Journal of Medicinal Chemistry
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was heated in a sealed tube at 100 °C overnight. The reaction was then
diluted with water and extracted with EtOAc, and the organic layer was
separated, dried over Na2SO4, filtered, and concentrated. Purified by
silica gel chromatography eluting with 0−50% EtOAc in hexanes to
afford 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-(tetrahydro-2H-pyran-4-yl-
methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol
mg, 0.381 mmol), tris(dibenzylideneacetone)dipalladium (0) (18.3
mg, 0.032 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)-
phosphine (RuPhos) (14.8 mg, 0.032 mmol), and sodium tert-
butoxide (122 mg, 1.27 mmol) were combined and suspended in
toluene (5 mL). Nitrogen gas was bubbled through the solution for 5
min. The reaction vial was sealed and heated to 100 °C for 15 h. The
reaction mixture was then diluted with water and EtOAc. The aqueous
mixture was extracted with EtOAc (2 × 20 mL). The organic extracts
were combined and dried over MgSO4, filtered, and concentrated. The
crude material was purified by purified via reverse-phase preparative
HPLC using a Phenomenex Gemini C18 column (30 mm × 150 mm,
10 μm) eluting with 0.1% TFA in MeCN/H2O (10% to 100% over 15
min) to afford 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-
morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-
2-propanol (23.0 mg, 12% yield). 1H NMR (400 MHz, CDCl3) δ 7.65
(d, J = 4.9 Hz, 1 H), 7.59 (m, 1 H), 7.54 (d, J = 8.8 Hz, 2 H), 7.17 (m,
1 H), 6.83 (d, J = 9.0 Hz, 2 H), 4.10 (m, 1 H), 3.91 (m, 1 H), 3.81 (m,
1 H), 3.69 (m, 1 H), 3.58 (m, 2 H), 3.46 (m, 1 H), 3.25 (m, 3 H), 2.75
(m, 1 H), 2.54 (m, 2 H), 2.39 (m, 1 H), 2.21 (m, 1 H), 1.97 (m, 1 H),
1.03 (d, J = 6.3 Hz, 3 H). m/z (ESI, +ve ion) 588.6 (M + H)+.
Procedure for the Preparation of Chiral 2-(4-Bromophenyl)-
1,1,1-trifluoro-2-propanol. A 500 mL round-bottomed flask was
charged with 1,4-dibromobenzene (30.3 g, 128 mmol) and 200 mL of
diethylether. After cooling to −78 °C, n-BuLi (2.5 M in hexanes, 59.0
mL, 148 mmol) was added. This mixture was stirred for 15 min at −78
°C, then 1,1,1-trifluoro-2-propanone (30.5 g, 24.2 mL, 257 mmol) was
added. Stirring was continued at −78 °C for 30 min, and then the
reaction was quenched with 100 mL of saturated aqueous NH4Cl. The
mixture was allowed to warm to rt and extracted with EtOAc (250
mL), dried (MgSO4), filtered, and concentrated to give an oil.
Purification via silica gel chromatography (0−30% EtOAc in hexanes)
gave 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (21.5 g, 64%) as a
colorless oil. The individual isomers were isolated using chiral SFC
(Chiralcel OJH column (250 mm × 30 mm, 50 μm) with 5% 2-
propanol in supercritical CO2 (total flow was 120 mL/min)) to give
both the R and S isomers with enantiomeric excesses >95%. The first
eluting peak was assigned as the R isomer based on literature
precedent.39
1
(20.0 mg, 4% yield) as a single enantiomer. H NMR (400 MHz,
CD3OD) δ = 7.92−7.87 (m, 1 H), 7.69−7.65 (m, 1 H), 7.56 (d, J =
8.8 Hz, 2 H), 7.31−7.24 (m, 1 H), 6.97 (d, J = 9.2 Hz, 2 H), 4.25−
4.15 (m, 1 H), 3.96−3.84 (m, 2 H), 3.81−3.69 (m, 2 H), 3.60−3.52
(m, 1 H), 3.42−3.37 (m, 1 H), 3.31−3.27 (m, 1 H), 2.76−2.67 (m, 1
H), 2.64−2.52 (m, 1 H), 1.88−1.77 (m, 1 H), 1.76−1.68 (m, 1 H),
1.63−1.39 (m, 3 H), 1.33−1.12 (m, 3 H). m/z (ESI, +ve ion) 572.9
(M + H)+.
1,1,1,3,3,3-Hexafluoro-2-(4-((2S)-2-(4-morpholinylmethyl)-4-(2-
thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (19). Using
morpholine and following the procedure given for compound 20
gave the desired product 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-(4-
morpholinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-
2-propanol (60.0 mg, 3% yield over five steps) after purification by
silica gel chromatography, eluting with 0−100% EtOAc in hexanes. 1H
NMR (400 MHz, CD3OD) δ = 7.87 (dd, J = 1.2, 5.1 Hz, 1 H), 7.64
(dd, J = 1.4, 3.7 Hz, 1 H), 7.53 (d, J = 8.8 Hz, 2 H), 7.25 (dd, J = 3.8,
5.0 Hz, 1 H), 6.95 (d, J = 9.2 Hz, 2 H), 4.17−4.09 (m, 1 H), 4.02−
3.96 (m, 1 H), 3.82−3.75 (m, 1 H), 3.54 (t, J = 4.6 Hz, 5 H), 3.28−
3.18 (m, 1 H), 2.80−2.70 (m, 1 H), 2.67−2.46 (m, 4 H), 2.40−2.25
(m, 3 H). m/z (ESI, +ve ion) 574.0 (M + H)+.
1,1,1,3,3,3-Hexafluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-
morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-
phenyl)-2-propanol (20). A 2 L round-bottomed flask was charged
with (S)-3-methylmorpholine (10.1 g, 100 mmol), HATU (39.7 g, 104
mmol), (R)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid
(30.0 g, 91 mmol), and 100 mL of DMF. To this was added Hunig’s
̈
base (20.3 mL, 114 mmol). After stirring at room temperature for 1 h,
the mixture was diluted with water (1 L) and then extracted with 750
mL of ether. The organic layer was separated and washed with water
(4 × 500 mL), saturated aqueous NaHCO3 (250 mL), brine (250
mL), dried with MgSO4, filtered, and concentrated to give (2R)-2-
(((3S)-3-methyl-4-morpholinyl)carbonyl)-1,4-piperazinedicarboxylate
(33.7 g, 90% yield) as a white solid.
(2R)-1,1,1-Trifluoro-2-(4-((2S)-2-(tetrahydro-2H-pyran-4-ylmeth-
yl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (23).
Using (3S)-3-(tetrahydro-2H-pyran-4-ylmethyl)-1-(2-
thiophenylsulfonyl)piperazine (from compound 18 experimental)
and following the procedure for compound 25 using (2R)-2-(4-
bromophenyl)-1,1,1-trifluoro-2-propanol gave the desired product
(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-
(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (5.00 mg,
1% yield) after purification by silica gel chromatography, eluting
A 1 L round-bottomed flask was charged with ((2R)-2-(((3S)-3-
methyl-4-morpholinyl)carbonyl)-1,4-piperazinedicarboxylate (33.7 g,
82.0 mmol) and 100 mL of THF. To this was added borane−THF
complex (1 M in THF, 327 mL, 327 mmol). The mixture was warmed
to 50 °C for 2 h, then cooled to 0 °C and slowly quenched with 100
mL of MeOH. The mixture was concentrated in vacuo and then
diluted with 200 mL of EtOAc. To this was added 100 mL of 4N HCl
in dioxane. The mixture was heated at 70 °C for 2.5 h, and the
resulting white precipitate was collected by filtration to give the amine
tris-HCl salt. This solid was suspended in 200 mL of CH2Cl2 and
triethylamine (57.0 mL, 408 mmol). After cooling to 0 °C, 2-
thiophenesulfonyl chloride (14.9 g, 82.0 mmol) was added. The
mixture was stirred at room temperature for 1 h and then diluted with
water and extracted with EtOAc. The combined organics were dried
(MgSO4), filtered, and concentrated to give an oil. Purification by
silica gel chromatography eluting with 0−10% MeOH in CH2Cl2 to
afford (3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-
piperazinyl)methyl)morpholine (20.2 g, 71% yield) as a white solid.
1H NMR (400 MHz, CD3OD) δ = 7.86 (dd, J = 1.2, 4.9 Hz, 1 H),
7.60 (dd, J = 1.2, 3.7 Hz, 1 H), 7.24 (dd, J = 3.8, 5.0 Hz, 1 H), 3.78−
3.70 (m, 2 H), 3.66 (d, J = 11.3 Hz, 2 H), 3.61−3.54 (m, 1 H), 3.29−
3.23 (m, 1 H), 3.07−3.01 (m, 1 H), 2.92−2.83 (m, 2 H), 2.83−2.76
(m, 1 H), 2.72−2.63 (m, 1 H), 2.51−2.43 (m, 1 H), 2.43−2.37 (m, 1
H), 2.36−2.29 (m, 1 H), 2.09 (s, 2 H), 0.96 (d, J = 6.3 Hz, 3 H).
The free base from the previous step was taken up in ether and
acidified with 4N HCl in dioxane (2 mL, 8 mmol), and the resulting
precipitate was collected to give the bis HCl salt as a white powder. In
a pressure tube (3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-
piperazinyl)methyl)morpholine dihydrochloride (133 mg, 0.318
mmol), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (123
1
with 0−50% EtOAc in hexanes. H NMR (400 MHz, CD3OD) δ =
7.86 (dd, J = 1.2, 5.1 Hz, 1 H), 7.63 (dd, J = 1.2, 3.9 Hz, 1 H), 7.44 (d,
J = 8.8 Hz, 2 H), 7.24 (dd, J = 3.8, 5.0 Hz, 1 H), 6.89 (d, J = 8.8 Hz, 2
H), 4.12−4.04 (m, 1 H), 3.91−3.80 (m, 2 H), 3.75−3.61 (m, 2 H),
3.48−3.41 (m, 1 H), 3.38−3.33 (m, 1 H), 3.28−3.21 (m, 1 H), 2.77−
2.66 (m, 1 H), 2.64−2.50 (m, 1 H), 1.80−1.69 (m, 2 H), 1.67 (s, 3 H),
1.59−1.43 (m, 2 H), 1.41−1.28 (m, 2 H), 1.27−1.06 (m, 2 H). m/z
(ESI, +ve ion) 518.9 (M + H)+.
(2S)-1,1,1-Trifluoro-2-(4-((2S)-2-(tetrahydro-2H-pyran-4-ylmeth-
yl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (24).
Using (3S)-3-(tetrahydro-2H-pyran-4-ylmethyl)-1-(2-
thiophenylsulfonyl)piperazine (from compound 18 experimental)
and following the procedure for compound 25 using (2S)-2-(4-
bromophenyl)-1,1,1-trifluoro-2-propanol gave the desired product
(2S)-1,1,1-trifluoro-2-(4-((2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-
(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (10.0 mg,
2% yield) after purification by silica gel chromatography, eluting
1
with 0−50% EtOAc in hexanes. H NMR (400 MHz, CD3OD) δ =
7.87 (dd, J = 1.3, 5.0 Hz, 1 H), 7.64 (dd, J = 1.4, 3.7 Hz, 1 H), 7.45 (d,
J = 8.8 Hz, 2 H), 7.25 (dd, J = 3.8, 5.0 Hz, 1 H), 6.90 (d, J = 9.0 Hz, 2
H), 4.12−4.06 (m, 1 H), 3.91−3.81 (m, 2 H), 3.76−3.63 (m, 2 H),
3.48−3.42 (m, 1 H), 3.39−3.34 (m, 1 H), 3.29−3.23 (m, 1 H), 2.75−
2.69 (m, 1 H), 2.59 (dt, J = 3.7, 11.4 Hz, 1 H), 1.81−1.73 (m, 2 H),
M
dx.doi.org/10.1021/jm4016735 | J. Med. Chem. XXXX, XXX, XXX−XXX