Journal of Medicinal Chemistry
Article
(
1R,5S)-3-((tert-Butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-
over Na SO , filtered, concentrated, and purified by flash chromatog-
2 4
carbaldehyde (Step b, 74). To a solution of (1R,5S)-3-((tert-
butyldiphenylsilyl)oxy)-N-methoxy-N-methylbicyclo[3.1.0] hexane-6-
carboxamide 74a (22.4 g, 52.9 mmol) in dry toluene (260 mL) at −78
raphy [0−50% of EtOAc/IPA (8:2) in hexanes] to give 77Et, as the first
eluting diastereomer, (776 mg, 2.6 mmol, 4% yield) white solid. MS
+
+ 1
(ES ) C H ClNO calculated 293; found 294 [M + H] . H NMR
1
6
20
2
°
C was added DIBAL-H (1 M in toluene, 58 mL, 58 mmol) dropwise
(500 MHz, CD OD): δ 7.79 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.5 Hz,
3
over 17 min, and the resulting colorless solution was stirred at −78 °C
for 3.5 h. To the reaction at −78 °C was added EtOAc (135 mL) and
allowed to warm in an ice bath for 15 min. To the reaction was added
water (2.4 mL) and stirred for 5 min, 15% aqueous NaOH (2.6 mL)
and stirred for 5 min, and then water (6 mL), and the reaction was
allowed to warm to RT for 30 min. To the stirring reaction was added
2H), 4.32−4.27 (m, 1H), 3.29−3.25 (m, 1H), 2.12−1.97 (m, 2H),
1.80−1.58 (m, 4H), 1.36−1.24 (m, 2H), 1.24−1.20 (m, 1H), 0.96 (t, J
= 7.4 Hz, 3H).
4-Chloro-N-(1-((1R,3r,5S,6r)-3-(quinolin-4-yloxy)bicyclo[3.1.0]-
hexan-6-yl)propyl)benzamide (Step h, 21). To a solution of 4-chloro-
N-(1-((1R,3r,5S,6r)-3-hydroxybicyclo[3.1.0]hexan-6-yl)propyl)-
benzamide 77Et (49 mg, 0.17 mmol) in DMSO (0.34 mL) under
nitrogen was added sodium hydride (60% in mineral oil, 15 mg, 0.38
mmol) and the mixture was stirred at RT for 30 min until gas evolution
ceased. To the resulting yellow mixture was added 4-bromoquinoline
MgSO and allowed stir at RT overnight. The reaction was filtered and
4
the filtrate was washed with (150 mL/each) saturated NH Cl, water,
4
and saturated NaCl, dried over MgSO , filtered, and concentrated. The
4
residue was purified via flash chromatography (0−30% EtOAc in
+
(
43 mg, 0.21 mmol), and the reaction was stirred at 80 °C overnight. To
hexanes) to give 74 (17.6 g, 48.4 mmol, 92% yield). MS (ES )
+
1
the mixture was added 2 drops of a saturated NH Cl. The mixture was
C H O Si calculated 364; found 387 [M + Na] . H NMR (600 MHz,
4
23
28
2
filtered (0.2 μM Whatman syringe filter), rinsed with DMSO (3 × 0.3
mL), and the filtrate was purified by mass-triggered preparative HPLC
CDCl ): δ 9.31−8.88 (m, 1H), 7.65−7.59 (m, 4H), 7.46−7.40 (m,
3
2
2
H), 7.39−7.34 (m, 4H), 4.41−3.79 (m, 1H), 2.54−2.20 (m, 1H),
.09−1.97 (m, 3H), 1.96−1.86 (m, 3H), 1.11−0.98 (m, 9H).
N-((E)-((1R,5S)-3-((tert-Butyldiphenylsilyl)oxy)bicyclo[3.1.0]-
(
mobile phase: A = 0.1% TFA/H O, B = 0.1% TFA/MeCN; gradient:
2
B = 20−50%; 12 min; column: C18) to give 21 as a glassy yellow solid
(55 mg, 62%). MS (ES ) C25H25ClN O calculated 420; found, 421 [M
+ H] . H NMR (600 MHz, CDCl ): δ 8.95 (d, J = 6.42 Hz, 1H), 8.48
+
hexan-6-yl)methylene)-2-methylpropane-2-sulfinamide (Step c,
5). To a solution of (1R,5S)-3-((tert-butyldiphenylsilyl)oxy)bicyclo-
3.1.0]hexane-6-carbaldehyde 74 (13 g, 36 mmol) in DCM (72 mL)
2 2
+
1
7
[
3
(d, J = 7.93 Hz, 1H), 8.41 (d, J = 8.69 Hz, 1H), 8.16−8.11 (m, 1H),
8.10−8.05 (m, 1H), 7.92 (ddd, J = 8.40, 7.08, 1.13 Hz, 1H), 7.80−7.75
(m, 2H), 7.48−7.43 (m, 2H), 7.40 (d, J = 6.80 Hz, 1H), 5.49 (t, J = 6.61
Hz, 1H), 3.45−3.37 (m, 1H), 2.60−2.48 (m, 2H), 2.31−2.21 (m, 2H),
1.82−1.73 (m, 1H), 1.73−1.65 (m, 1H), 1.63−1.58 (m, 1H), 1.55 (td, J
= 5.85, 3.40 Hz, 1H), 1.27 (dt, J = 9.06, 3.21 Hz, 1H), 0.97 (t, J = 7.36
Hz, 3H).
were added 2-methylpropane-2-sulfinamide (8.7 g, 72 mmol) and
anhydrous copper(II) sulfate (5.7 g, 36 mmol) and the resulting
mixture was stirred at RT overnight. The reaction was filtered through
Celite, concentrated, and purified via flash chromatography (0−15%
+
EtOAc in hexanes) to give 75 (14.5 g, 31 mmol, 86% yield). MS (ES )
+
1
C H NO SSi calculated 467; found 468 [M + H] . H NMR (600
27
37
2
MHz, CDCl ): δ 7.75 (d, J = 7.1 Hz, 1H), 7.65−7.59 (m, 4H), 7.45−
4-Chloro-N-(1-((1R,3s,5S,6r)-3-(quinolin-4-yloxy)bicyclo[3.1.0]-
hexan-6-yl) propyl)benzamide (22). 4-Chloro-N-(1-((1R,3s,5S,6r)-3-
hydroxybicyclo[3.1.0]hexan-6-yl)propyl)benzamide (Step g, 78Et).
From the flash chromatography purification of step g as described above
for compound 77Et, the title compound 78Et was isolated as the
second eluting diastereomer (0.21 g, 0.71 mmol, 11% yield) as a white
3
7
.40 (m, 2H), 7.40−7.34 (m, 4H), 4.38−3.92 (m, 1H), 2.59−2.19 (m,
H), 2.13−1.40 (m, 6H), 1.22−1.10 (m, 9H), 1.08−0.98 (m, 9H).
N-(1-((1R,5S)-3-((tert-Butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-
-yl)propyl)-2-methylpropane-2-sulfinamide (Step d, 76Et). To a
1
6
cooled −78 °C solution of N-((E)-((1R,5S)-3-((tert-
butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)methylene)-2-meth-
ylpropane-2-sulfinamide 75 (8 g, 17 mmol) in THF (64 mL) was added
EtMgBr (23 mL of 3 M solution in diethylether, 68 mmol). The
resulting mixture was stirred at −78 °C for ∼5 min, removed from the
cooling bath, and allowed to warm to RT overnight. The reaction was
+
+ 1
solid. MS (ES ) C H ClNO calculated 293; found 294 [M + H] . H
16 20
2
NMR (500 MHz, CD OD): δ 7.78 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6
3
Hz, 2H), 3.95−3.87 (m, 1H), 3.26−3.18 (m, 1H), 2.09 (ddd, J = 24.4,
1
7
2.6, 7.1 Hz, 2H), 1.75−1.55 (m, 4H), 1.35−1.23 (m, 2H), 0.94 (t, J =
.4 Hz, 3H), 0.71 (dt, J = 9.3, 3.2 Hz, 1H).
4
-Chloro-N-(1-((1R,3s,5S,6r)-3-(quinolin-4-yloxy)bicyclo[3.1.0]-
cooled in ice and quenched with saturated NH Cl (150 mL) and stirred
4
hexan-6-yl)propyl)benzamide (Step h, 22). To a solution of 4-chloro-
N-(1-((1R,3s,5S,6r)-3-hydroxybicyclo[3.1.0]hexan-6-yl)propyl)-
benzamide 78Et (27 mg, 0.084 mmol) in DMSO (0.17 mL) under
nitrogen was added sodium hydride (60% in mineral oil, 8.1 mg, 0.20
mmol) and the mixture was stirred at RT for 30 min. To the resulting
yellow mixture was added 4-bromoquinoline (25 mg, 0.12 mmol), and
the resulting mixture was stirred at 80 °C overnight. To the mixture was
for 1 h. The mixture was diluted with DCM (200 mL) and the organic
layer was separated. The aqueous layer was extracted with DCM. The
organic layers were combined, washed with saturated NaCl, dried over
MgSO , filtered, and concentrated to give 76Et (7.8 g, 16 mmol), which
4
+
was used directly in the next step. MS (ES ) C H NO SSi calculated
97; found 498[M + H] . H NMR (600 MHz, CDCl ): δ 7.66−7.58
m, 4H), 7.45−7.39 (m, 2H), 7.39−7.32 (m, 4H), 4.35−3.85 (m, 1H),
.21−2.49 (m, 1H), 2.40−0.78 (m, 31H).
1R,5S)-6-(1-Aminopropyl)bicyclo[3.1.0]hexan-3-ol (Step f). To a
solution of N-(1-((1R,5S)-3-((tert-butyldiphenylsilyl)oxy)bicyclo-
3.1.0]hexan-6-yl)propyl)-2-methylpropane-2-sulfinamide (3.2 g, 6.4
2
9
43
2
+
1
4
(
3
3
added two drops of a saturated NH Cl. The mixture was filtered (0.2
4
μM Whatman syringe filter), rinsed with DMSO (3 × 0.3 mL), and the
filtrate was purified by mass-triggered preparative HPLC (mobile
(
phase: A = 0.1% TFA/H O, B = 0.1% TFA/MeCN; gradient: B = 20−
2
[
+
5
0%; 12 min; column: C18) to give 22 (32.9 mg, 73%). HRMS (ES )
C H ClN O calculated 421.1677 [M + H] ; found 421.1671 [M +
H] . H NMR (600 MHz, CD OD): δ 8.94 (d, J = 6.80 Hz, 1H), 8.45
mmol) in MeOH (50 mL) cooled in an ice bath was added HCl in
MeOH [prepared immediately before use by the addition of AcCl (18.3
mL, 257 mmol) into MeOH (25 mL) cooled in an ice bath and stirred
for 5 min]. The reaction was removed from the ice bath and stirred at
RT overnight. The reaction was concentrated and the residual solvent
was azeotroped with ACN and toluene (3×) to give the title compound,
+
2
5
25
2
2
+
1
3
(
8
(
d, J = 7.93 Hz, 1H), 8.34 (d, J = 8.69 Hz, 1H), 8.14−8.09 (m, 1H),
.08−8.04 (m, 1H), 7.88 (ddd, J = 8.21, 6.89, 1.13 Hz, 1H), 7.84−7.79
m, 2H), 7.50−7.47 (m, 2H), 7.46 (d, J = 6.80 Hz, 1H), 5.17 (quin, J =
.89 Hz, 1H), 3.41 (qd, J = 8.62, 5.85 Hz, 1H), 2.61−2.65 (m, 1H), 2.56
6
+
HCl salt, off white solid, and used as is immediately. MS (ES )
(dd, J = 13.41, 6.99 Hz, 1H), 2.28−2.18 (m, 2H), 1.83−1.75 (m, 1H),
+
C H NO calculated 155; found 156 [M + H] .
9
17
1
.75−1.67 (m, 1H), 1.64 (td, J = 6.04, 3.40 Hz, 1H), 1.56 (td, J = 6.04,
.40 Hz, 1H), 1.00 (t, J = 7.37 Hz, 3H), 0.90 (dt, J = 8.69, 3.40 Hz, 1H).
4
-Chloro-N-(1-((1R,3r,5S,6r)-3-hydroxybicyclo[3.1.0]hexan-6-yl)-
3
propyl)benzamide (Step g, 77Et). The crude (1R,5S)-6-(1-
aminopropyl)bicyclo[3.1.0]hexan-3-ol hydrochloride was diluted with
DCM (50.0 mL) and to this were added DIEA (5.6 mL, 32 mmol),
HOBT (1.6 g, 9.6 mmol), 4-chlorobenzoic acid (1.1 g, 7.1 mmol), and
EDC (1.4 g, 7.1 mmol). The reaction was stirred at RT for 4 days. The
reaction was diluted with DCM and washed with NaOH (0.25 M),
citric acid (0.25 M), water, and brine. The aqueous washes were
extracted with DCM once. The organic layers were combined, dried
4
-Chloro-N-((R)-1-((1R,3S,5S,6r)-3-(5,6-difluoro-1H-benzo[d]-
imidazole-1-yl)bicyclo[3.1.0]hexan-6-yl)propyl)benzamide (62). (S)-
N-((E)-((1R,5S,6r)-3-((tert-Butyldiphenylsilyl)oxy)bicyclo[3.1.0]-
hexan-6-yl)methylene)-2-methylpropane-2-sulfinamide (Step c,
75(S)). (1R,5S,6r)-3-((tert-Butyldiphenylsilyl)oxy)bicyclo[3.1.0]-
hexane-6-carbaldehyde 74 (26.5 g, 72.7 mmol) was dissolved in
DCM (73 mL) and (S)-2-methylpropane-2-sulfinamide (17.6 g, 145
mmol) along with copper(II) sulfate (11.6 g, 72.7 mmol) were added.
R
J. Med. Chem. XXXX, XXX, XXX−XXX