A.D. Brown et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
then loaded onto the SCX2 cartridge and methanol (5 mL) added. The
desired compound eluted with methanolic ammonia). The methanolic
ammonia solution was concentrated to afford 30 mg (75%) of 16. 1H
NMR (300 MHz, DMSO‑d6): δ 12 (brs, 1H), 7.55–7.32 (m, 2H), 7.2 (d,
J = 8 Hz, 1H), 4.75 (d, J = 6 Hz, 1H), 3.9 (d, J = 6 Hz, 1H), 3.5–3.42
(m, 1H), 2.2 (brs, 2H), 1.6–1.5 (m. 1H), 1.32 (s, 9H), 0.86 (d, J = 8 Hz,
6H). HRMS for C16H26N3O1 MS m/z [M + H]+: Calc’d:276.2070,
Found: 276.2079.
dioxane and the reaction was stirred for 1hr at rt. The reaction mixture
was concentrated under reduced pressure, and the resulting solid was
triturated with EtOAc. The solid was dissolved in water, basified to pH
8 with a saturated solution of sodium hydroxide and extracted with
EtOAc. The organic layer was washed with water, dried over anhydrous
Na2SO4 and concentrated to give 100 mg of a solid which was washed
with 10% EtOH in pentane to afford 75 mg (51%) of 20. 1H NMR
(400 MHz, CDCl3) δ 10 (brs, 1H), 8.0 (m, 1H), 7.6 (m, 1H), 7.2 (m, 1H),
4.6 (m, 1H), 4.1 (m, 1H), 3.2 (brs, 1H), 1.2 (d, J = 9.8 Hz, 3H). HRMS
for C10H12F5N3O1S1 MS m/z [M + H]+: Calc’d: 318.0694, Found:
318.0692.
6.11. (1R,2R)-2-methoxy-1-(6-(trifluoromethoxy)-1H-benzo[d]imidazol-
2-yl)propan-1-amine (17)
To a stirred solution of tert-butyl ((1R,2R)-2-methoxy-1-(6-(tri-
fluoromethoxy)-1H-benzo[d]imidazol-2-yl)propyl)carbamate (1.63 g,
4.19 mmol) in dioxane (31 mL) was added 4 M HCl in dioxane (31 mL,
120 mmol). The solution turned dark blue/green in color and was
stirred at room temperature for 2.5 h. The reaction was reduced in
volume before loading (in MeOH) onto a SCX cartridge (10 g). MeOH
washed through to remove non basic components (pH ∼ 5
after ∼ 150 mL). Basic eluent (2 M NH3 in MeOH) then employed to
release product. Basic component concentrated in vacuo to afford a red
gummy solid which was left drying under vacuum for 4.5 days. This
was purified using silica gel chromatography (80 g SiO2, DCM/MeOH/
NH3 90:10:1). 17 was isolated as a white solid (1.15 g, 95%). 1H NMR
(400 MHz, DMSO‑d6) δ 7.55 (d, J = 8.59 Hz, 1H), 7.46 (br. s., 1H), 7.10
(d, J = 8.77 Hz, 1H), 3.99 (d, J = 4.69 Hz, 1H), 3.68 (dd, J = 4.88,
6.05 Hz, 1H), 3.31 (br. s., 2H), 3.21 (s, 3H), 1.06 (d, J = 6.25 Hz, 3H).
HRMS for C12H15F3N3O1 MS m/z [M + H]+: Calc’d: 290.1111, Found:
290.1095.
6.14. (R)-2,2-Dimethyl-4-(5-(1-methylcyclopropyl)-1H-benzo[d]imidazol-
2-yl)oxazolidine (22)
tert-Butyl (R)-2,2-dimethyl-4-(5-(1-methylcyclopropyl)-1-((2-(tri-
methylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)oxazolidine-3-
carboxylate (200 mg, 0.240 mmol) was dissolved in 3 mL of CH2Cl2.
Trifluoracetic acid (0.3 mL) was added and the reaction was stirred at
room temperature for 6 h. An additional 1 mL of TFA was added and the
reaction left to stir overnight. The solvent removed in vacuo and crude
material was purified by chromatography (ISCO 12 g silica column,
100% CH2Cl2 to 80:20:2 CH2Cl2:MeOH:NH4OH) to obtain 25 mg (45%)
of 22 as a clear gum. 1H NMR (400 MHz, CD3OD) δ 7.46(m, 2H),
7.20(dd, J = 8.4, 1.6 Hz, 1H), 4.41(m, 1H), 3.93(m, 2H), 1.42(s, 3H),
0.86(m, 2H), 0.74(m, 2H). HRMS for C13H18N3O1 MS m/z [M + H]+
:
Calc’d: 232.1444, Found: 232.1444.
6.15. (2R)-2-Amino-2-(5-(sec-butyl)-1H-benzo[d]imidazol-2-yl)ethan-1-
ol (23)
6.12. 2-(2-((1R,2R)-1-Amino-2-hydroxypropyl)-1H-benzo[d]imidazol-5-
yl)-2-methylpropanenitrile (19)
tert-Butyl (4R)-4-(5-(sec-butyl)-1H-benzo[d]imidazol-2-yl)-2,2-di-
methyloxazolidine-3-carboxylate (76 mg, 0.20 mmol) was dissolved in
2 mL of 4 M HCl in dioxane and stirred at room temp overnight. The
reaction was concentrated in vacuo to give a brown gum, which was
purified by chromatography (SiO2 column, 100% CH2Cl2 to 80:20:2
CH2Cl2:MeOH:NH4OH) and concentrated in vacuo to give 30 mg (63%)
23 as a clear gum. 1H NMR (400 MHz, CD3OD) δ 7.44 (d, J = 8.20 Hz,
1H), 7.33 (s, 1H), 7.07 (dd, J = 1.46, 8.30 Hz, 1H), 4.14–4.23 (m, 1H),
3.85–3.95 (m, 1H), 3.76–3.85 (m, 1H), 2.69 (qd, J = 7.00, 14.13 Hz,
1H), 1.57–1.71 (m, 2H), 1.27 (d, J = 6.83 Hz, 3H), 0.80 (t, J = 7.42 Hz,
3H) HRMS for C13H20N3O1 MS m/z [M + H]+: Calc’d: 234.1601,
Found: 234.1602.
The title compound was prepared in parallel from 2-(3,4-diamino-
phenyl)-2-methylpropanenitrile and N-Boc-L-threonine using the fol-
lowing protocol:
A 0.2 M solution of diamine in DMF (500 μL,
100 μmol) was added to a 0.2 M solution of acid in DMF (500 μL,
100 μmol) followed by HATU (100 μmol) and TEA (200 μmol). The
reaction was stirred at 60 °C for 16 h. The reaction was concentrated in
vacuo and AcOH (10 mL) was added to the residue. The reaction was
stirred at 80 °C for 12 h, cooled and concentrated in vacuo to afford
crude intermediate benzimidazole. To crude Intermediate benzimda-
zole was added CH3CN (20 mL) followed by MSC Dowex resin (150 mg)
and the reaction was stirred at 25 °C for 16 h. The resin was washed
with 1:1 CH3CN:MeOH followed by 5% NH3/MeOH. The combined
solvents were concentrated in vacuo, dissolved in DMSO (1 mL) and
purified using preparative HPLC to afford 19. LCMS QC
Method:Column: RESTEK C18 2.1x30mm 3μ, mobile phase A: 0.05%
formic acid in water; mobile phase B:Acetonitrile. Initial gradient 2% B;
0.75 min 2% B, 1.00 min 10% B, 2.00 min 98% B, 2.90 min 2% B,
3.00 min 2% B. Flow rate 1.5 mL/min. MS m/z [M + H]+ 259.
RT = 1.23 min. Preparative HPLC: Xterra 250x19mm, 10′ or X-Bridge
50x19mm, 5μ; mobile phase A: acetonitrile, mobile phase B: 0.05%
NH3 in water; eluting with 5–35% CH3CN over 7 min gradient time.
Flow rate 20 mL/min. HRMS for C14H1N4O1 MS m/z [M + H]+: Calc’d:
260.1582, Found: 260.1581.
6.16. 4-(2-((1R,2R)-1-Amino-2-methoxypropyl)-1H-benzo[d]imidazol-5-
yl)-3-fluorobenzonitrile (24)
tert-Butyl ((1R,2R)-1-(5-(4-cyano-2-fluorophenyl)-1H-benzo[d]imi-
dazol-2-yl)-2-methoxypropyl)carbamate (95 mg, 0.022 mmol) was dis-
solved in a mixture of TFA and DCM (1 mL/5 mL). The reaction was
stirred at room temperature for 3 h before concentrating in vacuo. The
residue was purified by filtering through Amberlist-21 followed by re-
verse phase column chromatography eluting with 0–40% acetonitrile in
0.1% formic acid in water to afford the title compound as the formate
salt (32 mg, 45%). 1H NMR (400 MHz, CD3OD) δ 7.83 (br. s., 1H),
7.61–7.79 (m, 4H), 7.50 (d, J = 8.40 Hz, 1H), 4.30 (br. s., 1H), 3.87 (m,
1H), 3.43 (s, 3H), 1.17 (d, J = 6.25 Hz, 3H). HRMS for C18H18F1N4O1
MS m/z [M + H]+: Calc’d: 325.1459, Found: 325.1460.
6.13. (1R,2R)-1-amino-1-(6-(pentafluorosulfanyl)-1H-benzo[d]imidazol-
2-yl)propan-2-ol (20).
6.17. 4-(2-((1S,2S)-1-amino-2-hydroxypropyl)-1H-benzo[d]imidazol-5-
yl)benzonitrile (25)
4 M HCl in dioxane (10 mL) was added to a stirred, ice cooled so-
lution of tert-butyl ((1R,2R)-2-hydroxy-1-(6-(pentafluorosulfanyl)-1H-
benzo[d]imidazol-2-yl)propyl)carbamate (193 mg, 0.463 mmol) in
4-(2-((1S,2S)-1-amino-2-hydroxypropyl)-1H-benzo[d]imidazol-5-
8