Synthesis of ribavirin analogues containing amino-acid residues

Article abstract of DOI:10.1081/SCC-200054185

A convenient procedure for coupling 1,2,3,5-tetra-O-acetyl-β-D- ribofuranose and 4-nitroimidazole was developed to obtain β-anomer as the major product. A novel category of nucleoside analogues with the introduction of natural L-amino acids to the base mo

Full text of DOI:10.1081/SCC-200054185

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Synthesis of Ribavirin Analogues Containing
Amino‐Acid Residues
Daliang Li a , Hongli Bao a , Qitao Tan a , Dongmei Cai a & Tianpa You a
a Chemistry Department , University of Science & Technology of China ,
Hefei, China
Published online: 16 Aug 2006.
To cite this article: Daliang Li , Hongli Bao , Qitao Tan , Dongmei Cai & Tianpa You (2005) Synthesis of
Ribavirin Analogues Containing Amino‐Acid Residues, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 35:8, 1017-1026, DOI: 10.1081/SCC-200054185
To link to this article: http://dx.doi.org/10.1081/SCC-200054185
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Synthetic Communicationsw, 35: 1017–1026, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200054185
Synthesis of Ribavirin Analogues
Containing Amino-Acid Residues
Daliang Li, Hongli Bao, Qitao Tan, Dongmei Cai, and Tianpa You
Chemistry Department, University of Science & Technology of China,
Hefei, China
Abstract: A convenient procedure for coupling 1,2,3,5-tetra-O-acetyl-b-D-ribofura-
nose and 4-nitroimidazole was developed to obtain b-anomer as the major product.
A novel category of nucleoside analogues with the introduction of natural L-amino
acids to the base moiety were designed and synthesized to develop selective and
effective antiviral agents.
Keywords: Amino acid, glycosidation, nucleoside, ribavirin
INTRODUCTION
Intensive efforts are underway worldwide to develop chemotherapeutic agents
that have effective antiviral or antitumor activity, especially nucleoside
analogues.[1] A number of these have been approved as effect therapeutic
drugs or are at different phases of clinical trials. Among them, Ribavirin 1,
a broad-spectrum antiviral nucleoside with 3-carboxamide triazole base
moiety, exhibits excellent antiviral activity.[2] On the other hand, recent
research suggests that nucleoside analogues containing amino-acid residues
would lead to significant biological activity,[3] because they could bind to
target enzymes or other target proteins more easily and effectively than the
natural nucleosides and other analogues.
Received in Japan October 13, 2004
Address correspondence to Tianpa You, Chemistry Department, University of
Science & Technology of China, Hefei 230026, China. Tel.: þ86-551-3606944;
Fax: þ86-551-3606168; E-mail: ytp@ustc.edu.cn

1018
D. Li et al.
The combination of the previously mentioned information, the novel
categories of nucleoside analogues 2 with an imidazole base moiety bearing
amino-acid residue, and 3 with 4-amide imidazole base moiety were
designed and synthesized (Fig. 1).
Compound 4 was conveniently reduced to 7 by hydrogenation. Because 7
is too unstable to separate,[4] it was therefore directly converted to 8 by con-
densation with formic acid or N-protected amino acids without further separa-
tion. Deprotection of the acetyl at the sugar moiety of 8a–e with ammonia/
methanol in almost quantitative yield, followed by deprotection of the benzyl-
oxylcarbonyl at the nucleobase, gave target products 2a–e smoothly, while
deprotection of the acetyl at the sugar moiety of 7f–g gave 3a–b
(Scheme 1). Many attempts had tried to remove N-protecting group benzylox-
ycarbonyl first, but failed. Only 20,30-acetyl at sugar moiety were removed and
the resulting products were not the desired products.
The methods so far reported for preparing the key intermediate 4,
however, all appeared with some deficiencies. Chavis et al. and Humphries
and Ramsden reported on the coupling of a metal salt of 4-nitroimidazole
with 2,3,5-tri-O-acetyl-D-ribofuranose bromide, which gave a mixture of the
isomers 4 and 5 (2:1) in moderate yield.[5,6]
More recently, Kumar et al. reported that coupling 2-nitro-1-trimethyl-
silylimidazole with some bromosugars gave almost quantitative yield;
however, only a-anomer was obtained.[7]
Our initial attempt to prepare 3 was made by coupling 4-nitro-1-tri-
methylsilylimidazole and commercially available 1,2,3,5-tetra-O-acetyl-b-
D-ribofuranose in the presence of SnCl4 in acetonitrile, which gave a
mixture of the isomers 4 and 6 (1:3) with the undesired a-anomer 6 as the
major product (Scheme 2). Drawing inspiration from Alauddin et al.’s
Figure 1. Ribavirin and target molecule.

Scheme 1. a) 1 atm H2, 5% Pd/C, acetonitrile; b) formic acid or N-protected amino acids, DCC, acetonitrile; c)
NH3/CH3OH, almost quantitative; d) 10% Pd/C, H2, CH3OH. Cbz ¼ COOCH2Ph.

1020
D. Li et al.
Scheme 2. a) HMDS/(NH4)2SO4, reflux; b) tetra-O-acetylribofuranose, SnCl4,
ClCH2CH2Cl, 90%.
recent discovery[8] and the addition of our own discovery, we finally carried
out the coupling reaction in 1,2-dichloroethane instead of acetonitrile in the
presence of SnCl4 and a catalytic amount of MgSO4. The b-anomer 4
turned out to be the major product (b-anomer 67.5%, a-anomer 22.5%,
b/a ¼ 3:1) and can be easily separated by recrystallization.†
In conclusion, 1-(b-D-2,3,5-tri-O-acetylribofuranosyl)-4-nitroimidazole 4
was prepared as the major product by coupling 4-nitro-1-trimethylsilylimida-
zole and commercially available 1,2,3,5-tetra-O-acetyl-b-D-ribofuranose in
the presence of SnCl4 and MgSO4. A series of ribavirin analogues was also
synthesized.
EXPERIMENTAL
Melting points were determined with an XT-4 apparatus and are uncorrected.
The 1HNMR spectra were measured with Bruker AV-300 and AV-500
spectrometers. The IR spectra were determiined with a Brucker Vetor 22 spec-
trometer. A P-E240C apparatus was used for elemental analysis. All chemicals
were analytically pure. 1,2-Dichoroethane was dried by anhydrous magnsium
sulfate and distilled.
General Procedure for 4-Nitroimidazole Glycosidation
4-Nitroimidazole (2.346 g, 20.75 mmol) was refluxed with 70 ml HMDS and
a catalytic amount of (NH4)2SO4 until a clear solution was obtained (in
about 4 h). The excess of HMDS was removed in vacuo. The silyated base
was dissolved in anhydrous 1,2-dichloroethane (180 ml). A solution of
†The ratio was obtained by chromatography and HPLC, which used a C18 reverse-
phase analytical column and an MeCN/H2O solvent system (MeCN/H2O ¼ 2:7) as
eluent. The product b appeared first at 12.967 min in the HPLC, and the compound
a emerged at 17.938 min.

Synthesis of Ribavirin Analogues
1021
1,2,3,5-tetra-O-acetylribofuranose (5.279 g, 16.60 mmol) in 50 ml 1,2-
dichloroethane and MgSO4 (0.2 eq) were added at rt. Then, SnCl4 (2.95 ml,
25.10 mmol) in 10 ml 1,2-dichloroethane was added dropwise below 08C at
the nitrogen atmosphere. The mixture was stirred at rt for 8–10 h. TLC
showed that the reaction had completed; the reaction mixture was diluted
with CH2Cl2 and quenched with saturated NaHCO3. The aqueous layer was
extracted with CH2Cl2 (3 ꢀ 50 ml). The combined organic phases were
washed with water, dried over MgSO4, and concentrated in vacuo. The
isomers of the product were separated by column chromatography (eluent:
petroleum ether ethyl acetate ¼ 2:1) to give 4 (4.157 g, 67.5%) and 6
(1.386 g, 22.5%). The structures of compounds 4 and 6 were determined by
1
NOE of H NMR. In compound 6, 10-H had a plus of 7.67% when 20-H was
irradiated. While in compound 4, 10-H had no plus when 20-H was irradiated.
1
Compound 4: H NMR (CDCl3, 500 MHz) d 8.06 (s, 1H, 2-H), 7.72 (s, 1H,
5-H), 5.87 (d, J ¼ 4.2 Hz, 1H, 10-H), 5.34 (dd, J ¼ 5.2, 4.2 Hz, 1H, 20-H),
5.30 (t, J ¼ 5.2 Hz, 1H, 30-H), 4.53 (m, 1H, 40-H), 4.40 (d, J ¼ 2.5 Hz, 2H,
50-H), 2.20 (s, 3H, CH3CO-), 2.16 (2s, 6H, 2 ꢀ CH3CO-). Compound 6:
1H NMR (CDCl3, 500 MHz) d 8.13 (s, 1H, 2-H), 8.06 (s, 1H, 5-H), 6.48
(s, 1H, 10-H), 5.54 (d, J ¼ 2.5 Hz, 1H, 20-H), 5.34 (dd, J ¼ 5.1, 2.5 Hz, 1H,
30-H), 4.50 (dd, J ¼ 5.1, 2.7 Hz, 1H, 40-H), 4.43 (d, J ¼ 2.7 Hz, 2H, 50-H),
2.18 (2s, 6H, 2 ꢀ CH3CO-), 2.08 (s, 3H, CH3CO-).
General Procedure for the Preparation of 8a–g
1-(b-D-2,3,5-tri-O-acetylribofuranosyl)-4-nitroimidazole 4 was dissolved in
anhydrous acetonitrile and reduced with 1 atm hydrogen in the presence of
5% Pd/C for 2–4 h at rt. When TLC showed that the reaction had completed,
formic acid or N-protected amino acid (1.2 equiv.) was added, and the
mixture was cooled to 25 to 108C. N,N0-Dicyclohexylcarbodiimide (DCC)
(1.5 equiv.) was added and stirred for 2–3 h, and then standed at rt overnight.
The catalysts were removed by filtration. The product was purified by column
chromatography (eluent: range from EtOAc to EtOAc/EtOH ¼ 10:1).
4-N-[2-(N-benzyloxylcarbonylamino)-acetyl]amino-1-(b-D-2,3,5-tri-O-acetyl-
ribofuranosyl)imidazole (8a). Yield: 70%. 1H NMR (CDCl3, 300 MHz) d 7.72
(s, 1H, 2-H), 7.59 (s, 1H, 5-H), 7.27–7.50 (m, 5H, Ar-H), 6.02 (d, J ¼ 5.4 Hz,
1H, 10-H), 5.53 (t, J ¼ 5.4 Hz, 1H, 20-H), 5.48 (dd, J ¼ 3.6, 1.8 Hz, 1H, 30-H),
5.12 (s, 2H, -OCH2Ph), 4.47 (dd, J ¼ 3.0, 3.6 Hz, 1H, 40-H), 4.38
(d, J ¼ 4.4 Hz, 2H, 50-H), 4.03 (s, 2H, NHCH2CO-), 2.20 (s, 3H), 2.13
(s, 3H), 2.06 (s, 3H); 13C NMR (CDCl3, 75 MHz) d 20.4, 20.6, 20.8, 44.5,
63.1, 67.2, 70.9, 74.5, 80.7, 88.4, 104.2, 128.6, 128.8, 132.4, 136.4, 138.3,
156.7, 166.5, 169.4, 169.6, 170.7; IR (KBr, cm21) 3332 (NHCO), 1747
(COO-), 1667 (CONH).

1022
D. Li et al.
4-N-[(s)-2-(N-benzyloxylcarbonylamino)-propionyl]amino-1-(b-D-2,3,5-tri-
1
O-acetylribofuranosyl)imidazole (8b). Yield: 65%. H NMR (CD3COCD3,
300 MHz) d 7.73 (s, 1H, 2-H), 7.61 (s, 1H, 5-H), 7.20–7.40 (m, 5H, Ar-H),
6.00 (d, J ¼ 5.6 Hz, 1H, 10-H), 5.54 (t, J ¼ 5.6 Hz, 1H, 20-H), 5.47 (dd,
J ¼ 3.6, 1.8 Hz, 1H, 30-H), 5.08 (s, 2H, OCH2Ph), 4.47 (m, 2H, 40-H and
NHCHRCO-), 4.37 (d, J ¼ 2.9 Hz, 2H, 50-H), 2.20 (s, 3H), 2.12 (s, 3H),
2.05 (s, 3H), 1.43 (d, J ¼ 7.1 Hz, 3H, -CH3); 13C NMR (CD3COCD3,
75 MHz) d 18.7, 20.3, 20.5, 20.8, 51.4, 64.0, 66.9, 71.6, 75.0, 81.2, 88.7,
104.3, 128.6, 129.2, 134.1, 138.0, 139.5, 156.9, 170.2, 170.4, 170.8, 171.1;
IR (KBr, cm21) 3317 (NHCO), 1747 (COO-), 1657 (CONH).
4-N-[(s)-2-(N-benzyloxylcarbonylamino)-3-phenyl-propionyl]amino-1-(b-D-
2,3,5-tri-O-acetylribofuranosyl)imidazole (8c). Yield: 56%. 1H NMR
(CD3COCD3, 300 MHz) d 7.77 (s, 1H, 2-H), 7.66 (s, 1H, 5-H), 7.08–7.37
(m, 10H, Ar-H), 6.01 (d, J ¼ 5.4 Hz, 1H, 10-H), 5.57 (t, J ¼ 5.4 Hz, 1H, 20-
H), 5.48 (dd, J ¼ 3.6, 1.8 Hz, 1H, 30-H), 5.02 (s, 2H, OCH2Ph), 4.74
(m, 1H, NHCHRCO), 4.48 (dd, J ¼ 3.0, 3.2 Hz, 1H, 40-H), 4.37
(d, J ¼ 4.4 Hz, 2H, 50-H), 3.24 (dd, J ¼ 9.4, 4.1 Hz, 1H, -CH2Ph), 3.03 (dd,
J ¼ 9.4, 4.1 Hz, 1H, 2CH2Ph), 2.18 (s, 3H), 2.12 (s, 3H), 2.05 (s, 3H); 13C
NMR (CD3COCD3, 75 MHz) d 20.3, 20.5, 20.8, 38.9, 57.1, 60.6, 64.0, 66.7,
71.5, 74.9, 81.1, 88.6, 104.5, 127.3, 128.4, 128.5, 129.0, 129.1, 130.1,
134.1, 137.8, 138.2, 139.3, 157.0, 169.6, 170.1, 170.4, 171.0; IR(KBr,
cm21) 3330 (NHCO), 1749 (COO-), 1660 (CONH).
4-N-[(s)-2-(N-benzyloxylcarbonylamino)-4-amido-butyryl]amino-1-(b-D-2,3,
5-tri-O-acetylribofuranosyl)imidazole (8d). Yield: 54%. 1H NMR (CD3COCD3,
300 MHz) d 7.77 (s, 1H, 2-H), 7.63 (s, 1H, 5-H), 7.20–7.36 (m, 5H, Ar-H),
6.00 (d, J ¼ 5.7 Hz, 1H, 10-H), 5.54 (t, J ¼ 5.4 Hz, 1H, 20-H), 5.47 (dd,
J ¼ 3.6, 1.8 Hz, 1H, 30-H), 5.08 (s, 2H, OCH2Ph), 4.47 (dd, J ¼ 3.0, 9.5 Hz,
2H, 40-H and NHCHRCO-), 4.37 (d, J ¼ 2.0 Hz, 2H, 50-H), 2.40
(d, J ¼ 2.20 Hz, 2H, b-CH2), 2.17 (s, 3H), 2.11 (s, 3H), 2.06 (m, 5H,
CH3CO- and g-CH2); 13C NMR (CD3COCD3, 75 MHz) d 19.5, 19.7, 20.0,
28.0, 31.3, 54.8, 63.1, 66.1, 70.7, 74.1, 80.3, 87.9, 103.7, 127.7, 128.3,
133.4, 137.0, 138.5, 138.6, 156.4, 169.3, 169.4, 169.7, 170.4, 172.7, 175.3;
IR (KBr, cm21) 3339 (NHCO), 1748 (COO-), 1672 (CONH).
4-N-[(s)-(N-benzyloxylcarbonylpyrrolidine)-2-carbonyl]amino-1-(b-D-2,3,5-
tri-O-acetylribofuranosyl)imidazole (8e). Yield: 48%. 1H NMR (CDCl3,
300 MHz) d 7.53 (s, 1H, 2-H), 7.45 (s, 1H, 5-H), 7.15–7.35 (m, 5H, Ar-H),
5.75 (d, J ¼ 5.9 Hz, 1H, 10-H), 5.38 (m, 2H, 20-H, 30-H), 5.12 (s, 2H,
OCH2Ph), 4.47 (m, 2H, 40-H and NCHRCO-), 4.33 (d, J ¼ 4.2 Hz, 2H, 50-
H), 3.55 (m, 2H, RCH2N), 2.22 (s, 3H), 2.13 (s, 3H), 2.07 (s, 3H), 1.85–
2.03 (m, 4H, b-, g-CH2); 13C NMR (CDCl3, 75 MHz) d 20.4, 20.6, 20.9,
23.6, 29.4, 47.4, 61.1, 63.2, 67.6, 70.9, 74.7, 80.6, 88.3, 104.0, 128.1, 128.6,

Synthesis of Ribavirin Analogues
1023
132.3, 136.4, 138.3, 156.7, 167.6, 169.3, 169.6, 170.6; IR (KBr, cm21) 3288
(NHCO), 1749 (COO-), 1698 (CONH).
4-N-Formylamino-1-(b-D-2,3,5-tri-O-acetylribofuranosyl)imidazole (8f).
Yield: 83%. 1H NMR (CDCl3, 300 MHz) d 8.30 (s, 1H, HCO 2 ), 7.56
(s, 1H, 2-H), 7.49 (s, 1H, 5-H), 5.77 (d, J ¼ 4.7 Hz, 1H, 10-H), 5.40 (m, 2H,
20,30-H), 4.38 (d, J ¼ 2.8 Hz, 1H, 40-H), 4.32 (d, J ¼ 2.8 Hz, 2H, 50-H), 2.21
(s, 3H), 2.11 (s, 3H), 2.06 (s, 3H); 13C NMR (CDCl3, 75 MHz) d 20.5, 20.7,
20.8, 63.1, 70.8, 74.7, 80.6, 88.4, 104.7, 132.3, 137.9, 157.8, 169.5, 169.7,
170.8; IR (KBr, cm21) 3300 (NHCO), 1748 (COO-), 1690 (CONH).
4-N-[2-(N-Acetylamino)-acetyl]amino-1-(b-D-2,3,5-tri-O-acetylribofuranosyl)
1
imidazole (8g).Yield: 61%. H NMR (CD3COCD3, 300 MHz) d 7.74 (s, 1H,
2-H), 7.58 (s, 1H, 5-H), 6.00 (d, J ¼ 5.6 Hz, 1H, 10-H), 5.53 (t, J ¼ 5.6 Hz,
1H, 20-H), 5.45 (dd, J ¼ 3.6, 1.8 Hz, 1H, 30-H), 4.47 (dd, J ¼ 3.0, 3.6 Hz,
1H, 40-H), 4.36 (d, J ¼ 3.0 Hz, 2H, 50-H), 4.03 (s, 2H, NHCH2CO), 2.20
(s, 3H), 2.12 (s, 3H), 2.05 (s, 3H), 2.00 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 20.4, 20.6, 20.9, 23.0, 43.0, 63.2, 70.8, 74.5, 80.7, 88.4, 104.2, 132.3,
137.9, 166.4, 169.5, 169.7, 170.7, 171; IR (KBr, cm21) 3285 (NHCO),
1748 (COO-), 1656 (CONH).
General Procedure for Deprotection
Compound 8 was dissolved in methanol and reacted with NH3 for 24–48 h.
The solvent was evaporated in vacuo. The product of 8a–e was dried in
vacuo, then dissolved in anhydrous methanol and reduced with 1 atm
hydrogen in the presence of 10% Pd/C (10–20% of 8, w/w). The catalyst
was removed, and the product was purified by chromatography (eluent:
range from EtOAc EtOH ¼ 1:8 to EtOH).
4-N-Formylamino-1-b-D-ribofuranosylimidazole (3a). Almost quantitive.
1
Oil. H NMR (D2O, 300 MHz) d 8.21 (s, 1H, HCO 2 ), 7.76 (s, 1H, 2-H),
7.47 (s, 1H, 5-H), 5.74 (d, J ¼ 5.4 Hz, 1H, 10-H), 4.45 (t, J ¼ 5.3 Hz, 1H,
20-H), 4.31 (t, J ¼ 4.6 Hz, 1H, 30-H), 4.16 (dd, J ¼ 4.0, 3.8 Hz, 1H, 40-H),
3.72–3.83 (m, 2H, 50-H); 13CNMR (D2O, 75 MHz) d 60.9, 69.9, 74.5, 84.5,
89.4, 105.9, 133.7, 134.7, 160.8; IR (KBr, cm21) 3288 (OH, NHCO), 1668
(CONH); Anal. calcd. for C9H13N3O5: C, 44.45; H, 5.39; N, 17.28. Found:
C, 44.19; H, 5.13; N, 17.03.
4-N-[2-(N-Acetylamino)-acetyl]amino-1-b-D-ribofuranosylimidazole (3b).
1
Almost quantitive. White solid. Mp: 200.4–201.08C. H NMR (DMSO-d6,
300 MHz) d 7.68 (s, 1H, 2-H), 7.34 (s, 1H, 5-H), 5.49 (d, J ¼ 5.9 Hz, 1H,
10-H), 4.11 (m, 1H, 20-H), 4.00 (m, 1H, 30-H), 3.86 (d, J ¼ 3.3 Hz, 1H,

1024
D. Li et al.
40-H), 3.82 (d, J ¼ 5.7 Hz, 2H, NHCH2CO), 3.52 (t, J ¼ 4.6 Hz, 2H, 50-H),
1.86 (s, 3H, CH3CO-); 13CNMR (DMSO-d6, 75 MHz) d 22.4, 42.0, 61.4,
70.5, 75.1, 85.2, 89.6, 103.8, 132.9, 137.9, 166.2, 169.6; IR (KBr, cm21
)
3276 (OH, NHCO), 1663 (CONH), 1638 (CONH); Anal. calcd. for
C12H18N4O6: C, 45.86; H, 5.77; N, 17.83. Found: C, 45.61; H, 5.54; N, 17.59.
4-N-(2-amino-acetyl)amino-1-b-D-ribofuranosylimidazole (2a). Yield: 70%.
Slightly yellow solid. Mp: 202.58C (decomp.). 1H NMR (DMSO-d6,
300 MHz) d 7.67 (s, 1H, 2-H), 7.36 (s, 1H, 5-H), 5.48 (d, J ¼ 4.4 Hz, 1H,
10-H), 4.11 (t, J ¼ 4.2 Hz, 1H, 20-H), 4.00 (dd, J ¼ 3.3, 2.9 Hz, 1H, 30-H),
3.86 (d, J ¼ 2.8 Hz, 1H, 40-H), 3.54 (m, 2H, 50-H), 3.22 (d, J ¼ 5.5 Hz, 2H,
NH2CH2CO); 13C NMR (DMSO-d6, 75 MHz) d 44.5, 61.4, 70.4, 75.0, 85.2,
89.6, 103.5, 132.9, 137.7, 170.2; IR (KBr, cm21) 3356 (OH, NHCO), 1675
(CONH); Anal. calcd. for C10H16N4O5: C, 44.12; H, 5.92; N, 20.58. Found:
C, 43.88; H, 5.75; N, 20.30.
4-N-[(s)-2-amino-propionyl]amino-1-b-D-ribofuranosylimidazole (2b). Yield:
1
65%. White solid. Mp: 207.58C (decomp.). H NMR (DMSO-d6, 300 MHz)
d 7.69 (s, 1H, 2-H), 7.38 (s, 1H, 5-H), 5.50 (d, J ¼ 5.6 Hz, 1H, 10-H), 4.13
(dd, J ¼ 4.9, 5.3 Hz, 1H, 20-H), 4.02 (d, J ¼ 2.8 Hz, 1H, 30-H), 3.88
(d, J ¼ 2.9 Hz, 1H, 40-H), 3.40–3.60 (m, 3H, 50-H and NHCHRCO), 1.20
(d, J ¼ 6.6 Hz, 3H, -CH3); 13C NMR (DMSO-d6, 75 MHz) d 18.8, 49.9,
61.5, 70.5, 75.2, 85.3, 89.7, 103.7, 133.0, 137.9, 171.7; IR (KBr, cm21
)
3271 (OH, NHCO), 1682 (CONH); Anal. calcd. for C11H18N4O5: C, 46.15;
H, 6.34; N, 19.57. Found: C, 45.92; H, 6.07; N, 19.30.
4-N-[(s)-2-amino-3-phenyl-propionyl]amino-1-b-D-ribofuranosylimidazole (2c).
1
Yield: 52%. Yellow solid. Mp: 210.58C (decomp.). H NMR (DMSO-d6,
300 MHz) d 7.69 (s, 1H, 2-H), 7.40 (s, 1H, 5-H), 7.15–7.35 (m, 5H, Ar-H),
5.50 (d, J ¼ 5.8 Hz, 1H, 10-H), 4.14 (dd, J ¼ 5.1, 5.3 Hz, 1H, 20-H), 4.01
(d, J ¼ 4.0 Hz, 1H, 30-H), 3.87 (d, J ¼ 3.0 Hz, 1H, 40-H), 3.42–3.65 (m, 3H,
50-H and NHCHRCO), 3.01 (m, 1H, -CH2Ph), 2.67 (m, 1H, -CH2Ph); 13C
NMR (DMSO-d6, 75 MHz) d 40.7, 55.8, 61.4, 70.4, 75.0, 85.2, 89.6, 103.7,
126.1, 128.1, 129.3, 133.0, 137.8, 138.5, 171.4; IR (KBr, cm21) 3337 (OH,
NHCO), 1673 (CONH); Anal. calcd. for C17H22N4O5: C, 56.35; H, 6.12; N,
15.46. Found: C, 56.09; H, 5.86; N, 15.20.
4-N-[(s)-4-amido-2-amino-butyryl]amino-1-b-D-ribofuranosylimidazole (2d).
Yield: 57%. White solid. Mp: 247.28C (decomp.). 1H NMR (D2O,
500 MHz) d 7.69 (s, 1H, 2-H), 7.43 (s, 1H, 5-H), 5.66 (d, J ¼ 5.6 Hz, 1H,
10-H), 4.41 (m, 1H, 20-H), 4.36 (t, J ¼ 5.4 Hz, 1H, 30-H), 4.22 (dd, J ¼ 4.6,
4.2 Hz, 1H, NHCHRCO), 4.08 (d, J ¼ 3.5 Hz, 1H, 40-H), 3.65–3.78 (m, 2H,
50-H), 2.51 (m, 1H, b-CH2), 2.40 (m, 2H, g-CH2), 2.08 (m, 1H, b-CH2);
13C NMR (D2O, 125 MHz) d 25.1, 29.2, 56.9, 61.1, 70.2, 74.7, 84.8, 89.6,

Synthesis of Ribavirin Analogues
1025
106.6, 134.4, 135.8, 172.5, 182.3; IR (KBr, cm21) 3460, 3386 (OH, NHCO),
1679 (CONH); Anal. calcd. for C13H21N5O6: C, 45.48; H, 6.16; N, 20.40.
Found: C, 45.22; H, 5.88; N, 20.27.
4-N-[(s)-pyrrolidine-2-carbonyl]amino-1-b-D-ribofuranosylimidazole (2e).
Yield: 55%. White solid. Mp: 205.28C (decomp.). 1H NMR (D2O,
300 MHz) d 7.68 (s, 1H, 2-H), 7.35 (s, 1H, 5-H), 5.65 (d, J ¼ 5.7 Hz, 1H,
10-H), 4.37 (t, J ¼ 5.4 Hz, 1H, 20-H), 4.22 (dd, J ¼ 3.9, 5.1 Hz, 1H, 30-H),
4.08 (t, J ¼ 3.7 Hz, 1H, 40-H), 3.94 (m, 1H, NHCHRCO), 3.65-3.78 (m, 2H,
50-H), 3.01 (m, 2H, NHCH2R), 2.18 (m, 1H, b-CH2), 1.74–1.86 (m, 3H,
b-CH2 and g-CH2); 13C NMR (D2O, 75 MHz) d 23.5, 29.4, 46.2, 59.6,
60.9, 69.9, 74.5, 84.6, 89.4, 106.1, 134.1, 135.4, 167.6; IR (KBr, cm21
)
3376 (OH, NHCO), 1682 (CONH); Anal. calcd. for C13H20N4O5: C, 49.99;
H, 6.45; N, 17.94. Found: C, 49.74; H, 6.20; N, 17.78.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (No. 20172049)
and our university for financial support.
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