Journal of Medicinal Chemistry
Article
1
product was used without further purification. H NMR (400 MHz,
stirring for 1 h. The organic phase was washed with water (3 × 15
mL) and brine (15 mL) and concentrated. The resulting crude was
purified by automated flash chromatography and evaporated. The
Boc-protected intermediate was deprotected with TFA (2 mL, 26
mmol) in CH Cl (5 mL) for 18 h. The reaction mixture was
CDCl ): δ 7.46 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 2.0 Hz, 2H), 6.80
dd, J = 8.2, 2.1 Hz, 2H), 3.63 (t, J = 6.7 Hz, 4H), 3.35 (s, 4H), 3.30−
.21 (m, 4H), 1.36 (h, J = 3.2 Hz, 8H). C NMR (101 MHz,
3
(
3
13
CDCl ): δ 170.1, 149.2, 135.5, 134.9, 134.1, 131.4, 129.1, 122.2, 59.7,
3
2
2
7
26
9
+
5
0.9, 44.3, 41.5, 26.1, 25.1. HRMS-ESI: C H Br Cl N NaO [M
concentrated, and the crude product was purified by RP automated
2
6
2
2
8
3
+
+
Na] calcd, 748.9764; found, 748.9777.
flash chromatography and lyophilized to afford 6a (160 mg, 7%) as
1
1
,3-Bis(4-azidobutyl)-5,5-bis(3,5-dibromobenzyl)pyrimidine-
,4,6-(1H,3H,5H)-trione (5e). To a stirred solution of 4e (239 mg,
the TFA salt. H NMR (400 MHz, CD OD): δ 7.58 (d, J = 8.1 Hz,
3
2
4H), 7.28 (d, J = 8.1 Hz, 4H), 3.71−3.58 (m, 4H), 3.57 (s, 4H),
0
.26 mmol) in DMF (3 mL) was added NaN (52 mg, 0.8 mmol).
2.96−2.75 (m, 4H), 1.42 (p, J = 7.3 Hz, 4H), 1.30 (p, J = 7.3 Hz,
3
1
3
2
The reaction was stirred overnight until completion was indicated by
TLC (5% EtOAc in CHCl ). Then, the reaction mixture was diluted
with EtOAc (15 mL) and washed with water (2 × 20 mL). The
organic phase was dried over Na SO , filtered, and concentrated. The
crude product was dissolved in CHCl and adsorbed onto Celite
before purification on a silica column using 0−5% EtOAc in CHCl to
afford 5e (194 mg, 91%). H NMR (400 MHz, CDCl ): δ 7.54 (s,
4H). C NMR (101 MHz, CD OD): δ 171.4, 162.9 (q, J = 34.7
3 C,F
2
3
Hz, TFA), 150.7, 140.9, 131.5, 131.0 (q, J = 32.6 Hz), 126.6 (q,
JC,F = 3.8 Hz), 125.5 (q, J = 272.3 Hz), 118.2 (q, J = 292.5 Hz,
C,F C,F
C,F
1
3
1
2
4
TFA), 61.1, 45.8, 42.0, 40.0, 25.6 (overlap, two carbons). HRMS-ESI:
+
+
3
C H F N O [M + H] calcd, 587.2452; found, 587.2460.
28 33 6 4 3
3
1,3-Bis(4-aminobutyl)-5,5-bis(naphthalen-2-yl-methyl)-
pyrimidin-2,4,6(1H,3H,5H)-trione (6b). To a stirred solution of 5b
1
3
2
4
1
H), 7.14 (s, 4H), 3.73−3.58 (m, 4H), 3.33 (s, 4H), 3.31−3.22 (m,
(438 mg, 0.73 mmol) and Et N (0.22 mL, 1.59 mmol) in i-PrOH/
3
1
3
H), 1.58−1.29 (m, 8H). C NMR (101 MHz, CDCl ): δ 169.9,
THF (1:1, 4 mL) was added 1,3-propanedithiol (0.1 mL, 0.99 mmol).
3
49.1, 138.4, 133.8, 131.4, 123.3, 59.9, 50.9, 44.2, 41.6, 26.1, 25.3.
The mixture was stirred for 5 min before addition of NaBH (68 mg,
4
7
9
−
−
HRMS-ESI: C H Br ClN O [M + Cl] calcd, 848.8555; found,
1.81 mmol). After a 72 h reaction time, Boc O (333 mg, 1.53 mmol)
26
26
4
8
3
2
8
48.8564.
,3-Bis(4-azidobutyl)-5,5-bis(3,5-bis(trifluoromethyl)benzyl)-
pyrimidine-2,4,6-(1H,3H,5H)-trione (5f). To a stirred solution of 4f
101 mg, 0.12 mmol) in DMF (1 mL) was added NaN (23 mg, 0.35
and NaHCO (244 mg, 2.90 mmol) were added, and the reaction was
3
1
stirred for 18 h before being filtered through a pad of Celite and
concentrated. The resulting crude was purified by automated flash
chromatography and evaporated. The Boc-protected intermediate
(305 mg) was deprotected with TFA (2 mL, 26.1 mmol) in CH Cl
(
3
mmol). The reaction was stirred overnight. When full conversion was
reached according to MS analysis, the reaction mixture was diluted
with EtOAc (15 mL) and washed with water (3 × 20 mL). The
organic phase was dried over Na SO , filtered, and concentrated to
2
2
(5 mL) overnight. When MS analysis showed full deprotection, the
reaction mixture was concentrated, and the crude product was
purified by RP automated flash chromatography and lyophilized to
2
4
1
1
afford the crude of 5f (63 mg, 68%) as a white powder. H NMR (400
MHz, CDCl ): δ 7.78 (s, 2H), 7.53 (s, 4H), 3.59 (s, 4H), 3.57−3.48
afford 6b (287 mg, 90%) as the TFA salt. H NMR (400 MHz,
3
CD OD): δ 7.90−7.68 (m, 6H), 7.60 (s, 2H), 7.52−7.43 (m, 4H),
3
(
4
m, 4H), 3.19 (t, J = 6.7 Hz, 4H), 1.42−1.31 (m, 4H), 1.31−1.20 (m,
7.19 (d, J = 8.3 Hz, 2H), 3.70 (s, 4H), 3.59−3.50 (m, 4H), 2.56−2.37
H). 13C NMR (101 MHz, CDCl ): δ 169.6, 148.6, 137.0, 132.3 (q,
13
3
(m, 4H), 1.30−0.96 (m, 8H). C NMR (101 MHz, CD OD): δ
3
2
3
JC,F = 33.6 Hz), 129.9, 123.0 (q, J = 272.9 Hz), 122.8−121.9 (m),
172.2, 162.8 (q, J = 35.2 Hz, TFA), 151.0, 134.7, 134.1, 134.0, 129.9,
129.4, 128.8, 128.7, 128.2, 127.6, 127.3, 118.1 (d, J = 292.3 Hz, TFA),
62.0, 46.6, 41.7, 39.8, 25.6, 25.5. HRMS-ESI: C H N O [M + H]+
C,F
−
5
9.8, 50.6, 44.5, 41.6, 26.0, 24.9. HRMS-ESI: C H ClF N O [M
3
0
26
12
8
3
−
+
+
Cl] calcd, 809.1630; found, 809.1622.
,3-Bis(4-azidobutyl)-5,5-bis(4-tert-butylbenzyl)pyrimidine-2,4,6-
1H,3H,5H)-trione (5g). To a stirred solution of bromide 4g (2.40 g,
.47 mmol) in DMF (15 mL) was added NaN (678 mg, 10.4 mmol)
3
4
39
4
3
1
calcd, 551.3017; found, 551.3020.
1,3-Bis(4-aminobutyl)-5,5-bis((4-fluoronaphthalen-1-yl)methyl)-
pyrimidin-2,4,6(1H,3H,5H)-trione (6c). To a stirred solution of 5c
(
3
3
and stirred for 18 h. The reaction mixture was diluted with EtOAc (50
mL) and washed with water (4 × 50 mL). The organic phase was
dried over Na SO , filtered, and concentrated. The crude product 5g
(67 mg, 0.105 mmol) and Et N (0.03 mL, 0.21 mmol) in i-PrOH/
THF (1:1, 4 mL) was added 1,3-propanedithiol (0.1 mL, 0.99 mmol).
3
The mixture was stirred for 5 min before addition of NaBH (8 mg,
2
4
4
1
was isolated as a clear oil (2.16 g, 100%). H NMR (400 MHz,
0.21 mmol). After a 72 h reaction time, Boc O (48 mg, 0.22 mmol)
2
CDCl ): δ 7.20 (d, J = 7.7 Hz, 4H), 6.97 (d, J = 7.8 Hz, 4H), 3.59 (s,
and NaHCO (35 mg, 0.42 mmol) were added, and the reaction was
3
3
4
H), 3.40 (s, 4H), 3.21 (s, 4H), 1.37−1.28 (m, 8H), 1.24 (s, 18H).
stirred for 18 h before being filtered through a pad of Celite and
concentrated. The resulting crude was purified by automated flash
chromatography and evaporated. The Boc-protected intermediate (72
13
C NMR (101 MHz, CDCl ): δ 171.0, 150.8, 150.0, 132.0, 129.3,
3
1
25.5, 60.7, 50.9, 45.1, 41.1, 34.6, 31.4, 26.0, 24.8. HRMS-ESI:
+
+
C H N O Na [M + Na] calcd, 637.3577; found, 637.3583.
mg) was deprotected with TFA (0.2 mL, 2.61 mmol) in CH Cl (5
2 2
34
46
8
3
1
,3-Bis(4-azidobutyl)-5,5-bis(3,5-di-tert-butylbenzyl)pyrimidine-
mL) overnight. When MS analysis showed full deprotection, the
reaction mixture was concentrated, and the crude product was
purified by RP automated flash chromatography and lyophilized to
2
0
,4,6-(1H,3H,5H)-trione (5h). To a stirred solution of 4h (630 mg,
.78 mmol) in DMF (10 mL) was added NaN (140 mg, 2.15 mmol).
3
1
The reaction was stirred overnight. When full conversion was reached
according to MS analysis, the reaction mixture was diluted with
EtOAc (50 mL) and washed with water 4 × 50 mL. The organic
phase was dried over Na SO , filtered, and concentrated, affording the
crude product 5h (463 mg, 80%). H NMR (400 MHz, CDCl ): δ
.25 (t, J = 1.9 Hz, 2H), 6.87 (d, J = 1.7 Hz, 4H), 3.56 (t, J = 7.2 Hz,
H), 3.45 (s, 4H), 3.14 (t, J = 6.5 Hz, 4H), 1.25 (s, 44H). C NMR
101 MHz, CDCl ): δ 171.1, 151.1, 150.0, 134.4, 123.8, 121.6, 60.6,
0.8, 46.5, 41.3, 34.8, 31.6, 25.9, 25.1. HRMS-ESI: C H N NaO
M + Na] calcd, 749.4838; found, 749.4838.
yield 6c (82 mg, 89%) as the TFA salt. H NMR (400 MHz,
CD OD): δ 8.34 (d, J = 7.9 Hz, 2H), 8.07 (d, J = 7.7 Hz, 2H), 7.74−
3
7.53 (m, 4H), 7.38−7.19 (m, 2H), 7.08 (t, J = 8.9 Hz, 2H), 4.13 (s,
4H), 3.39−3.33 (m, 4H), 2.60 (t, J = 6.8 Hz, 4H), 1.20−1.00 (m,
2
4
1
13
4H), 0.94−0.71 (m, 4H). C NMR (101 MHz, CDCl
): δ 172.2,
3
3
2
1
7
4
(
5
[
163.11 (q, JC,F = 34.1 Hz, TFA), 159.6 (d, JC,F = 251.5 Hz), 150.8,
134.5 (d, JC,F = 4.4 Hz), 129.3 (d, JC,F = 4.5 Hz), 128.4 (d, JC,F = 8.5
1
3
Hz), 128.2, 127.6 (d, JC,F = 1.1 Hz), 126.3 (d, JC,F = 2.4 Hz), 125.2 (d,
3
+
1
J
C,F = 15.6 Hz), 121.5 (d, JC,F = 6.2 Hz), 118.23 (q, JC,F = 292.8 Hz,
4
2
62
8
3
+
TFA), 109.76 (d, JC,F = 20.2 Hz), 61.0, 41.7, 41.3, 39.9, 25.3, 25.1.
+
+
Reduction of Azides (5) to Amines (6). 1,3-Bis(4-aminobutyl)-
HRMS-ESI: C34
H
F
37
N
2
4
O
3
[M + H] calcd, 587.2828; found,
5
(
,5-bis(4-(trifluoromethyl)benzyl)pyrimidin-2,4,6(1H,3H,5H)-trione
587.2828.
6a). To a stirred solution of 5a (1.86 g, 2.90 mmol) and Et N (0.96
1,3-Bis(4-aminobutyl)-5,5-bis(4-bromo-3-chlorobenzyl)-
pyrimidine-2,4,6(1H,3H,5H)-trione (6d). To a stirred solution of 5d
3
mL, 6.89 mmol) in i-PrOH/THF (1:1, 10 mL) was added 1,3-
propanedithiol (0.1 mL, 0.99 mmol). The mixture was stirred for 5
(588 mg, 0.81 mmol) and Et N (0.23 mL, 1.69 mmol) in i-PrOH/
3
min before addition of NaBH (316 mg, 8.35 mmol). After a 48 h
THF (1:1, 10 mL) was added 1,3-propanedithiol (0.164 mL, 1.76
4
reaction time, Boc O (1.75 g, 8.02 mmol) and K CO (1.91 g, 13.8
mmol) were added, and the reaction was stirred for 18 h and
evaporated before adding EtOAc (20 mL) and water (15 mL) and
mmol). After a 48 h reaction time, Boc O (528 mg, 2.42 mmol) was
added, and the reaction mixture was stirred for 18 h and evaporated.
To the crude mixture was added EtOAc (20 mL) and water (15 mL)
2
2
3
2
P
J. Med. Chem. XXXX, XXX, XXX−XXX