ChemMedChem
10.1002/cmdc.201900717
FULL PAPER
phe)13C NMR (DMSO-d
N1CH ), 41.9 (N3CH ), 42.0 (C6), 44.7 (C8), 50.5 (N9CH
27.9 (C4, phe), 129.2 (C6, phe), 129.5 (C5, phe), 129.9 (C3, phe), 132.7
C2, phe), 134.8 (C1, phe), 148.6 (C10a), 151.2 (C9a), 151.8 (C2), 153.0
), 21.2 (CH
), 21.4 (C7), 29.8
), 102.6 (C4a),
9-(2-chloro-6-fluorobenzyl)-1,3-diethyl-6,7,8,9-
tetrahydropyrimido[2,1-f]purine-2,4(1H,3H)-dione (16b)
6
) δ ppm: 11.7 (CH
3
2
(
1
(
(
3
2
2
Yield: 136 mg; 61 %; mp: 162-163 °C; 1H NMR (500 MHz, DMSO-d
6
) δ
C4). UPLC/MS purity 95.74 %, t
M+H] 388.18.
R
5 2
= 7.08, C19H22ClN O , MW 387,87,
ppm 1.03 (t, J=7.16 Hz, 3 H, N3CH
N1CH CH ) 1.95 - 2.01 (m, 2 H, C7H ) 3.20 - 3.24 (m, 2 H, C8H
J=6.87 Hz, 2 H, N3CH ) 3.89 (q, J=7.26 Hz, 2 H, , N1CH ) 4.01 (t, J=6.01
Hz, 2 H, C6H ) 4.75 (s, 2 H, N9CH ) 7.18 - 7.23 (m, 1 H, C4H, phe) 7.29 -
7.32 (m, 1 H, C3H, phe) 7.34 - 7.39 (m, 1 H, C5H, phe); 13C NMR
2 3
CH ) 1.11 (t, J=7.16 Hz, 3 H,
+
[
2
3
2
2
) 3.80 (q,
2
2
9-(2-chloro-6-fluorobenzyl)-1-methyl-3-propyl-6,7,8,9-
2
2
tetrahydropyrimido[2,1-f]purine-2,4(1H,3H)-dione (14b)
(
CHLOROFORM-d) δ ppm: 13.7 (N3CH
2
CH
3
), 13.9 (N1CH
2
CH
3
), 21.4
3
Yield: 125 mg; 57 %; mp: 157-158 °C; 1H NMR (300 MHz, DMSO-d
ppm 0.81 (t, J=7.33 Hz, 3 H, CH CH ) 1.42 - 1.56 (m, 2 H, N3CH CH
.95 - 2.03 (m, 2 H, C7H ) 3.20 (t, J=5.57 Hz, 2 H, C8H ) 3.32 (s, 3 H,
N1CH ) 3.70 - 3.77 (m, 2 H, N3CH ) 4.03 (t, J=6.15 Hz, 2 H, C6H ) 4.78
s, 2 H, N9CH ) 7.20 - 7.28 (m, 1 H, C4H, phe) 7.32 - 7.45 (m, 2 H,
(C7), 35.5 (N3CH ), 38.1 (N1CH
Hz, N9CH
2JC,F = 17.5 Hz, C1, phe), 126.2 (d, JC,F = 3.0 Hz, C3, phe), 131.1 (d, 3JC,F
2
2
), 41.8 (C6), 44.3 (C8), 44.6 (d, JC,F = 3.0
6
) δ
2
)
), 102.7 (C4a), 115.1 (d, 2JC,F = 22.9 Hz, C5, phe), 122.7 (d,
2
2
3
2
4
1
2
2
=
9.7 Hz, C4, phe), 135.7 (d, 3JC,F = 5.4 Hz, C2, phe), 148.0 (C10a), 150.6
C9a), 151,7 (C2), 152.9 (C4), 162.3 (d, 1JC,F = 249.3 Hz, C6, phe).
3
2
2
(
(
2
R 5 2
UPLC/MS purity 98.12 %, t = 7.14, C19H21ClFN O
, MW 405,86, [M+H]+
C3H/C5H, phe); 3C NMR (DMSO-d
1
) δ ppm: 11.64 (CH
), 21.3 (CH
), 43.9 (C6), 44.4
6
3
2
), 21.4
), 41.9 (d, 3
J
C,F = 11.5 Hz, N9CH
), 45.9 (C8), 102.5 (C4a), 115.1 (d, JC,F = 23 Hz, C5, phe), 121.4
d, 2JC,F = 17.3 Hz, C1, phe), 126.2 (d, 4JC,F = 3.4 Hz, C3, phe), 131.1 (d,
406.19.
(
(
(
C7), 29.7 (N1CH
3
2
2
N3CH
2
7-(3-Bromopropyl)-8-(hydroxymethyl)-1,3-dimethyl-1H-purine-
2,6(3H,7H)-dione (18)
3
C,F = 10.4 Hz, C4, phe), 135.6 (d, 3JC,F = 5.7 Hz, C2, phe), 148.5 (C10a),
J
1
51.2 (C9a), 151,6 (C2), 153.1 (C4), 160.5 (C6, phe). UPLC/MS purity
+
97.21 %, t
R
5 2
= 6.97, C19H21ClFN O , MW 405,86, [M+H] 406.19.
8-(hydroxymethyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (17) (2.10 g,
10.0 mmol) was dissolved in DMF (20 mL), and potassium carbonate (4.15
9
-(2-chlorobenzyl)-1-methyl-3-(prop-2-yn-1-yl)-6,7,8,9-
g, 30.0 mmol) and 1,3-dibromopropane (6.06 g, 30.0 mmol) were added.
The solution was stirred for 5 h at 110 °C. Then, the volatiles were removed
in vacuo and the residue was purified by flash chromatography (silica gel,
tetrahydropyrimido[2,1-f]purine-2,4(1H,3H)-dione (15a)
1
2 2
CH Cl /MeOH 19:1). Yield: 2.12 g, 65%; mp: 203 °C;
Yield: 99 mg; 47 %; mp: 230-232 °C; H NMR (300 MHz, DMSO-d
6
) δ ppm
2
.06 - 2.15 (m, 2 H, C7H
N1CH ) 3.35 (m, 2 H C8H
Hz, 2 H, N3CH ) 4.77 (s, 2 H, N9CH
phe) 7.44 - 7.50 (m, 1 H, C6H, phe); 13C NMR (DMSO-d
2
) 3.03 (t, J=2.34 Hz, 1 H, C≡CH) 3.30 (s, 3 H,
) 4.12 (t, J=5.86 Hz, 2 H, C6H ) 4.53 (d, J=2.34
) 7.28 - 7.38 (m, 3 H, C3H/C4H/C5H/,
) δ ppm: 21.1
), 41.9 (C6), 44.7 (C8), 50.5 (N9CH ),
2.9 (C≡CH), 80.5 (C≡CH), 102.4 (C4a), 127.9 (C4, phe), 129.3 (C6,
3
2
2
General procedure for tetrahydrodiazepino [2,1-f]purinediones (20a-
f)
2
2
6
(C7), 29.9 (N1CH
3
), 30.0 (N3CH
2
2
According to a previously published procedure [49] 7-(3-bromopropyl)-8-
7
(
6
hydroxymethyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (18) (2.20 g,
.71 mmol) was dissolved in CH Cl (60 mL) and cooled to 0 °C. A solution
of PBr (2.00 mL, 20.7 mmol) in CH Cl (40 mL) was added dropwise. The
solution was allowed to warm to room temperature and stirred for 1 h. Then
it was cooled again to 0 °C and excess PBr was hydrolysed by addition
of saturated aqueous NaHCO (25 mL). The organic layer was then
separated, and the aqueous layer extracted with CH Cl (2x50 mL). The
combined organic extracts were dried (MgSO ), and the solvent was
phe), 129.5 (C5, phe), 130.0 (C3, phe), 132.8 (C2, phe), 134.7 (C1, phe),
2
2
1
49.0 (C10a), 150.65 (C9a), 151.9 (C2), 152.0 (C4). UPLC/MS purity
3
2
2
+
96.71 %, t
R
5 2
= 6.60, C19H18ClN O , MW 383,84, [M+H] 384.13.
3
9-(2-chloro-6-fluorobenzyl)-1-methyl-3-(prop-2-yn-1-yl)-6,7,8,9-
3
tetrahydropyrimido[2,1-f]purine-2,4(1H,3H)-dione (15b)
2
2
4
Yield: 137 mg; 62 %; mp: 216-218 °C; 1H NMR (500 MHz, DMSO-d
evaporated in vacuo. The crude 7-(3-bromopropyl)-8-(bromomethyl)-1,3-
dimethylpurine-2,4-dione (19) was divided for six equal parts and used
directly in the next step. Compound 19 (~1.00 mmol), the appropriate
amine (2.00 mmol), n-propanol (2 ml) and TEA (0.4 ml) were heated in a
microwave reactor (300 Watt, Power Max On, 150 °C, 10 bar) for 1 h. The
solvent was removed under reduced pressure and the residue was purified
by flash chromatography (dichloromethane: methanol 9:1).
6
) δ
ppm 1.98 (br. s., 2 H, C7H
C8H ) 3.32 (s, 3 H, N1CH
H, N3CH
m, 1 H, C3H, phe) 7.36 - 7.41 (m, 1 H, C5H, phe); 3C NMR (DMSO-d
2
) 3.00 (br. s., 1 H, C≡CH) 3.19 (br. s., 2 H,
2
3 2
) 4.01 (t, J=5.44 Hz, 2 H, C6H ) 4.49 (br. s., 2
2
2
) 4.78 (s, 2 H, N9CH ) 7.20 - 7.25 (m, 1 H, C4H, phe) 7.31 - 7.35
1
(
6
) δ
), 41.9 (C6), 44.0 (C8),44.5
d, 3
2
JC,F = 3.0 Hz, N9CH ), 73.0 (C≡CH), 80.6 (C≡CH), 102.4 (C4a),
3 2
ppm: 21.3 (C7), 29.9 (N1CH ), 30.0 (N3CH
(
1
1
(
(
15.2 (d, 2JC,F = 22.3 Hz, C5, phe), 122.4 (d, 2
J
C,F = 17.5 Hz, C1, phe),
26.3 (d, JC,F = 3.1 Hz, C3, phe), 131.3 (d, 3JC,F = 9.6 Hz, C4, phe), 135.7
4
9-benzyl-1,3-dimethyl-7,8,9,10-tetrahydro-1H-[1,4]diazepino[2,1-
f]purine-2,4(3H,6H)-dione(20a)
d, 3JC,F = 6.0 Hz, C2, phe), 149.0 (C10a), 150.8 (C9a), 151,9 (C2), 152.0
C4), 160.5 (C6, phe). UPLC/MS purity 95.99 %, t
MW 401,83, [M+H] 402.14
R
= 6.48, C19
H
17ClFN
5
O ,
2
+
1
Yield: 278 mg, 82.1 %; mp: 195-196 °C; H NMR (400 MHz, DMSO-d6)
ppm 1.85 (br. s., 2 H, C7H2), 3.00 - 3.05 (m, 2 H, C8H
N3CH ), 3.40 (s, 3 H, N1CH ), 3.55 (s, 2 H, C10H ), 3.96 (s, 2 H, N9CH
4.58 - 4.63 (m, 2 H, C6H ), 7.26 - 7.34 (m, 5 H, phe); C NMR (DMSO-
d6) δ ppm: 25.24 (C7), 28.00 (N3CH ), 29.89 (N1CH ), 45.19 (C6), 52.13
(C10), 56.35 (N9CH ), 57.91 (C8), 107.14 (C4a), 127.55 (C4, phe), 128.70
C3, C5, phe), 129.23 (C2, C6, phe), 138.77 (C1, phe), 147.13 (C11a),
2
), 3.23 (s, 3 H,
9
-(2-bromobenzyl)-1,3-diethyl-6,7,8,9-tetrahydropyrimido[2,1-
3
3
2
2
),
13
f]purine-2,4(1H,3H)-dione (16a)
2
3
3
Yield: 126 mg; 53 %; mp: 145-147 °C; 1H NMR (300 MHz,
CHLOROFORM-d) δ ppm 1.26 (dt, J=18.17, 7.03 Hz, 6 H, 2 x CH CH
) 4.00 -
) 4.86 (s, 2 H, N9CH
.13 - 7.20 (m, 1 H, C5H, phe) 7.27 - 7.38 (m, 2 H, C6H/C4H, phe) 7.58
2
(
2
3
)
151.37 (C2), 154.40 (C4), 155.03 (C10a); UPLC/MS purity 99.45 %, tR =
.04, C18 , MW 339.39, [M+H]+ 340.13
2
4
7
.15 (dt, J=11.72, 5.86 Hz, 2 H, C7H
.12 (m, 4 H, CH CH ) 4.25 (t, J=5.86 Hz, 2 H, C6H
2 2
) 3.30 - 3.35 (m, 2 H, C8H
3
21 5 2
H N O
2
3
2
2
)
(
1
(
1
dd, J=7.62, 1.17 Hz, 1 H, C3H, phe); 13C NMR (CHLOROFORM-d) δ ppm:
3.4 (N3CH CH ), 13.5 (N1CH CH ), 21.5 (C7), 36.0 (N3CH ), 38.3
N1CH ), 41.7 (C6), 44.3 (C8), 52.7 (N9CH ), 103.3 (C4a), 123.8 (C2, phe),
27.7 (C5, phe), 129.2 (C4, phe), 129.6 (C6, phe), 133.0 (C3, phe), 136.0
9-(2-chlorobenzyl)-1,3-dimethyl-7,8,9,10-tetrahydro-1H-
[1,4]diazepino[2,1-f]purine-2,4(3H,6H)-dione (20b)
2
3
2
3
2
2
2
Yield: 248 mg, 66.2 %; mp 156-157 °C; 1H NMR (400 MHz, DMSO-d
6
)
(
C1, phe), 148.3 (C10a), 150.6 (C9a), 151.7 (C2), 153.8 (C4). UPLC/MS
ppm 1.89 (br. s., 2 H, C7H
2
), 3.06 - 3.10 (m, 2 H, C8H
2
), 3.22 (s, 3 H,
+
purity 99.43 %, t
R
5 2
= 7.41, C19H22BrN O , MW 432,32, [M+H] 434.18
N3CH ), 3.40 (s, 3 H, N1CH
2
2
), 3.60 (s, 2 H, C10H ), 4.00 (s, 2 H, N9CH
2
2
),
1
1
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