Journal of Medicinal Chemistry
Article
151.0, 151.7, 156.1, 159.7, 168.4, 170.6. HRMS calcd for
C35H47N8O5+ [M + H], 659.3664; found, 659.3676.
128.4, 129.7, 130.6, 132.0, 132.6, 133.1, 139.3, 140.1, 140.5,
140.6, 146.1, 154.3, 158.7, 161.0, 163.4, 171.4, 174.2. HRMS
calcd for C49H59N8O6+ [M + H], 855.4552; found, 855.4538.
2-(2-(4-N-(4-(1, 2-Dithiolane)pentanecarboxy)-
aminophenyl))ethylamino-N6-(2,2-diphenylethyl)adenosine-
5′-N-ethylcarboxamide (16c). General Procedure for Amide
Coupling. Compound 7b (160 mg, 0.26 mmol), 4-(1,2-
dithiolane)pentanoic acid (79 mg, 0.38 mmol), EDCI (73
mg, 0.38 mmol), HOBt (52 mg, 0.38 mmol), DIPEA (250 μL),
and DMF (2.5 mL), white solid (16c) (31 mg, 15%), Rf = 0.24
2-(2-(4-N-(3,5-di-tert-Butyl-4-hydroxyphenylcarboxy)-
aminophenyl))ethylaminoadenosine-5′-N-ethylcarboxamide
(15b). General Procedure for Isopropylidene Deprotection.
Compound 13b (150 mg, 0.21 mmol), MeCN (2 mL), and
1 M HCl (20 mL), 65 °C, 12 h, white solid (15b) (25 mg,
18%), Rf = 0.10 (9:1 EtOAc/MeOH), mp 230−235 °C (dec).
1H NMR (300 MHz, CD3OD) δ: 1.06 (t, J = 7.2 Hz, 3H), 2.90
(t, J = 7.2 Hz, 2H), 3.08−3.21 (m, 1H), 3.22−3.36 (m, 1H),
3.48−3.59 (m, 1H), 3.60−3.73 (m, 1H), 4.43 (s, 1H), 4.49−
4.54 (m, 1H), 5.02−5.06 (m, 1H), 5.96 (d, J = 6.3 Hz, 1H),
7.26 (d, J = 7.8 Hz, 2H), 7.59 (d, J = 7.8 Hz, 2H), 7.78 (s, 2H),
8.00 (s, 1H). 13C NMR (100 MHz, CD3OD) δ: 14.8, 30.6, 35.2,
35.7, 36.4, 44.3, 73.3, 74.7, 85.5, 90.1, 114.8, 122.8, 125.9, 12
7.0, 130.2, 137.3, 138.3, 138.7, 139.1, 153.1, 157.5, 158.9, 161.2,
1
(1:5 petroleum spirits/EtOAc), mp 107−112 °C. H NMR
(400 MHz, CD3OD) δ: 0.96 (t, J = 7.2 Hz, 3H), 1.37−1.52 (m,
2H), 1.55−1.72 (m, 4H), 1.75−1.86 (m, 1H), 2.28 (t, J = 7.4
Hz, 2H), 2.31−2.41 (m, 1H), 2.80 (t, J = 7.2 Hz, 2H), 2.93−
3.11 (m, 3H), 3.17−3.28 (m, 1H), 3.45−3.53 (m, 2H), 3.52−
3.64 (m, 1H), 4.12 (d, J = 7.1 Hz, 2H), 4.31 (d, J = 2.6 Hz,
1H), 4.32−4.36 (br m, 1H), 4.39 (t, J = 7.8 Hz, 1H), 4.82 (dd, J
= 5.2, 6.4 Hz, 1H), 5.76 (d, J = 6.6 Hz, 1H), 7.04 (d, J = 8.5 Hz,
2H), 7.07−7.13 (m, 2H), 7.15−7.24 (m, 8H), 7.35 (d, J = 8.5
Hz, 2H), 7.68 (s, 1H). 13C NMR (100 MHz, CD3OD) δ: 17.3,
29.2, 32.5, 37.7, 38.3, 38.9, 40.3, 41.9, 43.8, 46.8, 60.1, 75.8,
77.2, 88.0, 92.6, 117.3, 124.0, 132.8, 139.5, 140.5, 141.7, 155.6,
160.0, 163.6, 174.6, 176.9. HRMS calcd for C42H51N8O5S2+ [M
+ H], 811.3418; found, 811.3427.
+
170.1, 172.1. HRMS calcd for C35H47N8O6 [M + H],
675.3613; found, 675.3632.
2-(2-(4-N-(4-(1,2-Dithiolane)pentanecarboxy)-
aminophenyl))ethylaminoadenosine-5′-N-ethylcarboxamide
(15c). General Procedure for Isopropylidene Deprotection.
Compound 13c (50 mg, 0.08 mmol), MeCN (4 mL), and 1
M HCl (10 mL), 55 °C, 2 h, pale-yellow solid (15c) (13 mg,
28%), Rf = 0.10 (9:1 EtOAc/MeOH), mp 82−85 °C. 1H NMR
(400 MHz, CD3OD) δ: 1.05 (t, J = 7.2 Hz, 3H), 1.47−1.60 (m,
2H), 1.64−1.83 (m, 4H,), 1.86−1.96 (m, 1H), 2.39 (t, J = 7.2
Hz, 2H), 2.43−2.53 (m, 1H), 2.87 (t, J = 7.2 Hz, 2H), 3.07−
3.23 (m, 3H), 3.24−3.33 (m, 1H), 3.48−3.58 (m, 1H), 3.58−
3.69 (m, 2H), 4.42 (d, J = 2.8 Hz, 1H), 4.49−4.54 (m, 1H),
5.01 (t, J = 6.4 Hz, 1H), 5.95 (d, J = 6.4 Hz, 1H), 7.22 (d, J =
2-Fluoro-N6-(2,2-diphenylethyl)-2′,3′-O-isopropylideneade-
nosine-5′-N-methylcarboxamide (17). General Procedure for
N6-Substitution. Compound 1b (225 mg, 0.48 mmol), 2,2-
diphenylethylamine (142 mg, 0.72 mmol), DIPEA (250 μL),
and MeCN (15 mL), yellow solid (17) (203 mg, 80%), Rf =
1
0.38 (1:5 petroleum spirits/EtOAc); mp 92−95 °C. H NMR
13
(400 MHz, CD3OD) δ: 1.38 (s, 3H), 1.56 (s, 3H), 2.34 (s,
3H), 4.13−4.21 (m, 2H), 4.47 (t, 1H, J = 8.0 Hz), 4.60 (d, J =
1.2 Hz, 1H), 5.34 (dd, J = 6.1, 1.5 Hz, 1H), 5.46 (d, J = 1.7 Hz,
1H), 6.20 (d, J = 1.2 Hz, 1H), 7.14−7.19 (m, 2H), 7.22−7.33
(m, 8H), 8.00 (s, 1H). 13C NMR (101 MHz, CD3OD) δ: 25.3,
25.8, 27.1, 46.1, 51.7, 84.7, 85.0, 88.1, 92.4, 115.1, 118.9 (d, J =
4.0 Hz), 127.3 (×2), 129.3 (×4), 129.6 (×4), 142.0 (d, J = 3.0
Hz), 143.6 (d, J = 1.1 Hz), 149.8 (d, J = 20.5 Hz), 155.6 (d, J =
20.7 Hz), 160.5 (d, J = 210.0 Hz), 172.0. ESMS calcd for
C28H30N6O4F+ [M + H], 533.6; found, 533.8.
8.2 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 8.00 (s, 1H). C NMR
(100 MHz, CD3OD) δ: 17.3, 29.2, 32.5, 37.7, 38.3, 38.9, 40.3,
41.9, 43.8, 46.8, 60.1, 75.8, 77.2, 88.0, 92.6, 117.3, 124.0, 132.8,
134.9, 139.5, 140.5, 141.7, 155.6, 160.0, 163.6, 174.6, 176.9.
HRMS calcd for C28H39N8O5S2+ [M + H], 631.2479; found,
631.2475.
2-(2-(4-N-(3,5-di-tert-Butylphenylcarboxy)aminophenyl))-
ethylamino-N6-(2,2-diphenylethyl) adenosine-5′-N-ethylcar-
boxamide (16a). General Procedure for Amide Coupling.
Compound 7b (69 mg, 0.11 mmol), 3,5-di-tert-butylbenzoic
acid (29 mg, 0.13 mmol), EDCI (24 mg, 0.13 mmol), HOBt
(17 mg, 0.13 mmol), DIPEA (26 μL), and DMF (265 μL), tan
glassy solid (16a) (39 mg, 42%), Rf = 0.19 (1:5 petroleum
spirits/EtOAc), mp 124−128 °C. 1H NMR (300 MHz,
CD3OD) δ: 1.07 (t, J = 6.9 Hz, 3H), 1.40 (s, 18H), 2.92 (t,
J = 6.9 Hz, 2H), 3.07−3.39 (m, 2H), 3.52−3.68 (m, 2H), 4.22
(d, J = 6.6 Hz, 2H), 4.42 (s, 1H), 4.48 (s, 1H), 4.49−4.52 (m,
1H), 4.98−5.02 (m, 1H), 5.91 (s, J = 6.3 Hz, 1H), 7.19 (d, J =
7.5 Hz, 2H), 7.12−7.20 (m, 2H), 7.21−7.44 (m, 8H), 7.59 (d, J
= 7.5 Hz, 2H), 7.69 (s, 1H), 7.81 (s, 2H), 7.91 (s, 1H). 13C
NMR (100 MHz, CD3OD) δ: 14.8, 31.8, 35.2, 36.0, 36.8, 44.7,
46.0, 51.9, 73.1, 74.7, 85.6, 90.0, 114.9, 122.8, 122.9, 127.1,
127.7, 129.3, 129.7, 130.2, 135.8, 137.6, 138.0, 138.4, 144.1,
152.5, 156.1, 161.2, 170.0, 172.1. HRMS calcd for C49H59N8O5+
[M + H], 839.4603; found, 839.4642.
2-Fluoro-N6-(2,2-diphenylethyl)adenosine-5′-N-methylcar-
boxamide (18). General Procedure for Isopropylidene Depro-
tection. Compound 17 (60 mg, 0.11 mmol), MeCN (2 mL),
and 1 M HCl (10 mL), 50 °C, 2 h, white solid (18) (22 mg,
40%), Rf1= 0.29 (89:10:1 CH2Cl2/MeOH/NH4OH), mp 128−
131 °C. H NMR (400 MHz, CD3OD) δ: 2.87 (s, 3H), 4.15−
4.25 (m, 2H), 4.29 (dd, 1H), 4.46 (s, 1H), 4.49 (t, J = 8.1 Hz,
1H), 4.62 (dd, J = 7.7, 4.8 Hz, 1H), 5.91 (d, J = 7.8 Hz, 1H),
7.17−7.23 (m, 2H), 7.24−7.36 (m, 8H), 8.09 (s, 1H). 13C
NMR (101 MHz, CD3OD) δ: 25.8, 46.2, 51.7, 73.2, 78.9, 86.5,
90.6, 119.8 (d, J = 4.0 Hz), 127.2 (×2), 129.3 (×4), 129.6 (×4),
142.2 (d, J = 2.7 Hz), 143.6 (d, J = 1.1 Hz), 150.5 (d, J = 19.8
Hz), 157.8 (d, J = 20.3 Hz), 160.4 (d, J = 208.5 Hz), 172.6.
HRMS calcd for C25H26N6O4F+ [M + H], 493.1994; found,
493.2010.
2-(2-(4-N-(3,5-di-tert-Butyl-4-hydroxyphenylcarboxy)-
aminophenyl))ethylamino-N6-(2,2-diphenylethyl)adenosine-
5′-N-methylcarboxamide (20). General Procedure for 2-
Substitution. Compound 17 (188 mg, 0.35 mmol), 12b (169
mg, 0.46 mmol), DIPEA (250 μL), and MeCN, 150 °C (MW),
2 h, yellow solid (19) (229 mg, 74%).
General Procedure for Isopropylidene Deprotection. Compound
19 (200 mg, 0.23 mmol), MeCN (10 mL), and 1 M HCl (15 mL), 2 h,
white solid (20) (45 mg, 24%), Rf = 0.30 (89:10:1 CH2Cl2/MeOH/
NH4OH), mp 120−123 °C. 1H NMR (400 MHz, CD3OD) δ: 1.47 (s,
18H), 2.71 (s, 3H), 2.89 (t, J = 6.9 Hz, 2H), 3.53−3.60 (m, 1H),
3.65−3.72 (m, 1H), 4.20 (d, J = 6.4 Hz, 2H), 4.40 (s, 2H), 4.48 (t, J =
7.8 Hz, 1H), 4.97−4.99 (m, 1H), 5.85 (d, J = 7.0 Hz, 1H), 7.13−7.17
(m, 4H), 7.23−7.31 (m, 8H), 7.52 (d, J = 8.4 Hz, 2H), 7.76−7.78 (m,
3H). 13C NMR (101 MHz, CD3OD) δ: 26.3, 30.6, 35.6, 36.7, 44.6,
46.0, 51.9, 72.6, 74.7, 85.8, 90.0, 115.0, 122.8, 125.9, 127.0, 127.6,
2-(2-(4-N-(3,5-di-tert-Butyl-4-hydroxyphenylcarboxy)-
aminophenyl))ethylamino-N6-(2,2-diphenylethyl)adenosine-
5′-N-ethylcarboxamide (16b). General Procedure for Isopropy-
lidene Deprotection. Compound 14b (175 mg, 0.20 mmol),
MeCN (5 mL), and 1 M HCl (15 mL), 50 °C, 6 h, white solid
(16b) (20 mg, 12%), Rf = 0.23 (1:5 petroleum spirits/EtOAc),
1
mp 118−124 °C. H NMR (400 MHz, CDCl3) δ: 0.93 (t, J =
7.2 Hz, 3H), 1.37 (s, 18H), 2.75 (br t, J = 6.0 Hz, 2H), 2.91−
3.04 (m, 1H), 3.18−3.32 (m, 1H), 3.39−3.62 (br m, 2H), 4.13
(br s, 2H), 4.29 (t, J = 7.6 Hz, 1H), 4.39 (d, J = 2.4 Hz, 1H),
4.50 (br s, 1H), 4.69 (t, J = 5.5 Hz, 1H), 4.84−4.87 (m, 1H),
5.54 (br s, 1H), 5.63 (d, J = 6.0 Hz, 1H), 5.72 (br s, 1H), 7.03
(d, J = 8.2 Hz, 2H), 7.10−7.16 (m, 2H), 7.17−7.25 (m, 10H),
7.29 (br s, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.61 (s, 2H), 7.94 (s,
1H). 13C NMR (100 MHz, CDCl3/CD3OD) δ: 18.3, 33.9, 38.0,
38.3, 39.4, 47.1, 48.8, 54.5, 75.3, 76.8, 88.3, 93.4, 118.3, 124.9,
3531
dx.doi.org/10.1021/jm300206u | J. Med. Chem. 2012, 55, 3521−3534