Journal of Medicinal Chemistry
Article
1
3.20 Hz, 2H), 3.39 (d, J = 9.17 Hz, 1H), 2.63 (dd, J = 2.81, 13.94
tert-Butyl 4-(4-((4-(Hydroxymethyl)phenyl)ethynyl)benzyl)-
piperidine-1-carboxylate (55). A mixture of 54 (0.81 g, 1.9
mmol), (4-ethynylphenyl)methanol (0.76 g, 5.7 mmol), CuI (36
Hz, 1H), 2.48 (dd, J = 6.85, 14.06 Hz, 1H), 2.02 (s, 3H), 1.40 (t, J
=
+
+
7.15 Hz, 3H). MS (ESI ): m/z 374 [M + H] .
Ethyl rac-(R*,R*)-2-(Dibenzylamino)-3-hydroxy-4-
mg, 0.19 mmol), Pd(PPh ) Cl (0.13 g, 0.19 mmol), and Et N (10
3 2 2 3
(
(
methylsulfonyl)butanoate (50a). To a stirred solution of 49a
1.2 g, 3 mmol) in CHCl (10 mL) was added m-chloroperbenzoic
mL, 72 mmol) in DMF (10 mL) was stirred under a nitrogen
atmosphere at 60 °C for 7 h. After cooling to RT, the mixture was
passed through the Celite and washed with EtOAc. The filtrate was
concentrated under reduced pressure. The residue was purified with
OH-type silica gel chromatography (7−30% EtOAc/n-hexane) to
3
acid (2.0 g, 11.6 mmol) at 0 °C. The reaction mixture was stirred at
room temperature for 16 h, quenched with a saturated aqueous
sodium thiosulfate, and extracted with CHCl twice. The organic
3
1
layer was passed through a phase separator and concentrated in
vacuo onto ISOLUTE HM-N. The residue was purified with OH-
type silica gel column chromatography (8−100% EtOAc in n-
give the title compound (0.16 g, 20% yield) as a beige solid. H
NMR (400 MHz, CDCl ) δ 7.52 (d, J = 8.07 Hz, 2H), 7.45 (d, J =
3
8.07 Hz, 2H), 7.35 (d, J = 8.07 Hz, 2H), 7.12 (d, J = 8.07 Hz, 2H),
4.72 (br s, 2H), 3.95−4.18 (m, 2H), 2.58−2.70 (m, 2H), 2.55 (d, J
= 6.97 Hz, 2H), 1.58−1.70 (m, 3H), 1.45 (s, 9H), 1.07−1.22 (m,
hexane) to give the title compound (0.58 g, 47% yield) as a
1
colorless powder. H NMR (400 MHz, CDCl ) δ 7.26−7.40 (m,
1
Hz, 2H), 3.55 (br d, J = 15.04 Hz, 1H), 3.46 (d, J = 12.96 Hz, 2H),
3
+
+
0H), 4.58−4.66 (m, 1H), 4.28−4.48 (m, 2H), 3.87 (d, J = 13.08
2H). MS (ESI ): m/z 428 [M + Na] . LCMS condition: C. RT =
1.024 min.
3
.21 (d, J = 9.90 Hz, 1H), 3.07−3.15 (m, 1H), 2.93 (s, 3H), 2.62
(4-((4-(Piperidin-4-ylmethyl)phenyl)ethynyl)phenyl)-
methanol Hydrochloride (56). To a solution of 55 (0.14 g, 0.35
mmol) in 1,4-dioxane (4 mL) was added 4 mol/L HCl in 1,4-
dioxane (8 mL) at RT. The reaction mixture was stirred at RT for 4
h and concentrated in vacuo to give the title compound (0.13 g,
(
(
dd, J = 10.39, 15.04 Hz, 1H), 1.46 (t, J = 7.15 Hz, 3H). MS
ESI ): m/z 406 [M + H] . LCMS condition: C. RT = 0.847 min.
Ethyl rac-(R*,S*)-2-(Dibenzylamino)-3-hydroxy-4-
+
+
(methylsulfonyl)butanoate (50b). To a stirred solution of 49b
quant.) as a pale-yellow solid.
(
0.12 g, 0.32 mmol) in acetonitrile (10 mL) and water (5 mL) was
1
H NMR (400 MHz, DMSO-d ) δ 7.49 (d, J = 8.07 Hz, 2H),
added oxone (0.22 g, 0.35 mmol) at 0 °C. The reaction mixture was
stirred at room temperature for 16 h, quenched with a saturated
6
7
8
2
.44 (d, J = 8.07 Hz, 2H), 7.36 (d, J = 8.07 Hz, 2H), 7.20 (d, J =
.07 Hz, 2H), 5.27 (br t, J = 4.58 Hz, 1H), 4.52 (br d, J = 4.28 Hz,
H), 2.87 (br d, J = 12.23 Hz, 2H), 2.32−2.41 (m, 2H), 1.39−1.62
aqueous sodium thiosulfate, and extracted with CHCl twice. The
3
organic layer was passed through a phase separator and concentrated
in vacuo. The residue was purified with OH-type silica gel column
chromatography (0−100% EtOAc in n-hexane) to give the title
(
m, 3H), 1.03 (dq, J = 3.91, 11.98 Hz, 2H), (two proton signals
+
overlap with the DMSO solvent peak). MS (ESI ): m/z 306 [M +
+
1
H] . LCMS condition: B. Retention time (RT) = 0.543 min.
compound (80 mg, 61% yield) as a colorless powder. H NMR
rac-(R*,R*)-tert-Butyl (3-Hydroxy-1-(4-(4-((4-
(
400 MHz, CDCl ) δ 7.24−7.39 (m, 10H), 4.26−4.47 (m, 3H),
3
(
(
hydroxymethyl)phenyl) ethynyl)benzyl)piperidin-1-yl)-4-
4
3
1
.02 (br d, J = 13.08 Hz, 2H), 3.57 (br d, J = 13.20 Hz, 2H), 3.27−
methylsulfonyl)-1-oxobutan-2-yl)carbamate (57). To a stirred
.41 (m, 1H), 3.09 (dd, J = 8.50, 14.86 Hz, 1H), 2.94−3.02 (m,
+
solution of 56 (34 mg, 0.1 mmol) in DMF (2.0 mL), 53 (35 mg,
0.11 mmol), HATU (57 mg, 0.15 mmol), and DIPEA (52 μL, 0.54
mmol) were added. The mixture was stirred for 3 h at RT. The
reaction mixture was purified via prep-HPLC to give the title
H), 2.91 (s, 3H), 1.42 (t, J = 7.09 Hz, 3H). MS (ESI ) m/z 406
+
[
M + H] . X-ray: A single crystal was grown from ethanol. The
crystal details were as follows: triclinic space group P1
̅
, a =
1
1.9376(2) Å, b = 13.4893(3) Å, c = 15.7344(3) Å, α = 69.216(5)
+
compound (56 mg, 96% yield) as an amorphous solid. MS (ESI ):
°
, β = 83.333(6) °; γ = 88.323(6) °; R and wR values were 0.0931
+
m/z 607 [M + Na] . LCMS condition: C. RT = 0.786 min.
and 0.3597, respectively.
r a c - ( R * , R * ) - 2 - A m i n o - 3 - h y d r o x y - 1 - { 4 - [ ( 4 - { [ 4 -
Ethyl rac-(R*,R*)-2-Amino-3-hydroxy-4-(methylsulfonyl)-
butanoate (51). To a solution of 50a (0.40 g, 1 mmol) in
EtOH (9.9 mL) was added 10% palladium hydroxide on carbon (50
mg, catalytic). The mixture was stirred at room temperature for 16 h
under a hydrogen atmosphere. The reaction mixture was filtered,
and the filtrate was concentrated in vacuo to give crude 51 (0.24 g,
(
hydroxymethyl)phenyl]ethynyl} phenyl)methyl]piperidin-1-
yl}-4-(methanesulfonyl)butan-1-one (22). A solution of 57
53 mg, 0.9 mmol) in formic acid (1.5 mL, 40 mmol excess) was
(
stirred for 2 h at RT. The reaction mixture was diluted with CHCl3
and concentrated in vacuo. To the residue was added 7 mol/L
ammonia in MeOH (2 mL, excess), and the mixture was stirred for
quant.) as oil, which was used in the next step without further
purification. H NMR (400 MHz, CDCl ) δ 4.41 (ddd, J = 2.14,
1
0 min at RT. The reaction mixture was concentrated in vacuo and
1
3
purified with prep-HPLC to give the title compound (11 mg, 35%
yield) as a colorless powder. H NMR (500 MHz, CD OD) δ 7.47
5
.50, 9.48 Hz, 1H), 4.22−4.29 (m, 1H), 3.72 (q, J = 6.97 Hz, 1H),
1
3
3.64 (d, J = 5.50 Hz, 1H), 3.27 (dd, J = 9.90, 15.04 Hz, 1H), 3.19
(d, J = 8.23 Hz, 2H), 7.43 (d, J = 7.89 Hz, 2H), 7.36 (d, J = 8.23
(
br d, J = 14.70 Hz, 1H), 3.04 (s, 3H), 1.32 (t, J = 7.15 Hz, 3H).
Hz, 2H), 7.20 (br d, J = 7.89 Hz, 2H), 4.62 (s, 2H), 4.42−4.57 (m,
+
+
MS (ESI ): m/z 226 [M + H] . LCMS condition: B. RT = 0.258
min.
3
2
H), 3.92−4.00 (m, 1H), 3.36−3.47 (m, 1H), 3.11−3.23 (m, 1H),
.94−3.10 (m, 4H), 2.53−2.77 (m, 3H), 1.84−1.98 (m, 1H), 1.75
Ethyl rac-(R*,R*)-2-((tert-Butoxycarbonyl)amino)-3-hy-
droxy-4-(methylsulfonyl) butanoate (52). To a stirred solution
of 51 (0.17 g, 0.75 mmol as the crude material) in THF (3.8 mL)
13
(
br t, J = 12.60 Hz, 2H), 1.09−1.33 (m, 2H). C NMR (125 MHz,
CD OD) δ 163.2, 162.9, 143.4, 142.1, 141.9, 132.6, 132.6, 130.6,
3
1
5
3
30.5, 128.1, 123.7, 123.6, 122.6, 122.5, 90.1, 90.0, 66.4, 66.4, 64.9,
7.1, 57.0, 56.7, 47.4, 47.2, 44.2, 43.6, 43.4, 43.3, 39.2, 39.0, 33.7,
3.7, 33.0, 32.8, 31.1 (35 carbon signals are observed because of the
and EtOH (1.5 mL) were added (BOC) O (0.20 g, 0.92 mmol) and
2
potassium carbonate (0.27 g, 1.95 mmol). After stirring for 3 h at
room temperature, the reaction mixture was quenched with water
and extracted with CHCl3 three times. The organic layer was
concentrated in vacuo onto ISOLUTE HM-N. The residue was
purified with OH-type silica gel column chromatography (30−100%
EtOAc in n-hexane) to give 52 (0.27 g, quant.) as colorless oil. MS
+
+
rotational isomer). MS (ESI ): m/z 485 [M + H] . high-resolution
mass spectrometry (HRMS) (ESI /APCI) calcd. for [C H N O S
+
+
2
6
32
2
5
+
H] : 485.2105; found: 485.2089. LCMS condition: B. RT = 0.590
+
+
(ESI ): m/z 348 [M + Na] . LCMS condition: B. RT = 0.635 min.
Sodium rac-(R*,R*)-2-((tert-Butoxycarbonyl)amino)-3-hy-
droxy-4-(methylsulfonyl) butanoate (53). To a solution of 52
5
-[(4-Iodophenoxy)methyl]-2,2-dimethyl-5-nitro-1,3-diox-
(
0.28 g) in EtOH (2.9 mL) was added 10 mol/L aqueous sodium
ane (59). To a solution of 4-iodophenol (2.1 g, 9.6 mmol) in DMF
(96 mL) was added NaH (0.50 g, 12 mmol) and stirred for 1.5 h at
room temperature. To the reaction mixture was added 58 (3.6 g, 11
mmol) and stirred for an additional 16 h at 100 °C. The resulting
mixture was diluted with EtOAc and washed with water. The
hydroxide (0.26 mL, 2.6 mmol). After stirring for 3 h at room
temperature, the resulting precipitate was collected by filtration and
air-dried to afford the title compound (0.20 g, 73% yield) as a
−
−
colorless solid. MS (ESI ): m/z 296 [M − H] . LCMS condition:
A. RT = 0.879 min.
organic layer was dried over MgSO and concentrated in vacuo. The
4
K
J. Med. Chem. XXXX, XXX, XXX−XXX