572
A.C. Reiersølmoen et al. / European Journal of Medicinal Chemistry 155 (2018) 562e578
2
0
1
1
yellow oil, 1.14 g (2.30 mmol, 91%); ½
a
ꢄ
¼ ꢃ73.4 (c 1.01, CHCl
3
); H
): 8.19 (s, 1H), 7.60 (s, 1H), 7.44e7.42 (m,
H), 7.35e7.33 (m, 2H), 7.27e7.23 (m, 1H), 6.53e6.51 (m, 1H), 5.46
6
318 mg (0.509 mmol, 81%); H NMR (600 MHz, DMSO‑d ): 8.36 (s,
D
NMR (400 MHz, DMSO‑d
6
1H), 8.20 (s, 1H), 7.973e7.966 (m, 1H), 7.74 (s, 1H), 7.56e7.53 (m,
1H), 7.49e7.44 (m, 1H), 7.33e7.29 (m, 2H), 7.25e7.23 (m, 1H),
2
(
0
s, 2H) 5.50e5.43 (m, 1H), 3.38 (t, J ¼ 8.1, 2H), 1.57 (d, J ¼ 6.9, 3H),
7.20e7.15 (m, 1H), 5.51 (s, 2H), 5.24 (s, 2H), 3.51 (t, J ¼ 8.1, 2H), 0.83
13
13
.80 (t, J ¼ 8.1, 2H), ꢃ0.10 (s, 9H);
):155.9, 153.0, 150.7, 145.1, 130.7, 129.5 (2C), 127.9, 126.7
2C), 103.5 73.1, 66.5, 51.9, 50.2, 23.8, 18.0, ꢃ0.5 (3C); IR (neat,
C
NMR (100 MHz,
(t, J ¼ 8.1, 2H), ꢃ0.08 (s, 9H); C NMR (150 MHz, DMSO- d
6
): 162.2
DMSO‑d
(
6
(d, J ¼ 243.7), 153.4, 151.6, 150.3, 149.3, 139.7 (d, J ¼ 7.9), 132.9, 131.2,
130.6 (d, J ¼ 8.9), 123.3 (d, J ¼ 2.2), 122.7, 121.3, 120.9, 114.7 (d,
J ¼ 20.6), 114.6, 114.0 (d, J ¼ 21.9), 103.7, 72.2, 69.4 (d, J ¼ 1.5), 65.7,
ꢃ1
cm ): 3405 (w), 2947 (w, br), 1593 (s), 1547 (s), 1466 (m), 1075 (s),
9
4
1
9
28 (m), 831 (s), 694 (s), 651 (m); HRMS (APCI/ASAPþ, m/z): found
51.0, 17.1, ꢃ1.4 (3C); F NMR (376 MHz, DMSO‑d
6
, C
6
F
6
): ꢃ115.4 (s,
þ
ꢃ1
95.1075, (calcd C20
H
28
N
4
OSiI, 495.1077, [MþH] ).
dec.); IR (neat, cm ): 3377 (w), 2940 (w, br),1605 (s),1564 (s),1501
(
s), 1465 (s), 1247 (m), 1081 (s), 831 (s); HRMS (APCI/ASAPþ, m/z):
þ
4
(
.3.7. tert-Butyl-(R)-(4-(4-((1-phenylethyl)amino)-7-((2-
trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidin-5-yl)
found 625.0690, (calcd C25
H
28
N
4
O
2
FClSi, 625.0699, [MþH] ).
phenyl)carbamate (6)
4.3.10. 3-(4-((3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-7-
((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidin-5-
yl)phenol (9)
The synthesis was performed as described in Section 4.3.1, and
starting with compound 5 (350 mg, 0.707 mmol) and 4-(N-Boc-
amino)phenylboronic acid (203 mg, 0.856 mmol). The reaction
time was 10 min. Purification by silica-gel column chromatography
Compound 9 was made as described in Section 4.3.1 starting
with compound 8 (111 mg, 0.178 mmol) and (3-hydroxyphenyl)
boronic acid (156 mg, 0.250 mmol). The reaction mixture was stir-
(
n-pentane/EtOAc, 3/1, R
f
¼ 0.67) gave 352 mg (0.629 mmol, 89%) of
20
1
ꢂ
a white solid; ½
a
ꢄ
¼ ꢃ124.7 (c 1.08, CHCl
3
); H NMR (400 MHz,
red at 100 C for 67 h without going to completion. Silica-gel col-
D
DMSO‑d
6
): 9.49 (s, 1H), 8.20 (s, 1H), 7.59e7.57 (ap.d, 2H), 7.40e7.31
umn chromatography (n-pentane/EtOAc,13/7, R
gave the product 9 as a clear oil, 51 mg (0.087 mmol, 45%); H NMR
(600 MHz, DMSO‑d
f
¼ 0.65) and drying
1
(
ap.d, 2H), 7.37 (s, 1H), 5.76 (s, 2H), 7.31e7.26 (m, 4H), 7.23e7.19 (m,
1
H), 5.57e5.56 (m, 1H), 5.39e5.32 (m, 1H), 3.54 (t, J ¼ 8.1, 2H), 1.50
6
): 9.66 (s, 1H), 8.40 (s, 1H), 7.89 (d, J ¼ 2.7, 1H),
13
(
s, 9H), 1.39 (d, J ¼ 6.9, 3H), 0.83 (t, J ¼ 8.1, 2H), ꢃ0.08 (s, 9H);
C
7.57 (s, 1H), 7.56 (s, 1H), 7.47e7.44 (m, 1H), 7.34e7.27 (m, 4H),
7.19e7.15 (m, 2H), 6.99e6.97 (m, 1H), 6.95e6.94 (m, 1H), 6.82e6.80
(m, 1H), 5.59 (s, 2H), 5.21 (s, 2H), 3.58 (t, J ¼ 8.1, 2H), 0.85 (t, J ¼ 8.1,
6
NMR (100 MHz, DMSO‑d ): 155.3, 152.7, 151.8, 150.3, 144.3, 138.8,
128.9 (2C), 128.4 (2C), 127.8, 126.8, 125.7 (2C), 123.0, 118.5 (2C),
1
3
1
15.6, 100.4, 79.2, 72.2, 65.5, 49.5, 28.1 (3C), 23.0, 17.1, ꢃ1.4 (3C);
2H), ꢃ0.07 (s, 9H); C NMR (150 MHz, DMSO‑d
6
): 162.2 (d,
HRMS (APCI/ASAPþ, m/z): found 560.3057, (calcd C31
H
42
N
5
O
3
Si,
J ¼ 245.2),157.9, 153.5, 151.3, 150.9, 148.9, 139.7 (d, J ¼ 7.8), 135.4,
133.5, 130.5 (d, J ¼ 8.2), 130.2, 124.5, 123.3 (d, J ¼ 3.3), 122.0, 121.3,
þ
5
60.3057, [MþH] ).
1
20.1, 119.2, 115.9, 115.3, 114.8, 114.7 (d, J ¼ 22.0), 114.3, 114.0 (d,
19
4.3.8. (R)-2-Fluoro-5-(4-((1-phenylethyl)amino)-7-((2-
J ¼ 22.0), 101.1, 72.3, 69.4, 65.7, 17.2, ꢃ1.4 (3C); F NMR (376 MHz,
ꢃ1
(
trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)
DMSO‑d
6
, C
6
F
6
): ꢃ115.4 (s, dec.); IR (neat, cm ): 3362 (w), 2914 (w,
benzaldehyde (7)
br), 1607 (m), 1563 (m), 1496 (m), 1470 (m), 1446 (m), 1289 (m),
1216 (m), 1082 (s), 1015 (m), 841 (m), 784 (s), 681 (m), 587 (m);
The synthesis was performed as described in Section 4.3.1
starting with compound 5 (399 mg, 0.808 mmol) and 4-fluoro-3-
formylphenylboronic acid (163 mg, 0.969 mmol). The reaction
time was 2 h. Purification by silica-gel column chromatography (n-
HRMS (APCI/ASAPþ, m/z): found 590.1907, (calcd C31
32 4 3
H N O FSiCl,
.
þ
590.1916, M ).
pentane/EtOAc, 3/1, R
f
¼ 0.53) and drying gave the product 7 as a
4.3.11. (R)-5-(4-Aminophenyl)-N-(1-phenylethyl)-7H-pyrrolo-[2,3-
d]pyrimidin-4-amine (10)
2
0
yellow oil, 325 mg (0.662 mmol, 82%), ½
a
ꢄ
¼ ꢃ143.2 (c 1.02,
): 10.27 (s, 1H), 8.23 (s, 1H),
.93e7.92 (m,1H), 7.88e7.86 (m,1H), 7.58 (s,1H), 7.54e7.51 (m,1H),
.34e7.32 (m, 2H), 7.28e7.26 (m, 2H), 7.21e7.18 (m, 1H), 5.83e5.82
m, 1H), 5.55 (s, 2H), 5.42e5.37 (m, 1H), 3.55 (t, J ¼ 8.1, 2H), 1.41 (d,
D
DMSO); 1H NMR (600 MHz, DMSO‑d
7
7
(
J ¼ 6.9, 3H), 0.83 (t, J ¼ 8.1, 2H), ꢃ0.08 (s, 9H); C NMR (150 MHz,
DMSO‑d
): 187.8 (d, J ¼ 4.4), 162.4 (d, J ¼ 257.9), 155.3, 151.9, 150.8,
44.6, 136.3 (d, J ¼ 9.0), 131.4 (d, J ¼ 3.0), 128.7, 128.2 (2C), 126.6,
Compound 6 (334 mg, 0.597 mmol) was double deprotected by
6
mixing with CH
2
Cl
2
(10 mL) and TFA (3 mL, 39.3 mmol) under a
ꢂ
nitrogen atmosphere. The mixture was stirred at 50 C for 3 h
3
before the solvent was removed and MeOH (15 mL) and NH -so-
lution (15 mL, 25%) was added. The reaction mixture was stirred
18 h before the solvent was removed. Work-up and purification by
13
6
1
silica-gel column chromatography (EtOAc, R
f
¼ 0.20) gave 167 mg
ꢂ
20
D
1
26.0 (2C), 124.2, 123.8 (d, J ¼ 8.8), 117.4 (d, J ¼ 20.6), 113.9, 100.0,
(0.503 mmol, 86%) of a yellow powder, mp. 138e140 C; ½ ꢄ
a
19
1
7
C
2.3, 65.6, 49.7, 22.5, 17.1, ꢃ1.4 (3C); F NMR (376 MHz, DMSO‑d
6
,
¼ ꢃ198.0 (c 0.99, CHCl
3 6
). H NMR (400 MHz, DMSO‑d ): 11.63 (s,
ꢃ1
F
6 6
): ꢃ125.5 (s, dec.); IR (neat, cm ): 3434 (w), 2956 (w, br), 1699
1H), 8.10 (s, 1H), 7.32e7.19 (m, 5H), 7.16e7.13 (ap.d, 2H), 7.04e7.05
(m,1H), 6.68e6.66 (ap.d, 2H), 5.51e5.49 (m,1H), 5.39e5.32 (m,1H),
(
(
m), 1558 (m), 1465 (m), 1252 (m), 1184 (m), 1075 (m), 831 (s), 696
13
s); HRMS (APCI/ASAPþ, m/z): found 491.2272, (calcd
5.21 (s, 2H), 1.37 (t, J ¼ 6.9, 3H); C NMR (100 MHz, DMSO‑d
6
):
þ
C
27
32
H N
4
O
2
FSi, [MþH] ).
155.3, 151.3, 150.3, 147.9, 144.5, 129.5 (2C), 128.4 (2C), 126.7, 125.7
ꢃ1
(2C), 121.9, 118.8, 115.9, 114.1 (2C), 100.5, 49.1, 23.3; IR (neat, cm ):
4
(
.3.9. N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-5-iodo-7-((2-
trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-
amine (8)
3403 (w), 3112 (w, br), 1584 (s), 1465 (m); HRMS (APCI/ASAPþ, m/
þ
z): found 330.1714, (calcd C20
20
H N
5
, 330.1719, [MþH] ).
3
-Chloro-4-((3-fluorobenzyl)oxy)aniline (333 mg, 1.32 mmol)
4.3.12. (R)-N-(4-(4-((1-Phenylethyl)amino)-7-propionyl-7H-
pyrrolo-[2,3-d]pyrimidin-5-yl)phenyl)propionamide (11)
2 2
Compound 10 (155 mg, 0.470 mmol) was dissolved in CH Cl
and n-BuOH (10 mL) were added to compound 2 (257 mg,
.630 mmol) under a nitrogen atmosphere. The reaction mixture
0
was refluxed for 2.5 h. Water (15 mL) and EtOAc (15 mL) were
added and phase separated. The water phase was extracted with
more EtOAc (2 ꢁ 15 mL). The combined organic phases were dried
(3 mL) and N,N-diisopropylethylamine (0.100 ml, 0.560 mmol) and
cooled to 0 C. Propinoyl chloride (0.0450 mL, 0.520 mmol) was
added dropwise under a nitrogen atmosphere. The reaction
mixture was stirred for 2 h before the reaction was quenched with
ꢂ
2 4
over anhydrous Na SO , filtered and concentrated in vacuo. The
crude product was purified by silica-gel column chromatography
n-pentane/EtOAc, 3/1, R
¼ 0.65) and dried to give a light brown oil,
saturated aqueous NaHCO
phases separated, and the water phase was extracted with more
3
(30 mL). EtOAc (50 mL) was added, the
(
f