An improved procedure for the preparation of ribavirin

Full text of DOI:10.1080/00304948.2012.697741

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Organic Preparations and Procedures
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An Improved Procedure for the
Preparation of Ribavirin
Y. S. Li a , J. J. Zhang a , L. Q. Mei a & C. X. Tan b
a College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou, 310014, P. R. CHINA
b College of Chemical Engineering and Materials Science, Zhejiang
University of Technology, Hangzhou, 310014, P. R. CHINA
Version of record first published: 01 Aug 2012.
To cite this article: Y. S. Li , J. J. Zhang , L. Q. Mei & C. X. Tan (2012): An Improved Procedure for
the Preparation of Ribavirin, Organic Preparations and Procedures International: The New Journal for
Organic Synthesis, 44:4, 387-391
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Organic Preparations and Procedures International, 44:387–391, 2012
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2012.697741
An Improved Procedure for the Preparation
of Ribavirin
Y. S. Li,1 J. J. Zhang,1 L. Q. Mei,1 and C. X. Tan2
1College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou, 310014, P. R. CHINA
2College of Chemical Engineering and Materials Science, Zhejiang University of
Technology, Hangzhou, 310014, P. R. CHINA
In recent decades, there has been considerable interest in ribavirin (1-β-D-ribofuranosyl-
1,2,4-triazole-3-carboxamide, 4), as a broad-spectrum antiviral agent.1–3 Because of its
activity against both RNA and DNA viruses, it is extensively used for the treatment of
influenzas, hepatitis BandCvirus,4 SARS,5 syncytialvirus,6 anditsvaluehasbeenenhanced
since oral ribavirin was approved by the FDA in 1998, and became part of a combination
therapy for the treatment of hepatitis.7
There are two types of methods for the preparation of ribavirin, a chemical method8–11
and an enzymatic synthesis.12–15 A typical chemical protocol involves a three-step manufac-
turing process.11 Condensation of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (2), prepared by
the p-toluenesulfonic acid catalyzed acetylation of inosine (1a), with methyl 1,2,4-triazole-
3-carboxylate gave methyl 1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1H-1,2,4-triazole-3-
carboxylate (3) which is subsequently converted to ribavirin (4) by deacetylation and
ammonolysis (Scheme 1).
The process for the preparation of 2 from 1 suffer from drawbacks such as high
cost, low yields, need for large amounts of catalyst and work-ups unsuitable for industrial
production.10 A major factor affecting this reaction is the acidity of the catalyst; if the
catalyst is too acidic, the product decomposes while a catalyst of low acidity leads to long
reaction times or incomplete cleavage of the nucleoside bond. Herein we report a practical,
convenient and efficient process for the synthesis of 4 from inosine (1a, R1 = OH, R2 =
H), adenosine (1b, R1 = NH2, R2 = H), or guanosine (1c, R1 = OH, R2 = NH2) in three
steps.
Table 1 shows the results of acetylation and cleavage of purine nucleosides promoted
by various catalysts. According to published results, inosine, adenosine and guanosine can
be converted into 2 and to the corresponding acetyl purines with excess of acetic acid used
both as a catalyst and a solvent (Table 1, Entries 2–4). Better results were obtained by the
Received December 9, 2011.
Address correspondence to C. X. Tan, College of Chemical Engineering and Materials Sci-
ence, Zhejiang University of Technology, Hangzhou, 310014, P. R. CHINA. E-mail: tanchengxia@
zjut.edu.cn
387

388
Tan et al.
Scheme 1
use of p-Toluenesulfonic acid (Table 1, Entry 1). The acetylation and cleavage of purine
nucleosides required less catalyst and gave better yields. Our results show that 0.45%
of TFA was sufficient to accomplish this reaction (Table 1, Entries 5–7). Compared to
other reported catalysts, the amount of catalyst used was greatly reduced, the yields were
improved and reaction temperatures were milder.
Similarly, previous methods8,11,17,18 for the conversion of 2 to 3 suffers from
the need to use higher temperatures (−), longer reaction times (Table 2, Entries
Table 1
Comparison of Present Method with Previous Procedures for the Synthesis of 2a
Entry
Nucleoside
Catalyst
Amount of
Temp. (◦C)
Yield (%)b
catalyst% (mol)
1
2
3
4
5
6
7
inosine
TsOH
3.10
307
296
90
138
138
138
100
100
100
8410
8116
7316
8316
90
guanosine
adenosine
inosine
inosine
adenosine
guanosine
acetic acidc
acetic acidc
acetic acidc
TFA
296
0.45
0.45
0.45
TFA
TFA
84
86
aReaction mixtures containing 0.15 mol inosine or adenosine or guanosine and 1.5 mol acetic
anhydride.
bYield of 2 based on starting nucleosides.
cUsed as the catalyst and the solvent.

Procedure for the Preparation of Ribavirin
389
Table 2
Comparison of Present Catalysis with Other Procedures for the Synthesis of 3
Entry
Ribofuranose
(mol)
Methyl
Catalyst
Time (hrs)
Temp. (◦C)
Yield (%)a
1,2,4-triazole-3-
3-carboxylate/(mol)
1
2
3
4
5
6
0.10
1.26
0.19
0.01
0.01
0.15
0.1
(p-O2NPh)2PO2H
SnCl4
0.25–0.30
160–165
5–40
788
1.46
0.21
0.01
0.01
0.17
2
6
5
5
2
8017
7918
8018
7918
88
p-TosOH
80–90
PhSO3H
90–100
90–100
130–135
MeSO3H
CF3SO3H
aIsolated yield based on 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose.
3–5) and give lower yields (Table 2, Entries 1–5). Of several agents studied [bis-(p-
nitrophenyl)phosphinic acid, stannic chloride, p-toluenesulfonic, benzenesulfonic and
methanesulfonic acids), trifluoromethanesulfonic acid (TfOH)] (Table 2, Entry 6) was
found to be the best catalyst for the conversion of 2 to 3 (88%) in high purity at 135◦ in
2 hrs.
In conclusion, we have developed an improved method for the preparation of ribavirin
by using TFA as the catalyst for the conversion 1 to 2 and TfOH for the conversion 2 to 3.
The advantages of our procedure include short reaction times, easy work-up, low amount
of catalyst, good yields and purity of the products. A further advantage in using 1b and
1c is that the by-products, adenine and guanine obtained in the first step maybe useful in
the synthesis of adefovir and acyclovir respectively. The overall yields of 4 from 1a, 1b
and 1c were 75%, 70%, 71% respectively compared to 48%, 47%, 52% by the precious
method.11,15,18
Experimental Section
All the starting materials were purchased from commercial sources and used without further
purification. The IR spectra were obtained as KBr pellets on an AVATAR 370 FI-IR Thermon
Nicolet spectrometer. 1H NMR spectra were recorded on an AVANCE III (500 MHz) with
TMS as an internal standard. Mps were determined on a Yanagimoto micromelting point
apparatus and are uncorrected.
Typical Procedure for the Preparation of 1,2,3,5-Tetra-O-Acetyl-β-D-ribofuranose
(2) from 1c. A suspension of guanosine 1c (42.5 g, 0.15 mol) and acetic anhydride (153.0 g,
1.5 mol) was stirred in a three-neck 250 mL flask at 136◦C for 1 h. The temperature
was reduced to 60◦C and TFA (0.077 g, 0.68 mmol) was then added and heating at
100◦C was continued for 20–30 hrs. The progress of the reaction was monitored by TLC
(1:1 ethyl acetate-acetone). Upon cooling, the precipitate formed was collected and dried
to give 33.75 g (96%) of N2,N9-diacetylguanine. The filtrate was evaporated under re-
duced pressure and the residue was recrystallized from methanol to give 41.1 g (86%) of
the 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (2) as a white solid, mp. 82–83◦C, lit.8 mp.
80–82◦C.

390
Tan et al.
Typical Procedure for the Preparation of 3. A mixture of 1,2,3,5-tetra-O-acetyl-β-D-
ribofuranose (47.1 g, 0.15 mol) and methyl 1,2,4-triazole-3-carboxylate (21.6 g, 0.17 mol)
and TfOH (0.11 g, 0.75 mmol) was heated with vigorous stirring at 135◦C for 2 h under
vacuum (about 55 mmHg). The solid obtained was then recrystallized from methanol,
collected and dried to give 53.1 g (92%) of 3 as a white solid, mp. 106–108◦C, lit.8 mp.
107–109◦.
Typical Procedure for the Preparation of Ribavirin (4). A mixture of 1,2,3,5-tetra-O-
acetyl-β-D-ribofuranose (47.1 g, 0.15 mol) and methyl 1,2,4-triazole-3-carboxylate (21.6 g,
0.17 mol), TfOH (0.11 g, 0.75 mmol) was heated under vigorous stirring at 135◦ for 2 h under
vacuum(about 55 mmHg). Methanol (100 mL) was added and NH3 gas was introduced
into the reaction mixture for 40 hrs at 20◦. The solvent was removed by distillation, and
the residual solid was recrystallized from EtOH and dried under vacuum at 60◦ for 10 h to
give 31.1 g (83%) of 4 as a white soild, mp. 169–170◦C, lit.8 mp. 166–168◦C. The overall
yield from the former procedure was 71% based on guanosine.
Acknowledgement
The authors wish to thank the financial help provided by Zhejiang Chengyi Pharmaceutical
Co., Ltd.
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