Journal of Medicinal Chemistry
Article
reaction was stirred at room temperature for 4 h. At that point, the
reaction was diluted with EtOAc/H2O (30 mL, 1:1) and the layers
separated. The aqueous layer was basified to pH 10 with 6 N NaOH,
saturated by addition of solid K2CO3, and extracted with EtOAc (3 ×
15 mL). Combined organic fractions were dried over sodium sulfate,
and concentrated. The resulting light-yellow oil (0.527 g, 86%) was
clean by NMR and was used in the next step without further
purification. 1H NMR (500 MHz, CDCl3): δ 8.74 (d, J = 3.9 Hz, 1 H),
8.42 (s, 2 H), 7.48 (d, J = 6.9 Hz, 1 H), (7.42 (s), 7.34 (s), 3:2, 1 H),
7.20 (dd, J = 7.3, 4.9 Hz, 1 H), 3.66−3.54 (m, 2 H), 3.31 (s, 3 H),
3.24−3.03 (m, 4 H), 2.56 (t, J = 7.8 Hz, 2 H), 1.80 (p, J = 7 Hz, 2 H),
1.36 (s, 9 H). 13C NMR (126 MHz, CDCl3): δ 170.87, 165.81, 157.85,
155.27, 149.53, 147.30, 136.70, 135.74, 123.47, 123.37, 79.93, (47.30,
46.94, 1 C), 46.01, 39.05, (36.87, 36.33, 1 C), 30.11, (29.84, 29.58, 1
C), 28.25. MS (ESI) m/z [M + Na]+: calcd, 443.16; found, 443.03.
tert-Butyl 3-Cyanobenzyl-2-[2-(methylsulfonyl)pyrimidin-4-yl]-
ethyl Carbamate (54). Compound 54 (0.396 g, 91%) was obtained
as a colorless oil from 47 following the same procedure used to
Hz, 1 H), 7.88 (s, 1 H), 7.18 (q, J = 7.5 Hz, 1 H), 7.17−7.14 (m, 3 H),
(7.09 (s), 7.05 (s), 3:2, 1 H), 7.03 (d, J = 7.1 Hz, 1 H), 3.65−3.55 (m,
2 H), 3.25−3.14 (m, 2 H), 3.05−2.94 (m, 2 H), 2.57 (t, J = 7.7 Hz, 2
H), 1.83 (p, J = 7.6 Hz, 2 H), 1.39 (s, 9 H). 13C NMR (126 MHz,
CDCl3): δ 170.49, 158.39, (155.38, 155.21, 1 C), 154.40, 143.39,
136.01, 134.14, (130.34, 130.21, 1 C), 129.65, 128.34, 126.40, 126.15,
118.55, 116.54, 79.80, (47.27, 47.06, 1 C), (46.28, 46.12, 1 C), (36.99,
36.21, 1 C), 32.77, (29.91, 29.73, 1 C), 28.32. MS (ESI) m/z [M +
H]+: calcd, 442.19; found, 442.06.
tert-Butyl 2-[2-(1H-Imidazol-1-yl)pyrimidin-4-yl]ethyl[2-(3-
fluorophenyl)cyclopropyl]methylcarbamate (58). Pale-yellow oil
1
(0.366 g, 95%). H NMR (500 MHz, CDCl3): δ 8.60 (s, 1 H), 8.50
(d, J = 5.0 Hz, 1 H), 7.87 (s, 1 H), 7.17 (q, J = 8 Hz, 1 H), 7.14 (s, 1
H), (7.05 (s), 6.94 (d, J = 7.7 H), 2:3, 1 H), 6.87−6.78 (m, 2 H), 6.67
(dt, J = 2.5, 10.2 Hz, 1 H), 3.75−3.63 (m, 2 H), 3.41−3.30 (m, 1 H),
3.25−3.16 (m, 1 H), 3.08−2.95 (m, 2 H), 1.92−1.78 (m, 1 H), 1.41
(s, 9 H), 1.29−1.26 (m, 1 H), 0.98−0.93 (m, 2 H). 13C NMR (126
MHz, CDCl3): δ 170.40, (163.93, 161.98, d, J = 245.7 Hz, 1 C),
158.34, 155.26, 154.47, 145.25, 136.05, 130.44, (129.75, 129.68, d, J =
8.82 Hz, 1 C), 121.37, 118.41, 116.46, (112.53, 112.40, d, J = 16.38
Hz, 1 C), (112.40, 112.23, d, J = 21.42 Hz, 1 C), 79.89, (51.24, 50.73,
1 C), 46.24, (36.90, 36.07, 1 C), 28.32, 22.85, 22.08, 14.65. MS (ESI)
m/z [M + H]+: calcd, 438.2; found, 438.03.
1
synthesize 48 from 41. H NMR (500 MHz, CDCl3): δ 8.76 (d, J =
4.8 Hz, 1 H), 7.53 (d, J = 7.3 Hz, 1 H), 7.48−7.37 (m, 4 H), 4.46 (s, 2
H), 3.74−3.61 (m, 2 H), 3.33 (s, 3 H), 3.20−3.07 (m, 2 H), 1.38 (s, 9
H). 13C NMR (126 MHz, CDCl3): δ 170.46, 165.58, 157.79, (155.26,
154.98, 1 C), (139.96, 139.55, 1 C), (131.83, 131.28, 1 C), 130.75,
130.23, 129.26, 123.42, 118.36, 112.36, 80.49, (50.65, 49.71, 1 C),
45.59, 38.87, (36.34, 35.94, 1 C), 28.00. MS (ESI) m/z [M + Na]+:
calcd, 439.14; found, 438.99.
tert-Butyl 2-[2-(1H-Imidazol-1-yl)pyrimidin-4-yl]ethyl[2-(3-
fluorobenzyl)cyclopropyl]carbamate (59). Off-white sticky oil
1
(0.372 g, 91%). H NMR (500 MHz, CDCl3): δ 8.62 (s, 1 H), 8.52
(d, J = 5.0 Hz, 1 H), 7.88 (s, 1 H), 7.25−7.18 (m, 1 H), 7.16 (s, 1 H),
6.99 (s, 1 H), 6.96 (d, J = 7.6 Hz, 1 H), 6.91 (d, J = 9.8 Hz, 1 H), 6.87
(td, J = 8.5, 2.3 Hz, 1 H), (3.53 (t, J = 7 Hz), 3.50 (t, J = 7 Hz), 2:1, 2
H), 2.88 (t, J = 6.5 Hz, 2 H), 2.84 (dd, J = 10, 5 Hz, 1 H), 2.43 (dd, J =
14.0, 8.0 Hz, 1 H), 2.36 (dt, J = 7.2, 3.6 Hz, 1 H), 1.37 (s, 9 H), 1.23−
1.20 (m, 1 H), 0.86 (dt, J = 9.3, 5.3 Hz, 1 H), 0.72 (q, J = 6.1 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ 170.62, (163.80, 161.85, d, J = 245.7
Hz, 1 C), 158.30, 156.21, 154.36, (143.16, 143.11, d, J = 6.3 Hz, 1 C),
136.06, 130.30, (129.86, 129.80, d, J = 7.56 Hz, 1 C), (124.08, 124.06,
d, J = 2.52 Hz, 1 C), 118.39, 116.53, (115.29, 115.13, d, J = 20.16 Hz,
1 C), (113.09, 112.93, d, J = 20.16 Hz, 1 C), 79.83, 46.13, 37.67, 35.99,
34.88, 28.31, 23.02, 15.01. MS (ESI) m/z [2 M + Na]+: calcd, 897.43;
found, 897.32.
tert-Butyl 2-[2-(1H-Imidazol-1-yl)pyrimidin-4-yl]ethyl-3-fluoro-
phenethyl Carbamate (55). Compound 48 (0.335 g, 0.791 mmol)
was dissolved in MeCN (5 mL), and imidazole (0.269 g, 3.958 mmol)
and K2CO3 (0.22 g, 1.583 mmol) were added to the solution. The
resulting mixture was heated at 65 °C for 5 h, after which it was cooled
and diluted with CH2Cl2 (20 mL). Water (20 mL) was added to the
organic layer and the layers separated. The aqueous layer was washed
once with CH2Cl2 (15 mL), and the combined organics were dried
over anhydrous sodium sulfate, concentrated, and purified by flash
column chromatography using hexanes/EtOAc. The desired com-
pound (55) was obtained as an off-white viscous oil (0.247 g, 76%).
1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1 H), 8.53 (d, J = 4.9 Hz, 1
H), 7.88 (s, 1 H), 7.24 (q, J = 6.0 Hz, 1 H), 7.16 (s, 1 H), (7.08 (s),
6.97 (s), 3:2, 1 H), 6.94−6.82 (m, 3 H), (3.56 (t, J = 8.5 Hz), 3.47 (s),
3:2, 2 H), 3.43−3.36 (m, 2 H), (2.99 (t, J = 8.5 Hz), 2.90 (s), 3:2, 2
H), (2.84 (s), 2.79 (t, J = 7 Hz), 2:3, 2 H), 1.38 (s, 9 H). 13C NMR
(126 MHz, CDCl3): δ (170.39, 170.27, 1 C), (163.81, 161.85, d, J =
246.96 Hz, 1 C), (158.43, 158.33, 1 C), (155.18, 154.98, 1 C),
(154.55, 154.38, 1 C), (141.54, 141.47, d, J = 8.82 Hz, 1 C), 136.09,
(130.55, 130.47, 1 C), (130.00, 129.94, 1 C), (124.48, 124.46, d, J =
2.52 Hz, 1 C), 118.49, 116.48, (115.74, 115.57, d, J = 21.42 Hz, 1 C),
(113.38, 113.22, d, J = 20.16 Hz, 1 C), 79.87, (49.37, 49.23, 1 C),
(46.97, 46.21, 1 C), (36.84, 36.07, 1 C), (35.00, 34.29, 1 C), 28.23. MS
(ESI) m/z [M + H]+: calcd, 412.20; found, 412.08.
tert-Butyl 2-[2-(1H-Imidazol-1-yl)pyrimidin-4-yl]ethyl-3-(3-
1
pyridyl)propyl Carbamate (60). Pale-yellow oil (0.43 g, 84%). H
NMR (500 MHz, CDCl3): δ 8.57 (s, 1 H), 8.51 (d, J = 4.7 Hz, 1 H),
8.40 (s, 2 H), 7.84 (s, 1 H), 7.44 (s, 1 H), 7.17 (dd, J = 7.3, 4.9 Hz, 1
H), 7.12 (s, 1 H), (7.05 (s), 6.99 (s), 3:2, 1 H), 3.65−3.52 (m, 2 H),
3.25−3.14 (m, 2 H), 3.05−2.92 (m, 2 H), 2.56 (t, J = 7.8 Hz, 2 H),
1.82 (p, J = 7.6 Hz, 2 H), 1.36 (s, 9 H). 13C NMR (126 MHz,
CDCl3): δ 170.30, 158.33, 155.21, 154.43, 149.60, 147.38, 136.73,
136.03, 135.56, 130.45, 123.27, 118.40, 116.42, 79.76, (47.16, 46.97, 1
C), 46.22, (36.85, 36.09, 1 C), 30.14, (29.83, 29.58, 1 C), 28.22. MS
(ESI) m/z [M + H]+: calcd, 409.22; found, 409.08.
tert-Butyl 2-[2-(1H-Imidazol-1-yl)pyrimidin-4-yl]ethyl-(3-
cyanobenzyl)carbamate (61). Colorless oil (0.346 g, 90%). 1H
NMR (500 MHz, CDCl3): δ 8.57 (s, 1 H), 8.54 (d, J = 5.0 Hz, 1 H),
7.86 (s, 1 H), 7.52 (d, J = 7.3 Hz, 1 H), (7.46 (s), 7.42 (s), 1:1, 2 H),
7.40 (d, J = 7.4 Hz, 1 H), 7.15 (s, 1 H), (7.09 (s), 7.01 (s), 1:1, 1 H),
4.45 (s, 2 H), (3.71 (s), 3.64 (s), 1:1, 2 H), 3.04 (s), 3.00 (s), 1:1, 2
H), (1.45 (s), 1.38 (s), 1:1, 9 H). 13C NMR (126 MHz, CDCl3): δ
169.90, 158.35, (155.42, 155.02, 1 C), 154.26, 139.80, 135.85, 131.71,
131.17, 130.78, 130.57, 130.31, 129.21, 118.38, 116.31, 112.47, 80.52,
(50.73, 49.94, 1 C), 46.09, (36.33, 35.69, 1 C), 28.07. MS (ESI) m/z
[2 M + Na]+: calcd, 831.37; found, 831.33.
Chiral Resolution of 2-(3-Fluorobenzyl)cyclopropan-1-amine
(62). 2-(3-Fluorobenzyl)cyclopropan-1-amine (62; 0.851 g, 5.15
mmol) was diluted in CH2Cl2 (20 mL) and cooled to −20 °C. (S)-
(+)-α-Methoxylphenylacetic acid (1.0 g, 6.18 mmol) was added to the
resulting solution, followed by the addition of dicyclohexylcarbodii-
mide (1.275 g, 6.18 mmol). The reaction mixture was gradually
warmed to room temperature and stirred overnight. The resulting
suspension was filtered, and the white precipitate was washed with
cold CH2Cl2 (15 mL). The combined filtrate was concentrated and
Compounds 56−61 were synthesized from compounds 49−54
following the same procedures used to synthesize 55.
tert-Butyl 2-[2-(1H-Imidazol-1-yl)pyrimidin-4-yl]ethyl-3-(3-
fluorophenyl)propylcarbamate (56). Colorless viscous oil (0.587 g,
1
87%). H NMR (500 MHz, CDCl3): δ 8.59 (s, 1 H), 8.52 (d, J = 4.1
Hz, 1 H), 7.86 (s, 1 H), 7.21 (q, J = 7 Hz, 1 H), 7.15 (s, 1 H), (7.07
(s), 7.00 (s), 3:2, 1 H), 6.91 (d, J = 7.5 Hz, 1 H), 6.88−6.81 (m, 2 H),
3.66−3.54 (m, 2 H), 3.24−3.14 (m, 2 H), 3.04−2.94 (m, 2 H), 2.58 (t,
J = 7.7 Hz, 2 H), 1.83 (p, J = 7.6 Hz, 2 H), 1.38 (s, 9 H). 13C NMR
(126 MHz, CDCl3): δ (170.42, 170.32, 1 C), (163.79, 161.84, d, J =
245.7 Hz, 1 C), (158.40, 158.31, 1 C), (155.36, 155.12, 1 C), (154.54,
154.39, 1 C), (144.04, 143.90, d, J = 17.6 Hz, 1 C), 136.09, 130.52,
(129.81, 129.74, d, J = 8.82 Hz, 1 C), (123.84, 123.82, d, J = 2.52 Hz, 1
C), 118.43, 116.45, (115.08, 114.91, d, J = 21.42 Hz, 1 C), (112.87,
112.70, d, J = 21.42 Hz, 1 C), 79.73, (47.24, 46.97, 1 C), (46.27, 46.08,
1 C), (36.91, 36.15, 1 C), 32.76, (29.86, 29.60, 1 C), 28.27. MS (ESI)
m/z [2 M + Na]+: calcd, 873.43; found, 873.39.
tert-Butyl 2-[2-(1H-Imidazol-1-yl)pyrimidin-4-yl]ethyl-3-(3-
chlorophenyl)propylcarbamate (57). Colorless viscous oil (0.541 g,
1
91%). H NMR (500 MHz, CDCl3): δ 8.63 (s, 1 H), 8.54 (d, J = 4.9
Q
dx.doi.org/10.1021/jm501719e | J. Med. Chem. XXXX, XXX, XXX−XXX