1784 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Ku¨hler et al.
2-[[(4-Meth oxy-2-p yr id yl)m eth yl]th io]-1H-ben zim id a -
zole (7). The title compound was prepared on a 3.5 mmol
scale according to method III and recrystallized from EtOAc
saturated with ammonia, affording 549 mg (60%) of beige
crystals: 500 MHz 1H NMR (CH2Cl2-d2) δ 3.92 (s, 3H), 4.35
(s, 2H), 6.88 (dd, 1H), 6.96 (d, 1H), 7.22 (m, 2H), 7.57 (m, 2H),
8.52 (d, 1H). Method A (28 to 70% MeCN in 20 min, λ ) 285
nm), 99% at tR ) 8.8 min; method E, 98.9% at tR ) 3.2 min.
2-[[[4-[(Cyclopr opylm eth yl)oxy]-2-pyr idyl]m eth yl]th io]-
1H-ben zim id a zole (8). The title compound was prepared on
a 1.65 mmol scale according to method III, affording 540 mg
(95%) of the desired product as a solid: 300 MHz 1H NMR
(CHCl3-d) δ 0.37 (m, 2H), 0.68 (m, 2H), 1.27 (m, 1H), 3.88 (d,
2H), 4.28 (s, 2H), 6.79 (dd, 1H), 6.87 (d, 1H), 7.19 (m, 2H),
7.46 (b, 1H), 7.65 (b, 1H), 8.44 (d, 1H). Method A (40 to 70%
MeCN in 20 min, λ ) 280 nm), 96% at tR ) 8.25 min; method
E, 96.5% at tR ) 6.5 min.
48 mmol scale according to method III using EtOH rather than
MeOH. Recrystallization from CH3CN afforded 10.1 g (73%)
of white crystalline material: 500 MHz H NMR (CHCl3-d) δ
2.26 (s, 3H), 3.89 (s, 3H), 4.38 (s, 2H), 6.76 (d, 1H), 7.18 (m,
2H), 7.46 (b, 1H), 7.62 (b, 1H), 8.37 (d, 1H). Analytical LC;
LiChrosorbe RP-18 (125 × 4.00 mm, 5 µm), 40% MeCN/0.025
M Na2HPO4 buffer (pH 7.6), 0.8 mL/min, λ ) 214-287 nm,
98.2% at tR ) 5.2 min; method E, 96.7% at tR ) 4.4 min.
1
2-[[[4-[(Cyclop r op ylm et h yl)oxy]-3-m et h yl-2-p yr id yl]-
m eth yl]th io]-1H-ben zim id a zole (18). The title compound
was prepared on a 3.22 mmol scale according to method III
and recrystallized from EtOAc, leaving 600 mg (57%) of white
1
crystalline material: 500 MHz H NMR (CHCl3-d) δ 0.38 (m,
2H), 0.67 (m, 2H), 1.29 (m, 1H), 2.29 (s, 3H), 3.89 (d, 2H), 4.37
(s, 2H), 6.71 (d, 1H), 7.17 (m, 2H), 7.45 (b, 1H), 7.62 (b, 1H),
8.33 (d, 1H). Method B (40% MeCN, λ ) 280 nm), 98.2% at tR
) 14.2 min; method E, 97.3% at tR ) 13.8 min.
2-[[(2-P yr id yl)m et h yl]t h io]-1H -b en zim id a zole
(9).
2-[[[4-[(2-Me t h oxy-e t h yl)oxy]-3-m e t h yl-2-p yr id yl]-
m eth yl]th io]-1H-ben zim id a zole (19). The title compound
was prepared on a 0.42 mmol scale according to method III
and recrystallized from EtOAc saturated with ammonia leav-
ing 57 mg (35%) of white crystalline material: 300 MHz 1H
NMR (CHCl3-d) δ 2.29 (s, 3H), 3.46 (s, 3H), 3.80 (m, 2H), 4.20
(m, 2H), 4.38 (s, 2H), 6.77 (d, 1H), 7.18 (m, 2H), 7.48 (b, 1H),
7.60 (b, 1H), 8.36 (d, 1H). Method A (40 to 70% MeCN in 20
min, λ ) 280 nm), 99% at tR ) 6.5 min; method D (30% MeCN),
99.1% at tR ) 2.6 min.
2-[[(4-Met h oxy-3,5-d im et h yl-2-p yr id yl)m et h yl]t h io]-
1H-ben zim id a zole (22). SOCl2 (861 mL) in CH2Cl2 (3.7 L)
was added dropwise to a refluxing solution of 6637 (1032 g,
6.04 mol) in CH2Cl2 (6 L) over a period of 1.5 h and reacted
for 30 min. The mixture was taken to dryness and the residue
recrystallized from EtOH-diethyl ether, leaving 1235 g (90%)
of white crystalline 2-(chloromethyl)-4-methoxy-3,5-dimeth-
ylpyridine hydrochloride which was reacted with 2-mercapto-
1H-benzimidazole on a 99.1 mmol scale according to method
III. Recrystallization from CH3CN afforded 22.5 g (84%) of
white crystalline material: 90 MHz 1H NMR (CHCl3-d) δ 2.25
(s, 3H), 2.32 (s, 3H), 3.79 (s, 3H), 4.43 (s, 2H), 7.26 (m
coinciding with residual CHCl3 in CHCl3-d, estimated 2H), 7.62
(m, 2H), 8.32 (s, 1H), 9.41 (b, NH). Analytical LC; LiChrosorbe
RP-8 (150 × 4.00 mm, 5 µm), 40% MeCN/0.025 M Na2HPO4
buffer (pH 7.6), 0.8 mL/min, λ ) 280 nm, 98.8% at tR ) 8.4
min; method E, 98.3% at tR ) 5.5 min.
2-(Chloromethyl)pyridine (247 g, 1.5 mol) was added to a
mixture of 2-mercapto-1H-benzimidazole (225 g, 1.5 mol) in
EtOH (95%, 1500 mL) and NaOH (120 g, 30 mol) in H2O (100
mL). The mixture was refluxed for 2 h, cooled, and diluted
with H2O (2000 mL). The precipitate was collected, dried, and
recrystallized from toluene. The crystals were treated with
charcoal in isopropyl alcohol (1500 mL) acidified with concen-
trated HCl (101 mL). The solid collected from the chilled
filtrate was recrystallized from isopropyl alcohol, washed with
diethyl ether, and dried, leaving 277 g (70%) of white crystal-
line material: 300 MHz 1H NMR (DMSO-d6) δ 4.99 (s, 2H),
7.36 (m, 2H), 7.50 (distorted t, 1H), 7.63 (m, 2H), 7.75 (d, 1H),
8.01 (dt, 1H), 8.63 (d, 1H) 8.82 (b, NH). Analytical LC;
LiChrosorbe RP-8 (150 × 3.00 mm, 5 µm), 40% MeCN/0.025
M Na2HPO4 buffer (pH 7.6), 0.8 mL/min, λ ) 200 nm, 99.7%
at tR ) 4.3 min; method E, 99.0% at tR ) 2.8 min.
2-[[(4-Ch lor o-2-p yr id yl)m et h yl]t h io]-1H -b en zim id a -
zole (10). The title compound was prepared on a 5.3 mmol
scale according to method III and purified on silica gel (CH2-
Cl2/MeOH, 97/3 to 90/10), furnishing 950 mg (64%) of white
1
crystalline material: 500 MHz H NMR (CHCl3-d) δ 4.41 (s,
2H), 7.21 (m, 2H), 7.29 (dd, 1H), 7.44 (m, 2H), 7.67 (m, 1H),
8.53 (d, 1H). Direct inlet MS (EI) for C13H10ClN3S m/z (relative
intensity) 275 (M+, 100), 277 (M + 2, 40). Method D (30%
MeCN), 98.5% at tR ) 3.6 min; method E, 99.7% at tR ) 4.2
min.
2-[[(4-Met h yl-2-p yr id yl)m et h yl]t h io]-1H -b en zim id a -
zole (11). The title compound was prepared on a 24 mmol
scale according to method III and recrystallized from EtOAc
saturated with ammonia, affording 3.9 g (65%) of solid mate-
5-ter t-Bu t yl-2-[[(4-m et h oxy-3,5-d im et h yl-2-p yr id yl)-
m eth yl]th io]-1H-ben zim id a zole (23). The title compound
was prepared from 2-(chloromethyl)-4-methoxy-3,5-dimeth-
ylpyridine hydrochloride (cf. the synthesis of 22) and 5-tert-
butyl-2-mercapto-1H-benzimidazole16 on a 19.3 mmol scale
according to method III. Recrystallization from diethyl ether
furnished 6.7 g (97%) of white crystalline material: 500 MHz
1H NMR (DMSO-d6) δ 1.31 (s, 9H), 2.18 (s, 3H), 2.27 (s, 3H),
3.71 (s, 3H), 4.65 (s, 2H), 7.19 (dd, 1H), 7.36 (d, 1H), 7.40 (s,
1H), 8.17 (s, 1H). Method B (52% MeCN, λ ) 300 nm), 94.1%
at tR ) 8.8 min; method E, 89.8% at tR ) 32.6 min.
5-Ch lor o-2-[[(3,5-d im eth yl-2-p yr id yl)m eth yl]th io]-1H-
ben zim id a zole (24). SOCl2 (17.6 mL, 245 mmol) in CH2Cl2
(200 mL) was added dropwise to 65 (24.6 g, 163 mmol) in CH2-
Cl2 (300 mL) and allowed to react at 0 °C for 30 min. Isopropyl
alcohol was added, and the mixture was taken to dryness.
Recrystallization from CH3CN furnished 25 g (79%) of white
crystalline 2-(chloromethyl)-3,5-dimethylpyridine hydrochlo-
ride. The chloromethyl compound was reacted with 5-chloro-
2-mercapto-1H-benzimidazole16 on a 4.99 mmol scale according
to method III. Recrystallization from EtOAc-diethyl ether
afforded 826 mg (54%) of white crystalline material: 300 MHz
1H NMR (DMSO-d6) δ 2.25 (s, 3H), 2.37 (s, 3H), 4.68 (s, 2H),
7.16 (dd, 1H), 7.45 (m, 2H), 7.52 (s, 1H), 8.19 (s, 1H). Method
A (46 to 70% MeCN in 20 min, λ ) 280 nm), 99% at tR ) 10.4
min; method E, 93.7% at tR ) 13.4 min.
1
rial: 500 MHz H NMR (CHCl3-d) δ 2.39 (s, 3H), 4.32 (s, 2H),
7.12 (distorted dd, 1H), 7.20 (coinciding signals, m, 3H), 7.56
(b, 2H), 8.51 (d, 1H). Direct inlet MS (EI) for C14H13N3S m/z
(relative intensity) 255 (M+, 100), negative EI 254 (M - H,
100). Method D (30% MeCN), 98.0% at tR ) 2.5 min; method
E, 98.8% at tR ) 3.6 min.
5-Acet yl-2-[[(4-ter t-b u t yl-2-p yr id yl)m et h yl]t h io]-1H -
ben zim id a zole (12). The title compound was prepared on a
4.0 mmol scale according to method III and purified on silica
gel (EtOAc saturated with ammonia), furnishing 947 mg (70%)
1
of colorless oil: 500 MHz H NMR (CH2Cl2-d2) δ 1.37 (s, 9H),
2.67 (s, 3H), 4.44 (s, 2H), 7.41 (dd, 1H), 7.48 (d, 1H), 7.61 (d,
1H), 7.89 (dd, 1H), 7.22 (d, 1H), 8.61 (d, 1H). Method A (40 to
70% MeCN in 20 min, λ ) 280 nm), 98.1% at tR ) 8.2 min;
method E, 98.2% at tR ) 7.7 min.
5-Meth oxy-2-[[(4-th iom eth oxy-2-p yr id yl)m eth yl]th io]-
1H-ben zim id a zole (13). The title compound was prepared
on a 7.1 mmol scale according to method III using EtOH rather
than MeOH. Recrystallization from CH3CN/isopropyl alcohol
(1/1, v/v) afforded 1.2 g (67%) of white crystalline material:
1
90 MHz H NMR (CHCl3-d) δ 2.40 (s, 3H), 3.79 (s, 3H), 4.58
(s, 2H), 6.89 (dd, 1H), 7.06 (dd, 1H), 7.16 (d, 1H), 7.55 (d, 1H),
7.36 (d, 1H), 8.38 (d, 1H). Method D (30% MeCN), 99.2% at
tR ) 3.1 min; method E, 99.5% at tR ) 3.9 min.
5-Acet yl-2-[[(3,5-d im et h yl-2-p yr id yl)m et h yl]t h io]-1H-
ben zim id a zole (25). The title compound was prepared from
2-(chloromethyl)-3,5-dimethylpyridine hydrochloride (cf. the
synthesis of 24) and 5-acetyl-2-mercapto-1H-benzimidazole
2-[[(4-Met h oxy-3-m et h yl-2-p yr id yl)m et h yl]t h io]-1H -
ben zim id a zole (17). The title compound was prepared on a