Syntheses of 5-(2-radiohaloethyl)- and 5-(2-radiohalovinyl)-2′-deoxyuridines. Novel types of radiotracer for monitoring cancer gene therapy with PET

Article abstract of DOI:10.1002/jlcr.684

Syntheses of 5-(2-[¹⁸F]fluoroethyl)- (1) 5-(2-[⁸⁰Br] bromoethyl), (2), undeprotected (E)-5-(2-[¹⁸F]fluorovinyl)- (3) and (E)-5-(2-[⁸⁰Br]bromovinyl),2′-deoxyuridines (4) as the tracers for monitoring cancer gene therapy with positron emission tomography were described. Decay corrected radiochemical yield and synthesis time including labeling and HPLC purification from end of bombardment for 1 was 9.5% and 2 hours, respectively; yield and time for 2 was 16% and 2 hours, respectively. Chemical (approximate to radiochemical) yield and time for synthesis of 3 was 7.5% and 7 minutes, respectively. Radiochemical yield and synthesis time including labeling and HPLC purification of an analytical sample of 4 was 60% and 30 minutes, respectively. Both 2 and 4 received the side reactions during HPLC purification, i.e. ring closure and cleavage of glycosidic bond, respectively. Application of 2 and 4 needed to be confirmed by in vitro or in vivo experiments. Radiochemical yield of 1 could be optimized by employing a modified protocol for preparation of its precursor. The preparation of fluorovinyl counterparts had demonstrated the potential utility of the stannane, 3-tolyl-3′,5′-di-O-acetyl-(E)-5-(2-stannylvinyl)- 2′-deoxyuridine 7. Copyright

Full text of DOI:10.1002/jlcr.684

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2003; 46: 421–439.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.684
Research Article
Syntheses of 5-(2-radiohaloethyl)- and 5-(2-
radiohalovinyl)-20- deoxyuridines.
Novel types of radiotracer for monitoring
cancer gene therapy with PET
Chung-Shan Yu*,z, Joseph Eisenbarth, Armin Runz, Klaus Weber,
Stephan Zeisler and Franz Oberdorfery,}
Abteilung E0300-Radiochemie und Radiopharmakologie, German Cancer
Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg,
Germany
Summary
Syntheses of 5-(2-[18F]fluoroethyl)- (1), 5-(2-[80Br]bromoethyl)- (2), un-
deprotected (E)-5-(2-[18F]fluorovinyl)- (3) and (E)-5-(2-[80Br]bromovinyl)-20-
deoxyuridines (4) as the tracers for monitoring cancer gene therapy with
positron emission tomography were described. Decay corrected radiochemical
yield and synthesis time including labeling and HPLC purification from end of
bombardment for 1 was 9.5% and 2 hours, respectively; yield and time for 2
was 16% and 2 hours, respectively. Chemical (approximate to radiochemical)
yield and time for synthesis of 3 was 7.5% and 7 minutes, respectively.
Radiochemical yield and synthesis time including labeling and HPLC
purification of an analytical sample of 4 was 60% and 30 minutes, respectively.
Both 2 and 4 received the side reactions during HPLC purification, i.e. ring
closure and cleavage of glycosidic bond, respectively. Application of 2 and 4
needed to be confirmed by in vitro or in vivo experiments. Radiochemical yield
*Correspondence to: C-S. Yu, Abteilung E0300-Radiochemie und Radiopharmakologie, German
Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
E-mail: Cyu1231@chem.sinica.edu.tw
y E-mail: Oberdorfer@synthra.de
z Institute of Chemistry, Academia Sinica, 128 sec.2 Academia road, 115 Taipei, Taiwan
} Synthra GmbH, Klausenpfad 23, 69121 Heidelberg, Germany
Contract/grant sponsor: German Academic Exchange Service.
Copyright # 2003 John Wiley & Sons, Ltd.
Received 31 May 2002
Revised 16 August 2002
Accepted 25 November 2002

422
C-S. YU ET AL.
of 1 could be optimized by employing a modified protocol for preparation of
its precursor. The preparation of fluorovinyl counterparts had demonstrated
the potential utility of the stannane, 3-tolyl-30,50-di-O-acetyl-(E)-5-(2-stannyl-
vinyl)-20-deoxyuridine 7. Copyright # 2003 John Wiley & Sons, Ltd.
Key Words: PET cancer gene therapy; radiofluorination; radiobromination;
stannane; tosylate
Introduction
Recently, the application of positron-emitter labelled nucleosides with
positron emission tomography (PET) modality to monitor the success-
ful transfaction of gene product in vivo during cancer-prodrug therapy
has raised considerable attention.1 In this strategy, the suicide gene was
firstly transferred to the cancer cells. Followed by transfaction, the
prodrugs such as thymidine analogs were administered to form toxic
metabolites, which initiate the subsequent suicidal mechanism. Herpes
simplex virus type 1 thymidine kinase (HSV-1 TK) is the most
extensively studied suicide gene.2 Monitoring a successful transfer and
expression of HSV-1 TK gene before the introduction of prodrugs is
thus of value. Analogs of purine and pyrimidine nucleosides labelled
with radioisotopes as substrates for gene probes have been intensively
3,4
studied by several groups, 1e.
Typical examples for purine nucleo-
sides are which radiolabelled at the C-84 or acyclochain5 by F-18, e.g.
18F-labelled ganciclovir, 9-(4-[18F]-fluoro-3-hydroxymethylbutyl)gua-
nine ([18F]-FHBG) and 9-[(3-[18F]-fluoro-1-hydroxy-2-propoxy)methyl]-
guanine ([18F]-FHPG). As for the pyrimidine nucleosides, radiolabelling
at the side chain of C-5 and at the sugar moieties are mostly
encountered, e.g. (E)-5-(2-[125I]Iodovinyl)-20-deoxyuridine,6 and 20-
fluoro-20-deoxy-1-b-d-arabinofuranosyl-5-[131I]iodouracil (FIAU)7 and
2’-[18F]fluoro-5-methyldeoxyuracil-b-d-arabinofuranoside (FMAU),8
respectively. Considering the structure and reactivity (SAR), thymidine
analogs with the optimal activity against HSV-1 are those base-modified
deoxyuridines such as ethyl- or vinyl-groups as substituents at the C-5
of the pyrimidine ring.9–11 On the other hand, radiolabeling at
this side chain with positron emitters have been rarely reported,
especially for 5-(2-radiofluoroethyl) deoxyuridine7 and 5-(2-radiofluoro-
vinyl)deoxyuridine, due to either the low radiochemical yield
or unavailability of suitable precursors6 such as organostannan
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NOVEL TYPES OF RADIOTRACER
423
compounds.6,12 Additionally, due to the lack of hydroxy group at the C-
20 position of furanose moieties, thymidine derivatives are notoriously
labile to phosphorylitic cleavage in vivo.13 Yet, substitution at the C-2
position with fluorine atom in threo or erythro configuration reinforced
the hydrolysis and prolonged their half-life in vivo.14 Based on these
knowledge, approaching to ideal precursors could be accomplished via
two stages: firstly developing syntheses of suitable precursors which can
be efficiently radiohalogenated in the subsequent radiochemical synth-
esis and secondly, if needed, modifying these leading compounds to
improve their biostability in vivo. Thus, as the first priority, we focused
on approaching the former objective. Part of this work had been
published recently.15,16 Here we report the chemical and radiochemical
syntheses of these precursors (1, 2, 3, 4, 6, Figures 1, 2).
These positron-emitter labelled nucleosides such as 5-(2-[18F]fluoro-
ethyl)- (FEDU, 1), 5-(2-[80mBr]bromoethyl)- (BEDU, 2), (E)-5-(2-
[18F]fluorovinyl)- (FVDU,
3
after deprotection) and (E)-5-(2-
[
80mBr]bromovinyl)-20-deoxyuridines (BVDU, 4) were expected to be
the imaging candidates and their stability were also discussed in this
paper.
O
H
O
O
N
8
X
X
7
NH
NR1
O
5
1
H
N
O
5'
HO
R2O
O
4'
1'
OH
1 X = 18F
2 X = 80Br
OR2
3 X = 18F, R1 = Tol, R2 = Ac
4 X = 80Br, R1 = H, R2 = H
Figure 1. Positron-emitter labelled nucleosides
O7
H
O
N
OCH3
H
O
O
N
7a
5
Bu3Sn
AcO
TosO
Bu3Sn
HO
1 N
NTol
O
5a
N
NH
3
H
H
N
O
N
O
O
HO
TolO
O
O
O
OAc
OH
OTol
OH
5
8
7
6
Figure 2. Precursors leading to Positron-emitter labelled nucleosides
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C-S. YU ET AL.
Results and discussion
Synthesis of FEDU 1
The preparation of 4-O-methyl protected tosylate 5 via an eleven-step
synthesis had been described in the previous work.15 Described therein,
the cyclized byproduct 6 were the sole product during the nucleophilic
fluorination of the unprotected analog. On behalves of this protection,
the undesired ring closure was therefore tackled. The [18F]labelled 9 was
prepared by nucleophilic radiofluorination of 5 under the common
phase transfer catalyzed conditions (Scheme 1).
Identification of 9 was performed on the profile during development
of radio-TLC. Reference 9 was synthesized from the 5-(2-hydroxyethyl)
analog with DAST.15 Optimal conditions were achieved by using 19
equivalents of Kryptofix[2.2.2] for the nucleophilic radiofluorination of
5. The time needed for preparation of [18F]KF, nucleophilic radio-
fluorination of 5, cleavage of the 4-methoxy group and deprotection in 9
and subsequent C-18 HPLC analysis of 1 was 2 h from end-of-
bombardment (EOB). The radioactivity and the radiochemical yield
obtained at end-of-synthesis (EOS) were 49 MBq and 4.5% (9.5%,
decay corrected radiochemical yield), respectively, calculated from 1.1
GBq 18F- (no carrier added). Since the b- and a-radiolabeled anomers
1b, 1a could not be separated by the RP-18 HPLC, an anomerically
pure tosylate was required to carry out the labeling experiment. The
OCH3
N
OCH3
N
18
18F
[
F]KF, Kryptofix[2.2.2],
TosO
CH CN
3
o
N
O
N
O
85 C, 30 min
TolO
TolO
O
O
OTol
OTol
5
9
O
18F
NH
(a) NaI (12 eq), TMSCl (11 eq), CH CN, 3 min
3
N
O
HO
o
(b) NaOEt/EtOH, 85 C, 10 min
O
OH
1
Scheme 1. Nucleophilic radiofluorination of tosylate 5
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NOVEL TYPES OF RADIOTRACER
425
radiochemical yield of 1b could be further optimized by improving the
synthesis of its precursor.15 During fluorination in a nonradioactive
experiment, not only 5-vinyldeoxyuridine but also 5-(2-chloroethyl)-
deoxyuridine formed as the by-products and yielded in 24 and 26%,
respectively, compared to 5% of 1. Appearance of the chloro derivative
was due to chlorinated impurities. Preparation of the tosylate 5 was
inevitable to be contaminated by chlorinated impurities, originated
from the previous step during glycosylation.15 We had also reported
that these chlorinated impurities could be prevented by using an
adequate silylating reagent N,O-bistrimethylsilyltrifluoroacetimide.15
Thus the optimized tosylate would enhance the radiochemical yield in
radiofluorination.
Synthesis of [80mBr]BEDU 2
Though the direct nucleophilic bromination of the tosylate 5 is facial,
the following deprotection will remove this radiohalogen. We proposed
the cyclized ring compound 6 might be a candidate for introduction of
radiohalogen during ring opening (Scheme 2). In the radiolabeling
experiment, 11 MBq [80mBr]BEDU 2 were obtained from 93 MBq
[
80mBr]NH4Br (80Br/80mBr ꢀ 7:1). The half-life of 80Br is 17.66 m, while
for 80mBr is 4.42 h and 80mBr decays via IT to 80Br, which contains 2.2%
b+. Both isotopes 80Br and 80mBr share the neutron cross sections
during n; g reaction in the order of 8.5 and 2.6 Barns, respectively, and
both contributed to the radioactivity after EOB. Since the total time for
the procedure including nucleophilic radiobromo substitution of 6 and
subsequent HPLC separation was within 2 h (6.7 times of T1/2 of 80Br),
the final activity from the starting 80Br should be about 8 MBq. This
would be less than that from 80mBr as ascertained by the presence of 11
MBq [80mBr]BEDU 2. Calculating decay corrected radiochemical yield
O7
O
80mBr
7a
5
NH
1 N
NH4[80mBr]Br
85 oC, 30 min
5a
3
N
O
N
O
HO
HO
O
O
OH
OH
2
6
Scheme 2. Ring opening reaction
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C-S. YU ET AL.
was thus based on the decay profile of 80mBr. The overall radiochemical
yield was 12% (decay corrected yield: 16%). However, one unknown
radioactive compound with fast migrating properties, which eluted from
RP-18 HPLC during a repeated chromatography of purified 2, was
suspected to be [80Br]HBr. Indeed the reverse reaction, a ring closure
reaction, was demonstrated by using reference BEDU 2 as a probe and
the intramolecular cyclized product 6 was easily prepared in 82% yield.
We utilized this instability to initially prepare 6 from reference 2 by ring
closure and then introduced the radioactivity by ring opening. The
reference 2 was prepared by the selective nucleophilic bromination of 5-
(2-hydroxyethyl)-20-deoxyuridine according to literature.9(b) In a ring
opening reaction of 6 with NH4Cl, we were able to obtain 5-(2-
chloroethyl)-20-deoxyuridine (10, CEDU) in high yield (90%) after 24 h.
When the story comes to NH4F, the poor nucleophile F- did not yield
any significant amount of fluorinated product. The chloride ion was
thus the most efficient reagent for the ring opening of 6 and preparation
of [34mCl]CEDU 10 might be envisaged. The bromide ion could also act
as the ring-opening reagent, while the inherent reactivity of the bromo
analog 2 limited its radiochemical yield. The ring opening reaction was
also applicable to other isotopes of 80mBr such as 82Br or some other
clinically relevant isotopes, e.g. 75Br, 76Br and 77Br.
Synthesis of protected [18F]FVDU 3(E)+3(Z)
Preparation of the organostannane 7 described in the previous paper
was a four-step synthesis starting from 5-iododeoxyuridine and the yield
was 50%.16 Using the typical reaction conditions for radiofluorination
of arylstannanes,17 0.8 eq of [18F]F2 were bubbled through 7 (25 mmol)
in CFCl3 at – 708C (Scheme 3). Radioactivity of F2 from EOB was
estimated to be 0.25 GBq, while 0.38 GBq for the reaction mixture was
measured by ionization chamber.
Radio-TLC of an analytical sample of the mixture was developed and
the activity was measured (Figure 3). Since our HPLC purification was
planned to be carried out after deprotection, the radiochemical yield of
3 was attempted to be estimated by the TLC profile. We assumed the
radiolabeling agent [18F]F2 would not disturb the measurement of
radiofluorinated product for its easy volatility. Furthermore the
hydrolysed product [18F]F- with a high polarity was easily identified
from the immobilization of the migrating zone (P1). The unknown peak
P3 was assumed to be fluoroorganostannanes. According to the
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NOVEL TYPES OF RADIOTRACER
427
H
O
O
N
Bu3Sn
AcO
18F]F2 (0.8 eq)/CFCl3, - 70 oC, 7 min
NTol
O
[
H
OAc
7
H
H
H
H
O
N
H
O
O
N
O
N
18F
H
NTol
O
NTol
O
NTol
O
H
O
18F
+
+
AcO
AcO
1
AcO
O
OAc
OAc
Z)
OAc
3
:
3(E)
3(
11
7.5%
Scheme 3. Radiofluorination of stannane 7
Figure 3. Radio-TLC of the crude product from the reaction of [18F]F2 with 7
approximate calculation, about 0.2 GBq corresponding to the product
peak P2, which was about 50% of the total radioactivity of the mixture.
However, due to the inherent availability of one fluorine atom being 18
F
in F2, the radiochemical yield of 50% is not possible. Nevertheless the
radiochemical yield could be referred to the yield of the nonradioactive
3. The mixture after 48 h for decay was submitted to purification by
chromatography on SiO2 to afford the fractions corresponding to that
of P2 of the above radio-TLC profile. The collected fractions were
analyzed by ESI-MS and 1H- and 19F-NMR. The amount of compound
3 obtained was about 0.9 mg according to the proportion of compounds
3 and 11 on ESI-MS in a behavior of 1:7. Thus chemical yield of
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C-S. YU ET AL.
compound 3 to the initial carrier F2 was 7.5%. This should be relevant
to the radiochemical yield. The time for synthesis was 7 min. The
estimation of radiochemical yield in Figure. 3 reveled the major activity
in P2 was not originated from compound 3. To have a better calculation
of radiochemical yield, these fractions needed to be purified by HPLC.
The chemical shifts and coupling constants from 19F NMR analysis
demonstrated the presence of two isomers, (E)-fluorovinyl analog 3(E)
and (Z)-fluorovinyl analog 3(Z) in a 2:1 ratio.16 At our hands, we did
not try to separate the (E), (Z) mixture. We kept the work concerning
the deprotection together with the following separation by HPLC as an
on-going program.
Synthesis of BVDU (4)
A radioactive experiment of the stannane 8 with [80Br]NH4Br and CAT
was carried out according to the published procedure for the arabinosyl
analog of 812(Scheme 4). CAT was used to oxidize the bromide ion Br-
to bromine Br0. This oxidation was quenched by aminoethanethiohy-
drochloride (AET). The best yield (99%, determined by radio-TLC) of
radiobrominated 4 was obtained 1 min after addition of the oxidant
CAT. However, during HPLC analysis, instability of 4 was observed. A
deglycosylated product, (E)-5-2-[80Br]bromovinyl uracil (BVA) 12, was
obtained after HPLC purification. This phenomenon might be
explained in terms of an equilibration between the two tautomeric
isomers 12 and 13 (Scheme 5). The bromo substitutent might favor
the formation of imide tautomer 13 by acquiring the resonance
stabilization.
To overcome this side reaction, modification of the glycosidic bond
should be necessary. On the other hand, chlorination as side reaction
H
O
O
N
H
O
N
80m
Bu3Sn
HO
80mBr
Br]Br/Chloramine T,
a. NH [
4
NH
NH
1 min
H
H
O
O
HO
b. AET
O
OH
OH
4
8
Scheme 4. Electrophilic radiobromination
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NOVEL TYPES OF RADIOTRACER
429
H
O
O
N
H
O
Br
H
OH
NH
Br
HPLC
Br
NH
H
N
O
H
H
HO
N
H
O
N
OH
12
OH
H
OH
4
Br
N
H
N
OH
13
Scheme 5. Proposed resonance stabilization leading to cleavage
had been noted during oxidation by CAT in radiobromination.
This side reaction could probably occur, though we did not observe
another peak besides 4 from UV chromatogram in HPLC. The
time required for radiochemical synthesis and HPLC analysis was
30 min. The decay-corrected radiochemical yield of 4 was 60% from
EOB based on the calculation of an analytical sample as described
for [80mBr]BEDU 2.
Conclusions
Syntheses of 18F and 80mBr labelled 5-(2-haloethyl)- and 5-(2-halovinyl)-
deoxyuridine analogs 1, 2, 3, 4 were reported. Comparing with the
carrier-added reactions for compounds 2, 3 and 4, the product 1 was
prepared from no-carrier-added source 18F- and could provide a more
high specific activity. Radiochemical yield of products prepared in this
study was decreasing in the order of 4 > 2 ꢁ 1 ꢁ 3. Radioactivity of
1, 2 and 4 obtained in this study were sufficient to carry out in vitro or in
vivo experiment. On the other hand, compound 3 after deprotection was
believed to have enough quantities of activity for the same purpose.
Preparation of 2 and 4 could be further optimized by using appropriate
columns. Whether the cyclization of compound 2 or the cleavage of
compound 4 limited their applications is still needed to be confirmed by
in vitro or in vivo experiments. For serving as medical-interested
monitoring tools, the two fluorinated compounds 1 and 3 provided
alternatives to 8-[18F]fluoroganciclovir, [18F]-FHPG and [18F]-FMAU.
A relative more-step required procedure for preparing the precursor 5
was probably an efficient approach. The preparation of fluorovinyl
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C-S. YU ET AL.
counterparts had demonstrated the potential utility of stannane 8. The
only five-step required synthesis of 8 showed another advantage
compared to the alkyl tosylate 5. All the precursors presented here, 5,
6, 7 and 8 fulfilled the requirements of least steps for deprotection.
Experimental
General
Chemicals were purchased from Aldrich. Acetonitrile was DNA-
synthesis grade from Merck-Schuchardt. Fluorine gas was purchased
from Messer-Griessheim (mixture of 3% F2 in Ne). Melting points were
.
determined with a Buchi 535 apparatus and not corrected. Elemental
.
analysis was performed at the Max Planck Institut fur Medizinische
Forschung in Heidelberg. Electrospray ionization mass analysis (ESI-
MS) were recorded with a Finnigan TSQ 7000 triple-quadrupole system.
1H NMR and 13C NMR (DEPT-135) were recorded with a Bruker AC-
250 spectrometer in the Central Department of Spectroscopy of DKFZ.
Coupling constants (J) were expressed in Hz. Cation exchange resin
(H+ form, AG 50W-X8, 200-400 mesh) was purchased from Bio-Rad.
Radio-TLC was analysed by digital autoradiography employing the
multiwire proportional chamber LB 287 DAR of EG & G, Berthold.
Radioactive 18F and 80Br were obtained from the Scanditronix MC 32
NI cyclotron and the TRIGA Heidelberg II nuclear reactor, both at the
German Cancer Research Center (DKFZ). The neutron flux was
2 ꢂ 1012 n/cm2 S.
Radiochemical synthesis
1-(2-deoxy-b-d-erythro-pentafuranosyl)-5-(2-[18F]fluoroethyl)pyrimidin-
2,4(3 H)dione 1
(1) K [18F]F Production
[18F]F- was produced by irradiation of 1.5 ml of enriched water
[18O]H2O (98%) with 18 MeV protons at a beam current of 5-6 mA for
1 h. The yield was 22 GBq. We used an amount of 1.1 GBq of [18F]F- for
carrying out the following fluorination reaction. A mixture of [18F]F-
(1.1 GBq, measured by an ion chamber), Kryptofix[2.2.2] (26 mg,
0.069 mmol) in CH3CN (800 ml), K2CO3 (2.6 mg, 0.026 mmol) in
distilled water (100 ml), and CH3CN (5 ml) were heated in the reaction
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NOVEL TYPES OF RADIOTRACER
431
vessel at 1058C. It was heated until the solvents had completely
evaporated. After drying, CH3CN (1 ml) was added and heated to
1058C. Repeating this process and finally the solution was cooled to rt.
The entire procedure required 30 min.
(2) HPLC methods
(i) Analytical column: Knauer Eurosphere 100-C18 column,
250 ꢂ 4.6 mm (5 mm). Merck Hitachi L6200 solvent pump with a
U6 K Waters injection valve with a 5 ml sample loop.
(ii) UV and radioactivity detection was carried out using
Waters 996 PAD programmable multi wavelength detector at
260 nm and Canberra FLOW-ONE A200 detection system (cell
size 500 ml).
(iii) HPLC buffers A=50 mM Na3PO4/H3PO4 at pH=5.7 and
B=95% ethanol was applied at a flow rate of 1 ml min-1, gradient:
0–30% B 0–10 min, isocratic: 30% B 10–25 min.
(3) Synthesis
The experiment was carried out in an automatic synthesis module
designed for radiolabelling experiments. The K[18F]F, tosylate 5 (5 mg,
7.4 mmol), a solution of Kryptofix[2.2.2] (26mg, 0.069mmol) in CH3CN
(800ml), and CH3CN (5ml) were introduced into the reaction vessel. The
mixture was heated to 858C for 30min, transferred to a cartridge packed
with Al2O3 (neutral) and filtered. After collecting the filtrate, the cartridge
was further washed with CH3CN (3ml). The combined filtrates collected
were then transferred into a 10 ml round-bottomed flask. To this stirred
solution were sequentially added 14mg (0.092mmol, 12 eq) NaI and
10.4 ml (0.082mmol, 11 eq) (CH3)3SiCl. Stirring was continued at rt for
3 min. The solvent was then evaporated at 508C under reduced pressure
(20 mbar). To the residue was added 1 ml of dry ethanol and 40ml
(40 mmol, 5.4 eq) of 1N NaOEt/EtOH and the solution was stirred at
858C for 10min. It was then neutralized with cation exchange resin (H+),
filtered through a short cartridge (0.45mm filter, milipore) and washed
with ethanol (0.5 ml). The combined filtrates (1.3 ml) were concentrated
and chromatographed by RP-18 HPLC with the analytical column. The
radiolabeled product 1 was obtained in an amount of 49 MBq (measured
by an ionization chamber). The tR of 1 was 14.5min.
1-(2-deoxy-b-d-erythro-pentafuranosyl)-5-(2-[80Br]bromoethyl)
pyrimidin-2,4(3 H)dione 2
(1) [80Br]bromide production
Solid target (NH749Br) was contained in a capsule with a volume 1 ml.
Enriched NH749Br (90%, 1 mg, 0.01 mmol) was irradiated with slow
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thermal neutrons (0.1 eV) according to 79Br(n,g)80mBr. The irradia-
tion was continued for 4 h. An amount of 0.74 GBq (EOB, mea-
sured by an ionization chamber) was obtained. Multichannel
analyzer (MCA, 2080 channel) coupled with a Ge(Li) detector with
4000 Volt was used to analyze the radioactivity at various radiation
(g-) energy. The range from 504 to 521 keV and from 609 to 631 keV
was chosen for counting of radioactivity. The detection efficiency
was 30%.
(2) HPLC methods
Semi-preparative column: Hibar RP-18, 250ꢂ 10 mm (10 mm material).
Flow rate was 3 ml min-1. Elution buffer, gradient elution mode, pump,
UV and radioactivity detection was carried out as above described for
synthesis of [18F]FEDU 1.
(3) Synthesis
Starting material 6 (5 mg, 0.02 mmol) was dissolved in DMF (1 ml)
with stirring at rt. NH4[80+80mBr]Br (0.74 GBq) was added, and the
mixture was stirred at 85oC for 30 min. The stirring was continued for
30 min. One product (Rf=0.59) corresponding to reference 2 was
observed by radio-TLC (MeOH/CHCl3 1:4). The mixture was purified
with the semi-preparative HPLC (RP18). The retention time (tR) of 2
was 18.0 min. An amount of 300 ml of the reaction solution (1 ml) was
chromatographed and separated fraction was collected. This process
had been repeated twice. The radioactivity of the three combined
fractions was measured by a Ge(Li) detector. The total time for the
procedure including nucleophilic radiobromination (30 min) and sub-
sequent C-18 HPLC separation (90 min) was 120 min. After calibrating
the detector efficiency, an amount of 11 MBq was obtained. The
radiochemical yield of 2 was 12% based on 72 MBq of 80mBr; decay
corrected radiochemical yield was 16%.
1-(3,5-di-O-acetyl-2-deoxy-b-d-erythro-pentafuranosyl)-3-tolyl-
(E)-,(Z)-5-(2-[18F]fluorovinyl)pyrimidin-2,4-dione 3(E), 3(Z)
(1) [18F]F2 Production
A stainless steel target with volume 145 ml was filled with 20Ne
containing 3% F2. The amount of fluorine in the vessel was 0.6 mmol.
The fluorine was further diluted to 0.7% by pressurizing with the target
gas 20Ne to 15 bar. The target was irradiated with B14 MeV deuterons
at a beam current 15 mA for 2 h to generate fluorine-18 in 0.25 GBq/mAh
yield. An amount of 19 mmol (70 ml of the total volume at 1 atm)
carrier-added [18F]F2, corresponding to 0.25 GBq by estimation, was
used for the radiofluorination of 7.
Copyright # 2003 John Wiley & Sons, Ltd.
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NOVEL TYPES OF RADIOTRACER
433
(2) Synthesis
The stannylated precursor 7 (19 mg, 25 mmol) was dissolved in CFCl3
(20 ml) and cooled to –708C. The 19 mmol [18F]F2 were bubbled through
the cooled solution with a flow rate 10 ml min-1 for 7 min. A white
suspension was formed. The radioactivity of the crude mixture was 0.38
GBq as measured by an ionization chamber.
1-(2-deoxy-b-d-erythro-pentafuranosyl)-(E)-5-(2-[80Br]bromo-
vinyl)pyrimidin-2,4(3 H)dione (4, BVDU)
(1) [80Br]Bromide production
Enriched NH749Br (91%, 1 mg, 0.01 mmol) was introduced into a
capsule with volume 1 ml, and EtOH (400 ml) and H2O (50 ml) were
added. A supersonic vibrator then mixed the mixture. A clear solution
was obtained. This solution was used as a liquid target, and was
irradiated with thermal neutrons for 4 h. An amount of 0.37 GBq (EOB)
of NH4[80Br]Br was obtained. A portion of the stock solution was used
as reference for counting of the decay-corrected yield.
(2) HPLC methods
(i) Semi-preparative column: Hibar Lichrospher Si100 column,
250 ꢂ 10 mm (10 mm material).
(ii) Waters 510 solvent pump with a motor valve with a 5 ml
sample loop. UV and radioactivity detection was carried out using
a Knauer variable wavelength detector at 260 nm and radioisotope
calibrator CRC-100R.
(iii) EtOH/CH2Cl2 1:9 was applied at a flow rate of 4 ml minꢃ1
(3)Synthesis
Compound 8 (6 mg, 0.01 mmol) was dissolved in ethanol (100 ml) with
stirring at rt. To this stirred solution was added the solution of
NH4[80Br]Br (0.37 GBq) and then CAT (9 mg, 0.04 mmol, 4 eq). The
stirring was continued at rt for 1 min. Quenching reagent AET (27 mg,
0.24 mmol, 24 eq) was then added. Only one spot (Rf=0.59)
corresponding to the reference 4 was observed by radio-TLC (solvent:
MeOH/CHCl3 1:4). Yield of this spot was 99%. Methanol (1 ml)
was added to the mixture and one tenth of this volume (150 ml) was
injected into HPLC. The retention time of 4 was tR=12.4 min in the
radioactive-chromatogram. An amount of 250 ml from the separated
fraction (16 ml) was further chromatographed by HPLC purification.
An increased peak of [80Br]BVU (tR=5.1 min) 11 and a decreased peak
of 4 were observed. The radiolabelled 4 was obtained in 60%
radiochemical yield (decay corrected) based on the calculation of the
analytical volume.
Copyright # 2003 John Wiley & Sons, Ltd.
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434
C-S. YU ET AL.
5.3. Precursor syntheses
1-(2-deoxy-b-d-erythro-pentafuranosyl)-5-(2-fluoroethyl)pyrimidin-
2,4(3 H)-dione 1
Preparation of this compound had been reported by Griengl et al.9(a)
1b: pale yellow foam [lit.9(a), 152–1538C], anal. C11H15FN2O5, MW:
274.25,
ESI+Q1MS,
M=274
(m/z);
[M+H]+
=274.8,
[M+Na]+=296.9, [2M+Na]+=571.1, [3M+Na]+=845.1; ESI -
Q1MS, M=274 (m/z); [M-H]ꢃ=272.7, [M+35Cl]ꢃ=308.7, [2M-
H]ꢃ=547.0,
[2M+35Cl]ꢃ=582.9,
[3M-H]ꢃ=821.1;
1H-NMR
0
2.21 (ddd, J2 (a),2 (b)=13.6, J2 (a),1 =7.2,
0
0
0
(500 MHz, CD3OD)
0
d
J2 (a),3 =6.3 Hz, 1 H, H-20(a)), 2.28 (ddd, J2 (b),2 (a)=13.6, J2 (b),1 =6.3,
0
0
0
0
0
J2 (b),3 =3.7 Hz, 1 H, H-20(b)), 2.69 (ddddd, J7,F=23.1, J7,8(a)=6.2,
0
0
4
J7,8(b)=6.2, J7(a),7(b)=2.2 Hz, J7,6=0.9 Hz, 2 H, H-7), 3.72 (dd,
0
0
0
0
0
0
J5 (a),5 (b) =12.0, J5 (a),4 =3.7 Hz, 1 H, H-5 (a)), 3.78 (dd, J5 (b),5 (a)=12.0,
0
0
0
0
0
0
0
J5 (b),4 =3.3 Hz, 1 H, H-5 (b)), 3.91 (ddd, J4 ,5 (a)=3.7, J4 ,3 =3.7,
0
J4 ,5 (b)=3.3 Hz, 1 H, H-40), 4.39 (dddd, J3 ,2 (a)=6.3, J3 ,2 (b)=3.7,
0
0
0
0
0
0
J3 ,4 =3.7, J3 ,1 =0.4 Hz, 1 H, H-30), 4.51 (dddd, J8,F=47.2,
0
0
0
0
J8,7(a)=6.2 Hz, J8,7(b)=6.2, J8(a),8(b)=2.6 Hz, 2 H, H-8), 6.26 (ddd,
4
J1 ,2 (a)=7.2, J1 ,2 (b)=6.3, J1 ,3 =0.4 Hz, 1 H, H-10), 7.89 (t, J6,7=0.9 Hz,
1 H, H-6). 13C-NMR (125.76 MHz, CD3OD): d 29.10 (d, J7,F=21.6 Hz,
C-7), 41.30(C-20), 62.77 (C-50), 72.13 (C-30), 82.71 (d, J8,F=167.0 Hz, C-
8), 88.39 (C-10), 91.15 (C-40), 110.02 (d, J5,F=6.0 Hz, C-5), 140.68 (C-6),
152.31 (C-2), 165.96 (C-4). 19F-NMR (235.34 MHz, CD3OD): d -143.11.
1a
0
0
0
0
0
0
coloruless foam [lit.9(a), 1288C]. anal. C11H15FN2O5, MW: 274.25,
ESI+Q1MS, M=274 (m/z); [M+H]+ =274.8, [M+Na]+=296.8,
[2M+H]+=549.0, [2M+Na]+=571.0, [3M+Na]+=845.1; ESI -
Q1MS, M=274 (m/z); [M-H]ꢃ=272.7, [M+35Cl]ꢃ=308.7, [2M-
H]ꢃ=547.0, [2M+35Cl]ꢃ=583.0; 1H-NMR (500 MHz, CD3OD) d
0
0
0
0
0
0
0
0
2.05 (dddd, J2 (a),2 (b)=14.6, J2 (a),1 =2.6, J2 (a),3 =2.1 J2 (a),4 =0.7 Hz,
1 H, H-20(a)), 2.66 (ddd, J2 (b),2 (a)=14.6, J2 (b),1 =7.4, J2 (b),3 =6.2 Hz,
0
0
0
0
0
0
4
1 H, H-20(b)), 2.69 (ddd, J7,F=23.5, J7,8=6.2, J7,6=0.9 Hz, 2 H,
H-7), 3.56 (dd, J5 (a),5 (b)=12.0, J5 (a),4 =4.6 Hz, 1 H, H-50(a)),
0
0
0
0
0
0
3.59 (dd, J5 (b),5 (a)=12.0, J5 (b),4 =4.4 Hz, 1 H, H-5 (b)), 4.28 (dddd,
0
0
0
J4 ,5 (a)=4.6, J4 ,5 (b)=4.4, J4 ,3 =2.3, J4 ,2 (a)=0.7 Hz, 1 H, H-40), 4.35
0
0
0
0
0
0
0
0
(ddd, J3 ,2 (b)=6.2, J3 ,4 =2.3, J3 2 (a)=2.1, Hz, 1 H, H-30), 4.50 (dt,
0
0
0
0
0 0
0
J8,F=47.3, J8,7=6.2 Hz, 2 H, H-8), 6.19 (dd, J1 ,2 (b)=7.4,
0
4
J1 ,2 (a)=2.6 Hz, 1 H, H-10), 7.85 (t, J6,7=0.9 Hz, 1 H, H-6). 13C-NMR
0
0
(125.76 MHz, CD3OD): d 29.20 (d, J7,F=21.6 Hz, C-7), 41.73 (C-20),
Copyright # 2003 John Wiley & Sons, Ltd.
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NOVEL TYPES OF RADIOTRACER
435
63.48 (C-50), 72.47 (C-30), 82.61 (d, J8,F=166.9 Hz, C-8), 86.51 (C-10),
88.87 (C-40), 110.84 (d, J5,F=6.0 Hz, C-5), 139.94 (C-6), 152.18 (C-2),
165.69 (C-4).
1-(2-deoxy-b-d-erythro-pentafuranosyl)-5-(2-bromoethyl)pyrimidin-
2,4(3 H)-dione 2
Compound 2 was prepared according to the literature9(b) with slight
modification. Mixture of a,b-anomers of 5-(2-hydroxyethyl)-20-deox-
yuridine (500 mg, 1.84 mmol)9(b) and triphenyl phosphine (1.5 g,
5.71 mmol, 3 eq) in DMF (8 ml) was stirred at rt for 20 min (lit.:
10 min). NBS (655 mg, 3.68 mmol, 2 eq) was added and it was stirred at
rt for 30 min. After adding quenching reagent n-butanol (2 ml), the
solution was concentrated under vacuum (4 mbar) at 458C. The residue
was purified by silica gel column chromatography with MeOH/CHCl3
1:9 to give product 2 (b/a 5:1) in 40% yield (247 mg). The left solvent
DMF might be not completely removed after chromatography. A
repeated chromatography with MeOH/CHCl3 1:9 could solve this
problem, pink crystals, 157-1598C [lit.9(b)
,
161-163 C] anal.
C11H15BrN2O5, calcd: C 39.42, H 4.51, N 8.36, Br 23.84; found: C
39.51, H 4.80, N 8.37, Br 24.15. anal. C11H15BrN2O5, MW: 335.16,
ESI+Q1MS,
M=335
(m/z);
[M+Na]+
=356.9,
358.9,
[2M+Na]+=693.0, [2M-H+2Na]+=715.0; ESI - Q1MS, M=335
(m/z), [M+35Cl]ꢃ=370.9; H-NMR (250 MHz, CD3OD) d 2.19 (ddd,
1
J2 (a),2 (b)=13.6, J2 (a),3 =7.0, J2 (a),1 =6.6 Hz, 1 H, H-20(a)), 2.27 (ddd,
0
0
0
0
0
0
J2 (b),2 (a)=13.6, J2 (b),1 =6.3, J2 (b),3 =4.0 Hz, 1 H, H-20(b)), 2.80 (dddd,
0
0
0
0
0
0
4
J7(a),7(b)=21.8, J7(a),8(a)=7.3, J7(a),8(b)=7.3, J7(a),6=0.8 Hz, 1 H, H-
7(a)), 2.86 (dddd, J7(b),7(a)=21.8, J7(b),8(a)=6.8, J7(b),8(b)=6.8,
4J7(b),6=0.8 Hz, 1 H, H-7(b)), 3.55 (ddd, J8,7(a)=7.3 Hz, J8,7(b)=6.8,
0
0
0
0
J8(a),8(b)=1.5 Hz, 2 H, H-8), 3.71 (dd, J5 (a),5 (b) =12.1, J5 (a),4 =3.6 Hz,
1 H, H-50(a)), 3.79 (dd, J5 (b),5 (a)=12.1, J5 (b),4 =3.1 Hz, 1 H, H-5 (b)),
0
0
0
0
0
3.91 (ddd, J4 ,3 =3.7, J4 ,5 (a)=3.6, J4 ,5 (b)=3.1 Hz, 1 H, H-40), 4.39 (ddd,
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
J3 ,2 (a)=7.0, J3 ,2 (b)=4.0, J3 ,4 =3.7 Hz, 1 H, H-3 ), 6.25 (dd, J1 ,2 (a)=6.6,
4
4
J1 ,2 (b)=6.3 Hz, 1 H, H-10), 7.92 (t, J6,7(a)=0.8, J6,7(b)=0.8 Hz, 1 H, H-
6). 13C-NMR (62.90 MHz, CD3OD): d 31.70 (d, J7,F=21.6 Hz, C-7),
31.92 (C-8), 41.43(C-20), 62.78 (C-50), 72.11 (C-30), 86.46 (C-10), 88.92
(C-40), 112.45 (C-5), 140.10 (C-6), 152.12 (C-2), 165.49 (C-4).
3-(2-deoxy-b-d-erythro-pentafuranosyl)-5,6-dihydrofuropyrimidin-2-one
6
0
0
Methanol (60 ml) was saturated with ammonia at 08C. To the
solution was added 2 (320 mg, 0.95 mmol) at rt and it was stirred for
50 min. After concentration of the solution under reduced pressure at
Copyright # 2003 John Wiley & Sons, Ltd.
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436
C-S. YU ET AL.
408C, the crystallized product 6 was obtained in 82% yield (210 mg),
colourless crystals, 184–1878C (the sample may contain water), lit.9(b)
206–2088C, anal. C11H14N2O5, calcd: C 51.97, H 5.55, N 11.02; found:
C 48.37, H 5.97, N 10.70; MW: 254.24, ESI+Q1MS, M=254 (m/z),
[M+H]+: 255.0, [M+NH4]+: 272.0, [M+Na]+: 277.0, [2M+H]+:
509.2, [2M+NH4]+: 526.2, [2M+Na]+: 531.2; ESI – Q1MS, M=254
(m/z), [M-H]ꢃ: 252.9, [M+35Cl]ꢃ: 289.0, [2M-H]ꢃ: 507.2, [M+Br]ꢃ:
332.9/334.9, [2M+Br]ꢃ: 587.1/589.1; UV (MeOH): lmax=287.8 nm;
l
min=247.4 nm; TLC (MeOH/CHCl3 1:4) Rf=0.33; 1H-NMR
0
0
0
0
(250 MHz, DMSO-d6): d 1.95 (ddd, J2 (a),2 (b)=13.2, J2 (a),3 = 6.9,
0
0
J2 (a),1 =6.2 Hz, 1 H, H-2 a), 2.20 (ddd, J2 (b),2 (a)=13.2, J2 (b),1 =6.0,
0
0
0
0
0
0
0
0
J2 (b),3 =3.5 Hz, 1 H, H-2 b), 3.03 (td, J5,6=8.2, J5,4=1.6 Hz, 2 H, H-5),
3.57 (ddd, J5 (a),5 (b)=11.9}, J5 ,5 (OH)=5.3, J5 ,4 =3.6 Hz, 2 H,
0
0
0
0
0
0
H-50a+H-50b), 3.81 (q, J4 ,5 (a)=3.6, J4 ,5 (b)=3.6, J4 ,3 =3.6 Hz, 1 H,
0
0
0
0
0
0
H-40), 4.21 (dddd, J3 ,2 (a)=6.9, J3 ,3 (OH)=4.3, J3 ,4 =3.6, J3 ,2 (b)
0
0
0
0
0
0
0
0
=3.5 Hz, 1 H, H-30), 4.63 (t, J6,5=8.2 Hz, 2 H, H-6), 4.97 (t, J5
0
(OH),50
=5.3 Hz, 1 H, 50-OH), 5.17 (d, J3 (OH),3 =4.3 Hz, 1 H, 3 -OH), 6.13 (dd,
0
0
0
J1 ,2 (a)=6.2, J1 ,2 (b)=6.0 Hz, 1 H, H-10), 8.09 (t, J4,5=1.6 Hz, 1 H, H-4);
13C-NMR (62.90 MHz, DMSO-d6): d 23.91 (C-5), 40.66 (C-20), 61.06
(C-50), 70.07 (C-30), 71.71 (C-6), 85.85 (C-10), 87.52 (C-40), 103.97 (C-5a),
137.29 (C-4), 155.51 (C-2), 177.38 (C-7a)
0
0
0
0
Typical procedure for the ring-opening reaction of 6 using non-
radioactive ammonium halides. NH4Cl as an example
6 (10 mg, 0.039 mmol) was dissolved in DMF (1 ml) with stirring at rt.
To the stirred solution was added NH4Cl (3 mg, 0.056 mmol, 1.4 eq).
The stirring was continued at 858C for 24 h. After concentration of the
solution under vacuum (4 mbar) at 458C, the residue was chromato-
graphed with MeOH/CHCl3 1:9 to give product 5-(2-chloroethyl)deox-
yuridine 10 in 90% yield (10 mg), colorless needles, 161–1648C [lit.9(b)
,
166-1678C], anal. C11H15ClN2O5,k calcd: C 45.45, H 5.20, N 9.64;
found: C 45.01, H 5.30, N 9.22 anal. anal. C11H15ClN2O5, MW: 290.70,
ESI+Q1MS, M=290 (m/z); [M+Na]+ =312.8; ESI - Q1MS, M=290
(m/z), [M-H]ꢃ=288.7, [M+35Cl]ꢃ=324.6; 1H-NMR (250 MHz,
0
0
0
0
0
0
CD3OD) d 2.19 (ddd, J2 (a),2 (b)=13.5, J2 (a),1 =7.0, J2 (a),3 =6.0 Hz, 1 H,
H-20(a)), 2.27 (ddd, J2 (b),2 (a)=13.5, J2 (b),1 =6.3, J2 (b),3 =3.9 Hz, 1 H,
H-20(b)), 2.72 (dddd, J7(a),7(b)=21.6, J7(a),8(a)=7.4, J7(a),8(b)=7.4,
4J7(a),6=0.8 Hz, 1 H, H-7(a)), 2.75 (dddd, J7(b),7(a)=21.6, J7(b),8(a)=6.7,
0
0
00
0
0
0
} J was measured; but almost no difference in chemical shift values was observed.
k Due to the limited amount of samples obtained, we did not analyse the Cl content.
Copyright # 2003 John Wiley & Sons, Ltd.
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NOVEL TYPES OF RADIOTRACER
437
4
J7(b),8(b)=6.7, J7(b),6=0.8 Hz, 1 H, H-7(b)), 3.63 (ddd, J8,7(a)=7.4 Hz,
0
J8,7(b)=6.7, J8(a),8(b)=1.1 Hz, 2 H, H-8), 3.72 (dd, J5 (a),5 (b) =12.1,
0
0
0
0
0
0
0
0
J5 (a),4 =3.9 Hz, 1 H, H-5 (a)), 3.78 (dd, J5 (b),5 (a)=12.1, J5 (b),4 =3.3 Hz,
1 H, H-50(b)), 3.90 (ddd, J4 ,5 (a)=3.9, J4 ,3 =3.5, J4 ,5 (b)=3.3 Hz, 1 H, H-
0
0
0
0
0
0
40), 4.38 (ddd, J3 ,2 (a)=6.0, J3 ,2 (b)=3.9, J3 ,4 =3.5 Hz, 1 H, H-3 ),
0
0
0
0
0
0
0
4
6.25 (dd, J1 ,2 (a)=7.0, J1 ,2 (b)=6.3 Hz, 1 H, H-10), 7.92 (dd, J6,7(a)=0.8,
4J6,7(b)=0.8 Hz, 1 H, H-6). 13C-NMR (62.90 MHz, CD3OD):
d 31.70 (C-7), 41.43 (C-20), 43.55 (C-8), 62.78 (C-50), 72.14 (C-30),
86.49 (C-10), 88.94 (C-40), 111.66 (C-5), 140.23 (C-6), 152.17 (C-2),
165.60 (C-4).
0
0
0
0
1-(2-deoxy-b-d-erythro-pentafuranosyl)-(E)-5-(2-bromovinyl)
pyrimidin-2,4(3 H)-dione (BVDU) 4
4 was prepared according to a published method for synthesis of 1-(b-
d-arabino-pentafuranosyl)-(E)-5-(2-bromovinyl)uracil, an analog of 418.
The yield of 4 was 28% from 5-iodo-20-deoxyuridine, white crystals,
164-1668C19, 1588C], anal. C11H13BrN2O5, calcd: C 39.66, H 3.93, N
* *
8.41; found: C 39.07, H 4.17, N 8.02.
ESI+Q1MS, M=333 (m/z); [M+H]+ =332.9, 334.9, [M+Na]+
=354.9, 356.9, [2M+H]+=667.0, [2M+Na]+=689.0; ESI - Q1MS,
M=333 (m/z), [M-H]ꢃ=330.9, 332.9, [M+35Cl]ꢃ=368.8, [2M-H]ꢃ
=664.6, [2M+35Cl]ꢃ=700.9; 1H-NMR (250 MHz, DMSO-d6) d (2.11–
2.15 m, 2 H, H-20), 3.53-3.63 (m, 2 H, H-50), 3.91 (ddd, J4 ,3 =3.7,
0
0
J4 ,5 (a)=3.6, J4 ,5 (b)=3.1 Hz, 1 H, H-40), 4.22-4.28 (m, 1 H, H-30), 5.03 (t,
0
0
0
0
J5 (OH),5 =5.2 Hz, 1 H, H-50), 5.19 (d, J3 (OH),3 =4.4 Hz, 1 H, H-30), 6.12
0
0
00
0
(dd, J1 ,2 (a)=6.6, J1 ,2 (b)=6.6 Hz, 1 H, H-10), 6.83 (dd, J8,7=13.6 Hz, 1 H,
0
0
0
0
H-8), 7.22 (d, J7,8=13.6 Hz, 1 H, H-7), 8.06 (s, 1 H, H-6), 11.50 (bs, 1 H,
13
-NH). C-NMR (62.90 MHz, DMSO-d6): d 39.78 (C-20), 60.93 (C-50),
69.86 (C-30), 84.48 (C-10), 87.47 (C-40), 106.38 (C-8), 109.59 (C-5),
129.75 (C-7), 139.28 (C-6), 149.16 (C-2), 161.54 (C-4).
Acknowledgements
The German Academic Exchange Service (DAAD) provided C.-S. Yu
the scholarship to carry out his research at DKFZ, which we are
gratefully. Dr. William E. Hull, Mrs. Gabriele Schwebel-Schilling
and Mr. Gerhard Erben carried out the NMR and mass spectro-
scopic analyses and contributed fruitful discussions for which we are
grateful.
* * The impurities were assumed to be EtOH or water. anal. C11H13BrN2O5, MW: 333.14.
Copyright # 2003 John Wiley & Sons, Ltd.
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C-S. YU ET AL.
References
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