S.J. Kaspersen et al. / Bioorganic Chemistry 44 (2012) 35–41
37
2.5.1.1. (S)-6-(4-Methoxyphenyl)-N-(1-phenylethyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-amine ((S)-20e). The compound was prepared as
described in Section 2.5.1 starting with 4-chloro-6-(4-methoxy-
phenyl)-7H-pyrrolo[2,3-d]pyrimidine (14) (159 mg, 0.61 mmol)
and (S)-1-phenylethanamine (19e) (222 mg, 1.84 mmol). This gave
179 mg (0.52 mmol, 85%) of a white solid, mp. 226–228 °C,
(285 mg, 1.66 mmol). This gave 162 mg (0.41 mmol, 74%) of a
white solid, mp. 274–276 °C, ½a D20
= ꢃ432 (c 0.37, DMSO). Spectro-
ꢂ
scopic properties were in correspondence with that reported previ-
ously for the racemate [37]. 1H NMR (400 MHz, DMSO-d6) d: 11.93
(s, 1H, NH, H-7), 8.24 (d, J = 8.2, 1H), 8.04 (s, 1H, H-2), 7.94 (m, 1H),
7.87 (m, 1H), 7.81 (m, 1H), 7.71–7.64 (m, 3H), 7.59–7.45 (m, 3H),
7.01 (m, 2H), 6.97 (s, 1H, H-5), 6.27 (m, 1H), 3.79 (s, 3H), 1.67 (d,
J = 6.8, 3H). IR (neat, cmꢃ1): 3131, 2962 1624, 1251, 828, 775.
HRMS (EI): 394.1783 (calcd C25H22N4O, 394.1794, M+).
½
a 2D0
= + 289 (c 0.17, DMSO). Spectroscopic properties were in cor-
ꢂ
respondence with that reported previously for the (R)-enantiomer
[40]. 1H NMR (400 MHz, DMSO-d6) d: 11.92 (s, 1H, NH, H-7), 8.04
(s, 1H, H-2), 7.73 (m, 3H), 7.43 (m, 2H), 7.30 (m, 2), 7.19 (m, 1H),
7.02 (d, J = 8.8, 2H), 6.96 (bs, 1H, H-5), 5.50 (m, 1H), 3.80 (s, 3H),
1.53 (d, J = 7.0, 3H). HRMS (EI): 344.1634 (calcd C21H20N4O,
344.1632, M+).
2.5.1.6. (R)-N-(1-(Naphthalen-1-yl)ethyl)-6-phenyl-7H-pyrrolo[2,3-
d]pyrimidin-4-amine ((R)-21p). The compound was prepared as
described in Section 2.5.1 starting with 4-chloro-6-(4-phenyl)-
7H-pyrrolo[2,3-d]pyrimidine (15) (87 mg, 0.38 mmol) and (R)-1-
(naphthalen-1-yl)ethanamine (19p) (195 mg, 1.14 mmol). This
gave 107 mg (0.29 mmol, 76%) of a white solid. The solid melted
at 155–157 °C, but partly re-solidified to a solid melting at
2.5.1.2. (R)-6-(4-Methoxyphenyl)-N-(1-(4-methoxyphenyl)ethyl)-7H-
pyrrolo[2,3-d]pyrimidin-4-amine ((R)-20h). The compound was
prepared as described in Section 2.5.1 starting with 4-chloro-6-
(4-metoxyphenyl)-7H-pyrrolo-[2,3-d]-pyrimidine (14) (238 mg,
200 °C, ½a 2D0
ꢂ
= ꢃ481 (c 1.00, DMSO), purity: 98% (by HPLC). 1H
0.92 mmol)
and
(R)-(4-methoxyphenyl)ethanamine
(19h)
NMR (400 MHz, DMSO-d6) d: 12.07 (s, 1H, NH, H-7), 8.26–8.24
(m, 1H), 8.08 (s, 1H, H-2), 8.01–7.93 (m, 2H), 7.82–7.77 (m, 3H),
7.67–7.66 (m, 1H), 7.59–7.41 (m, 5H), 7.30–7.27 (m, 1H), 7.14 (s,
1H, H-5), 6.32–6.25 (m, 1H), 1.68 (d, J = 6.8, 3H). 13C NMR
(100 MHz, DMSO-d6) d: 155.3, 152.3, 152.0 141.3, 133.92, 133.87,
132.3, 131.1, 129.42 (2C), 129.1, 127.7, 127.6, 126.6, 126.0, 125.9,
124.9 (2C), 123.8, 122.7, 104.4, 60.2, 96.7, 22.3. IR (neat, cmꢃ1):
2976, 1586, 1471, 1311, 774, 749. HRMS (EI): 364.1683 (calcd
(288 mg, 1.90 mmol). This gave 220 mg (0.59 mmol, 64%) of an
off-white solid, mp. 249–251 °C, ½a D20
= ꢃ330.1 (c 0.14, DMSO),
ꢂ
purity > 99% (by HPLC). 1H NMR (400 MHz, DMSO-d6) d: 11.89 (s,
1H, NH, H-7), 8.04 (s, 1H), 7.71 (d, J = 8.9, 2H), 7.64 (d, J = 8.4, 1H,
NH), 7.34 (d, J = 8.7, 2H), 7.02 (d, J = 8.9, 2H), 6.94 (s, 1H, H-5),
6.86 (d, J = 8.7, 2H), 5.45 (m, 1H), 3.80 (s, 3H), 3.71 (s, 3H), 1.50
(d, J = 7.0, 3H). 13C NMR (100 MHz, DMSO-d6) d: 158.6, 157.9,
154.8, 151.3 (2C), 137.5, 133.4, 127.2 (2C), 125.9 (2C), 124.5,
114.4 (2C), 113.5 (2C), 103.9, 94.6, 55.2, 55.0, 48.0, 22.9. HRMS
(ESI): 375.1814 (calcd C22H22N4O2, 375.1816, M + H+). IR (neat,
cmꢃ1): 3099, 2973, 1588, 1244, 830.
C
24H20N4, 364.1682, M+).
2.5.1.7. (S)-N-(1-(Naphthalen-1-yl)ethyl)-6-phenyl-7H-pyrrolo[2,3-
d]pyrimidin-4-amine ((S)-21p). The compound was prepared as
described in Section 2.5.1 starting with 4-chloro-6-(4-phenyl)-
7H-pyrrolo[2,3-d]pyrimidine (15) (70 mg, 0.30 mmol) and (S)-1-
phenylethanamine (19e) (156 mg, 0.91 mmol). This gave 84 mg
2.5.1.3. (S)-N-(1-(4-Bromophenyl)ethyl)-6-(4-methoxyphenyl)-7H-
pyrrolo[2,3-d]pyrimidin-4-amine ((S)-20i). The compound was pre-
pared as described in Section 2.5.1 starting with 4-chloro-6-(4-
methoxyphenyl)-7H-pyrrolo-[2,3-d]-pyrimidine (14) (190 mg,
0.73 mmol) and (S)-1-(4-bromophenyl)ethanamine (19i) (439 mg,
2.19 mmol). This gave 245 mg (0.58 mmol, 79%) of a white solid,
(23 mmol, 77%) of a white solid, mp. 162–166 °C, ½a D20
ꢂ
= +422 (c
1.00, DMSO), purity: 98% (by HPLC). The spectroscopic properties
corresponded with that reported for (S)-21p in Section 2.5.1.6.
HRMS (EI): 364.1682 (calcd C24H20N4, 364.1682, M+).
mp. 274–275 °C, ½a D20
ꢂ
= +309 (c 0.21, DMSO). Spectroscopic proper-
ties were in correspondence with that reported previously for the
(R)-enantiomer [37]. 1H NMR (400 MHz, DMSO-d6) d: 11.93 (s,
1H, NH, H-7), 8.03 (s, 1H, H-2), 7.76 (s, 1H, NH), 7.73 (m, 2H),
7.49 (m, 2H), 7.38 (m, 2H), 7.02 (m, 2H), 6.94 (d, J = 1.8, 1H, H-5),
5.44 (m, 1H), 3.80 (s, 3H), 1.51 (d, J = 7.0, 3H). HRMS (EI):
422.0739 (calcd C21H19BrN4O, 422.0737, M+)
2.5.1.8.
(R)-6-(4-Fluorophenyl)-N-(1-(naphthalen-1-yl)ethyl)-7H-
pyrrolo[2,3-d]pyrimidin-4-amine ((R)-22p). The compound was
prepared as described in Section 2.5.1 starting with 4-chloro-6-
(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine
(16)
(64 mg,
0.26 mmol) and (R)-1-(naphthalen-1-yl)ethanamine
(19p)
(133 mg, 0.78 mmol). This gave 70 mg (0.18 mmol, 70%) of a white
solid, mp. 147–150 °C, ½a D20
= ꢃ444 (c 0.40, DMSO), purity: 99% (by
ꢂ
2.5.1.4. 6-(4-Methoxyphenyl)-N-(1-naphthalen-1-ylmethyl)-7H-pyr-
rolo[2,3-d]pyrimidin-4-amine (20o). The compound was prepared
as described in Section 2.5.1 starting with 4-chloro-6-(4-methoxy-
phenyl)-7H-pyrrolo[2,3-d]pyrimidine (14) (154 mg, 0.59 mmol)
and naphthalen-1-ylmethanamine (19o) (280 mg, 1.78 mmol).
This gave 173 mg (0.45 mmol, 77%) of a white solid, mp 278–
281 °C. 1H NMR (400 MHz, DMSO-d6) d: 11.98 (s, 1H, NH, H-7),
8.21–8.19 (m, 1H), 8.14 (s, 1H, H-2), 7.97–7.94 (m, 2H), 7.86–
7.84 (m, 1H), 7.71–7.69 (m, 2H), 7.57–7.52 (m, 3 H), 7.49–7.46
(m, 1H), 7.01–7.00 (m, 2H), 6.89 (s, 1H, H-5), 5.20 (d, J = 5.6, 2H),
3.79 (s, 3H). 13C NMR (100 MHz, DMSO-d6), d: 159.1, 155.8, 151.8
(2C, overlap), 135.7, 134.2, 133.8, 131.5, 128.9, 127.8, 126.6,
126.4 (2C), 126.2, 125.9, 125.7, 124.9, 124.0, 114.9 (2C), 104.4,
95.0, 55.6, 41.9. IR (neat, cmꢃ1): 3152, 1597,1254,769. HRMS (EI):
380.1632 (calcd C24H20N4O, 380.1632, M+).
HPLC). 1H NMR (400 MHz, DMSO-d6) d: 12.07 (s, 1H, NH, H-7),
8.26–8.24 (m, 1H), 8.08 (s, 1H, H-2), 7.99–7.93 (m, 2H), 7.82–
7.80 (m, 3H), 7.67–7.65 (m, 1H), 7.58–7.45 (m, 3H), 7.31–7.27
(m, 2H), 7.09 (s, 1H, H-5), 6.31–6.25 (m, 1H), 1.68 (d, J = 6.8, 3H).
13C NMR (100 MHz, DMSO-d6), d: 161.9 (d, J = 244.5), 155.3,
152.3 (2C), 152.0, 141.3, 139.9, 133.0, 131.1, 129.1, 128.9 (d,
J = 2.9), 127.6, 126.9 (d, J = 7.9), 126.6, 126.0 (d, J = 3.5, 2C), 123.8,
122.7, 116.4 (d, J = 21.7, 2C), 104.4, 96.6, 60.2, 22.2. 19F NMR
(564 MHz, DMSO-d6, C6F6) d: ꢃ117.1 (m). IR (neat, cmꢃ1): 2985,
1585, 1496, 1312, 1233, 834, 774. HRMS (EI): 382.1585 (calcd
C
24H19FN4, 382.1586, M+).
2.5.1.9. (S)-6-(4-Fluorophenyl)-N-(1-(naphthalen-1-yl)ethyl)-7H-pyr-
rolo[2,3-d]pyrimidin-4-amine ((S)-22p). The compound was
prepared as described in Section 2.5.1 starting with 4-chloro-6-
(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine
(16)
(66 mg,
2.5.1.5. (R)-6-(4-Methoxyphenyl)-N-(1-(naphthalen-1-yl)ethyl)-7H-
pyrrolo[2,3-d]pyrimidin-4-amine ((R)-20p). The compound was
prepared as described in Section 2.5.1 starting with 4-chloro-6-
(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (14) (144 mg,
0.27 mmol) and (S)-1-phenylethanamine (19p) (137 mg,
0.80 mmol). This gave 76 mg (0.20 mmol, 74%) of a white solid,
mp. 149–152 °C, ½a D20
ꢂ
= +380 (c 0.13, DMSO), purity: 98% (by HPLC).
The spectroscopic properties corresponded with that reported for
0.55 mmol)
and
(R)-1-(naphthalen-1-yl)ethanamine
(19p)
(R)-22p in Section 2.5.1.8.