A. Mochizuki et al. / Bioorg. Med. Chem. 19 (2011) 1623–1642
1637
Obtained orange solid was washed with hexane to give the title
5.1.42. N-(2-{[(4-Chlorobenzoyl)amino]methyl}phenyl)-5-
methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-
carboxamide hydrochloride (4B)
compound (2.23 g, 8.84 mmol, 88%) as an orange solid. 1H NMR
(CDCl3) d: 1.43 (9H, s), 4.57 (2H, d, J = 6.3 Hz), 5.34 (1H, br s),
7.42–7.49 (1H, m), 7.59–7.66 (2H, m), 8.06 (1H, d, J = 8.1 Hz). ESI-
Compound 4B was synthesized in a similar manner to com-
pound 4A. Compound 39 (intermediate of compound 4A)
(155 mg, 0.413 mmol), DMF (4.0 mL), 4-chlorobenzoic acid
(64.7 mg, 0.413 mmol), HOBt (55.8 mg, 0.413 mmol), EDCÁHCl
t
MS m/z: 275 (M+Na)+, 197 (MÀ Bu)+, 153 (MÀBoc)+.
5.1.40. tert-Butyl {2-[(5-methyl-4,5,6,7-
tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-
(119 mg, 0.620 mmol) and triethylamine (115 lL, 0.826 mmol)
carbonyl)amino]benzyl}carbamate (38)
were treated to obtain the title compound (112 mg, 0.231 mmol,
Compound 37 (2.23 g, 8.84 mmol) was dissolved in AcOEt
(50 mL), and wet 10% palladium on carbon (50% water containing,
70 mg) was added to this solution. After stirring for 1 h under
hydrogen atmosphere, catalyst was removed by filtration. Filtrate
was concentrated in vacuo to obtain a white solid. This solid was
dissolved in DMF (30 mL), and to this solution were added 5-
methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbox-
ylic acid hydrochloride (2.49 g, 10.6 mmol), HOBt (1.19 g,
8.84 mmol), EDCÁHCl (2.54 g, 13.3 mmol) and triethylamine
(2.46 mL, 17.7 mmol). The mixture was stirred overnight at room
temperature. After removing the solvent in vacuo, the residue
was partioned between AcOEt (200 mL) and saturated NaHCO3
aqueous solution (200 mL). Organic layer was washed with brine,
dried over MgSO4 and concentrated in vacuo. Obtained pale yellow
powder was washed with Et2O to obtain the title compound
(2.93 g, 7.28 mmol, 82%) as a pale yellow solid. 1H NMR (CDCl3)
d: 1.45 (9H, s), 2.52 (3H, s), 2.86 (2H, t, J = 5.8 Hz), 2.99 (2H, t,
J = 5.8 Hz), 3.72 (2H, s), 4.34 (2H, d, J = 5.9 Hz), 5.13 (1H, br s),
7.19 (1H, td, J = 7.8, 1.2 Hz), 7.31–7.38 (2H, m), 7.92 (1H, dd,
J = 7.8, 1.2 Hz), 9.52 (1H, br s). ESI-MS m/z: 403 (M+H)+.
56%) as a white powder. MP: 262–264 °C (Dec.). IR (ATR) cmÀ1
:
3334, 3095, 2918, 2441, 2345, 1655, 1591, 1552, 1516, 1479,
1454, 1435, 1363, 1296, 1265, 1194, 1128, 1092, 1078, 1045,
1012, 962, 893, 847, 764, 721, 683, 652, 588, 573, 525, 465, 434.
1H NMR (DMSO-d6) d: 2.93 (3H, s), 3.18 (2H, br s), 3.35–3.69 (2H,
m), 4.45 (2H, d, J = 5.6 Hz), 4.46–4.73 (2H, m), 7.25 (1H, td,
J = 7.5, 1.6 Hz), 7.31 (1H, td, J = 7.5, 1.6 Hz), 7.38 (1H, dd, J = 7.5,
1.6 Hz), 7.49–7.57 (3H, m), 7.88 (2H, d, J = 8.6 Hz), 9.17 (1H, t,
J = 5.6 Hz), 10.74 (1H, s), 11.18–11.64 (1H, m). ESI-MS m/z: 441
[(M+H)+, 35Cl], 443 [(M+H)+, 37Cl]. Anal. Calcd for
C
22H21ClN4O2SÁHClÁ0.25H2O: C, 54.83; H, 4.71; Cl, 14.71; N,
11.63; S, 6.65. Found: C, 54.69; H, 4.41; Cl, 14.39; N, 11.55; S, 6.74.
5.1.43. N-(2-{[(4-Chloropyridine-2-
yl)carbonylamino]methyl}phenyl)-5-methyl-4,5,6,7-
tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride (4C)
Compound 4C was synthesized in a similar manner to com-
pound 4A. Compound 39 (intermediate of compound 4A)
(155 mg, 0.413 mmol), DMF (4.0 mL), 4-chloropyridine-2-carbox-
ylic acid (65.1 mg, 0.413 mmol), HOBt (55.8 mg, 0.413 mmol),
5.1.41. N-[2-({[(5-Chloropyridin-2-
EDCÁHCl (119 mg, 0.620 mmol) and triethylamine (115
lL,
yl)carbonyl]amino}methyl)phenyl]-5-methyl-4,5,6,7-
tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide
hydrochloride (4A)
0.826 mmol) were treated to obtain the title compound (105 mg,
0.142 mmol, 34%) as a white powder. MP: 262–264 °C (Dec.). IR
(ATR) cmÀ1: 3267, 2989, 2945, 2667, 2580, 2538, 1695, 1653,
1587, 1520, 1454, 1360, 1300, 1267, 1236, 1188, 1119, 1070,
1047, 1020, 997, 960, 899, 835, 768, 739, 690, 634, 609, 580, 517,
463, 430. 1H NMR (DMSO-d6) d: 2.92 (3H, s), 3.22 (2H, br s), 3.58
(2H, br s), 4.51 (2H, d, J = 6.2 Hz), 4.54–4.63 (2H, m), 7.25 (1H, t,
J = 7.6 Hz), 7.31 (1H, t, J = 7.6 Hz), 7.43 (1H, d, J = 7.6 Hz), 7.48
(1H, d, J = 7.6 Hz), 7.78 (1H, dd, J = 5.4, 2.1 Hz), 8.04 (1H, d,
J = 2.1 Hz), 8.64 (1H, d, J = 5.4 Hz), 9.49 (1H, t, J = 6.2 Hz), 10.85
(1H, s). ESI-MS m/z: 442 [(M+H)+, 35Cl], 444 [(M+H)+, 37Cl]. Anal.
Calcd for C21H20ClN5O2SÁHClÁH2O: C, 50.81; H, 4.67; Cl, 14.28; N,
14.11; S, 6.46. Found: C, 50.44; H, 4.70; Cl, 14.18; N, 14.19; S, 6.54.
Compound 38 (302 mg, 0.751 mmol) was dissolved in CH2Cl2
(3 mL). To this solution was added 4 M HCl solution in dioxane
(5 mL). After the mixture was stirred at room temperature for
1 h, solvent was distilled off in vacuo to obtain N-(2-aminomethyl-
phenyl)-5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-
2-carboxamide dihydrochloride (compound 39) (255 mg). This
compound was used in the next step without purification.
Compound 39 (255 mg) was dissolved in DMF (10.0 mL). To the
solution were added 5-chlorothiophene-2-carboxylic acid (118 mg,
0.751 mmol), HOBt (101 mg, 0.751 mmol), EDCÁHCl (216 mg,
1.13 mmol) and triethylamine (209 lL, 1.50 mmol). After the mix-
ture was stirred at room temperature for 2 h, solvent was distilled
off in vacuo. The residue was partitioned between CH2Cl2 (50 mL)
and saturated NaHCO3 aqueous solution (50 mL). Organic layer
was dried over Na2SO4 and concentrated in vacuo. The residue
was purified by flash chromatography on silica gel (5% MeOH–
CH2Cl2) to give the free form of the title compound. To the free
form of the title compound was added 1 M HCl aqueous solution
and the mixture was concentrated in vacuo. The obtained solid
was washed with AcOEt to obtain the title compound (297 mg,
0.609 mmol, 81%) as a white powder. MP: 265–269 °C (Dec.). IR
(ATR) cmÀ1: 3323, 1662, 1591, 1554, 1500, 1454, 1429, 1367,
1303, 1240, 1196, 1105, 1074, 1014, 962, 868, 831, 773, 721,
688, 631, 577, 525, 440. 1H NMR (DMSO-d6) d: 2.94 (3H, s), 3.28
(2H, br s), 3.37–3.70 (2H, m), 4.49 (2H, d, J = 6.3 Hz), 4.53–4.71
(2H, m), 7.25 (1H, td, J = 7.3, 1.5 Hz), 7.31 (1H, td, J = 7.3, 1.5 Hz),
7.43 (1H, dd, J = 7.3, 1.5 Hz), 7.48 (1H, dd, J = 7.3, 1.5 Hz), 8.04
(1H, d, J = 8.5 Hz), 8.14 (1H, dd, J = 8.5, 2.3 Hz), 8.71 (1H, d,
J = 2.3 Hz), 9.44 (1H, t, J = 6.3 Hz), 10.87 (1H, s), 11.22 (1H, br s).
ESI-MS m/z: 442 [(M+H)+, 35Cl], 444 [(M+H)+, 37Cl]. Anal. Calcd
for C21H20ClN5O2SÁHClÁ0.5H2O: C, 51.75; H, 4.55; Cl, 14.55; N,
14.37; S, 6.58. Found: C, 51.61; H, 4.51; Cl, 14.51; N, 14.33; S, 6.67.
5.1.44. N-(2-{[(3-Chlorobenzoyl)amino]methyl}phenyl)-5-
methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-
carboxamide hydrochloride (4D)
Compound 4D was synthesized in a similar manner to com-
pound 4A. Compound 39 (intermediate of compound 4A)
(155 mg, 0.413 mmol), DMF (4.0 mL), 3-chlorobenzoic acid
(64.7 mg, 0.413 mmol), HOBt (55.8 mg, 0.413 mmol), EDCÁHCl
(119 mg, 0.620 mmol) and triethylamine (115 lL, 0.826 mmol)
were treated to obtain the title compound (68.0 mg, 0.136 mmol,
33%) as a white powder. MP: 144–146 °C (Dec.). IR (ATR) cmÀ1
:
3317, 3068, 2947, 2667, 2576, 1695, 1655, 1630, 1587, 1568,
1520, 1454, 1358, 1317, 1298, 1248, 1186, 1161, 1119, 1070,
1018, 995, 957, 899, 837, 758, 717, 681, 613, 580, 507, 471, 428.
1H NMR (DMSO-d6) d: 2.92 (3H, s), 3.18 (2H, br s), 3.58 (2H, br
s), 4.47 (2H, d, J = 5.6 Hz), 4.58 (2H, br s), 7.27 (1H, t, J = 7.4 Hz),
7.33 (1H, t, J = 7.4 Hz), 7.40 (1H, d, J = 7.4 Hz), 7.48–7.55 (2H, m),
7.61 (1H, d, J = 7.4 Hz), 7.83 (1H, d, J = 7.4 Hz), 7.91 (1H, s), 9.22
(1H, t, J = 5.6 Hz), 10.72 (1H, s), 11.48 (1H, br s). ESI-MS m/z: 441
[(M+H)+, 35Cl], 443 [(M+H)+, 37Cl]. Anal. Calcd for
C
22H21ClN4O2SÁHClÁ1.25H2O: C, 52.86; H, 4.94; Cl, 14.18; N,
11.21; S, 6.41. Found: C, 52.82; H, 4.68; Cl, 14.44; N, 11.21; S, 6.63.