S. C. Wilson et al. / Bioorg. Med. Chem. 19 (2011) 6949–6965
6959
1.17 + 1.25 (2 Â d, 3H, J = 6.32+6.16 Hz, –NHCH(CH2CH3)CH
(CH3)OH) 1.57 (d, 6H, J = 6.79 Hz, –CH)CH3)2), 1.77–2.09 (m, 2H,
–NHCH(CH2CH3)CH(CH3)OH), 3.91–4.03 (m, 2H, –NHCH(CH2CH3)
CH(CH3)OH), 4.58–4.69 (m, 1H, –CH(CH3)2), 4.83–5.00 (m, 3H,
–HNCH2-Pyr + OH), 6.16 (m, 1H, –NHCH(CH2CH3)CH(CH3)OH),
7.24–7.33 (m, 3H, 2 Â Pyr-H + –N@CH–N–), 7.55 (m, 1H, Pyr-H),
7.74 (d, 1H, J = 7.42 Hz, Pyr-H), 8.67 (m, 1H, HNCH2-Pyr). FABMS
m/z (relative intensity): 370 ([M+H]+, 100), 324 (35), 289 (37), 243
(65), 199 (85). Accurate mass (M+H): actual: 370.2355, measured:
370.2347.
1.08 (m, 6H, –NHCH(CH2CH3)CH(CH2CH3)OH), 1.56 (d, 6H,
J = 6.79 Hz, –CH)CH3)2), 1.44–1.69 (m, 4H, –NHCH(CH2CH3)
CH(CH2CH3)OH), 3.45 (d, 1H, J = 6.32 Hz, OH), 3.56–3.70 (m, 1H, –
NHCH(CH2CH3)CH(CH2CH3)OH), 3.91–4.06 (m, 1H, –NHCH(CH2
CH3)CH(CH2CH3)OH), 4.58–4.69 (m, 1H, –CH(CH3)2), 4.73–5.01
(m, 2H, –HNCH2-Bz), 5.16–5.32 + 6.01–6.22 (2 Â m, 1H, –NHCH
(CH2CH3)CH(CH2CH3)OH),
7.22–7.43
(m,
6H,
5 Â Bz-H +
HNCH2-Bz), 7.52 (s, 1H, –N@CH–N). FABMS m/z (relative intensity):
383 ([M+H]+, 100), 323 (55), 296 (21). Accurate mass (M+H):
actual: 383.2559, measured: 383.2542.
4.3.16. 6-Benzylamino-2-[(1R,2RS)-1-ethyl-2-hydroxybutyla-
4.3.17. 2-[(1R,2RS)-1-Ethyl-2-hydroxybutylamino]-9-isopropyl-
mino]-9-isopropylpurine (aR-28)
6-[(pyridin-2-ylmethyl)-amino]purine (aR-16)
To a stirred solution of (R)-2-(trityl-amino)-butyraldehyde (R-
6), 1.5 g, 1 equiv, 4.53 mmol) in ether (150 mL) under an argon
atmosphere at À78 °C, was added ethylmagnesium bromide (3 M
in ether, 1.51 mL, 1 equiv, 4.53 mmol) dropwise. The solution
was stirred at À78 °C for 2 h, then allowed to warm to room tem-
perature over 16 h. The mixture was recooled to 0 °C, H2O (150 mL)
added, and the organic phase separated. The aqueous phase was
extracted with more ether (2 Â 50 mL), and the combined organic
phase washed with brine (50 mL), dried (MgSO4) and evaporated in
vacuo. The residue was purified by silica gel column chromatogra-
phy, eluted with hexane/ether (90:10) to afford (4R)-4-(trityl-ami-
no)-hexan-3-ol (R-7f) as a light yellow oil; yield: 1.13 g (69%) (57%
3S,4R: 43% 3R,4R). 1H NMR (DMSO-d6, 250 MHz): d 0.45 + 0.69
(t + m, 6H, J = 7.43 Hz, –NHCH(CH2CH3)CH(CH2CH3)OH), 1.12–
1.29 (m, 4H, –NHCH(CH2CH3)CH(CH2CH3)OH), 2.16 (m, 1H,
–NHCH(CH2CH3)CH(CH2CH3)OH), 2.54 (m, 1H, –NHCH(CH2CH3)-
CH(CH2CH3)OH), 3.21–3.40 (m, 1H, –NHCH(CH2CH3)CH(CH2CH3)
OH), 4.29 + 4.39 (2 Â d, 1H, J = 4.42+5.37 Hz, –NHCH(CH2CH3)CH
(CH2CH3)OH), 7.15–7.52 (m, 15H, 3 Â Bz). To a stirred solution of
the foregoing (R-7f), 1.13 g, 1 equiv, 3.14 mmol) in DCM (15 mL)
under an argon atmosphere at room temperature, was added triflu-
oroacetic acid (7 mL) dropwise, and the solution was stirred at this
temperature for 4 h. The solvent was evaporated in vacuo, EtOH
(20 mL) added, and removed in vacuo, and this process repeated
a further two times. The residue was precipitated from ether
(5 mL) with hexane (40 mL) with stirring to give a yellow oil. The
solvent was decanted from the oil, and the oil was washed with
hexane (30 mL) and dried in vacuo to afford (4R)-4-amino-hex-
an-3-ol (R-8f) as a light yellow oil; yield: 0.37 g (100%) (57%
3S,4R: 43% 3R,4R). 1H NMR (DMSO-d6, 250 MHz): d 0.79 + 0.92
(t + m, 6H, J = 7.42 Hz, NH2CH(CH2CH3)CH(CH2CH3)OH), 1.30–1.67
(m, 4H, NH2CH(CH2CH3)CH(CH2CH3)OH), 2.70 (m, 1H, NH2CH
(CH2CH3)CH(CH2CH3)OH), 2.84 + 2.96 (2 Â m, 1H, NH2CH(CH2CH3)
CH(CH2CH3)OH), 3.41 + 3.56 (2 Â m, 1H, NH2CH(CH2CH3)CH
(CH2CH3)OH), 7.71 (br s, 2H, NH2CH(CH2CH3)CH(CH2CH3)OH). To
a stirred solution of 6-benzylamino-2-fluoro-9-isopropylpurine
(4d, 40 mg, 1 equiv, 0.14 mmol) in n-BuOH/DMSO (3.75 mL, 4:1)
at room temperature under an argon atmosphere was added DIEA
(0.24 mL, 9.8 equiv, 1.38 mmol) followed by the foregoing ((R-8f),
110 mg, 6.7 equiv, 0.93 mmol). The reaction mixture was placed
in a preheated oil bath at 140 °C and stirred at this temperature
for 72 h, when TLC DCM/ether/MeOH (55:40:5) indicated that
the reaction had gone to completion. The reaction mixture was al-
lowed to cool to room temperature and the solvent was evaporated
in vacuo. The residue was partitioned between EtOAc (50 mL) and
brine/water (1:1, 100 mL), the aqueous phase was extracted with
more EtOAc (2 Â 50 mL), and the combined organic phase was
washed with brine (50 mL), dried (MgSO4) and evaporated in va-
cuo. The residue was purified by gradient column chromatography
on silica gel eluted with hexane/ether/MeOH (50:50:0?50:50:2)
to afford 6-benzylamino-2-[(1R)-1-ethyl-2-hydroxybutylamino]-
To a stirred solution of 2-fluoro-9-isopropyl-6-[(pyridin-2-yl-
methyl)-amino]purine (4a, 20 mg, 1 equiv, 0.07 mmol) in n-
BuOH/DMSO (3.75 mL, 4:1) at room temperature under an argon
atmosphere was added DIEA (0.18 mL, 15 equiv, 1.03 mmol) fol-
lowed by (3RS,4R)-4-amino-hexan-3-ol ((R-8f), 110 mg, 13 equiv,
0.94 mmol) (prepared as described for (aR-28): see above). The
reaction mixture was placed in a preheated oil bath at 140 °C
and stirred at this temperature for 72 h. The reaction mixture
was allowed to cool to room temperature and the solvent was
evaporated in vacuo. The residue was partitioned between EtOAc
(50 mL) and brine/water (1:1, 100 mL), the aqueous phase was ex-
tracted with more EtOAc (2 Â 25 mL), and the combined organic
phase was washed with brine (50 mL), dried (MgSO4) and evapo-
rated in vacuo. The residue was purified by gradient column chro-
matography on silica gel eluted with CHCl3/MeOH (100:0?98:2),
to afford 2-[(1R)-1-ethyl-2-hydroxypropylamino]-9-isopropyl-6-
[(pyridin-2-ylmethyl)-amino]purine
(aR-16) as a white solid;
yield: 11 mg (41%) (57% 1R,2S: 43% 1R,2R). 1H NMR (CDCl3,
250 MHz): d 0.85–1.06 (m, 6H, –NHCH(CH2CH3)CH(CH2CH3)OH),
1.57 (d, 6H, J = 6.79 Hz, –CH)CH3)2), 1.42–1.65 (m, 4H,
–NHCH(CH2CH3)CH(CH2CH3)OH), 3.45 (d, 1H, J = 6.31 Hz, OH),
3.57–3.70 (m, 1H, –NHCH(CH2CH3)CH(CH2CH3)OH), 3.91–4.03 (m,
1H, –NHCH(CH2CH3)CH(CH2CH3)OH), 4.57–4.76 (m, 1H, –CH
(CH3)2), 4.86–4.98 (m, 2H, –HNCH2-Pyr), 5.18–5.29 (m, 1H, –NHCH
(CH2CH3)CH(CH2CH3)OH), 6.73–6.89 (m, 1H, –HNCH2-Pyr),
7.15–7.25 (m, 1H, Pyr-H), 7.38 (d, 1H, J = 7.90 Hz, Pyr-H), 7.56
(s, 1H, –N@CH–N–), 7.63–7.70 (m, 1H, Pyr-H), 8.60 (d, 1H,
J = 4.42 Hz, Pyr-H). FABMS m/z (relative intensity): 384 ([M+H]+,
100), 324 (35), 307 (37), 297 (25), 289 (20). Accurate Mass
(M+H): actual: 384.2512, measured: 384.2523.
4.3.18. 2-[(1R,2RS)-1-Ethyl-2-hydroxybutylamino]-9-isopropyl-
6-[(pyridin-3-ylmethyl)-amino]purine (aR-22)
To a stirred solution of 2-fluoro-9-isopropyl-6-[(pyridin-3-yl-
methyl)-amino]purine (4b, 20 mg, 1 equiv, 0.07 mmol) in n-
BuOH/DMSO (3.75 mL, 4:1) at room temperature under an argon
atmosphere was added DIEA (0.18 mL, 15 equiv, 1.03 mmol) fol-
lowed by (3RS,4R)-4-amino-hexan-3-ol ((R-8f), 110 mg, 13 equiv,
0.94 mmol) (prepared as described for (aR-28): see above). The
reaction mixture was placed in a preheated oil bath at 140 °C
and stirred at this temperature for 72 h. The reaction mixture
was allowed to cool to room temperature and the solvent was
evaporated in vacuo. The residue was partitioned between EtOAc
(50 mL) and brine/water (1:1, 100 mL), the aqueous phase was ex-
tracted with more EtOAc (2 Â 25 mL), and the combined organic
phase was washed with brine (50 mL), dried (MgSO4) and evapo-
rated in vacuo. The residue was purified by gradient column chro-
matography on silica gel eluted with CHCl3/MeOH (100:0?98:2),
to afford 2-[(1R)-1-ethyl-2-hydroxypropylamino]-9-isopropyl-6-
[(pyridin-3-ylmethyl)-amino]purine
(aR-22) as a white solid;
yield: 23 mg (75%) (57% 1R,2S: 43% 1R,2R). 1H NMR (CDCl3,
250 MHz): d 0.87–1.07 (m, 6H, –NHCH(CH2CH3)CH(CH2CH3)OH),
9-isopropylpurine
(aR-28) as a white solid; yield: 31 mg
(58%).(57% 1R,2S: 43% 1R,2R). 1H NMR (CDCl3, 250 MHz): d 0.92–
1.56 (d, 6H, J = 6.63 Hz, –CH)CH3)2), 1.43–1.63 (m, 4H,
–