Synthesis of AZT analogues: 7-(3-azido-2hydroxypropyl)-, 7-(3-amino-2-hydroxypropyl)-, 7-(3-triazolyl-2-hydroxypropyl)theophyllines

Article abstract of DOI:10.1080/15257770500544495

Nucleophilic displacement of the tosyloxy group in 7-(2-hydroxy-3- p -toluenesulfonyloxypropyl)theophylline (1) with azide anion afforded 7-(3-azido-2-hydroxypropyl)theophylline (2). Reduction of the 3-azido group in 2 with Ph 3 P/Py/NH 4 OH afforded the 3-amino derivative 4, alternatively obtained by regioselective amination of 7-(2,3-epoxypropyl)theophylline (3). Selective acetylation of 4 gave the N-acetyl derivative 5. 1,3-Dipolar cycloaddition of the azide group in 2 with N 1 -propargyl thymine (6) afforded the regioisomeric triazole 7. Copyright Taylor & Francis Group, LLC.

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Synthesis of AZT analogues: 7-(3-
azido-2hydroxypropyl)-, 7-(3-amino-2-
hydroxypropyl)-, 7-(3-triazolyl-2-
hydroxypropyl)theophyllines
El Sayed H. El Ashry a , Adel Abdel-Rahman a , Nagwa Rashed a
Laila F. Awad a & Hanaa A. Rasheed a
a Department of Chemistry, Faculty of Science , Alexandria
University , Alexandria, Egypt
,
Published online: 23 Aug 2006.
To cite this article: El Sayed H. El Ashry , Adel Abdel-Rahman , Nagwa Rashed , Laila F. Awad &
Hanaa A. Rasheed (2006) Synthesis of AZT analogues: 7-(3-azido-2hydroxypropyl)-, 7-(3-amino-2-
hydroxypropyl)-, 7-(3-triazolyl-2-hydroxypropyl)theophyllines, Nucleosides, Nucleotides and Nucleic
Acids, 25:3, 299-305, DOI: 10.1080/15257770500544495
To link to this article: http://dx.doi.org/10.1080/15257770500544495
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Nucleosides, Nucleotides, and Nucleic Acids, 25:299–305, 2006
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770500544495
SYNTHESIS OF AZT ANALOGUES: 7-(3-AZIDO-2-
HYDROXYPROPYL)-, 7-(3-AMINO-2-HYDROXYPROPYL)-,
7-(3-TRIAZOLYL-2-HYDROXYPROPYL)THEOPHYLLINES
El Sayed H. El Ashry, Adel Abdel-Rahman, Nagwa Rashed,
Laila F. Awad, and Hanaa A. Rasheed
Department of Chemistry, Faculty
2
of Science, Alexandria University, Alexandria, Egypt
Nucleophilic displacement of the tosyloxy group in 7-(2-hydroxy-3-p-toluenesulfonyloxy-
2
propyl)theophylline (1) with azide anion afforded 7-(3-azido-2-hydroxypropyl)theophylline (2).
Reduction of the 3-azido group in 2 with Ph3P/Py/NH4OH afforded the 3-amino derivative 4,
alternatively obtained by regioselective amination of 7-(2,3-epoxypropyl)theophylline (3). Selective
acetylation of 4 gave the N-acetyl derivative 5. 1,3-Dipolar cycloaddition of the azide group in 2 with
N1-propargyl thymine (6) afforded the regioisomeric triazole 7.
Keywords AZT; Azido-2-Hydroxypropyltheophylline; Thymine; Triazo¯le; Cycloaddition
INTRODUCTION
Significant progress has been accomplished in the search for new thera-
peutic agents for treatment of viral diseases,[1] where nucleoside analogues
are of great interest.[2−8] Among these nucleoside analogues, 3ꢁ-azido-3ꢁ-
deoxythymidine (AZT)[9,10] has been used for the treatment of human
immunodeficiency virus (HIV) and became a lead nucleoside in antiviral
therapy. However, the clinical use of such anti-HIV nucleosides is ham-
pered by drug resistance[9] and toxicity problems.[10] These limitations
had led to a search for new agents possessing more selective antiviral ac-
tivities with low toxicity problems. In this regard, replacing the furanosyl
moiety by a more simplified one such as that in acyclonucleosides has pre-
sented analogues of potential value as new leads.[2] Theophylline analogues
with an acyclic moiety became attractive AZT analogues. The 7-(3-azido-2-
hydroxypropyl)theophylline and its 3-amino as well as 3-(1,2,3-triazolyl) ana-
logues have been selected as target compounds in this publication. The latter
Received 16 August 2005; accepted 28 December 2005.
Address correspondence to E. El Ashry, Department of Chemistry, Faculty of Science, Alexandria
University, Alexandria, Egypt. E-mail: eelashry60@hotmail.com; eelashry60@link.net
299

300
E. S. H. El Ashry et al.
analogue would possess three important heterocyclic rings linked to each
other by flexible methylene and propyl groups as linkers, which could result
in better flexibility of the thymine, triazole, and theophylline rings when
adopted in a biological target.[11]
RESULTS AND DISCUSSION
Two approaches were used for the synthesis of the target compounds. The
first approach was done by a nucleophilic displacement of a leaving group
at the C-3ꢁ of 7-[(2-hydroxy-3-p-toluenesulfonyloxy)propyl]theophylline
(1),[12] available by selective tosylation of the primary hydroxylgroup of 7-
(2,3-dihydroxypropyl)theophylline, with sodium azide in DMF at 80◦C for
6 h to give (3-azido-2-hydroxypropyl)theophylline (2) in 87% yield. The
structure of the 3-azido derivative 2 was verified by the presence of azide
absorption band at 2099 cm−1 in its IR spectrum. Both of H-3ꢁ and H-3ꢁꢁ
1
are shieled in the H NMR spectrum, as a result of the azido group, and
resonated as doublet of doublets at δ 3.39 and 3.53, compared to those in 1
that appear at δ 4.03.[12] Conversion of the azido group in 2 to the amino
group was carried out by treatment with triphenylphosphine and concen-
trated ammonium hydroxide solution in pyridine at room temperature to
give the respective 3ꢁ-amino derivative 4.
The second approach toward the amination at the C-3ꢁ was carried out
via opening of an oxirane ring such as that in 3. The latter was prepared by
treatment of 1 with sodium hydroxide solution in DMSO at 0◦C to furnish the
corresponding 7-(2,3-epoxypropyl) theophylline 3 in 75% yield. Its structure
was established on the basis of 1H NMR spectral data that showed the absence
of the signal corresponding to the 2ꢁ-hydroxyl group as well as an upfield shift
of the signals of H-3ꢁ and H-3ꢁꢁ to resonate at δ 2.53 and 2.84, whereas H-2ꢁ, H-
1ꢁ, and H-1ꢁꢁ were assigned to downfield signals. Regioselective base-catalyzed
oxirane ring cleavage of 3 with concentrated ammonium hydroxide solution
at room temperature for three days gave 4 in 95% yield. The mass spectrum
of 4 showed a molecular ion peak at m/z 253 in agreement with its molecular
formula C10H15N5O3. Selective acetylation of the amino group was done
by reaction of 4 with acetic anhydride in absolute methanol and cadmium
acetate as a catalyst to give 5. The 1H NMR spectrum of the N-acetyl derivative
5 in CDCl3 showed signals corresponding to the NH proton at δ 7.93 as a
singlet (D2O exchangeable) in addition to the OH proton at δ 5.24 (D2O
exchangeable). Acetylation of the amino group resulted in a downfield shift
of the of H-3ꢁ and H-3ꢁꢁ signals in 5 from δ 2.70 and 2.93 respectively, in its
precursor 4 (Scheme 1).
Ribavirin, a powerful antiviral nucleoside having a broad spectrum of
activity against RNA and DNA viruses.[13] is representative of 1,2,4-triazole-
nucleosides, which exhibit pronounced biological activities. Also, 1,2,3-
triazole analogues[14] showed potent anti-HIV-1 activities. Both findings

Synthesis of AZT Analogues
301
SCHEME 1
attracted attention toward the synthesis of their analogues. 1,3-Dipolar cy-
cloaddition reaction of azides to acetylenes is an efficient method to ob-
tain 1,2,3-triazole rings in acyclo- and carboacyclonucleosides.[14−17] It is
known[14] that the reaction is controlled by electronic and steric factors.
In general, such addition tends to give mainly the isomer with electron-
withdrawing groups at the 4-position and electron-donating group at the
5-position. On the other hand, the sterically less hindered isomer tends to
be the major isomer. Although both 4- and 5-substituted 1,2,3-triazole deriva-
tives have been obtained from such reactions, the former regioisomer was
the major one.[15−17] Reaction of azide 2 and 1-(propargyl)thymine (6) in
refluxing toluene for 50 h gave only the sterically less hindered regioisomer
7, in 43% yield, rather than 8 (Scheme 2). The structure of 7 was established

302
E. S. H. El Ashry et al.
from its 1H NMR spectrum, which showed a singlet signal for H-5 at δ 8.06
in agreement with the formation of the 4-methylene 1,2,3-triazole derivative
7.[14,18,19]
SCHEME 2
EXPERIMENTAL
Melting points were determined on a Mel-Temp apparatus and are un-
corrected. IR spectra were recorded with a Unicam SP1025 spectrometer. EI
1
mass spectra were recorded on a Varian MAT 311A spectrometer. H NMR
spectra were recorded with a Bruker AC 300 MHz spectrometer. The chemi-
cal shifts are expressed on the δ scale using Me4Si as a standard and J-values
are given in Hz. TLC was performed on Merck Silica Gel 60 F254 with detec-
tion by UV light. Microanalyses were performed in the unit of Microanalysis
at the Faculty of Science, Cairo University.
7-(3-Azido-2-hydroxypropyl)theophylline (2). A mixture of 1[12] (2.00 g,
4.9 mmol) and sodium azide (0.39 g, 6.0 mmol) in dry DMF (10 mL) was
heated for 3 h at 80◦C. The solvent was then removed under reduced pressure
and the resulting residue was purified by column chromatography using
hexane:ethyl acetate (4:1) to afford 2 (1.18 g, 87% yield) as white crystals; mp
100–102◦C; IR(KBr): 1647, 1662 (CON), 2099 (N3), and 3441 cm−1 (OH).

Synthesis of AZT Analogues
303
1H NMR, (CDCl3) δH: 3.27, 3.49 (2s, 3 H each, 2 NMe), 3.39 (dd, 1 H, J2 ,3
ꢁ
ꢁ
4.8 Hz, J3 ,3 12.6 Hz, H-3ꢁ), 3.53 (dd, 1 H, J2 ,3 3.3 Hz, H-3ꢁꢁ), 4.25 (m, 2 H,
ꢁ
ꢁꢁ
ꢁ
ꢁꢁ
H-1ꢁ,2ꢁ), 4.51 (d, 1 H, J1 ,1 10.2 Hz, H-1ꢁꢁ), 4.76 (bs, 1 H, D2O exchangeable,
OH), 7.72 (s, 1 H, H-8). Anal. Calcd. for C10H13N7O3 (279.11): C, 43.01; H,
4.69; N, 35.11. Found: C, 43.90; H, 5.10; N, 35.16.
ꢁ
ꢁꢁ
7-(2,3-Epoxypropyl)theophylline (3).
A stirred solution of sodium hy-
droxide (0.16 g, 4 mmol) in water (3 mL) and DMSO (2 mL) at 0◦C, com-
pound 1 (0.5 g, 1.22 mmol) was added over 5 min. After an additional 15 min
of stirring, the solution was poured into ice water and the mixture was ex-
tracted with ether. The organic layer was dried over anhydrous sodium sulfate
and then evaporated in vacuo. The residue was purified by column chro-
matography using petroleum ether:ethyl acetate (5:1) to give 3 (0.21 g, 75%
yield) as white crystals; mp 130–134◦C; IR (KBr): 1262 (epoxide), 1656 and
1
1696 cm−1 (CON). H NMR (CDCl3) δH: 2.53 (t, 1 H, J2 ,3 2.4 Hz, H-3ꢁ),
ꢁ
ꢁ
2.84 (t, 1 H, J2 ,3 4.2 Hz, H-3ꢁꢁ), 3.34, 3.53 (2s, 3 H each, 2 NMe), 4.11–4.16
ꢁ
ꢁꢁ
(m, 2 H, H-1ꢁ, H-2ꢁ), 4.32 (dd, 1 H, J1 ,2 2.7 Hz, J1 ,1 13.2 Hz, H-1ꢁꢁ), 7.55 (s,
1 H, H-8). Anal. Calcd. for C10H12N4O3 (236.09): C, 50.84; H, 5.12; N, 23.72.
Found: C, 50.36; H, 4.77; N, 23.36.
ꢁꢁ
ꢁ
ꢁ
ꢁꢁ
7-(3-Amino-2-hydroxypropyl)theophylline (4).
Method a: A mixture of azide 2 (0.56 g, 2.0 mmol) and triphenylphos-
phine (0.85 g, 3.3 mmol) in pyridine (5 mL) was kept at room tempera-
ture for 1 h, then concentrated ammonium hydroxide solution (10 mL) was
added and the reaction mixture was allowed to stand for an additional 3 h.
The solvent was removed in vacuo and the residue was dissolved in water.
The solution was extracted with ether (3 × 20 mL) and then benzene (3 ×
20 mL). The aqueous layer was evaporated and the residue was crystallized
from ethanol to afford 4 as white crystals (0.25 g, 50% yield), mp 258–260◦C;
1H NMR (DMSO-d6, 300 MHz) δH: 2.63–2.70 (m, 1 H, H-3ꢁ), 2.93 (dd, 1 H,
J2 ,3 2.7 Hz, J3 ,3 12.9 Hz H-3ꢁꢁ), 3.29, 3.42 (2s, 6 H, 2 NMe), 4.13 (br m,
ꢁ
ꢁꢁ
ꢁ
ꢁꢁ
1 H, H-2ꢁ), 4.29 (dd, 1 H, J1 ,2 7.2 Hz, J1 ,1 13.5 Hz, H-1ꢁ), 4.42 (dd, 1 H,
ꢁ
ꢁ
ꢁ
ꢁꢁ
J1 ,2 4.5 Hz, H-1ꢁꢁ), 8.04 (s, 1 H, H-8). The Ms: m/z 253(M+). Anal. Calcd. for
C10H15N5O3 (253.12): C, 47.42; H, 5.97; N, 27.65. Found: C, 47.91; H, 6.22;
N, 27.88.
ꢁꢁ
ꢁ
Method b: Compound 3 (0.1 g, 0.42 mmol) was stirred with concentrated
ammonium hydroxide (28%, 5 mL) at room temperature in a closed flask
for 3 days. The reaction mixture was evaporated in vacuo to afford the amino
compound 4 (0.095 g, 95% yield); it was identical with that from method a.
7-(3-Acetamido-2-hydroxypropyl)theophylline (5). Compound4(0.50 g,
2.0 mmol), cadmium acetate (0.40 g, 1.5 mmol) and acetic anhydride
(3.0 mL) were shaken with absolute methanol (10 mL) for 3 h at room

304
E. S. H. El Ashry et al.
temperature then heated under reflux for 10 min. The reaction mixture was
evaporated in vacuo and the residue was dissolved in water (10 mL), then
extracted with methylene chloride (4 × 20 mL). The organic layers were col-
lected and evaporated. The residue was crystallized from ethanol to give 5
(0.32 g, 55% yield) as white crystals; mp 180–182◦C. IR(KBr): 1604 (C N)
1
and 1666 (OCN), 1708(NAc), 3121 (NH). H NMR (DMSO-d6, 300 MHz)
δH: 1.83 (s, 3 H, Ac), 3.07–3.09 (m, 1 H, H-3ꢁ), 3.22, 3.42 (2s, 3 H each, 2
NMe), 3.49–3.83 (m, 2 H, H-1ꢁ, H-2ꢁ), 4.08 (dd, 1 H, J1 ,2 8.4 Hz, J1 ,1 13.3 Hz,
ꢁ
ꢁ
ꢁ
ꢁꢁ
H-3ꢁꢁ), 4.35 (dd, 1 H, J1 ,2 3.1 Hz, J1 ,1 13.7 Hz, H-1ꢁꢁ), 5.24 (d, 1 H, J2 ,OH
5.1 Hz, D2O exchangeable, OH), 7.93 (s, 1 H, D2O exchangeable, NH), 7.96
(s, 1 H, H-8). Anal. Calcd. for C12H17N5O4 (295.13): C, 48.81; H, 5.80; N,
23.72. Found: C, 49.31; H, 6.12; N, 24.31.
ꢁꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
7-{3-[4-(Thymin-1-yl-methyl)-1,2,3-triazol-1-yl]-2-hydroxypropyl}theoph-
ylline (7).
A mixture of compounds 2 (0.08 g, 0.5 mmol) and 6 (0.14 g,
0.5 mmol) in dry toluene (5 mL) was heated under reflux for 50 h. The
product was filtered off then washed with ethanol. It was crystallized from
ethanol to afford 7 (0.096 g, 43% yield) as buff crystals, mp 275–277◦C.
1H NMR (DMSO-d6, 300 MHz) δH: 1.81 (s, 3 H, CH3), 3.28, 3.49 (2s, 3 H
each, 2 NMe), 4.24–4.36 (m, 3 H, H-2ꢁ,3ꢁ,3ꢁꢁ), 4.48, 4.58 (2d, 2 H, J1 ,1
ꢁ
ꢁꢁ
11.7 Hz, H-1ꢁ,1ꢁꢁ), 4.95 (s, 2 H, NCH2), 5.60 (d, 1 H, J2 ,OH 4.5 Hz, OH),
7.65 (s, 1 H, thymine-H-6), 8.04 (s, 1 H, theophylline H-8), 8.06 (s, 1 H,
triazole-H-5), 11.25 (bs, 1 H, NH). Anal. Calcd. for C18H21N9O5 (443.17):
C, 48.26; H, 4.77; N, 28.22. Found: C, 48.26; H, 4.34; N, 28.22.
ꢁ
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