Deuterated batracylin: Deuterium-hydrogen exchange during synthesis and mass spectral analysis

Article abstract of DOI:10.1002/jlcr.1847

Deuterium-labeled analogs of the topoisomerase inhibitor batracylin were prepared for metabolism studies to further its evaluation as an antitumor agent. Established syntheses of unlabeled batracylin were adapted for the preparation of deuterated batracyl

Full text of DOI:10.1002/jlcr.1847

Research Article
Received 6 June 2010,
Revised 27 August 2010,
Accepted 11 October 2010
Published online 29 December 2010 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1847
Deuterated batracylin: deuterium–hydrogen
exchange during synthesis and mass spectral
analysis
Ã
Herbert H. Seltzman,a Scott E. Fix,a and Prabhakar Risboodb
Deuterium-labeled analogs of the topoisomerase inhibitor batracylin were prepared for metabolism studies to further its
evaluation as an antitumor agent. Established syntheses of unlabeled batracylin were adapted for the preparation of
deuterated batracylin that was trideuterated in the quinazoline ring (d3-batracylin 5), tetradeuterated in the isoindolo ring
(d4-batracylin 11), and heptadeuterated in both rings (d7-batracylin 12). Extensive exchange of deuterium or hydrogen in
the quinazoline ring was observed from an intermediate in the final concentrated sulfuric acid promoted deblocking/
cyclodehydration step of the synthesis. Introduction of deuterated concentrated sulfuric acid in the final step both retained
the label in the quinazoline-labeled product and enabled extended labeling of a more exhaustively deuterated analog.
Batracylin itself did not readily exchange aromatic protons under the reaction conditions but did loose and scramble
deuterium atoms during mass spectral analysis leading to an under calculation of the deuterium content in the quinazoline
ring. These results identify a chemical exchange process that can either undo, maintain, or facilitate the labeling process
and also mass spectral analyses issues that must be taken into account to characterize and utilize these analogs and, more
broadly, that can be recognized as potentially applicable to other classes of compounds.
Keywords: batracylin; deuterium; ortho exchange; mass spectrum
(6.58 g, 83.2 mmol), and the mixture was cooled to 01C. Ethyl
chloroformate (6.62 g, 61.0 mmol) was added dropwise to the
cooled solution over 20 min. The reaction was allowed to warm
to room temperature overnight. The reaction mixture was then
washed with H2O (2 Â 50 mL) followed by brine (2 Â 50 mL). An
insoluble white cloud of material that remained between the
aqueous layer and the organic layer was successfully extracted
into CH2Cl2:THF (3:1) (3 Â 25 mL). The combined organics were
dried over Na2SO4, filtered, and the solvents were removed
under reduced pressure. The resulting white solid was
recrystallized from EtOH affording 3.00 g (44%) of compound
2. The filtrate from the recrystallization was evaporated
affording another 2.45 g (32%) of crude product. MS deuterium
incorporation: d3 8.43%, d4 83.89%, d5 7.69%. 1H NMR d ppm:
1.23 (t, J = 7.16 Hz, 6 H), 4.10 (q, J = 7.16 Hz, 4 H), 9.46 (br. s., 2 H).
Introduction
Batracylin is a topoisomerase II inhibitor with antitumor activity
in a number of cell lines.1–4 d3-Deuterium-labeled batracylin
labeled in the quinazoline aromatic ring (4) and d4-deuterium-
labeled batracylin labeled in the isoindolo aromatic ring (6)
with high incorporation at each site was sought for use in
metabolism studies. Syntheses employing unlabeled 1 have
been reported,1–4 from which we proposed the adaptation
shown in Scheme
1
for the synthesis of [6,7,9-2H3]-8-
amino-10,12-dihydro-isoindolo[1,2-b]quinazolin-12(10H)-one (5),
[2H3]-batracylin, and Scheme 3 for the synthesis of [1,2,3,4-2H4]-
8-amino-10,12-dihydro-isoindolo[1,2-b]quinazolin-12(10H)-one
(11), [2H4]-batracylin.
Experimental
Compound (4)
General methods
To a solution of N-hydroxymethylpthalimide (1.91 g, 11.7 mmol)
in concentrated sulfuric acid (15 mL) was added the carbamate 2
1H NMR spectra were obtained in DMSO-d6 on a 300-MHz
Brucker Advance 300. Mass spectra were run in electrochemical
ionization positive ion mode obtained on a PE SCIEX API 150EX
mass spectrometer (electrospray) for intermediates and on an
HP 5989A DIP mass spectrometer (direct ion probe) for the
batracylins.
aCenter for Organic and Medicinal Chemistry, Research Triangle Institute,
Research Triangle Park, NC 27709, USA
bDrug Synthesis and Chemistry Branch, Developmental Therapeutics Program,
Division of Cancer Treatment and Diagnostics, National Cancer Institute,
National Institutes of Health, Bethesda, MD 20892, USA
Compound (2)
*Correspondence to: Herbert H. Seltzman, Center for Organic and Medicinal
Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
E-mail: hhs@rti.org
To a solution of 98 atom% 1,4-phenylenediamine-2,3,5,6-d4
(1, 3.00 g, 26.7 mmol) in CHCl3 (100 mL) was added pyridine
J. Label Compd. Radiopharm 2011, 54 206–210
Copyright r 2010 John Wiley & Sons, Ltd.

H. H. Seltzman et al.
Scheme 1.
Scheme 2.
(3.00 g, 11.7 mmol) portion-wise. The mixture was stirred at the dropwise addition of NH4OH (40 mL) at which time a yellow
room temperature until all solids had dissolved in solution at solid precipitated from solution. The solids were collected and
which time the reaction was heated at 501C for 3 h. The mixture washed with water (50 mL) followed by cold EtOH (50 mL). The
was poured into an ice/H2O mixture (100 mL) causing a solid to yellow solids were dried in the vacuum oven overnight at 501C
crash out of solution. Et2O (50 mL) was added to the mixture and at which time they were suspended a second time in H2O
the solids were collected. The solids were washed with Et2O (75 mL). The suspension was stirred at room temperature for
(25 mL) followed by H2O (25 mL). The yellow solids were 15 min. The yellow solids were then collected, washed with
collected and placed in the vacuum oven overnight at 501C cold EtOH (25 mL), and placed in the vacuum oven for 48 h
affording compound 4 (3.13 g, 65%). MS deuterium incorpora- affording the desired compound 5 (1.10 g, 4.36 mmol, 58%).
tion: d1 4.54%, d2 6.24%, d3 84.54%, d4 0.00, d5 4.68%. MS: m/e (1ion) = 253 M11; m/e (- ion) = 251 M-1. Integration of
Integration of the dicarbamoylphenyl resonances calculated to quinazoline 6.46, 6.51, and 7.13 d resonances calculated to be
1
1
8.2% of 1H3 versus 1H4 of the phthalimide ring indicative of 4.5% of H3 versus H4 of the isoindolo ring indicative of 95.5%
1
91.8% deuterium retention. H NMR d ppm: 1.15 (t, J = 7.16 Hz, deuterium incorporation.
3 H), 1.23 (dt, J = 7.16, 2.83 Hz, 3 H), 4.02 (q, J = 7.16 Hz, 2 H), 4.09
MS deuterium incorporation: d0 0.14%, d1 0.70%, d2 20.46%,
(q, J = 7.16 Hz, 2 H), 4.70 (s, 2 H) 7.84–7.98 (m, 4 H), 8.96 (br. s., 1 d3 71.93%, d4 6.72%. 1H NMR (dmso-d6) d ppm: 4.81 (s, 2 H),
H), 9.47 (s, 1 H).
5.55 (s, 2 H), 7.70 (dd, J = 7.50, 7.00 Hz, 1 H), 7.77 (dd, J = 7.54,
7.16 Hz, 1 H), 7.86 (d, J = 7.16 Hz, 1H), 7.95 (d, J = 7.54 Hz,
1 H) HPLC (Waters Nova-Pak C-18 4 mM; 8 mm  100 mm;
30:70 CH3CN–H2O; 2 mL/min; 254 nM):498% Rt = 5.06 min.
d3-batracylin (5)
A solution of 4 (3.13 g, 7.56 mmol) in 99.5% deuterated TLC (MK6F SiO2; 70:30 CH2Cl2: (CHCl3:MeOH: NH4OH (28%),
concentrated sulfuric acid (15 mL) was heated at 1001C for 5 h. 80:18:2), Rf= 0.56. Elemental analysis: calcd for C15H8D3N3O Á
The reaction was cooled to room temperature and poured into (H2O)0.5 Á (EtOH)0.25: C 68.24, H 4.93, N 15.40; found: C 68.40, H
an ice–H2O mixture (100 mL). The mixture was made basic with 4.29, N 15.09.
J. Label Compd. Radiopharm 2011, 54 206–210
Copyright r 2010 John Wiley & Sons, Ltd.
www.jlcr.org

H. H. Seltzman et al.
Scheme 3.
Compounds 13 and 14 – deuterium exchange of precursor 4
and batracylin
Integration of quinazoline 6.47, 6.52, and 7.13 d resonances
calculated to be 88% of 1H3 versus 1H4 of the isoindolo ring
indicative of 12% deuterium incorporation.
The trideuterated precursor 4 was heated in protio H2SO4 at
1001C for 5 h, as described above for the preparation of 5 but
without the resuspension in water and subsequent vacuum
oven drying. The resulting batracylin (13) showed major losses
of deuterium content from the quinazoline ring, versus the
precursor 4, by 1H NMR (calculating to 28% remaining of the
theoretical 2H3) and isotope incorporation mass spectrometry:
d0 59.29%, d1 28.60%, d2 11.06%, and d3 1.05%.
Unlabeled batracylin was heated in 99.5% deuterated
concentrated sulfuric acid at 1001C for 5 h as for the above.
The resulting batracylin (14) showed minimal deuterium uptake
by 1H NMR (calculating to 12% of the quinazoline ring
theoretical 2H3) and isotope incorporation mass spectrometry:
d0 95.74%, d1 0.00%, d2 2.65%, and d3 1.62%.
Compound (7)
To a solution of 99.5 atom % 3,4,5,6-d4 phthalimide (6, 2.00 g,
13.2 mmol) in H2O (4 mL) was added 38% formaldehyde
(1.62 mL) and the reaction mixture was heated at 1051C for
4 h. The reaction was allowed to cool to room temperature at
which time white crystals had precipitated out of solution. The
white crystals were filtered, washed with H2O (10 mL), and
placed in the vacuum oven overnight affording the desired
compound 7 (2.22 g, 93%). 1H NMR d ppm: 4.97 (d, J = 7.16 Hz,
2 H) and 6.40 (t, J = 6.97 Hz, 1H).
Compound (9)
To a solution of 1,4-phenylenediamine (8, 3.00 g, 27.7mmol) in
CHCl3 (100 mL) was added pyridine (6.58g, 83.2mmol) and the
mixture was cooled to 01C. Ethyl chloroformate (6.62 g, 61.0 mmol)
was added dropwise to the cooled solution over 20min. The
reaction was allowed to warm to room temperature overnight.
The reaction mixture was then washed with H2O (2Â 50mL)
followed by brine (2 Â 50mL). An insoluble white cloud of material
remained between the aqueous layer and the organic layer. After
fruitless attempts of extracting the material into various solvents
(CH2Cl2, CHCl3, EtOAc), we were able to get a nice separation
extracting with a mixture of CH2Cl2–THF (3:1) (3 Â 25 mL). The
combined organics were dried over Na2SO4, filtered, and the
solvent was removed under reduced pressure. The resulting
white solid was recrystallized from EtOH affording the desired
compound 9 (6.09 g, 87%). 1H NMR d ppm: 1.22 (t, J = 6.97 Hz, 6 H),
4.09 (q, J = 7.16Hz, 4 H), 7.33 (s, 4 H), and 9.47 (s, 2 H).
Compound 13
1H NMR d ppm: 4.81 (s, 2 H), 5.56 (s, 2 H), 6.46 (s, 0.85 H), 6.51 (d,
J = 4.90 Hz, 0.85 H), 7.13 (d, J = 8.29 Hz, 0.48 H), 7.70 (dd, J = 7.50,
7.00 Hz, 1 H), 7.77 (dd, J = 7.54, 7.16 Hz, 1 H), 7.86 (d, J = 7.16 Hz, 1
H), and 7.95 (d, J = 7.54 Hz, 1 H).
Integration of quinazoline 6.46, 6.51, and 7.13 d resonances
calculated to 72% of 1H3 versus 1H4 of the isoindolo ring
indicative of 28% deuterium retention.
Compound 14
1H NMR d ppm: 4.80 (s, 2 H), 5.55 (s, 2 H), 6.47 (s, 1 H), 6.51 (d,
J = 4.90 Hz, 1 H), 7.13 (d, J = 8.29 Hz, 1 H), 7.70 (dd, J = 7.50,
7.00 Hz, 1 H), 7.77 (dd, J = 7.54, 7.16 Hz, 1 H), 7.85 (d, J = 7.54 Hz, 1
H), and 7.95 (d, J = 7.54 Hz, 1 H).
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J. Label Compd. Radiopharm 2011, 54 206–210

H. H. Seltzman et al.
Compound (10)
4.81 (s, 2 H), 5.55 (s, 2 H), 6.46 (s, 0.25 H), 6.51 (d, J = 8.67 Hz, 0.4
H), 7.13 (t, J = 4.33 Hz, 0.53 H). MS deuterium incorporation: d4
1.54%, d5 19.93%, d6 19.71%, d7 45.86%, d8 9.96%, d9 2.24%, and
d10 0.77%.
To a solution of N-hydroxymethylphthalimide-d4 (7, 2.22 g,
12.5 mmol) in concentrated sulfuric acid (10 mL) was added the
carbamate 9 (3.09 g, 12.5 mmol) portion-wise. The mixture was
stirred at room temperature until all solids had dissolved into
solution at which time the reaction was heated at 501C for 3 h.
The mixture was poured into an ice–H2O mixture (100 mL)
causing the solid to precipitate from solution. Et2O (50 mL) was
added to the mixture, and the solids were collected by filtration.
The solids were washed with Et2O (25 mL) followed by H2O
(25 mL). The yellow solids were collected and placed in the
vacuum oven overnight at 501C affording compound 10 (1.24 g,
25%). 1H NMR d ppm: 1.16 (t, J = 7.16 Hz, 3 H), 1.24 (t, J = 7.16 Hz,
3 H), 4.03 (q, J = 7.16 Hz, 2 H), 4.09 (q, J = 7.16 Hz, 2 H), 4.59–4.79
(m, 2 H), 7.04–7.41 (m, 3 H), 8.97 (br. s., 1 H), 9.47 (s, 1 H).
Results and discussion
d3-batracylin
The labeled synthesis started with commercially available 1,4-
phenylenediamine-2,3,5,6-d4 (1), which was acylated with ethyl
chloroformate to afford the carbamate 2 (Scheme 1). The
purified
2 was condensed with commercially available
N-hydroxymethylphthalimide (3) in concentrated sulfuric acid
at 501C to provide labeled 4. Heating 4 at 1001C in protio
concentrated sulfuric acid yielded batracylin that contained only
28% of the theoretical three deuteriums (1H NMR, compound
13). In retrospect, it is clear that the deuterium atoms adjacent
to the phenylenediamine nitrogens (at positions equivalent to 6,
7, and 9 in batracylin 5) exchanged out with the protio
concentrated sulfuric acid. The fact that 4 itself was prepared in
protio concentrated sulfuric acid, and retained 92% 2H3 as
d4-batracylin, compound (11)
A solution of 10 (1.24 g, 3.00 mmol) in protio concentrated
sulfuric acid (15 mL) was heated at 1001C for 5 h. The reaction
was cooled to room temperature and poured into an ice–H2O
mixture (100 mL). The mixture was made basic with the
dropwise addition of cNH4OH (40 mL) at which time an orange
solid precipitated from solution. The solids were collected and
washed with water (50 mL) followed by cold EtOH (50 mL). Poor
solubility severely impeded workup and purification methodol-
ogy. The yellow solids were dried in the vacuum oven overnight
at 501C at which time they were taken up a second time in H2O
(75 mL). The suspension was stirred at room temperature for
15 min. The yellow solids were then collected, washed with cold
EtOH (25 mL), and placed in the vacuum oven for 48 h affording
the desired compound 11 (695 mg, 2.74 mmol, 92%). MS: m/e
(1ion) = 254 M11; m/e (Àion) = 252 M-1. MS deuterium
1
shown by H NMR, indicates that the deuteriums were stable in
the carbamate 4 at 501C. Furthermore, unlabeled batracylin did
not incorporate significant deuterium (12% by 1H NMR) when
heated at 1001C for 5 h in 99.5% atom percent deuterium-
labeled concentrated sulfuric acid indicating the resistance to
exchange of the batracylin aromatic protons (Scheme 2,
compound 14).
The labeled synthesis was repeated with the difference that
the final step, conversion of 4 to 5, was conducted in 99.5%
atom percent deuterium-labeled concentrated sulfuric acid. This
preserved the quinazoline deuteriums in the transition of 4 to
afford d3-batracylin (5). Batracylin d3 even had 6.7% of d4 by MS
incorporation: d0 0.30%, d1 0.46%, d2 2.49%, d3 0.00, and d4
¨
1
1
95.24%. H NMR a ppm: 4.81 (s, 2 H), 5.56 (s, 2 H), 6.39–6.62 (m, 2
and a reduced proton integration in the H NMR for the 8-NH2
supportive of residual deuterium from 8-ND2 as a consequence
of incomplete exchange from the suspended, poorly soluble 5.
Complete dissolution in dilute aqueous solution should
complete this exchange.
Interpretation of the mass spectral data of quinazoline-
labeled batracylin needs to take into account the loss of
deuterium in the mass spectrometer that leads to an under-
representation of the deuterium content of the compound.
Thus, we observed varying levels of deuterium incorporation of
the intermediates and the product from the synthesis when the
H), 7.13 (d, J = 8.29 Hz, 1H). HPLC (Waters Nova-Pak C–18 4 mM;
8 mm  100 mm; 30:70 CH3CN-H20; 2 mL/min; 254 nM):498%
Rt = 5.06 min. TLC MK6F SiO2; 70:30 CH2Cl2–(CHCl3–MeOH–cN-
H4OH, 80:18:2), UV detection Rf = 0.56, 498%. Elemental
analysis: calculated for C15H7D4N3O (H2O)0.5 Á (EtOH)0.25
68.24. H 4.93, N 15.40; found C 68.41, H 4.23, N 15.03.
: C
d7-batracylin compound 12; via cyclodehydration of inter-
mediate (10)
A
solution of tetradeuterated intermediate 10 (0.654 g, measurements were by mass spectrometry. Specifically, starting
1.57 mmol) in 99.5% deuterated concentrated sulfuric acid 1, reported by the vendor as 98 atom % deuterium, showed 74%
(5 mL) was heated at 1001C for 5 h. The reaction was cooled to M11 for d4; 2 showed 84% M11 for d4; 4 showed 85% M11 for
room temperature and poured into cold D2O (100 mL). The d3; and 5 showed 72% M11 for d3. It is unreasonable that
mixture was made basic with the dropwise addition of NH4OH deuterium content in 2 would increase over that in 1. Rather,
(40 mL) at which time an orange solid began falling out of these results indicate that when the amino moiety of the
solution. The solids were collected and washed with water starting 1 or the target 5 is unprotected, then deuterium is lost
(50 mL) followed by cold EtOH (50 mL). Column chromatography in the mass spectrometer and anomalously low incorporation
of the solids was attempted but was probably a bad idea due to levels of the target M11 ion are calculated. This interpretation is
solubility issues. The chromatography on an Isco Companion supported by 1H NMR spectra of 1–5 that showed minimal
(40 g silica column, gradient from CHCl3–MeOH–cNH4OH proton content for the phenylenediamine and quinazoline
1
(80:18:2)/CH2Cl2 (1:9) to (3:7) afforded d7 batracylin (105 mg, aromatic rings in all compounds. H NMR integration of 1 and
0.41 mmol, 26%). The poor yield was probably due to the lack of 5, for example, showed 99 and 95.5% deuterium content,
solubility of the material during chromatography. The resulting respectively.
batracylin showed 39% of retained proton in the quinazoline
ring, which calculates to 61% incorporation of deuterium, ortho to
preferentially in the 7- and 9-positions, by 1H NMR d ppm: chemically,5–7 as our results above also demonstrate, and it is
Furthermore, exchange of aromatic protons or deuterons
a
heteroatom substituent is well precedented
J. Label Compd. Radiopharm 2011, 54 206–210
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H. H. Seltzman et al.
not surprising that it is observed in the mass spectrometer as exchange-promoting solvents (MeOH, H2O), which were used
well. For example, an unusually high level of abstraction of one to infuse the sample into the MS, which then redistributed into
deuterium from d4 1 (observed as d3) and from d3 5 (observed the remaining d7 molecules, characteristic of the quinazoline
as d2) was observed in the mass spectral deuterium incorpora- ring.
tion calculations. This abstraction by exchange-promoting
solvents (MeOH and H2O) employed in the sample infusion Conclusions
into the mass spectrometer has a corollary effect of exchanging
Exchange-promoting conditions in the synthesis of batracylin
the abstracted deuteriums from a portion of the molecules into
result in exchange of protons or deuterium in the final
the remaining molecules, producing higher mass incorporations
intermediate phenylenediamine ring. This occurs when the
amino moieties are not protected, such as by carbamoyl groups,
such as d5 for compounds 1, 2, and 4.
The chemical and mass spectral behavior of quinazoline-
in the cyclodehydration with concentrated sulfuric acid. This can
deuterated batracylin described above would need to be
result in labeling being reduced, increased, or maintained in the
quinazoline ring of batracylin. Furthermore, all the intermediates
accounted for in any interpretation of metabolic studies.
and especially the target batracylin gave anomalously low
calculated deuterium incorporation levels when determined
d4- and d7-batracylin
The synthesis shown in Scheme 3 was chosen for the deuterium
labeling since the deuterated precursor, phthalimide-1,2,3,4-d4
(6), was commercially available and the conversion of 6 to
N-hydroxymethylpthalimide (7) has been reported for the
unlabeled analog.8 Thus, phthalimide-1,2,3,4-d4 (6) was heated
with formaldehyde in water to afford the crystalline 7 in 93%
yield. Unlabeled 8 was acylated to provide the carbamate 9 in
87% yield. Coupling 7 and 9 in concentrated sulfuric acid gave
10 by precipitation in an atypically low 25% yield (vs 65% for the
synthesis of the quinazoline-labeled analog). Finally, decarba-
moylaton and subsequent cyclodehydration yielded 92% of the
target d4 batracylin 11.
from mass spectral data due to similar exchange processes
during analysis. This behavior needs to be taken into account
when using such analogs in studies such as metabolism. Finally,
the frequent occurrence of aryl amines in pharmaceuticals point
to the potential generality of these observations.
Acknowledgements
Informative discussions with Drs James Mathews and Timothy
Fennell of RTI International are acknowledged. This work was
funded by the National Cancer Institute on Contract No. N02-
CM-62228.
Characterization of the product showed a 95% d4 incorpora-
tion by mass spectrometry. 1H NMR showed the absence of
significant protons in the isoindolo ring. HPLC indicated 498%
purity while TLC indicated a single spot by UV detection.
When the d4 intermediate 10 was subjected to decarbamoy-
lation and cyclodehydration in 99.5% deuterated concentrated
sulfuric acid, the isolated batracylin was substantially labeled in
the previously unlabeled quinazoline ring to the extent of 61%
of full incorporation (1H NMR) to afford mostly d7-batracylin
(compound 12) (MS). The labeling occurred preferentially in the
7- and 9-positions with 69% of two deuteriums incorporated
compared with 46% of one deuterium in the 6-position (1H
NMR). Negligible deuteriums were observed at the 8-NH2
position. The major MS ions of the molecular ion cluster were
d5–7 but levels of d8–10 were also observed. This is attributed to
exchange of deuteriums from the quinazoline ring into
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J. Label Compd. Radiopharm 2011, 54 206–210