Synthesis and Antiviral Evaluation of AZT Analogues
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1-(3-(2-O-Acetyl-3-azido-5-O-benzoyl-3-deoxy-D-ribofuranosyloxy)
propyl)-thymine (7b). Compound 7b was prepared according to the
procedure described for 7 a starting from 1-(3-hydroxypropyl)-thymine (64
mg, 0.349 mmol) and 6 (127 mg, 1 eq.). Yield: 72% (122 mg), Rf = 0.53
(CH2Cl2/ MeOH; 95/5; V/V), IR: 3184 (NH), 2929 (CH alkyl), 2109 (N3),
1682 (C O Thym), 1282 (C-O-C), RMN 1H (CDCl3, δ): thymine: 8.27 (s, 1H,
NH), 6.93 (q, 1H, J 6,CH3 = 1.1 Hz, H6), 1.91 (d, 3H, J CH3,6 = 1.1 Hz, CH3),
N-alkyl: 3.83 (dt, 1H, J α,β = 5.1 Hz, J α,α = 9.8 Hz, Hα), 3.73 (t, 2H, J γ ,β
=
7.4 Hz, Hγ ), 3.46 (dt, 1H, J α,β = 4.9 Hz, J α,α = 9.8 Hz, Hα), 1.67 (m, 2H,
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Hβ), ose: 5.24 (d, 1H, J 2 ,3 = 4.6 Hz, H2 ), 4.98 (br s, 1H, H1 ), 4.60 (dd, 1H,
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J 5 a,4 = 4.4 Hz, J 5 a,5 b = 11.8 Hz, H5 a), 4.41 (dd, 1H, J = 4.4 Hz, J = 11.8
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Hz, H5 b), 4.35 (dt, 1H, J 4 ,5 = 4.4 Hz, J 4 ,3 = 8.1 Hz, H4 ), 4.16 (dd, 1H,
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J 3 ,2 = 4.6 Hz, J 3 ,4 = 8.1 Hz, H3 ), benzoyl: 8.07 (dd, 2H, J = 1.2 Hz, J = 8.4
Hz), 7.59 (tt, 1H, J = 1,2 Hz, J = 7.4 Hz), 7.46 (br t, 2H, J = 7.8 Hz), acetyl:
1.60 (s, 3H, CH3).
1-(3-(2-O-Acetyl-3-azido-5-O-benzoyl-3-deoxy-D-ribofuranosyloxy)ethyl)-
thymine (7c). Compound 7c was prepared according to the procedure
described for 7a starting from 1-(3-hydroxyethyl)-thymine (80 mg, 0.468
mmol) and 6 (170 mg, 1 eq.). Yield: 76% (168 mg), Rf = 0.55 (CH2Cl2/
MeOH; 95/5; V/V), IR: 3189 (NH), 2925 (CH alkyl), 2109 (N3), 1689
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(C O Thym), 1272 (C-O-C), RMN H (CDCl3, δ): thymine: 8.37 (s, 1H,
NH), 6.93 (q, 1H, J 6,CH3 = 1.1 Hz, H6), 1.91 (d, 3H, J CH3,6 = 1.1 Hz, CH3),
N-alkyl: 3.84 (m, 2H, Hα and Hβ), 3.64 (ddd, 1H, J α,β = 2.9 Hz, J α,β = 4.6
Hz, J = 10.1 Hz, Hα or Hβ), 3.58 (ddd, 1H, J α,β = 2.9 Hz, J α,β = 4.3 Hz, J
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= 10.3 Hz, Hα or Hβ), ose: 5.23 (d, 1H, J 2 ,3 = 4.8 Hz, H2 ), 4.98 (br s, 1H,
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H1 ), 4.61 (dd, 1H, J 5 a,4 = 3.7 Hz, J 5 a5 b = 11.7 Hz, H5 a), 4.40 (dd, 1H,
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J 5 b4 = 4.9 Hz, J 5 a5 b = 11.7 Hz, H5 b), 4.35 (m,1H, H4 ), 4.12 (dd, 1H, J 3 ,2
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= 4.8 Hz, J 3 ,4 = 7.6 Hz, H3 ), benzoyl: 8.06 (dd, 2H, J = 1.2 Hz, J = 8.4 Hz),
7.60 (tt, 1H, J = 1.2 Hz, J = 7.4 Hz), 7.47 (br t, 2H, J = 7.8 Hz), acetyl: 1.88
(s, 3H, CH3).
1-(4-(3-Azido-3-deoxy-β-D-ribofuranosyloxy)butyl)-thymine (8a). Com-
pound 7a (130 mg, 0.26 mmol) was stirred with methanolic ammonia (7
N) (50 eq., 1.85 mL) in 3 mL of solvent mix: methanol/CH2Cl2 (3/1)
at room temperature during 48 hours. The solvent was removed under
reduced pressure and the crude residue was purified by preparative thin
layer chromatography on silica gel (CH2Cl2/ EtOH) to yield compound 8 a
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as a viscous oil in 70% (63 mg), [α]D = -15.897◦ (c 0.26; CH3OH), Rf =
0.46 (CH2Cl2/MeOH; 9/1;V/V), IR: 3406 (OH), 2107 (N3), 3021 (CH ar.),
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2946 (CH alkyl), 1676 (C O Thym), 1451 (C-C), 1273 (C-O-C), RMN H
(CD3OD, δ): thymine: 7.42 (q, 1H, J 6,CH3 = 0.9 Hz, H6), 1.86 (d, 3H, J CH3,6
= 0.9 Hz, CH3), N-alkyl: 3.74–3.76 (m, 1H, Hα), 3.65 (t, 2H, J δ,γ = 7.6 Hz,
Hδ), 3.41 (dt, 1H, J α,β = 6.2 Hz, J α,α = 9.6 Hz, Hα), 1.73 (quin, 2H, J =
7.6 Hz, Hγ ), 1.58 (tt, 2H, J β,α = 6.2 Hz, J β,γ = 7.6 Hz, Hβ), ose: 4.86 (br
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s, 1H, H1 ), 4.12 (br d, 1H, J 2 ,3 = 4.6 Hz, H2 ), 4.06 (dt, 1H, J 4 ,5 = 5.5