 3H), 2.64 (s,
3H), 3.29 (s, 3H), 3.90 (s, 3H), 7.78 (s, 1H), 8.34 (s, 1H); IR
(KBr) 1722, 1705, 1437, 1304, 1251 cm-1. Anal. (C12H14O5S)
C, H, S.
3H), 3.10 (d, J ) 13.8, 1H), 3.17 (d, J ) 13.8, 1H), 3.42 (d, J )
13.4, 1H), 3.78 (d, J ) 13.4, 1H), 3.87 (s, 3H), 6.34 (s, 1H),
7.15 (m, 2H), 7.27 (m, 3H), 7.36 (s, 1H), 8.06 (s, 1H); IR (KBr)
3466, 1729, 1289, 1259 cm-1. Anal. (C18H18O5S) C, H, S.
3-H yd r oxy-2,2,3,5-t et r a m et h yl-1,1-d ioxo-2,3-d ih yd r o-
1H-1λ6-ben zo[b]th iop h en e-6-ca r boxylic a cid m eth yl es-
ter (24 g): 18% yield; mp 151-152 °C (CH2Cl2/MeOH); NMR
δ 1.19 (s, 3H), 1.34 (s, 3H), 1.48 (s, 3H), 2.63 (s, 3H), 3.87 (s,
3H), 6.11 (s, 1H), 7.66 (s, 1H), 8.07 (s, 1H); IR (KBr) 3460,
1710, 1279, 1162, 1089 cm-1. Anal. (C14H18O5S) C, H, S.
2,2,5-Tr im eth yl-3-m eth ylen e-1,1-d ioxo-2,3-d ih yd r o-1H-
1λ6-b en zo[b]t h iop h en e-6-ca r b oxylic a cid m et h yl est er
(25c) was prepared from 24g according to method I in 98%
yield: mp 141-142 °C (EtOAc); NMR δ 1.49 (s, 6H), 2.63 (s,
3H), 3.87 (s, 3H), 5.66 (s, 1H), 6.22 (s, 1H), 7.98 (s, 1H), 8.15
(s, 1H); IR (KBr) 1735, 1292, 1249, 1095 cm-1
(C14H16O4S) C, H, S.
.
Anal.
3-Eth yl-5-m eth yl-1,1-d ioxo-2,3-d ih yd r o-1H-1λ6-ben zo-
[b]th iop h en e-6-ca r boxylic Acid Meth yl Ester (27a ). De-
hydratation of hydroxy compound 24a according to method I
gave a mixture of olefins 25a and 26a , which was hydroge-
nated using method D to yield 37% 27a in all: mp 88 °C [(i-
Pr)2O]; NMR δ 0.96 (t, J ) 7.4, 3H), 1.58-1.76 (m, 1H), 1.93-
2.09 (m, 1H), 2.61 (s, 3H), 3.37 (dd, J ) 13.2, J ) 7.9, 1H),
3.57 (m, 1H), 3.77 (dd, J ) 13.2, J ) 5.2, 1H), 3.86 (s, 3H),
7.59 (s, 1H), 8.03 (s, 1H). Anal. (C13H16O4S) C, H, S.
3,5-Dim et h yl-1,1-d ioxo-2,3-d ih yd r o-1H -1λ6-b en zo[b]-
th iop h en e-6-ca r boxylic a cid m eth yl ester (27d ) was pre-
pared as above from 24e via the mixture of 25b and 26b in
70% overall yield: mp 134-135 °C; NMR δ 1.43 (d, J ) 6.9,
3H), 2.61 (s, 3H), 3.30 (dd, J ) 13.3, J ) 5.8, 1H), 3.69 (m,
1H), 3.82 (dd, J ) 13.3, J ) 7.6, 1H), 3.86 (s, 3H), 7.62 (s, 1H),
8.04 (s, 1H); IR (KBr) 1700, 1296, 1260, 1132, 1102 cm-1. Anal.
(C12H14O4S) C, H, S.
3-Eth yl-5-m eth yl-1,1-d ioxo-2,3-d ih yd r o-1H-1λ6-ben zo-
[b]th iop h en e-6-ca r boxylic a cid (27b) was prepared from
27a by alkaline hydrolysis (method E): 75% yield; mp 172-
174 °C; NMR δ 0.96 (t, J ) 7.4, 3H), 1.58-1.75 (m, 1H), 1.92-
2.09 (m, 1H), 2.62 (s, 3H), 3.36 (dd, J ) 13.4, J ) 5.4, 1H),
3.56 (sept, J ) 4.4, 1H), 3.76 (dd, J ) 13.3, J ) 7.9, 1H), 7.56
(s, 1H), 8.01 (s, 1H), 13.25 (s br, 1H); IR (KBr) 1703, 1308,
1107 cm-1. Anal. (C12H14O4S) C, H, S.
2,2,3,5-Tetr a m eth yl-1,1-d ioxo-2,3-d ih yd r o-1H-1λ6-ben -
zo[b]th iop h en e-6-ca r boxylic a cid m eth yl ester (27f) was
prepared from olefin 25c by catalytic hydrogenation (method
D): 48% yield; white crystals; mp 104 °C [(i-Pr)2O]; NMR δ
1.15 (s, 3H), 1.32 (d, J ) 7.0, 3H), 1.37 (s, 3H), 2.61 (s, 3H),
3.30 (q, J ) 7.2, 1H), 3.86 (s, 3H), 7.55 (s, 1H), 8.07 (s, 1H); IR
(KBr) 1705, 1286, 1248, 1163 cm-1. Anal. (C14H18O4S) C, H,
S.
4-Br om o-5-(eth ylsu lfon yl)-2-m eth ylben zoic a cid eth yl
ester (29a) was prepared according to method A from 2-bromo-
4-methyl-5-carboxybenzenesulfinic acid4 and EtI in 1-methyl-
2-pyrrolidinone (NMP) at 60 °C: 63% yield; white crystals; mp
78-79 °C [CH2Cl2/(i-Pr)2O]; NMR δ 1.14 (t, J ) 7.4, 3H), 1.34
(t, J ) 7.0, 3H), 2.61 (s, 3H), 3.51 (q, J ) 7.4, 2H), 4.35 (q, J
) 7.2, 2H), 7.94 (s, 1H), 8.39 (s, 1H); IR (KBr) 1724, 1315, 1253,
1150, 1092 cm-1. Anal. (C12H15BrO4S) C, H, Br, S.
4-Acetyl-2-m eth yl-5-(pr opyl-2-su lfon yl)ben zoic acid iso-
p r op yl ester (23d ) was prepared as above from 2b in 81%
overall yield: mp 97 °C (petroleum ether); NMR δ 1.19 (d, J
) 6.7, 6H), 1.35 (d, J ) 6.0, 6H), 2.57 (s, 3H), 2.63 (s, 3H),
3.52 (sept, J ) 6.8, 1H), 5.18 (sept, J ) 6.3, 1H), 7.74 (s, 1H),
8.18 (s, 1H); IR (KBr) 1717, 1705, 1358, 1303, 1245, 1138, 1098
cm-1. Anal. (C16H22O5S) C, H, S.
Meth od M. 3-Hyd r oxy-3,5-d im eth yl-1,1-d ioxo-2,3-d i-
h ydr o-1H-1λ6-ben zo[b]th ioph en e-6-car boxylic Acid Meth -
yl Ester (24e). To a freshly prepared solution of Na (2.4 g,
104 mmol) in dry MeOH (120 mL) was added 4-acetyl-2-
methyl-5-(methylsulfonyl)benzoic acid methyl ester (23c, 12
g, 44.4 mmol), and the mixture was stirred under a N2
atmosphere at 40 °C for 45 min. After dilution with ice/water
(350 mL), the mixture was immediately acidified with HCl and
extracted with EtOAc (3 × 100 mL). The combined organic
phases were washed with H2O, dried, and evaporated, and the
residue was recrystallized from Et2O to give 24e (10.8 g,
90%): mp 116-118 °C; NMR δ 1.61 (s, 3H), 2.63 (s, 3H), 3.57
(d, J ) 13.4, 1H), 3.84 (d, J ) 13.2, 1H), 3.87 (s, 3H), 6.24 (s,
1H), 7.69 (s, 1H), 8.04 (s, 1H); IR (KBr) 1721, 1605, 1565, 1433,
1303, 1273, 1178, 1095 cm-1. Anal. (C12H14O5S) C, H, S.
Analogously prepared were the following compounds.
3-Eth yl-3-h yd r oxy-5-m eth yl-1,1-d ioxo-2,3-d ih yd r o-1H-
1λ6-b en zo[b]t h iop h en e-6-ca r b oxylic a cid m et h yl est er
(24a ): 80% yield; mp 105-107 °C [(i-Pr)2O]; NMR δ 0.90 (t, J
) 7.5, 3H), 1.77-2.01 (m, 2H), 2.62 (s, 3H), 3.49 (d, J ) 13.7,
1H), 3.86 (d, 13.7, 1H), 3.87 (s, 3H), 6.12 (s, 1H), 7.63 (s, 1H),
8.04 (s, 1H); IR (KBr) 3473, 1726, 1289, 1257, 1100 cm-1. Anal.
(C13H16O5S) C, H, S.
4-Cya n o-5-(eth ylsu lfon yl)-2-m eth ylben zoic Acid Eth yl
Ester (30a ). A mixture of the foregoing compound 29a (15 g,
44.7 mmol), CuCN (6.01 g, 67.1 mmol), and NMP (120 mL)
was stirred under a N2 atmosphere at 160 °C for 16 h. This
was poured into H2O (500 mL); EtOAc (400 mL) was added,
and the mixture was stirred for an additional 30 min. After
filtration through Celite, the aqueous layer was separated and
extracted with EtOAc (2 × 200 mL). The combined organic
layers were washed with H2O (4 × 300 mL), dried, and
evaporated to give compound 30a (11.2 g, 89%) as beige
crystals on recrystallization from CH2Cl2/(i-Pr)2O: mp 105-
106 °C; NMR δ 1.18 (t, J ) 7.4, 3H), 1.35 (t, J ) 7.2, 3H), 2.65
(s, 3H), 3.48 (q, J ) 7.4, 2H), 4.38 (q, J ) 7.0, 2H), 8.24 (s,
1H), 8.35 (s, 1H); IR (KBr) 2225, 1721, 1460, 1328, 1305, 1257,
1139, 1106 cm-1. Anal. (C13H15NO4S) C, H, N, S.
3-Ben zyl-3-h yd r oxy-5-m et h yl-1,1-d ioxo-2,3-d ih yd r o-
1H-1λ6-ben zo[b]th iop h en e-6-ca r boxylic a cid m eth yl es-
ter (24c): 85% yield; mp 140-142 °C (Et2O); NMR δ 2.54 (s,
Similarly prepared were the following compounds.