Synthesis of 8-Methoxypenciclovir and 8-Methoxyganciclovir through Methyl Triflate, a New Potential Approach to Label Penciclovir and Ganciclovir with Carbon-11

Article abstract of DOI:10.1055/s-2003-42454

In an effort to make HSV-tk gene reporter probes 8-FPCV and 8-FGCV labeled with fluorine-18, via the nucleophilic substitution reaction of PCV and GCV quaternized methylamine salt precursors with KF/Kryptofix 2.2.2, a new and unusual reaction through methyl triflate was discovered. Subsequently, new compounds 8-MeOPCV and 8-MeOGCV were synthesized from PCV and GCV in six steps with 12% and 20% overall chemical yield, respectively, and a novel potential approach to label PCV and GCV with carbon-11 has been proposed.

Full text of DOI:10.1055/s-2003-42454

PAPER
2785
Synthesis of 8-Methoxypenciclovir and 8-Methoxyganciclovir through Methyl
Triflate, a New Potential Approach to Label Penciclovir and Ganciclovir with
Carbon-11
S
ynthesis of 8-Me
i
thoxyp
-
nciclov
H
uanciclovir ang Zheng,* Ji-Quan Wang, Xiangshu Fei, Gary D. Hutchins
Department of Radiology, Indiana University School of Medicine, 1345 West 16th Street, L-3 Room 202, Indianapolis, IN 46202-2111,
USA
Fax +1(317)2789711; E-mail: qzheng@iupui.edu
Received 4 August 2003; revised 15 September 2003
utility is important. However, the limited commercial
Abstract: In an effort to make HSV-tk gene reporter probes 8-
availability, complicated synthetic procedure and high
costs of starting materials PCV and GCV can present an
obstacle to more widespread evaluation of these intrigu-
FPCV and 8-FGCV labeled with fluorine-18, via the nucleophilic
substitution reaction of PCV and GCV quaternized methylamine
salt precursors with KF/Kryptofix 2.2.2, a new and unusual reaction
through methyl triflate was discovered. Subsequently, new com- ing agents. Wishing to study these compounds in this lab-
pounds 8-MeOPCV and 8-MeOGCV were synthesized from PCV
oratory, we decided to make our own material by
and GCV in six steps with 12% and 20% overall chemical yield, re-
following the literature methods. Although several papers
spectively, and a novel potential approach to label PCV and GCV
dealing with the synthesis of [18F]FPCV, [18F]FHBG and
with carbon-11 has been proposed.
[18F]FGCV, [18F]FHPG from PCV and GCV have ap-
Key words: gene reporter probes, herpes simplex virus thymidine
peared, there are gaps in synthetic detail among them, and
kinase (HSV-tk), positron emission tomography (PET), 8-methox-
certain key steps gave poor yields or were difficult to re-
ypenciclovir, 8-methoxyganciclovir
peat in our hands. Consequently, we investigated alternate
approaches and modifications to make radiolabeled PCV
and GCV analogs. In our previous works, we have report-
Gene transfer technology has shown significant potential
ed an improved total synthesis of [18F]FHBG and
in treating several common cancers using a variety of viral
[18F]FHPG starting from very starting materials 1,3-
and non-viral vectors.1–7 Among these, herpes simplex vi-
dibenzyloxy-2-propanol and guanine, and triethyl-1,1,2-
rus thymidine kinase (HSV-tk) has been used as a key pro-
ethanetricarboxylate and 2-amino-6-chloropurine.34–36 In
drug-converting enzyme for a number of anticancer gene
this ongoing study, we devoted our effort to make
therapy approaches.8,9 The enzyme has a broad substrate
[18F]FPCV and [18F]FGCV. However, a new and unex-
specificity and can convert less toxic penciclovir {PCV,
9-[4-hydroxy-3(hydroxymethyl)butyl]guanine, 1} or gan-
pected reaction resulted in the synthesis of new com-
pounds 8-methoxypenciclovir (8-MeOPCV) and 8-
ciclovir {GCV, 9-[(1,3-dihydroxy-2-propoxy)meth-
methoxyganciclovir (8-MeOGCV) from PCV and GCV,
yl]guanine, 2} into toxic compounds that result in cell
respectively, and the discovery of a novel potential ap-
proach to label PCV and GCV with carbon-11.
HSV-tk reporter probes [18F]FHBG and [18F]FHPG ap-
death.10 Imaging of HSV-tk expression is reliant on the
use of enzyme imaging agents, fluorinated (fluorine-18)
prodrugs such as fluorinated PCV and GCV analogs 8-
[18F]fluoropenciclovir ([18F]FPCV, 3), 9-(4-[18F]fluoro-3-
hydroxymethylbutyl)guanine ([18F]FHBG, 5) and 8-
[18F]fluoroganciclovir ([18F]FGCV, 4), 9-{(3-[18F]fluoro-
1-hydroxy-2-propoxy)methyl}guanine ([18F]FHPG, 6),
coupled with biomedical imaging technique positron
emission tomography (PET).11–33 Considerable efforts
have been devoted to the synthesis of these gene reporter
probes and numerous improved synthesis were reported in
the literature,11,12,25,29,30 in which [18F]FPCV and
[18F]FGCV were labeled with fluorine-18 at 8-position of
guanine ring of PCV and GCV; [18F]FHBG and [18F]FH-
PG were labeled with fluorine-18 at the side chain of PCV
and GCV. The potential importance of these compounds
as gene therapy imaging tools is great, and broader re-
search investigation to fully explore and validate their
pear often in the literature, however, only a few papers re-
ported the synthesis of [18F]FPCV and [18F]FGCV, and
PET imaging study using these two tracers. The key prob-
lem is the difficulty in the synthetic methodology of
[18F]FPCV and [18F]FGCV (Scheme 1), which limited
their utility. The current method for labeling 8-position of
a guanosine with fluorine-18 is an approach by the elec-
trophilic reaction of the guanosine with elemental fluo-
rine-18 gas,37 which is produced by a cyclotron equipped
with a special gas target. Since fluorine gas is the most re-
active chemical that can even ignite metal, the gas target
and the system cost very high. Therefore fluorine-18 gas
target is not available to most cyclotrons. This restrains
the availability and research work of radiotracers
[18F]FPCV and [18F]FGCV.
To circumvent this problem, we investigated the synthesis
of [18F]FPCV and [18F]FGCV through the alternative ap-
proach by the nucleophilic substitution reaction of a pre-
cursor having a leaving group at 8-position of the
SYNTHESIS 2003, No. 18, pp 2785–2794
Advanced online publication: 23.10.2003
DOI: 10.1055/s-2003-42454; Art ID: M03403SS.pdf
© Georg Thieme Verlag Stuttgart · New York
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Scheme 1
guanosine with potassium [18F]fluoride (K18F)/Kryptofix The precursor N2-(p-anisyldiphenylmethyl)-8-bromo-9-
2.2.2 (K2.2.2). K18F is used to produce 2-[18F]fluoro-2- [(4-p-anisyldiphenylmethoxy)-3-p-anisyldiphenylmeth-
deoxy-D-glucose (FDG), which is the only PET imaging oxymethylbutyl]guanine (MTr–PCV–Br, 7) was synthe-
agent used clinically at this point in time and is available sized as shown in Scheme 3. PCV, 1 was reacted with
to all PET imaging centers.38 Since K18F is available to dilute bromine water solution39 at room temperature to af-
most cyclotrons, we designed several possible precursors ford 8-bromopenciclovir (BrPCV, 11) in 76% yield. The
as shown in Scheme 2, which might lead to the synthesis protection of all of the hydroxyl and 2-amino groups of
of [18F]FPCV by a nucleophilic substitution reaction with BrPCV with 4-methoxytrityl chloride gave the precursor
K18F.
7 in 67% yield. The selection of crowd methoxytrityl
group as protecting group was based on its easily leaving
Scheme 2
Scheme 3
Synthesis 2003, No. 18, 2785–2794 © Thieme Stuttgart · New York

PAPER
Synthesis of 8-Methoxypenciclovir and 8-Methoxyganciclovir
2787
Scheme 4
under mild acidic condition. The mixture of 7 and anhy- Finally, we attempted to construct a PCV quaternized me-
drous KF and phase transfer catalyst K2.2.2 or 18-crown-6 thylamine salt MTr–PCV–N+Me3, 9 (Scheme 5) as a pos-
in anhydrous CH3CN or DMF or DMSO was heated at el- sible precursor for the synthesis of FPCV. 11 was reacted
evated temperature for up to 2 days. No halogen exchange with aqueous (CH3)2NH solution42,43 to provide
reaction occurred, and only starting material was isolated Me2NPCV, 16 in 95% yield. The protection of all of the
from the reaction mixture. Thus it was unable to make hydroxyl and 2-amino groups of 16 by 4-methoxytrityl
MTr–PCV–F, 12 through this approach.
chloride gave the MTr–PCV–NMe2, 17 in 52% yield. The
reaction of 17 with methyl triflate44 gave a possible inter-
mediate N2-(p-anisyldiphenylmethyl)-7-methyl-8-dime-
thylamino-9-[(4-p-anisyldiphenylmethoxy)-3-p-anisyl-
diphenylmethoxymethylbutyl]guanine-8-triflate (18) in
98% yield, rather than quaternary ammonium salt 9, the
product anticipated to arise via the methylation of com-
pound 17, since the 1H NMR spectrum of 18 showed dis-
crete single peaks of 7-CH3 and 8-NMe2. The subsequent
reaction of 18 with KF/K2.2.2 failed to give 12, and only the
starting material was recovered.
The effort to prepare another possible precursor MTr–
PCV–OTf, 8 was designed in Scheme 4. 11 was reacted
with HOAc–NaOAc40 to give 8-hydroxy-9-[4-acetoxy-3-
(acetoxymethyl)butyl]guanine (13) in 88% yield. Two
acetyl groups of 13 were easily removed by aqueous
CH3NH2 solution41 to afford 8-hydroxypenciclovir
(HOPCV, 14) in 81% yield. 14 could not selectively block
aliphatic hydroxyl and 2-amino groups, thus it was unable
to prepare MTr–PCV–OH, 15. Subsequently, it is difficult
to synthesize MTr–PCV–OTf, 8, because 8-OTf group
could only be introduced by the reaction of 8-OH group The construction of a similar PCV quaternized methyl-
with triflic anhydride (Tf2O).
amine salt Ac–PCV–N+Me3, 10 (Scheme 6) was also at-
Scheme 5
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2788
Q.-H. Zheng et al.
PAPER
Scheme 6
tempted. The protection of all of the hydroxyl and 2- To further study the existence of the intermediate of PCV
amino groups of 16 by Ac2O gave Ac–PCV–NMe2, 19 in analogs reacted with methyl triflate and the unexpected
74% yield. Similarly, the reaction of 19 with methyl tri- reaction led to synthesis of MeOPCV, another synthetic
flate gave a possible intermediate N2-acetyl-7-methyl-8- approach was designed as shown in Scheme 7. PCV, 1
dimethylamino-9-[4-acetoxy-3-(acetoxymethyl)butyl]-
was reacted with Ac2O to afford Ac–PCV, 24 in 55%
guanine-8-triflate (20) in nearly quantitative yield, rather yield. The reaction of 24 with methyl triflate gave a pos-
1
than quaternary ammonium salt 10. Likewise, the H sible intermediate N2-acetyl-7-methyl-9-[4-acetoxy-3-
NMR spectrum of 20 observed two different methyl pro- (acetoxymethyl)butyl]guanine-8-triflate (25) in nearly
ton NMR resonances of 7-CH3 and 8-NMe2. The com- quantitative yield. The subsequent reaction of 25 with KF/
pound 20 was fairly stable when it was heated, but it was
K2.2.2 failed to provide 21. Therefore, we can conclude that
decomposed after it was stored for a few days. The subse- 8-dimethylamino group is necessary for the unexpected
quent reaction of 20 with KF/K2.2.2 failed to afford Ac– reaction.
PCV–F, 23, the product anticipated to arise via the nu-
In view of the novelty of the synthesis of MeOPCV, we
cleophilic substitution reaction. Instead, an unusual reac-
investigated the utility of the unexpected reaction for the
tion through methyl triflate was discovered, and there was
synthesis of 8-methoxyganciclovir (MeOGCV, 31) as
obtained an unexpected product Ac–PCV–OMe, 21 in
30% yield. 21 was easily deprotected by aqueous CH3NH2
solution to give 8-methoxypenciclovir (MeOPCV, 22) in
77% yield.
shown in Scheme 8. GCV, 2 was reacted with dilute bro-
mine water solution39 at room temperature to afford 8-bro-
moganciclovir (BrGCV, 26) in 62% yield. 26 was reacted
Scheme 7
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PAPER
Synthesis of 8-Methoxypenciclovir and 8-Methoxyganciclovir
2789
Scheme 8
with aqueous (CH3)2NH2 solution to provide Me2NGCV, 29 with KF/K2.2.2 afforded Ac-GCV-OMe, 30 in 48%
27 in 94% yield. The protection of all of the hydroxyl and yield. 30 was easily deprotected by aqueous CH3NH2 so-
2-amino groups of 27 by Ac2O gave the Ac–GCV–NMe2, lution to give MeOGCV, 31 in 87% yield.
28 in 81% yield. The reaction of 28 with methyl triflate
The mechanism for the possible pathway to the observed
8-methoxy derivatives of guanines via sequential treat-
gave a possible intermediate N2-acetyl-7-methyl-8-dime-
thylamino-9-[(1,3-diacetoxy-2-propoxy)methyl]guanine-
ment of MeOTf and KF/K2.2.2 was speculated in
8-triflate (29) in nearly quantitative yield. The reaction of
Scheme 9. 8-Dimethylaminoguanine derivative (19 or 28)
Scheme 9
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PAPER
Scheme 10
All commercial reagents and solvents were used without further pu-
rification unless otherwise specified. Melting points were deter-
mined on a MEL-TEMP II capillary tube apparatus and were
reacted with MeOTf through several ylide transition
structures or iminium (urea) species as intermediates to
form one of the possible intermediates (20 or 29). Then
base KF attacked the trifyl group in the intermediate
through another ylide transition structure or iminium
(urea) species intermediate to give 8-methoxyguanine de-
rivative (21 or 30), or directly to give an unstable iminium
(urea) species intermediate, which quickly isomerized to
compound 21 or 30. This mechanism speculation is sup-
ported by the evidence of the observation of two different
methyl proton NMR resonances of the possible intermedi-
ates 18, 20, 25 and 29.
1
uncorrected. H NMR spectra were recorded on a Bruker QE 300
MHz NMR spectrometer using TMS as an internal standard. Chem-
ical shift data for the proton resonances were reported in ppm ( )
relative to internal standard TMS ( = 0.0). The low-resolution mass
spectra were obtained using a Bruker Biflex III MALDI-Tof mass
spectrometer, and the high-resolution mass measurements were ob-
tained using a Kratos MS80 mass spectrometer, in the Department
of Chemistry at Indiana University. Chromatographic solvent pro-
portions are expressed on a v/v basis. TLC was run using Analtech
silica gel GF uniplates (5 × 10 cm2). Plates were visualized by UV
light. Normal phase flash chromatography was carried out on EM
Science silica gel 60 (230–400 mesh) with a forced flow of the in-
dicated solvent system in the proportions described below. All
moisture-sensitive reactions were performed under a positive pres-
sure of N2 maintained by a direct line from a N2 source.
Since the 8-methoxy group in MeOPCV and MeOGCV
was introduced through methyl triflate, this might be a
new potential methodology to label PCV and GCV with
[11C]methyl triflate45–48 to produce 8-[11C]methoxy-PCV
and 8-[11C]methoxy-GCV. A potential approach to label
PCV and GCV with carbon-11 has been proposed as
shown in Scheme 10.
The starting materials PCV and GCV were synthesized in our pre-
vious work.34–36
8-Bromo-9-[4-hydroxy-3-(hydroxymethyl)butyl]guanine
(BrPCV, 11); Typical Procedure
In summary, MeOPCV was synthesized from PCV in six
steps with 12% overall chemical yield, and MeOGCV was
synthesized from GCV in six steps with 20% overall
chemical yield, a new and unusual reaction through meth-
yl triflate to introduce methoxyl group to C-8 position of
the guanine derivatives PCV and GCV was discovered,
which provides a novel potential synthetic access to car-
bon-11 labeled PCV and GCV analogs. The possible
PCV, 1 (1.00 g, 3.95 mmol) was suspended in water (50 mL). Under
vigorous stirring, Br2 water solution (0.20 M, 30 mL, 5.86 mmol)
was added dropwise in a period of 30 min using a syringe. The mix-
ture became homogeneous, and later precipitate formed. After addi-
tion the mixture was stirred at r.t. for another 30 min. The solid was
filtered, washed with water (2 × 5 mL) and acetone (5 mL), and
dried under vacuum to give an off-white solid 11 (1.09 g, 76%); mp
236–238 ºC; Rf 0.21 (CH3CN–H2O, 95:5).
mechanism of the unexpected reaction was suggested. 1H NMR (DMSO-d6): = 10.68 (s, 1 H, 1-NH), 6.57 (s, 2 H, 2-
NH2), 4.43 (s, 2 H, OH), 3.97 (t, J = 7.35 Hz, 2 H, 1 -CH2), 3.20–
3.55 (m, 4 H, 4 -CH2), 1.56–1.76 (m, 2 H, 2 -CH2), 1.35–1.56 (m, 1
H, 3 -CH).
LRMS (CI, CH4): m/z (%) = 252.1 (100), 331.0 (41) [M+].
More extensive investigation will be required to deter-
mine the details of the mechanism, the roles of methyl tri-
flate and KF/K2.2.2 involved in the reaction, and the
adducts of methyl triflate with PCV and GCV derivatives.
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PAPER
Synthesis of 8-Methoxypenciclovir and 8-Methoxyganciclovir
2791
HRMS (CI, CH4): m/z calcd for C10H14BrN5O3: 331.0280; found:
solid was filtered off and dried under vacuum to give 16 (0.071 g).
331.0280
The filtrate was absorbed on silica gel, dried under vacuum, trans-
ferred on the top of a silica gel column, and eluted with CH3CN–
H2O (12:1) to give 16 (0.014 g, 95%); mp 250 °C; Rf 0.24 (CH3CN–
H2O, 9:1).
1H NMR (DMSO-d6): = 10.35 (s, 1 H, 1-NH), 6.29 (s, 2 H, 2-
NH2), 4.41 (t, J = 5.15 Hz, 2 H, OH), 3.88 (t, J = 7.36 Hz, 2 H, 1 -
CH2), 3.25–3.50 (m, 4 H, 4 -CH2), 2.72 (s, 6 H, 8-NCH3), 1.62–1.75
(m, 2 H, 2 -CH2), 1.36–1.49 (m, 1 H, 3 -CH).
N2-(p-Anisyldiphenylmethyl)-8-bromo-9-[(4-p-anisyldiphenyl-
methoxy)-3-p-anisyldiphenylmethoxymethylbutyl]guanine
(MTr-PCV-Br, 7); Typical Procedure
The mixture of 11 (0.10 g, 0.30 mmol), 4-methoxytrityl chloride
(MTrCl, 0.40 g, 1.30 mmol), DMAP (0.010 g, 0.082 mmol), DMF
(10 mL), and Et3N (0.4 mL, 2.87 mmol) was stirred at 50–60 ºC for
3 h. After cooling to r.t., the mixture was diluted with EtOAc, and
washed with water. The aq layer was extracted with another portion
of EtOAc. The combined organic layer was washed once with brine,
and dried to give a yellowish solid. The solid residue was dissolved
in small amount of CH2Cl2, transferred to the top of a silica gel col-
umn and eluted with 2.5% MeOH–CH2Cl2 to give 7 (0.23 g, 67%);
mp >135 ºC (dec.); Rf 0.33 (4% MeOH–CH2Cl2).
1H NMR (CDCl3): = 6.60–7.45 (m, 42 H, aromatic), 3.75 (s, 6 H,
9-OCH3), 3.67 (s, 3 H, 2-OCH3), 3.56 (br s, 2 H, 1 -CH2), 3.00–3.20
(m, 4 H, 4 -CH2), 1.70–1.84 (m, 1 H, 3 -CH), 1.40–1.53 (m, 2 H, 2 -
CH2).
LRMS (EI): m/z (%) = 296.2 (100) [M+] (100).
HRMS (EI): m/z (%) calcd for C12H20N6O3: 296.1597; found:
296.1593.
N2-(p-Anisyldiphenylmethyl)-8-dimethylamino-9-[(4-p-anisyl-
diphenylmethoxy)-3-p-anisyldiphenylmethoxymethylbutyl]-
guanine (MTr-PCV-NMe2, 17); Typial Procedure
16 (0.19 g, 0.64 mmol), MTrCl (0.79 g, 2.56 mmol) and DMAP
(0.019 g, 0.16 mmol) were dissolved in anhyd DMF (20 mL) and
Et3N (0.8 mL, 5.74 mmol). The mixture was stirred at 50–60 °C for
3 h. After cooling to r.t., the mixture was diluted with EtOAc, and
washed with brine. The aq layer was extracted with another portion
of EtOAc. The combined organic layer was washed with brine,
dried over MgSO4, and evaporated under vacuum. The brown liquid
residue was transferred to the top of a silica gel column and eluted
with 2.5–3.0% MeOH–CH2Cl2 to give 17 (0.37 g, 52%); mp 140
°C (dec.); Rf 0.30 (5% MeOH–CH2Cl2).
LRMS (EI): m/z (%) = 273 (100), 1148 (1.9) [M + H]+.
HRMS (FAB): m/z calcd for C70H63BrN5O6: 1148.3962; found:
1148.3925.
8-Hydroxy-9-[4-acetoxy-3-(acetoxymethyl)butyl]guanine (13);
Typical Procedure
The mixture of 11 (0.050 g, 0.15 mmol), NaOEt (0.070 g, 0.85
mmol) and AcOH (5 mL) was heated to reflux (160 ºC) for 4 h. Af-
ter cooling, solvent was removed at reduced pressure. MeOH was
added to dissolve the solid residue, and then silica gel was added to
absorb the MeOH solution. MeOH was then stripped, and the dry
silica gel was transferred to the top of a silica gel column and eluted
with CH2Cl2–MeOH (15:1–6:1) to afford 13 (0.047 g, 88%); mp 65
ºC (dec.); Rf 0.18 (CH2Cl2–MeOH, 15:1).
1H NMR (DMSO-d6): = 10.35 (s, 1 H, 1-NH, D2O exchangeable),
7.48 (s, 1 H, 2-NH, D2O exchangeable), 6.60–7.35 (m, 42 H, aro-
matic), 3.73 (s, 6 H, 4 -OCH3), 3.60 (s, 3 H, 2 -OCH3), 3.12–3.26
(m, 2 H, 1 -CH2), 2.62–2.89 (m, 4 H, 4 -CH2), 2.49 (s, 6 H, 8-
NCH3), 1.56–1.72 (m, 1 H, 3 -CH), 1.00–1.18 (m, 2 H, 2 -CH2).
LRMS (EI): m/z (%) = 273.0 (100), 1113.5 (0.1) [M + H]+.
HRMS (FAB): m/z calcd for C72H69N6O6: 1113.5278; found:
1H NMR (DMSO-d6): = 10.68 (br s, 1 H, 8-OH), 10.54 (s, 1 H, 1-
NH), 6.46 (s, 2 H, 2-NH2), 3.91–4.09 (m, 4 H, 4 -CH2), 3.65 (t, J =
7.35 Hz, 2 H, 1 -CH2), 1.98 (s, 6 H, 4 -CH3CO2), 1.85–2.00 (m, 1 H,
3 -CH), 1.60–1.72 (m, 2 H, 2 -CH2).
1113.5230.
N2-(p-Anisyldiphenylmethyl)-7-methyl-8-dimethylamino-9-[(4-
p-anisyldiphenylmethoxy)-3-p-anisyldiphenylmethoxymethyl-
butyl]guanine-8-triflate (18); Typical Procedure
17 (0.050 g, 0.045 mmol) was dissolved in anhyd CH2Cl2 (10 mL).
Under an ice-salt bath methyl triflate (6 L, 0.053 mmol) was add-
ed. The solution was stirred and allowed to warm to r.t slowly over-
night. The solvent was removed under vacuum, and the residue was
dried under vacuum overnight to give a brown solid 18 (0.056 g,
98%); mp 100 °C (dec.); Rf 0.38 (7% MeOH–CH2Cl2).
LRMS (CI, CH4): m/z (%) = 353.1 (100) [M+].
HRMS (CI, CH4): m/z calcd for C14H19N5O6: 353.1335; found:
353.1329.
8-Hydroxy-9-[4-hydroxy-3-(hydroxymethyl)butyl]guanine
(HOPCV, 14); Typical Procedure
13 (0.030 g, 0.085 mmol) was dissolved in aq CH3NH2 solution
(40%, 5 mL). The solution was heated at 75 ºC for 2 h. After cooling
to r.t., the reaction mixture was evaporated to dryness. The colorless
solid was washed with cold water, and dried under vacuum to give
a white solid 14 (0.019 g, 81%); mp 285 °C (dec.).
1H NMR (DMSO-d6): = 10.49 (br s, 2 H, 1-NH, 8-OH, D2O ex-
changeable), 6.45 (s, 2 H, 2-NH2, D2O exchangeable), 4.35 (br s, 2
H, OH, D2O exchangeable), 3.64 (t, J = 6.25 Hz, 2 H, 1 -CH2), 3.20–
3.50 (m, 4 H, 4 -CH2), 1.50–1.68 (m, 2 H, 2 -CH2), 1.38–1.50 (m, 1
H, 3 -CH).
1H NMR (DMSO-d6): = 11.13 (s, 1 H, 1-NH, D2O exchangeable),
7.98 (s, 1 H, 2-NH, D2O exchangeable), 6.59–7.38 (m, 42 H, aro-
matic), 3.73 (s, 6 H, OCH3), 3.64 (s, 3 H, 7-CH3), 3.59 (s, 3 H,
OCH3), 3.26–3.43 (m, 2 H, 1 -CH2), 2.93 (s, 6 H, 8-NCH3), 2.60–
2.96 (m, 4 H, 4 -CH2), 1.78–1.94 (m, 1 H, 3 -CH), 1.04–1.29 (m, 2
H, 2 -CH2).
N2-Acetyl-8-dimethylamino-9-[4-acetoxy-3-(acetoxymethyl)bu-
tyl]guanine (19); Typical Procedure
The solution of 16 (0.050 g, 0.17 mmol), DMAP (0.0040 g, 0.33
mmol) and Ac2O (0.2 mL, 2.12 mmol) in pyridine (5 mL) was re-
fluxed under N2 for 1 h until TLC showed that the starting material
was gone. After cooling to r.t., water (0.5 mL) was added and the
mixture was stirred for 15 min. After evaporation of volatiles, the
brown residue was dissolved in a small amount of CH2Cl2, and
transferred to the top of a silica gel column and eluted with CH2Cl2–
MeOH (20:1 ) to afford 19 (0.053 g, 74%); mp 155–157 °C; Rf 0.32
(CH2Cl2–MeOH, 15:1).
LRMS (EI): m/z (%) = 167.0 (100), 269.1 (42) [M+].
HRMS (EI): m/z calcd for C10H15N5O4: 269.1124; found: 269.1121.
8-Dimethylamino-9-[4-hydroxy-3-(hydroxymethyl)butyl]gua-
nine (Me2NPCV, 16); Typical Procedure
A solution of 11 (0.10 g, 0.30 mmol) in (CH3)2NH (40% aq solution,
5 mL) was heated at 130 °C for 48 h until TLC showed that the start-
ing material was gone. Volatiles were evaporated to dryness. The
residue was dissolved in hot water, filtered, concentrated to a small
volume, and then cooled down at 4 °C for recrystallization. A white
1H NMR (DMSO-d6): = 11.95 (br s, 1 H, NH, D2O exchangeable),
11.59 (br s, 1 H, NH, D2O exchangeable), 3.93–4.09 (m, 6 H, 1 -
Synthesis 2003, No. 18, 2785–2794 © Thieme Stuttgart · New York

2792
Q.-H. Zheng et al.
PAPER
N2-Acetyl-9-[4-acetoxy-3-(acetoxymethyl)butyl]guanine (Ac-
CH2 and 4 -CH2), 2.79 (s, 6 H, 8-NCH3), 2.16 (s, 3 H, 2-CH3CON),
1.98 (s, 6 H, CH3CO2), 1.74–1.91 (m, 3 H, 2 -CH2 and 3 -CH).
PCV, 24); Typical Procedure
The mixture of PCV, 1 (0.10 g, 0.40 mmol), Ac2O (0.2 mL, 2.12
mmol) and 1-methylpyrrolidone (5 mL) was heated to 150 ºC for 5
h. The volatiles were removed under vacuum. To the residue was
added MeOH to dissolve it, and then was added silica gel to absorb
the solution. The silica gel was dried under vacuum, transferred to
the top of a silica gel column, and eluted with CH2Cl2–MeOH
(15:1–10:1) to afford a white solid 25 (0.082 g, 55%); Rf 0.42
(CH2Cl2–MeOH, 15:1).
1H NMR (DMSO-d6): = 11.47–12.29 (br s, 2 H, 1-NH and 2-NH),
8.01 (s, 1 H, 8-CH), 4.13 (t, J = 7.00 Hz, 2 H, 1 -CH2), 4.00 (d, J =
5.15 Hz, 4 H, 4 -CH2), 2.17 (s, 3 H, 2-CH3CON), 1.98 (s, 6 H, 4 -
CH3CO2), 1.78–1.95 (m, 3 H, 2 -CH2, 3 -CH).
LRMS (EI): m/z (%) = 422.2 (100) [M+].
HRMS (EI): m/z calcd for C18H26N6O6: 422.1914; found; 422.1924.
N2-Acetyl-7-methyl-8-dimethylamino-9-[4-acetoxy-3-(acetoxy-
methyl)butyl]guanine-8-triflate (20); Typical Procedure
To the cold solution of 19 (0.050 g, 0.12 mmol) in anhyd CH2Cl2
(10 mL) was added methyl triflate (16 L, 0.14 mmol) dropwise un-
der an ice-salt bath. The solution was stirred and allowed to warm
up to r.t. slowly overnight. Volatiles were removed under vacuum
to give a brown solid 20 (0.069 g, ca 100%); Rf 0.18 (CH2Cl2–
MeOH, 15:1).
1H NMR (DMSO-d6): = 12.47 (s, 1 H, NH, D2O exchangeable),
11.97 (s, 1 H, NH, D2O exchangeable), 4.15 (t, J = 7.36 Hz, 2 H, 1-
CH2), 4.03 (d, J = 5.14 Hz, 4 H, 4 -CH2), 3.85 (s, 3 H, 7-CH3), 3.15
(s, 6 H, 8-NCH3), 2.21 (s, 3 H, 2-CH3CON), 2.01 (s, 6 H, CH3CO2),
1.94–2.06 (m, 1 H, 3 -CH), 1.74–1.88 (m, 2 H, 2 -CH2).
LRMS (EI): m/z (%) = 278.1 (100), 379.2 (71) [M+].
HRMS (EI): m/z calcd for C16H21N5O6: 379.1492; found: 379.1501.
N2-Acetyl-7-methyl-9-[4-acetoxy-3-(acetoxymethyl)butyl]gua-
nine-8-triflate (25); Typical Procedure
N2-Acetyl-8-methoxy-9-[4-acetoxy-3-(acetoxymethyl)butyl]-
guanine (Ac–PCV–OMe, 21); Typical Procedure
Compound 24 (0.068 g, 0.18 mmol) was dissolved in anhyd CH2Cl2
(10 mL). Under an ice-salt bath methyl triflate (25 L, 0.22 mmol)
was added. The solution was stirred and allowed to warm to r.t.
slowly overnight. The solvent was removed under vacuum, and the
residue was dried under vacuum overnight to give a brown solid 25
(0.097 g, ca 100%); Rf 0.20 (CH2Cl2–MeOH, 15:1).
1H NMR (DMSO-d6): = 12.57 (s, 1 H, 1-NH), 12.12 (s, 1 H, 2-
NH), 9.48 (s, 1 H, 8-CH), 4.31 (t, J = 7.35 Hz, 2 H, 1 -CH2), 4.07 (s,
3 H, 7-CH3), 4.04 (d, J = 5.14 Hz, 4 H, 4 -CH2), 2.22 (s, 3 H, 2-
CH3CON), 2.01 (s, 6 H, CH3CO2), 1.84–2.11 (m, 3 H, 2 -CH2 and
3 -CH).
To a 10 mL V-vial containing anhyd KF (0.36 g, 6.20 mmol) and
K2.2.2 (0.36 g, 0.96 mmol) was added a solution of 20 (0.21 g, 0.36
mmol) in anhyd CH3CN (8 mL). Under N2 flow the mixture was
heated to 110 °C to remove any moisture in the system by azeotro-
ping. The second portion of anhyd CH3CN (8 mL) was added to ac-
complish the azeotroping. When the mixture was nearly anhydrous,
the third portion of CH3CN (8 mL) was added. The V-vial was
sealed and heated at 125 °C overnight. After removal of solvent, the
residue was dissolved in EtOAc, and washed with water, dried over
MgSO4, and evaporated under vacuum. The resulting residue was
dissolved in a small amount of CH2Cl2, and transferred to the top of
a silica gel column and eluted with CH2Cl2–MeOH (40:1) to give a
white solid 21 (0.044 g, 30%); mp 105–107 °C; Rf 0.13 (CH2Cl2–
MeOH, 40:1).
1H NMR (CDCl3): = 11.92 (s, 1 H, 1-NH), 9.68 (s, 1 H, 2-NH),
4.06–4.25 (m, 4 H, 4 -CH2), 3.83 (t, J = 6.27 Hz, 2 H, 1 -CH2), 3.56
(s, 3 H, 8-OCH3), 2.27 (s, 3 H, 2-CH3CON), 2.03 (s, 6 H, CH3CO2),
1.94–2.00 (m, 1 H, 3 -CH), 1.72–1.78 (m, 2 H, 2 -CH2).
13C NMR (CDCl3): = 172.22 (s), 171.49 (s), 152.36 (s), 150.24 (s),
146.90 (s), 144.74 (s), 104.70 (s), 63.94 (t), 37.77 (t), 34.70 (d),
29.07 (q), 27.90 (t), 24.23 (q), 21.11 (q).
8-Bromo-9-[(1,3-dihydroxy-2-propoxy)methyl]guanine
(BrGCV, 26); Typical Procedure
GCV, 2 (0.53 g, 2.08 mmol) was suspended in water (20 mL). Un-
der vigorous stirring, Br2 water solution (0.20 M, 16 mL, 3.12
mmol) was added dropwise in a period of 30 min using a syringe.
The mixture became homogeneous, and later precipitate formed.
After addition the mixture was stirred at r.t. for another 30 min. The
solid was filtered, washed with water (2 × 5 mL) and acetone (5
mL), and dried under vacuum to give an off-white solid 26 (0.43 g,
62%); mp >300 °C.
1H NMR (DMSO-d6): = 10.72 (s, 1 H, 1-NH), 6.62 (br s, 2 H, 2-
NH2), 5.38 (s, 2 H, 1 -CH2), 4.18 (br s, 2 H, OH), 3.50–3.65 (m, 1
H, 3 -CH), 3.20–3.50 (m, 4 H, 4 -CH2).
LRMS (EI): m/z (%) = 409.2 (100) [M+].
HRMS (EI): m/z calcd for C17H23N5O7: 409.1598; found: 409.1611.
8-Dimethylamino-9-[(1,3-dihydroxy-2-propoxy)methyl]gua-
nine (Me2NGCV, 27); Typical Procedure
8-Methoxy-9-[4-hydroxy-3-(hydroxymethyl)butyl]guanine
(MeOPCV, 22); Typical Procedure
A solution of 26 (0.20 g, 0.60 mmol) in (CH3)2NH (40% aq solution,
10 mL) was heated at 130 °C for 48 h until TLC showed that the
starting material was gone. After cooling to r.t., silica gel was added
to absorb the solution, dried under vacuum, and transferred to the
top of a silica gel column and eluted with 12:1 CH3CN–H2O to give
a white solid 27 (0.17 g, 94%); mp >225 °C (dec.), Rf 0.28
(CH3CN–H2O, 9:1).
1H NMR (DMSO-d6): = 10.46 (s, 1 H, 1-NH, D2O exchangeable),
6.33 (s, 2 H, 2-NH2, D2O exchangeable), 5.26 (s, 2 H, 1 -CH2), 4.57
(t, J = 5.88 Hz, 2 H, OH, D2O exchangeable), 3.65–3.74 (m, 1 H, 3 -
CH), 3.30–3.54 (m, 4 H, 4 -CH2), 2.82 (s, 6 H, 8-NCH3).
The solution of 21 (0.030 g, 0.073 mmol) in aq CH3NH2 solution
(40%, 5 mL) was heated at 75 °C for 2 h until TLC showed that
starting material was gone. After cooling to r.t., silica gel was added
to absorb the solution, dried under vacuum, and transferred to the
top of a silica gel column and eluted with CH2Cl2–MeOH (15:1),
then with CH3CN–H2O (9:1) to give 22 (0.016 g, 77%); mp 250 °C
(dec.); Rf 0.30 (CH3CN–H2O, 9:1).
1H NMR (DMSO-d6): = 10.80 (br s, 1 H, 1-NH, D2O exchange-
able), 6.52 (s, 2 H, 2-NH2, D2O exchangeable), 4.35 (br s, 2 H, OH,
D2O exchangeable), 3.67 (t, J = 6.62 Hz, 2 H, 1 -CH2), 3.25–3.45
(m, 4 H, 4 -CH2), 3.30 (s, 3 H, 8-OCH3), 1.50–1.60 (m, 2 H, 2 -
CH2), 1.36–1.47 (m, 1 H, 3 -CH).
LRMS (EI): m/z (%) = 194.1 (100), 298.1 (23) [M+].
HRMS (EI): m/z calcd for C11H18N6O4: 298.1390; found: 298.1380.
LRMS (EI): m/z (%) = 181 (100), 283 (17) [M+].
HRMS (EI): m/z calcd for C11H17N5O4: 283.1281; found: 283.1288.
Synthesis 2003, No. 18, 2785–2794 © Thieme Stuttgart · New York

PAPER
Synthesis of 8-Methoxypenciclovir and 8-Methoxyganciclovir
2793
N2-Acetyl-8-dimethylamino-9-[(1,3-diacetoxy-2-propoxy)meth-
yl]guanine (Ac-GCV-NMe2, 28); Typical Procedure
HRMS (FAB): m/z calcd for C10H15N5NaO5: 308.0971; found:
308.0971.
The solution of 27 (0.20 g, 0.67 mmol), DMAP (0.016 g, 0.13
mmol) and Ac2O (0.8 mL, 8.48 mmol) in anhyd pyridine (15 mL)
was refluxed under N2 for 2 h until TLC showed that the starting
material was gone. After cooling to r.t., water (3 mL) was added and
the mixture was stirred for 15 min. After evaporation of volatiles,
the brown residue was dissolved in a small amount of CH2Cl2, and
transferred to top of a silica gel column and eluted with CH2Cl2–
MeOH (30:1) to afford 28 (0.229 g, 81%); mp 90 °C (dec.); Rf 0.18
(CH2Cl2–MeOH, 25:1).
Acknowledgment
This work was partially supported by the Susan G. Komen Breast
Cancer Foundation grant IMG02-1550 (to QHZ), the Indiana Uni-
versity American Cancer Society (ACS) Institutional Grant Com-
mittee grant IRG-84-002-17 (to QHZ), the Indiana University Cores
Centers of Excellence in Molecular Hematology (CCEMH) pilot
and feasibility (P/F) grant (to QHZ), the National Institutes of He-
alth/National Cancer Institute grant P20CA86350 (to GDH), the In-
diana 21st Century Research and Technology Fund (to GDH), and
the Lilly Endowment Inc. [to the Indiana Genomics Initiative (IN-
GEN) of Indiana University]. The referees’ criticisms and editor’s
comments for the revision of the manuscript are greatly appreciated.
1H NMR (DMSO-d6): = 12.00 (s, 1 H, NH), 11.55 (s, 1 H, NH),
5.36 (s, 2 H, 1 -CH2), 3.98–4.22 (m, 5 H, 3 -CH and 4 -CH2), 2.89
(s, 6 H, 8-NCH3), 2.18 (s, 3 H, 2-CH3CON), 1.91 (s, 6 H, CH3CO2).
LRMS (EI): m/z (%) = 236 (100), 424 (27) [M+].
HRMS (EI): m/z calcd for C17H24N6O7: 424.1706; found: 424.1713.
N2-Acetyl-7-methyl-8-dimethylamino-9-[(1,3-diacetoxy-2-pro-
poxy)methyl]guanine-8-triflate (29); Typical Procedure
To the cold solution of 28 (0.15 g, 0.35 mmol) in anhyd CH2Cl2 (20
mL) was added methyl triflate (48 L, 0.42 mmol) dropwise under
an ice-salt bath. The solution was stirred and allowed to warm up to
r.t. slowly overnight. Volatiles were removed under vacuum to give
a brown solid 29 (0.21 g, ca 100%); Rf 0.20 (CH2Cl2–MeOH, 15:1).
1H NMR (DMSO-d6): = 12.49 (s, 1 H, NH), 11.90 (s, 1 H, NH),
5.52 (s, 2 H, 1 -CH2), 4.00–4.30 (m, 5 H, 3 -CH and 4 -CH2), 3.86
(s, 3 H, 7-CH3), 3.24 (s, 6 H, 8-NCH3), 2.23 (s, 3 H, 2-CH3CON),
1.99 (s, 6 H, CH3CO2).
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To a 10 mL V-vial containing anhyd KF (0.36 g, 6.20 mmol) and
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1H NMR (CDCl3): = 11.95 (s, 1 H, 1-NH), 9.16 (s, 1 H, 2-NH),
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Synthesis 2003, No. 18, 2785–2794 © Thieme Stuttgart · New York

2794
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