Journal of Medicinal Chemistry
Article
equiv) and acetyl chloride (1.0−1.2 equiv) were carefully added at 0
°C. The resulting solution was stirred at room temperature (2−4 h).
The resulting solution was washed with an aqueous 10% citric acid
solution followed by a saturated aqueous NaHCO3 solution. The
organic layer was dried (Na2SO4) and concentrated in vacuo. The
residue was purified by column chromatography on SiO2 and/or
recrystallized with EtOAc/hexanes.
(R)-N-(4″-Fluorobiphenyl-4′-yl)methyl 2-Acetamido-3-me-
thoxypropionamide ((R)-4). Using method 1, (R)-56 (3.17 g, 7.9
mmol) and 4 M HCl (6.90 mL, 27.6 mmol) followed by Et3N (2.42
mL, 17.3 mmol) and AcCl (0.61 mL, 8.7 mmol) gave (R)-4 as a white
solid (2.50 g, 92%): Rf = 0.40 (MeOH/CH2Cl2 1/20); mp 189−190
°C; [α]26D −17.8° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 2.04 (s, 3H),
3.40 (s, 3H), 3.44−3.48 (m, 1H), 3.83 (dd, J = 3.9, 9.0 Hz, 1H), 4.45−
4.59 (m, 3H), 6.43−5.46 (br d, 1H), 6.81−6.85 (m, 1H), 7.12 (t, J =
8.6 Hz, 2H), 7.32 (d, J = 7.6 Hz, 2H), 7.49−7.54 (m, 4H); addition of
excess (R)-(−)-mandelic acid to a CDCl3 solution of (R)-4 gave only
one signal for the acetyl methyl and one signal for the ether methyl
protons; 13C NMR (DMSO-d6) δ 22.6, 41.8, 52.7, 58.2, 72.1, 115.7 (d,
J = 21.3 Hz, 2C), 126.5, 127.6, 128.5 (d, J = 8.0 Hz, 2C), 136.4 (d, J =
2.9 Hz), 137.6, 138.6, 161.8 (d, J = 242.4 Hz), 169.5, 169.8; LRMS
(ESI+) 367.1 [M + Na]+ (calcd for C19H21FN2O3Na+ 367.1). Anal.
(C19H21FN2O3) C, H, F, N.
H]+ (100%); HRMS (ESI+) 405.0814 [M + H]+ (calcd for
C19H2179BrN2O3H+ 405.0814). Anal. (C19H21BrN2O3) C, H, Br, N.
(R)-N-(3″-Iodobiphenyl-4′-yl)methyl 2-Acetamido-3-me-
thoxypropionamide ((R)-8). Using method 1, 4 M HCl in dioxane
(2.0 mL), (R)-60 (670 mg, 1.3 mmol), Et3N (515 mg, 3.9 mmol), and
AcCl (123 mg, 1.6 mmol) gave compound (R)-8 as a white solid (515
mg, 87%): Rf = 0.41 (1:20 MeOH/CH2Cl2); mp 161−163 °C; [α]26
D
1
−11.0° (c 1.0, CHCl3); H NMR (CDCl3) δ 2.05 (s, 3H), 3.41 (s,
3H), 3.43−3.50 (m, 1H), 3.84 (dd, J = 4.3, 9.3 Hz, 1H), 4.46−4.55
(m, 2H), 4.57−4.60 (m, 1H), 6.45 (d, J = 6.8 Hz, 1H), 6.83 (t, J = 4.8
Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.34 (d, J = 8.2 Hz, 2H), 7.48−7.55
(m, 3H), 7.68 (d, J = 7.8 Hz, 1H), 7.92 (s, 1H); addition of excess (R)-
(−)-mandelic acid to a CDCl3 solution of (R)-8 gave only one signal
for the acetyl methyl and one signal for the ether methyl protons; 13C
NMR (CDCl3) δ 23.2, 43.2, 52.4, 59.1, 71.6, 94.8, 126.3, 127.4, 127.9,
130.4, 136.0, 136.2, 137.6, 138.9, 142.9, 170.0, 170.3; HRMS (ESI+)
453.0675 [M + H]+ (calcd for C19H21IN2O3H+ 453.0673). Anal.
(C19H21IN2O3) C, H, I, N.
(R)-N-(3″-Cyanobiphenyl-4′-yl)methyl 2-Acetamido-3-me-
thoxypropionamide ((R)-9). Using method 1, (R)-61 (3.10 g, 7.6
mmol) and 4 M HCl (9.5 mL) followed by Et3N (2.30 g, 22.7 mmol)
and AcCl (0.71 g, 9.1 mmol) gave the desired product (R)-9 (2.00 g,
75%) as a white solid: Rf = 0.42 (CH2Cl2/CH3OH 19/1); mp 122−
123 °C; [α]24.5D −16.0° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 2.03 (s,
3H), 3.40 (s, 3H), 3.47−3.52 (m, 1H), 3.79−3.84 (m, 1H), 4.48−4.54
(m, 2H), 4.59−4.63 (m, 1H), 6.56−6.59 (br d, 1H), 7.03−7.07 (br t,
1H), 7.36 (d, J = 8.4 Hz, 2H), 7.48−7.64 (m, 4H), 7.76−7.82 (m,
2H); addition of excess (R)-(−)-mandelic acid to a CDCl3 solution of
(R)-9 gave only one signal for the acetyl methyl and one signal for the
ether methyl protons; 13C NMR (CDCl3) δ 23.4, 43.3, 52.7, 59.3, 71.9,
113.2, 119.0, 127.5, 128.3, 129.8, 130.8, 130.9, 131.6, 138.2, 138.5,
142.9, 170.4, 170.6; LRMS (ESI+) 352.2 [M + H]+ (calcd for
(R)-N-(3″-Chlorobiphenyl-4′-yl)methyl 2-Acetamido-3-me-
thoxypropionamide ((R)-5). Using method 1, (R)-57 (4.00 g, 9.6
mmol) and 4 M HCl (8.36 mL, 33.4 mmol) followed by Et3N (2.93
mL, 21.0 mmol) and AcCl (0.74 mL, 10.5 mmol) gave (R)-5 as a
white solid (2.85 g, 83%): Rf = 0.40 (MeOH/CH2Cl2 1/20); mp 172−
1
173 °C; [α]26 −15.8° (c 1.1, CHCl3); H NMR (CDCl3) δ 2.00 (s,
D
3H), 3.37 (s, 3H), 3.49 (dd, J = 7.0, 9.0 Hz, 1H), 3.78 (dd, J = 4.0, 9.0
Hz, 1H), 4.43 (1/2HH′q, J = 5.8, 15.0 Hz, 1H), 4.49 (1/2HH′q, J =
5.8, 15.0 Hz, 1H), 4.62−4.67 (m, 1H), 6.71 (d, J = 6.8 Hz, 1H), 7.15−
7.18 (m, 1H), 7.30−7.52 (m, 8H); addition of excess (R)-
(−)-mandelic acid to a CDCl3 solution of (R)-5 gave only one signal
for the acetyl methyl and one signal for the ether methyl protons; 13C
NMR (CDCl3) δ 23.3, 43.3, 52.7, 59.2, 72.1, 125.3, 127.3, 127.5,
128.1, 130.2, 134.8, 137.9, 139.1, 142.6, 170.3, 170.6; the remaining
aromatic peak was not detected and is believed to overlap with the
observed signals; LRMS (ESI+) 383.1 [M + Na]+ (calcd for
C19H21ClN2O3Na+ 383.1). Anal. (C19H21ClN2O3) C, H, Cl, N.
(R)-N-(4″-Chlorobiphenyl-4′-yl)methyl 2-Acetamido-3-me-
thoxypropionamide ((R)-6). Using method 1, (R)-58 (2.80 g, 6.7
mmol), and 4 M HCl (6.70 mL, 26.7 mmol) followed by Et3N (2.10
mL, 14.7 mmol) and AcCl (0.52 mL, 7.4 mmol) gave (R)-6 as a white
solid (1.83 g, 76%): Rf = 0.40 (MeOH/CH2Cl2 1/20); mp 215−216
°C; [α]26D −16.9° (c 1.1, CHCl3); 1H NMR (CDCl3) δ 2.03 (s, 3H),
3.39 (s, 3H), 3.44−3.48 (m, 1H), 3.82 (dd, J = 4.0, 9.2 Hz, 1H), 4.45−
4.61 (m, 3H), 6.45−6.49 (br d, 1H), 6.86−6.91 (m, 1H), 7.32 (d, J =
8.0 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.48−7.52 (m, 4H); addition of
excess (R)-(−)-mandelic acid to a CDCl3 solution of (R)-6 gave only
one signal for the acetyl methyl and one signal for the ether methyl
protons; 13C NMR (CDCl3) δ 23.4, 43.4, 52.7, 59.3, 71.9, 127.5, 128.2,
128.5, 129.2, 133.7, 137.5, 139.3, 139.4, 170.3, 170.5; LRMS (ESI+)
361.2 [M + H]+ (calcd for C19H21ClN2O3H+ 361.2). Anal.
(C19H21ClN2O3) C, H, Cl, N.
+
C20H22N3O3+ 352.2); HRMS (ESI+) 352.1660 [M + H]+ (calcd for
C20H22N3O3 352.1661). Anal. (C20H21N3O3) C, H, N.
(R)-N-(3″-Trifluoromethylbiphenyl-4′-yl)methyl 2-Acetami-
do-3-methoxypropionamide ((R)-10). Using method 1, 4 M HCl
in dioxane (3.0 mL), (R)-62 (1.34 g, 3.0 mmol), Et3N (896 mg, 8.9
mmol), and AcCl (348 g, 4.4 mmol) gave compound (R)-10 as a white
solid (1.02 g, 88%): Rf = 0.42 (1:20 MeOH/CH2Cl2); mp 161−162
°C; [α]24D −13.7° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 2.03 (s, 3H),
3.40 (s, 3H), 3.49 (dd, J = 4.3, 9.3 Hz, 1H), 3.81 (dd, J = 4.3, 9.3 Hz,
1H), 4.45−4.58 (m, 2H) 4.61−4.64 (m, 1H), 6.58 (d, J = 7.0 Hz, 1H),
7.04 (t, J = 5.3 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.51−7.62 (m, 4H),
7.73 (d, J = 7.4 Hz, 1H), 7.80 (s, 1H); addition of excess (R)-
(−)-mandelic acid to a CDCl3 solution of (R)-10 gave only one signal
for the acetyl methyl and one signal for the ether methyl protons; 13C
NMR (CDCl3) δ 23.1, 43.1, 52.5, 59.1, 71.7, 123.7 (q, J = 4.0 Hz),
124.0 (q, J = 4.0 Hz), 124.1 (q, J = 272.0 Hz), 126.0, 127.4, 129.2,
130.2, 131.2 (q, J = 32.0 Hz), 137.9, 138.9, 141.4, 170.1, 170.4; MS
+
(ESI+) 395.2 [M + H]+ (calcd for C20H22F3N2O3 395.2); HRMS
+
(ESI+) 395.1583 [M + H]+ (calcd for C20H22F3N2O3 395.1582).
Anal. (C20H21F3N2O3) C, H, F, N.
(R)-N-(3″-Trifluoromethoxybiphenyl-4′-yl)methyl 2-Acet-
amido-3-methoxypropionamide ((R)-11). Using method 1, (R)-
63 (2.14 g, 4.6 mmol) and 4 M HCl (4.00 mL, 16.0 mmol) followed
by Et3N (1.40 mL, 10.1 mmol) and AcCl (0.36 mL, 5.0 mmol) gave
(R)-11 as a white solid (1.69 g, 90%): Rf = 0.40 (MeOH/CH2Cl2 1/
(R)-N-(3″-Bromobiphenyl-4′-yl)methyl 2-Acetamido-3-me-
thoxypropionamide ((R)-7). Using method 1, 4 M HCl in dioxane
(3.5 mL), (R)-59 (1.30 g, 2.8 mmol), Et3N (862 mg, 8.5 mmol), and
AcCl (268 mg, 3.4 mmol) gave compound (R)-7 as a white solid (620
20); mp 139−140 °C; [α]26 −13.5° (c 1.3, CHCl3); 1H NMR
D
(CDCl3) δ 2.03 (s, 3H), 3.40 (s, 3H), 3.47 (dd, J = 7.4, 9.2 Hz, 1H),
3.82 (dd, J = 4.0, 9.2 Hz, 1H), 4.46−4.61 (m, 3H), 6.49 (d, J = 6.4 Hz,
1H), 6.89−6.93 (m, 1H), 7.18−7.21 (m, 1H), 7.33−7.54 (m, 7H);
addition of excess (R)-(−)-mandelic acid to a CDCl3 solution of (R)-
11 gave only one signal for the acetyl methyl and one signal for the
ether methyl protons; 13C NMR (DMSO-d6) δ 22.5, 41.7, 52.7, 58.2,
72.1, 119.1, 119.6, 120.1 (q, J = 254.9 Hz), 125.7, 126.7, 127.7, 130.8,
136.8, 139.5, 142.3, 149.0, 169.4, 169.8; LRMS (ESI+) 433.1 [M +
Na]+ (calcd for C20H21F3N2O4Na+ 433.1). Anal. (C20H21F3N2O4) C,
H, F, N.
mg, 54%): Rf = 0.44 (1:20 MeOH/CH2Cl2); mp 171−173 °C; [α]26
D
1
−17.3° (c 1.0, CHCl3); H NMR (CDCl3) δ 2.00 (s, 3H), 3.37 (s,
3H), 3.45−3.49 (m, 1H), 3.79 (dd, J = 4.0, 9.0 Hz, 1H), 4.40−4.55
(m, 2H), 4.56−4.66 (m, 1H), 6.60 (d, J = 6.4 Hz, 1H), 6.98−7.08 (br
s, 1H), 7.24−7.35 (m, 3H), 7.39−7.56 (m, 4H), 7.68 (s, 1H); addition
of excess (R)-(−)-mandelic acid to a CDCl3 solution of (R)-7 gave
only one signal for the acetyl methyl and one signal for the ether
methyl protons; 13C NMR (CDCl3) δ 23.1, 43.1, 52.5, 59.1, 71.8,
122.9, 125.6, 127.3, 127.9, 130.0, 130.2, 130.3, 137.6, 138.8, 142.7,
170.1, 170.3; LRMS (ESI+) 405.0 [M + H]+ (100%), 407.0 [M + 2 +
(R)-N-(4″-Trifluoromethoxybiphenyl-4′-yl)methyl 2-Acet-
amido-3-methoxypropionamide ((R)-12). Using method 1, (R)-
6179
dx.doi.org/10.1021/jm500707r | J. Med. Chem. 2014, 57, 6165−6182