Molecules 2019, 24, 983
14 of 18
1
0.5 (dichloromethane–methanol = 10:1). H NMR (DMSO-d6, 400 MHz)
δ
7.77–7.84 (m, 1H, Ar-H), 7.21
(d, J = 3.2 Hz, 1H, Ar-H), 6.96 (s, 2H, NH2), 6.61–6.69 (m, 1H, Ar-H), 6.02 (d, 1H, J = 4.4 Hz, 10-H), 5.34
(d, 1H, J = 6.0 Hz, 20-OH), 5.09 (d, J = 4.2 Hz, 1H, 30-OH), 4.76 (t, J = 5.6 Hz, 1H, 50-OH), 4.54–4.61 (m,
1H, 20-H), 4.17–4.26 (m, 1H, 30-H), 4.05 (s, 1H, CH3), 3.84–3.91 (m, 1H, 40-H), 3.41–3.64 (m, 2H, CH2);
ESI-MS m/z: 364.2 [M + H]+. HRMS calcd for C15H18N5O6 364.1257 [M + H]+, found 364.1258.
Synthesis of 6-amino-4-methoxy-3-phenyl-1-(
stirred mixture of 6-amino-3-iodo-4-methoxy-1-(
β
-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine (15): To a
-D-ribofuranosyl)-1H-pyrazolo[3,4-d] pyrimidine
β
3
(800 mg, 1.9 mmol), phenylboronic acid (346 mg, 2.8 mmol, 1.5 eq) and potassium carbonate (387 mg,
2.8 mmol, 1.5 eq) in 60 mL of DME–water (2:1) was added Pd(PPh3)4 (115 mg, 0.09 mmol, 0.05 eq). The
◦
reaction mixture was stirred at 90 C for 4 h. Upon completion of the reaction as monitored by TLC, the
mixture was concentrated under reduced pressure. The residue was purified by flash chromatography
on a silica gel column to provided 570 mg of product 15 as a white solid in 80% yield with an HPLC
1
purity of 96%. Rf = 0.6 (dichloromethane–methanol = 10:1). H NMR (DMSO-d6, 400 MHz)
δ 7.90–8.00
0
(m, 2H, Ar-H), 7.39-7.54 (m, 3H, Ar-H), 6.92 (s, 2H, NH2), 6.07 (d, 1H, J = 4.0 Hz, 1 -H), 5.36 (d, 1H, J =
5.6 Hz, 20-OH), 5.008 (d, J = 5.6 Hz, 1H, 30-OH), 4.76 (t, J = 6.0 Hz, 1H, 50-OH), 4.54–4.62 (m, 1H, 20-H),
0
4.21–4.31 (m, 1H, 3 -H), 3.99 (s, 3H, CH3), 3.85–3.92 (m, 1H, 4 -H), 3.43–3.65 (m, 2H, CH2); ESI-MS m/z:
374.1 [M + H]+. HRMS calcd for C17H20N5O5 374.1464 [M + H]+, found 374.1461.
Synthesis of 6-amino-3-ethynyl-4-methoxy-1-(
β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine (16): To a
stirred mixture of compound (600 mg, 1.42 mmol), Pd (PPh3)4 (169 mg, 0.14 mmol, 0.1 eq), CuI
3
(53 mg, 0.28 mmol, 0.2 eq) and triethylamine (0.6 mL, 4.26 mmol, 3.0 eq) in DMF (20 mL) was
added trimethylsilylacetylene (1.2 mL, 8.52 mmol, 6.0 eq). The reaction mixture was stirred at room
temperature overnight. Upon completion of the reaction as monitored by TLC, the mixture was
concentrated under reduced pressure. The resulting residue was directly deprotected by treatment
with K2CO3 (39 mg, 0.3 mmol, 0.2 eq) in MeOH (30 mL) at room temperature for 2 h. Upon completion
of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure. The residue
was purified by flash chromatography on a silica gel column to provided 300 mg of product 16 as a
white solid in 65% overall yield with an HPLC purity of 96%. Rf = 0.45 (dichloromethane–methanol =
1
10:1). H NMR (DMSO-d6, 400 MHz)
δ
7.03 (s, 2H, NH2), 5.95 (d, 1H, J = 4.2 Hz, 10-H), 5.37 (d, 1H, J =
6.0 Hz, 20-OH), 5.10 (d, J = 4.2 Hz, 1H, 30-OH), 4.75 (t, J = 6.0 Hz, 01H, 50-OH), 4..45–4.55 (m, 2H, 20-H,
0
CH), 4.10–4.17 (m, 1H, 3 -H), 3.98 (s, 3H, CH3), 3.81–3.90 (m, 1H, 4 -H), 3.37–3.58 (m, 2H, CH2). HRMS
calcd for C13H16N5O5 322.1151 [M + H]+, found 322.1150.
Synthesis
of
6-amino-4-methoxy-3-[N-(trifluoroacetyl)aminopropyn-1-yl]-1-(β-D-ribofuranosyl)-1H-
pyrazolo[3,4-d]pyrimidine (17): The mixture of compound 3 (500 mg, 1.18 mmol), Pd (PPh3)4 (145 mg,
0.12 mmol, 0.1 eq), CuI (44.5 mg, 0.25 mmol, 0.2 eq), N-(2-propynyl)-2,2,2-trifluoroacetamide (1.07 g,
7.08 mmol, 6.0 eq) and triethylamine (0.5 mL, 3.54 mmol, 3.0 eq) in DMF (20 mL) was stirred at room
temperature overnight. Upon completion of the reaction as monitored by TLC, the mixture was
concentrated under reduced pressure. The residue was purified by flash chromatography on a silica
gel column to provided 310 mg of product 17 as a white solid in 60% yield with an HPLC purity of
1
95%. Rf = 0.40 (dichloromethane–methanol = 10:1). H NMR (DMSO-d6, 400 MHz)
δ 10.16 (s, 1H, NH),
7.03 (s, 2H, NH2), 5.95 (d, 1H, J = 4.2 Hz, 10-H), 5.36 (d, 1H, J = 6.0 Hz, 20-OH), 5.10 (d, J = 4.2 Hz, 1H,
30-OH), 4.74 (t, J = 5.6 Hz, 1H, 50-OH), 4.44–4.55 (m, 1H, 20-H), 4.07–4.17 (m, 1H, 30-H), 3.96 (s, 3H,
CH3), 3.76–3.88 (m, 1H, 40-H), 3.37–3.56 (m, 2H, CH2). ESI-MS m/z: 447.1 [M + H]+.
4.2.5. Procedure for Preparation of Glycosylated Products 28–29
Synthesis of 6-amino-4-methoxy-1-(2-deoxy-3,5-di-(O-p-toluoyl)-
28) and 6-amino-4-methoxy-1-(2-deoxy-3,5-di-(O-p-toluoyl)- -D-ribofuranosyl)-1H- pyrazolo[3,4-d]pyrimidine
29): To a stirred suspension of tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1) (411 mg, 1.3 mmol, 0.03
α-D-ribofuranosyl)-1H-pyrazolo [3,4-d]pyrimidine
(
β
(