Journal of Medicinal Chemistry
Article
exotherm was observed). The mixture was stirred at −70 °C for 2 h,
and then, it was poured into 1 L of MTBE and 1 L of aq. 1 M HCl
slowly at 0−10 °C. The material was extracted with EtOAc (2 × 2 L),
and the combined organic layers were washed with water (2 L), aq. 1
M HCl (2 L), and brine (2 × 2 L), dried over Na2SO4, filtered, and
concentrated to dryness. Purification by flash chromatography
[gradient of petroleum ether/EtOAc (100:0 to 50:1)] afforded 106
(22 g, 96 mmol) was dissolved in anhydrous THF (330 mL) under a
nitrogen atmosphere. The solution was cooled at −78 °C. 1 M lithium
bis(trimethylsilyl)amide in THF (100 mL) was added dropwise over
a period of 15 min. The reaction mixture was stirred at −78 °C for 1
h. Iodomethane (7.7 mL, 120 mmol) was added to the reaction
mixture at −78 °C, and the reaction mixture was allowed to warm
slowly to −20 °C. The reaction was quenched by the addition of
saturated NH4Cl (100 mL). The layers were separated, and the
aqueous phase was extracted with ethyl acetate (250 mL). The
combined organic layer was dried over anhydrous magnesium sulfate,
filtered, and concentrated to afford ( )-methyl 2-(2-bromophenyl)-
1
g of 3 as yellow oil (71% yield, two steps). H NMR (300.13 MHz,
DMSO-d6): δ (ppm): 10.37 (s, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.27 (d,
J = 8.5 Hz, 1H), 2.22−2.13 (m, 1H), 1.08−1.02 (m, 2H), 0.77−0.71
(m, 2H).
1
(R)-1-(2,6-Dichloro-3-cyclopropyl-phenyl)ethanamine [(R)-4].
(S)-(−)-2-Methylpropanesulfinamide (27.3 g, 225.5 mmol) and
cesium carbonate (73.5 g, 225.5 mmol) were added to a stirred
solution of 3 (50.0 g, 225.5 mmol) in DCM (0.5 L). A condenser with
a nitrogen inlet was fitted, and the mixture refluxed for 1.5 h. The
mixture was cooled and then filtered through a silica pad (1 cm
depth), rinsing with DCM (1.5 L). The filtrate was concentrated
under reduced pressure to afford (S,E)-N-[(2,6-dichloro-3-cyclo-
propyl-phenyl)methylene]-2-methyl-propane-2-sulfinamide as yellow
oil which solidified slowly upon standing (72.5 g, 99% yield).
MS(ESI) m/z (35Cl/37Cl): 318/320/322 [M + H]+; 1H NMR
(400.15 MHz, CDCl3): δ 8.91 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 6.98
(d, J = 8.4 Hz, 1H), 2.22−2.13 (m, 1H), 1.32 (s, 9H), 1.09−1.02 (m,
2H), 0.71−0.64 (m, 2H).
(S,E)-N-[(2,6-Dichloro-3-cyclopropyl-phenyl)methylene]-2-meth-
yl-propane-2-sulfinamide (58.0 g, 178.6 mmol) and cupric bromide
(2.0 g, 8.9 mmol, 5 mol %) were combined in DCM (0.6 L) under
nitrogen and cooled to 5 °C (internal). Methylmagnesium bromide
(3.0 M in diethyl ether, 87.0 mL, 261.0 mmol) was added using a
syringe pump at a rate of 1 mL/min. After 2 h, 1 M aq. hydrochloric
acid (0.3 L) was added slowly, and the mixture was stirred vigorously
for 10 min. The phases were separated, and the organic phase was
filtered, washed with water (0.12 L) and brine (0.12 L), dried over
MgSO4, and filtered. The filtrate was concentrated by approx. half
under reduced pressure and then eluted through a silica pad (2 cm
depth), rinsing with 1:4 MTBE/DCM. The filtrate was concentrated
under reduced pressure to afford crude (S)-N-[(1R)-1-(2,6-dichloro-
3-cyclopropyl-phenyl)ethyl]-2-methyl-propane-2-sulfinamide (96%
de, 58.5 g, 96% yield), which was used without further purification.
MS(ESI) m/z: (35Cl/37Cl): 334/336/338 [M + H]+; 1H NMR
(400.21 MHz, CDCl3): δ 7.25−7.09 (m, 1H), 6.88−6.76 (m, 1H),
5.63−5.35 (m, 1H), 4.47−4.26 (m, 1H), 2.22−2.04 (m, 1H), 1.79−
1.63 (m, 3H), 1.15 (br s, 9H), 1.07−0.94 (m, 2H), 0.71−0.56 (m,
2H).
propanoate (24.9 g, quant.) as orange oil. H NMR (300.16 MHz,
DMSO-d6): 7.62 (dd, J = 8.0 and 1.1 Hz, 1H), 7.41−7.32 (m, 2H),
7.24−7.19 (m, 1H), 4.13 (q, J = 7.2 Hz, 1H), 3.60 (s, 3H), 1.40 (d, J
= 7.1 Hz, 3H).
A round-bottomed flask was charged with potassium acetate (1.25
g, 12.7 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)-
dichloride dichloromethane complex (260 mg, 0.32 mmol), and
4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
1,3,2-dioxaborolane (2.43 g, 9.57 mmol). After 3 cycles of vacuum/
nitrogen, a solution of ( )-methyl 2-(2-bromophenyl)propanoate
(1.55 g, 6.38 mmol) in anhydrous 1,4 dioxane (16 mL) was added.
The reaction mixture was stirred and heated at 90 °C overnight. The
reaction mixture was cooled to rt, diluted with ethyl acetate (50 mL),
and washed with water (25 mL) and brine (15 mL). The organic layer
was dried over anhydrous magnesium sulfate, filtered, and
concentrated to afford black oil (3.43 g). The residue was loaded
onto an 80 g silica gel column and purified by flash chromatography
eluting with a gradient of hexane/EtOAc 3%−10% (in 10 CV) to
provide ( )-6 (1.46 g, 79% yield) as colorless oil. MS(ESI) m/z: 291
[M + H]+; 1H NMR (400.13 MHz, CDCl3): 7.81 (d, J = 7.4 Hz, 1H),
7.42−7.36 (m, 1H), 7.30−7.20 (m, 2H), 4.67 (q, J = 7.0 Hz, 1H),
3.64 (d, J = 2.0 Hz, 3H), 1.47 (d, J = 7.0 Hz, 3H), 1.35 (s, 12H).
6-Bromo-1-[(1R)-1-(2,6-dichloro-3-Cyclopropyl-phenyl)ethyl]-
imidazo[4,5-c]pyridine [(R)-7)]. A solution of (1R)-1-(2,6-dichloro-3-
cyclopropyl-phenyl)ethanamine [(R)-4] (20.0 g, 86.9 mmol) in 2-
methyltetrahydrofuran (50 mL) was added to a stirred mixture of 2,4-
dibromo-5-nitropyridine (25.0 g, 86.9 mmol) and potassium
carbonate (25.0 g, 180.9 mmol) in 2-methyltetrahydrofuran (100
mL). Triethylamine (25.0 mL, 179.4 mmol) was added, and the
mixture was stirred at 70 °C for 20 min. The mixture was cooled and
washed with water, half-saturated brine, and brine (each 100 mL).
The organics were passed and eluted through a 4 cm pad of silica
under suction, eluting with further 2-methyltetrahydrofuran. The
eluate was concentrated under reduced pressure to afford crude 2-
bromo-N-[(1R)-1-(2,6-dichloro-3-cyclopropyl-phenyl)ethyl]-5-nitro-
pyridin-4-amine (38.9 g, 76.7 mmol, 88%) as a thick orange gum.
LCMS purity 92% (3% regioisomer). MS(ESI) m/z: (35Cl/37Cl):
430/432/434 [M + H]+; 1H NMR (300.13 MHz, DMSO-d6): δ 8.85
(s, 1H), 8.82 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.06 (d, J =
8.4 Hz, 1H), 6.82 (s, 1 H), 5.68−5.51 (m, 1H), 2.22−2.06 (m, 1H),
1.73 (d, J = 6.9 Hz, 3H), 1.08−0.93 (m, 2H), 0.77−0.60 (m, 2H).
A solution of crude 2-bromo-N-[(1R)-1-(2,6-dichloro-3-cyclo-
propyl-phenyl)ethyl]-5-nitro-pyridin-4-amine (37.0 g, 85.8 mmol)
and trimethyl orthoformate (74 mL, 676.4 mmol) and acetic acid
(0.37 L) was prepared in a round-bottomed flask with a mechanical
stirrer. The mixture was heated in an 80 °C block and treated with
iron powder (37.0 g, 662.5 mmol). After the initial exotherm
subsided, the heating block temperature was increased to 90 °C. After
a total of 3 h, heating was stopped, and diatomaceous earth and
ethanol (0.5 L) were added. The cooled mixture was filtered through
a pad of diatomaceous earth, and the pad was rinsed with further
ethanol. The filtrate was concentrated under reduced pressure, and
the residue partitioned between isopropyl acetate (0.5 L) and 1 M aq.
HCl (0.3 L). The phases were separated, and the organics were
washed with 0.1 L portions of 1 M aq. HCl, 1 M aq. NaOH (×4), and
brine and then eluted through a 3 cm silica pad under suction, rinsing
with ethyl acetate. The eluate was concentrated under reduced
pressure, taken up in MTBE (70 mL), and stirred overnight. The
resulting thick slurry was diluted with further MTBE, and the solid
A stirred solution of this compound (45.0 g, 131.9 mmol) in
methanol (67.5 mL) was cooled in an ice-water bath. HCl (4 M in
dioxane, 67.5 mL, 270 mmol) was added over a period of 10 min.
Stirring was continued for 15 min in the ice bath and then for 30 min
at room temperature. The mixture was concentrated under reduced
pressure, and the residue partitioned between MTBE (0.25 L) and
water (0.25 L). The phases were separated, and the organic phase was
extracted with water (2 × 50 mL). The aqueous portions were
combined and washed with MTBE (2 × 0.1 L); the MTBE portions
were discarded. The aqueous was stirred with a fresh portion of
MTBE (0.25 L) and treated with 2 M aq. NaOH to pH 10. The
phases were separated, and the aqueous was discarded. The MTBE
extract was washed with water (50 mL) and brine (50 mL), dried over
Na2SO4, filtered, and concentrated under reduced pressure to afford
(1R)-1-(2,6-dichloro-3-cyclopropyl-phenyl)ethanamine [(R)-4] as
pale brown oil (95% ee, 5.9 g, 83% yield). Chiral CE method used
to determine ee: 50 μM × 30 cm capillary, −15 kV, 20 °C; running
buffer 5% beta−HS−CD, 25 mM phosphate, retention time of 3.69
min for (R)-4, 3.86 min for (S)-4. MS(ESI) m/z: (35Cl/37Cl): 230/
1
232/234 [M + H]+; H NMR (400.21 MHz, CDCl3): δ 7.16 (d, J =
11.2 Hz, 1H), 6.79 (d, J = 10.8 Hz, 1H), 5.09−4.83 (m, 1H), 2.21−
2.06 (m, 1H), 2.00 (br s, 2H), 1.55 (d, J = 9.2 Hz, 3 H), 1.04−0.95
(m, 2H), 0.67−0.59 (m, 2H).
Methyl 2-[2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]propanoate [( )-6]. Methyl 2-(2-bromophenyl)acetate (5)
3445
J. Med. Chem. 2021, 64, 3439−3448