Synthesis of isotope-labeled HSP90 inhibitor: [13CD3] and [14C]-TAK-459

Article abstract of DOI:10.1002/jlcr.3217

[¹³CD₃]-TAK-459 (1A), an HSP90 inhibitor, was synthesized from [¹³CD₃]-sodium methoxide in three steps in an overall yield of 29%. The key intermediate [¹³CD ₃]-2-methoxy-6-(4,4,5,5-tetrame

Full text of DOI:10.1002/jlcr.3217

Research Article
Received 17 April 2014,
Revised 21 May 2014,
Accepted 05 June 2014
Published online 3 July 2014 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3217
Synthesis of isotope-labeled HSP90 inhibitor:
13
14
[ CD3] and [ C]-TAK-459
*
Mihaela Plesescu, Eric L. Elliott, Yuexian Li, and Shimoga R. Prakash
[
13CD3]-TAK-459 (1A), an HSP90 inhibitor, was synthesized from [13CD3]-sodium methoxide in three steps in an overall yield
of 29%. The key intermediate [13CD3]-2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was synthesized in
two steps from 2,6-dibromopyridine and stable isotope-labeled sodium methoxide. [14C]-TAK-459 (1B) was synthesized from
[
14C(U)]-guanidine hydrochloride in five steps in an overall radiochemical yield of 5.4%. The key intermediate, [14C]-(R)-2-
amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one, was prepared by microwave-
assisted condensation.
Keywords: [13CD3]-TAK-459; [14C]-TAK-459; microwave chemistry; HSP90 inhibitor
within the molecule could be alkylated, leading to undesired
Introduction
by-products.
Heat shock or stress dramatically increases cellular production of
Attention was therefore focused on adapting the previously
highly conserved chaperone proteins, commonly known as heat
developed nonlabeled synthetic methodology for construction
shock proteins (HSPs).1 Many HSPs are molecular chaperons
organized into families according to their size or function (e.g.
HSP100, HSP90, HSP70, HSP60, HSP40, and small HSPs).2 The
HSP90 family represents one of the most cellular abundant
proteins (1–2% of unstressed cells; 4–6% of stressed cells). HSP90
exerts its chaperone function via a cycle that involves many
oncogenic signaling proteins,3 and therefore, a rationale exists
for the development of HSP90 inhibitors for the treatment of many
cancers.4 TAK-459, (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-
2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-
one O-(S)-3,4-dihydroxybutyl oxide (1, Figure 1), is a potent and
selective HSP90 inhibitor that has demonstrated antitumor
activities in preclinical studies.5
The stable isotope-labeled TAK-459 was required for bioanalytical
studies. In general, a labeled version that is at least 3 amu higher
than the unlabeled version is required as an Mass Spectrometry
(MS) internal standard. As described in the succeeding texts,
[13CD3]-TAK-459 (1A) was rapidly synthesized in three steps from
the labeled sodium methoxide.
of TAK-459 (pathway B).6 This procedure was centered on the
Suzuki cross-coupling between a labeled pyridine boronate
derivative (4A) and the late-stage intermediate of TAK-459 (3)
available from early development work in the Process Chemistry
Research and Development department. The synthesis of
compound 3 is not presented in this manuscript.
Our first attempt to label the 2-methoxy-6-methylpyridine
boronate adapted a procedure described by Gray et al., in which
2-hydroxy-6-methylpyridine, silver carbonate, and iodomethane
were stirred in chloroform protected from light for 40 h.7
Unfortunately, this method did not work when using an analog
substrate, 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-
2-ol (Scheme 2, right side). We suspected the purity and stability
of the pyridine boronate 5 to be the culprit for the reaction failure.
An alternative preparation of the desired labeled boronate
involved the two-step synthesis illustrated in Scheme 2, left side.
According to the literature procedure described by Nguyen et al.,
2,6-dibromopyridine can be selectively converted to 2-bromo-6-
methoxypyridine.8 Replacing methanol with 13CD3OD resulted in
the production of 7A in 90% yield. Classical Suzuki conditions
using bis(pinacolato)diboron in the presence of potassium
acetate and PdCl2dppf in Dimethyl sulfoxide (DMSO) did not yield
the desired boronate ester 4A.9 In a different approach, compound
7A was first converted to the lithiated species by the treatment with
n-butyl lithium at À78 °C, followed by graduate additions of
The radiolabeled version was prepared to support metabolite
profiling and whole body autoradiography in experimental
animals. [14C]-TAK-459 (1B) was prepared in five steps from
commercially available [14C(U)]-guanidine hydrochloride (9B).
The key step in this synthesis was the microwave-assisted
guanidine condensation.
Results and discussion
Department of Drug Metabolism and Pharmacokinetics, Isotope Chemistry
Group, Millennium Pharmaceuticals Inc, 40 Landsdowne Street, Cambridge, MA
At first glance, the easiest synthetic approach to the labeled TAK-459
appears to be demethylation of the pyridine moiety, followed 02139, USA
by realkylation with stable isotope-labeled methyl iodide
(Scheme 1, pathway A). However, this method would likely
require additional steps for the protection and deprotection
*Correspondence to: Mihaela Plesescu, Department of Drug Metabolism and
Pharmacokinetics, Isotope Chemistry Group, Millennium Pharmaceuticals Inc,
40 Landsdowne Street, Cambridge, MA 02139, USA.
of the terminal diol 2. It is also possible that other moieties E-mail: Miki.Plesescu@takeda.com
J. Label Compd. Radiopharm 2014, 57 574–578
Copyright © 2014 John Wiley & Sons, Ltd.

M. Plesescu et al.
immediately subjected to Suzuki coupling conditions5 to give the
desired internal standard of TAK-459 (1A) in 32.5% two-step yield.
For the preparation of [14C]-TAK-459, we chose a metabolically
stable position as determined by the early in vitro studies. According
to the published patent application,11 the enamine 8 can be
condensed with guanidine to afford 2-amino-7,8-dihydro-6H-pyrido
[4,3-d]pyrimidin-5-one compound 10B. The use of microwaves
resulted in accelerated completion of this reaction. Under the
superheated and elevated conditions possible with microwaves,
the condensation that took 24 h of refluxing in a conventional
jacketed reactor was instead completed in 60 min. In addition, the
reaction was carried out with less impurities and radioactive waste.
Conversion of lactam 10B to the more reactive thiolactam 11B
Figure 1. Structure of TAK-459.
triisopropylborate and pinacol, and final quench with acetic acid.10 was effected with Davy’s reagent.5 No other sulfonation reagent
Because of its poor stability, the crude boronic ester 4A was gave the same yield and clean product as reported internally by
Scheme 1. Retrosynthetic analysis of stable isotope-labeled TAK-459.
Scheme 2. Synthesis of [13CD3]-TAK-459.
J. Label Compd. Radiopharm 2014, 57 574–578
Copyright © 2014 John Wiley & Sons, Ltd.
www.jlcr.org

M. Plesescu et al.
Scheme 3. Synthesis of [14C]-TAK-459.
employed a LabLogic β-ram model 4 flow detector using Ultima-Flo M
scintillant (Perkin-Elmer Life Sciences, Waltham, MA, USA) at 3mL/min. MS
determinations were performed on Agilent (Agilent Technologies, Inc.,
Santa Clara, CA, USA) and Thermo LCQ mass spectrometers (Thermo Fisher
Scientific Inc., Waltham, MA, USA).
the Process Chemistry researchers. It was followed by the
treatment with the substituted alkoxyamine 12. Lastly, diol
deprotection under acidic conditions followed by Suzuki
coupling with the suitable boronic ester gave the desired final
compound (1B) (Scheme 3).
[13CD3]-2-Bromo-6-methoxypyridine (7A)
Conclusion
A solution of [13CD3]-sodium methoxide in methanol {freshly prepared
from sodium (0.7 g, 30 mmol) in anhydrous [13CD3]-methanol (7 mL)}
was added to a suspension of 2,6-dibromopyridine (6, 4 g, 0.5 eq) in
anhydrous [13CD3]-methanol (8 mL), and the resulting mixture was
refluxed for 24 h. The reaction mixture was allowed to cool to room
temperature and was then quenched by adding cold 5% aq. NaHCO3
in D2O. The product was extracted into ether, washed with brine (NaCl
in D2O), and dried over K2CO3. The filtrate was concentrated by rotary
evaporation and then dried a few hours under high vacuum. The crude
product was used as it is in the next step (3 g, 90%).
In summary, a practical method for the preparation of stable
isotope-labeled 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)pyridine was established. This key intermediate was
added to the TAK-459 precursor in the final synthetic step providing
[13CD3]-TAK-459 in a short sequence with 29% overall yield.
In order to address the lengthy and high temperature requirements
for the enamine cyclization with radiolabeled guanidine, we found
that microwave chemistry was a fast and clean alternative. The
radiolabeled version of TAK-459 was prepared in five steps from
commercially available [14C(U)]-guanidine hydrochloride with
5.4% radiochemical yield.
1H-NMR (DMSO): δ 7.63–7.69 (1H, dd), 7.21–7.25 (1H, d), 6.85–6.89 (1H, d).
MS (ESI+): m/z 192 (M + 1, 100%), 193 (M + 2, 20%), 194 (M + 3, 77%),
195 (M + 4, 12%).
Experimental
[13CD3]-2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
pyridine (4A)
General
All commercial reagents and solvents were used as supplied unless otherwise
noted. [14C(U)]-Guanidine hydrochloride was purchased from American
Radiolabeled Chemicals, Inc. (St. Louis, MO, USA) Column chromatography
A slurry of 2.5 M butyllithium in hexanes (4.5 mL, 11 mmol, 1.2 eq) in
tetrahydrofuran (8 mL) was cooled at À78 °C under an atmosphere of
nitrogen. To this mixture was added slowly a solution of [13CD3]-2-bromo-6-
was carried out using a Teledyne Isco Combiflash Companion (Teledyne Isco, methoxypyridine (7A, 1.73 g, 9 mmol) in 1.5-mL tetrahydrofuran. The resulting
Inc Lincoln, NE, USA) purification system or a Biotage Flash System (Biotage, dark yellow solution was allowed to react at this temperature for 45 min. A
NC, USA) with their respective prepacked silica gel columns. The microwave solution of triisopropyl borate (2.5 mL, 11 mmol, 1.2 eq) in 1.5-mL THF was
chemistry was carried out on a Biotage Initiator microwave synthesizer using
their 2–5 mL reaction vials. 1H-NMR spectra were recorded on Varian 300 MHz
or Bruker 500 MHz spectrometers. Radioactivity was quantified by liquid
scintillation counting using Beckman LS6500 counter (Beckman Coulter,
Inc., CA, USA). Purities were determined by HPLC (Agilent 1100) using
Phenomenex Luna C18(2) 4.6 × 150 mm, 5 μm column, using the solvent
combination of A (water, 0.1% formic acid) and B (acetonitrile, 0.1% formic
added dropwise. The mixture was allowed to warm to room temperature
and stirred for an additional hour. It became cloudy and yellow in color.
A solution of 2,3-dimethyl-2,3-butanediol (1.4 g, 12 mmol, 1.3 eq) in
2.5-mL THF was added, and the mixture turned milky white. After
5 min, acetic acid (0.6 mL, 10 mmol, 1 eq) was added, and the solution
precipitated as a gel. It was filtered through a pad of celite, extracted
by 5% aq. NaOH solution (15 mL). Some water was added, and the layers
acid) at 1 mL/min under gradient conditions: time 0–1 min 5%B; time separated. The resulting aqueous layer was collected and acidified to
14–17 min 90%B; time 17.1–20 min 5%B. Radioactive detection
pH 6–7 by adding dropwise a solution of 10% HCl, while keeping the
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M. Plesescu et al.
14C]-(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-
internal temperature below 5 °C. At the same temperature, the aqueous
layer was extracted with methylene chloride (3 × 20 mL) and the organic
extracts were kept over ice bath. The combined organic extracts were
dried over Na2SO4, filtered, and concentrated to an oil. The crude product
was used immediately in the next step (1 g, 50%).
[
dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-2-((S)-2,2-dimethyl-1,3-
dioxolan-4-yl)ethyl oxime (13B)
To a solution of [14C]-(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,
1H-NMR (DMSO): δ 7.63–7.69 (1H, dd), 7.21–7.25 (1H, d), 6.85–6.89 (1H, d), 8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione (11B, 214 mg, 0.6 mmol) in
1.30–1.35 (6H, s), 1.05–1.10 (6H, s).
MS (ESI+): m/z 240 (M + 1).
3 mL toluene was added (S)-O-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)
hydroxylamine (12, 650 mg, 4mmol) and mercury (II) acetate (647 mg,
2 mmol). The mixture was heated to 100 °C till completion by Liquid
Chromatography - Mass Spectrometry (LC-MS) (2h). It was cooled, filtered
through celite, and rinsed with ethyl acetate. The filtrate was concentrated
and purified by column chromatography using 40% ethyl acetate in hexane
to obtain brown foamy solid (227 mg, 46%, 98.5% radiochemical purity).
MS (ESI+): m/z 496 (M + 0, 100), 497 (M + 1, 20%), 498 (M + 2, 86%), 499
(M + 3, 17%), 500 (M + 4, 4%).
[13CD3]-(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-
4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(S)-3,4-
dihydroxybutyl oxime (1A)
To a solution of (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-
dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(S)-3,4-dihydroxybutyl oxime
(3, 100 mg, 0.2 mmol) in DMF (3 mL) was added [13CD3]-2-methoxy-6-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4A) in 2 M sodium
carbonate solution (2mL, 4 mmol). The mixture was placed under vacuum
and purged with nitrogen alternatively for three times. After 20 min was
added bis(triphenylphosphine) palladium(II) chloride (20 mg, 0.03 mmol),
and the reaction was heated in 85°C oil bath overnight. The reaction was
diluted with ethyl acetate and water, and the layers were separated. The
organic extract was dried over sodium sulfate and concentrated to a crude
residue. It was purified by column chromatography, using a slow gradient
0–5% methanol in dichloromethane, to give yellow oil that solidified
overnight. Upon adding 2 mL methylene chloride, a tan solid precipitated.
The suspension was cooled in an ice bath for 30min then filtered and
washed with additional ice-cold methylene chloride (1.5mL). It was dried
under high vacuum to yield the desired compound 1A (70mg, 65%).
1H-NMR (CD3OD): δ 7.71–7.75 (1H, dd), 7.55–7.67 (1H, dd), 7.24–7.15 (2H, m),
7.05–7.13 (1H, d), 6.73–6.82 (1H, d), 6.21–6.28 (1H, s), 4.92–5.02 (1H, m), 4.07–4.23
(2H, m), 3.67–3.79 (1H, m), 3.43–3.51 (2H, m), 3.05–3.16 (1H, m), 2.91–3.03
(1H, m), 2.58–2.66 (3H, s), 1.90–2.04 (1H, m), 1.59–1.74 (1H, m).
[
14C]-(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-
dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(S)-3,4-dihydroxybutyl
oxime (3B)
To
a
round bottom flask containing [14C]-(R,Z)-2-amino-7-(2-bromo-4-
fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-2-((S)-
2,2-dimethyl-1,3-dioxolan-4-yl)ethyl oxime (13B, 227 mg, 0.46 mmol) was
added 3.0 M HCl solution, and the mixture was stirred at room temperature.
After 2 h, a brown cloudy solution was observed, and the completion of the
reaction was determined by LC-MS. To this mixture was added 5 mL of 5%
aq. NaHCO3 solution and 3 mL 1 N NaOH to make it basic (pH > 10). A tan
foamy suspension was formed, and after stirring at room temperature for
30 min, it was filtered and washed with 5 mL water. The tan solid was dried
under high vacuum overnight to give the title compound 3B (189 mg, 91%,
98.5% radiochemical purity).
MS (ESI+): m/z 456 (M + 0), 457 (M + 1, 20%), 458 (M + 2, 97%), 459
(M + 3, 17%), 460 (M + 4, 4%).
MS (ESI+): m/z 487 (M + 1, 100%), 488 (M + 2, 35%), 489 (M + 3, 2%).
[14C]-(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido
[4,3-d]pyrimidin-5(6H)-one (10B)
[14C]-(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-
methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(S)-3,4-
dihydroxybutyl oxime (1B)
The reaction was carried out in two separate batches. Into a microwave
glass vial (2–5mL), [14C(U)]-guanidine hydrochloride (9B, 195mg, 2 mmol,
50 mCi/mmol) was dissolved in 2-mL methanol. To this solution was added
1M of potassium t-butoxide in t-butyl alcohol, and the reaction mixture
turned cloudy and tan in color. After stirring for 15min, (R,E)-6-(2-bromo-
4-fluorophenyl)-3-(1-hydroxyethylidene)piperidine-2,4-dione (8, 450mg,
1.4mmol) and 1-propanamine (0.6mL, 7 mmol) were added, and the
mixture turned bright yellow. It was then submitted to microwave
irradiation for 1 h at 140 °C. A pressure of 7–8 barr was reported by the
microwave synthesizer. After the reaction was completed, all solvent was
removed, and upon adding water (7mL), a yellow solid precipitated out.
It was filtered, washed well with water, and dried under high vacuum to
obtain the desired compound (359mg, 74%, 96% radiochemical purity).
MS (ESI+): m/z 353 (M + 0, 100%), 354 (M + 1, 20%), 355 (M + 3, 90%),
356 (M + 4, 15%).
To a solution of [14C]-(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,
8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-(S)-3,4-dihydroxybutyl oxime
(3B, 189 mg 0.41 mmol) in DMF (3 mL) was added 2-methoxy-6-(4,4,5,
5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4, 498 mg, 2.12 mmol), PdCl2
(PPh3)2 (29 mg, 0.041 mmol) and 2 ml of 2 N solution of Na2CO3 in water.
The resulting mixture was heated at 90 °C overnight. The reaction mixture
was cooled to room temperature, diluted with ethyl acetate (10 mL), and
filtered through celite. The filtrate was treated with water (5 mL), and the
layers separated. Aqueous extract was further washed with ethyl acetate
and the combined organic extracts were dried over Na2SO4, filtered, and
concentrated to brown oil. It was subjected to purification by column
chromatography using a gradient of methanol in methylene chloride up to
10%. Fractions of interest were combined and concentrated to yellow oil that
solidified under high vacuum (13.7 mCi). Upon adding 3 mL methylene
chloride, a precipitate was formed, and it was heated to reflux (more solvent
was added to dissolve all solids). The solution was cooled slowly to room
temperature and finally in ice bath for 2 h to afford a solid that was filtered
and dried under high vacuum (93 mg, 9.7 mCi, 96% radiochemical purity).
[14C]-(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido
[4,3-d]pyrimidine-5(6H)-thione (11B)
A sealed vial containing [14C]-(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-
methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (10B, 359 mg) and In order to improve the purity, the solid was subjected to another silica
Davy methyl reagent (340 mg, 1.2 mmol) in 1,4-dioxane (3 mL) was column normal-phase purification using 0–3% ethyl acetate in methanol,
heated at 90 °C for 4 h. Upon completion, the reaction was cooled to
room temperature, diluted with ethyl acetate (5 mL), and washed with
brine (3 × 3 mL). Combined aqueous washes were back extracted into
ethyl acetate (3 mL). Both organic extracts were dried over Na2SO4,
filtered, and concentrated to brown foam that was used directly in the
next step (214 mg, 57%, 97.4% radiochemical purity).
followed by the same crystallization procedure to afford 62.5 mg title
compound (31%, 99.3% radiochemical purity).
1H-NMR (CD3OD): δ 7.73–7.78 (1H, dd), 7.60–7.64 (1H, dd), 7.14–7.21 (2H, m),
7.09–7.12 (1H, d), 6.76–6.80 (1H, d), 6.20–6.23 (1H, s), 4.95–5.00 (1H, m),
4.10–4.20 (2H, m), 3.88–3.93 (3H, s), 3.70–3.78 (1H, m), 3.43–3.51 (2H,
m), 3.08–3.10 (1H, m), 2.94–3.01 (1H, m), 2.60–2.65 (3H, s), 1.92–2.02
(1H, m), 1.64–1.73 (1H, m).
MS (ESI+): m/z 369 (M + 0, 100%), 370 (M + 1, 20%), 371 (M + 2, 94%),
373 (M + 3, 13%), 374 (M + 4, 5%).
MS (ESI+): m/z 485 (M + 1, 100), 486 (M + 2, 26%), 487 (M + 3, 4%).
J. Label Compd. Radiopharm 2014, 57 574–578
Copyright © 2014 John Wiley & Sons, Ltd.
www.jlcr.org

M. Plesescu et al.
[3] L. Whitesell, S. L. Lindquist, Nat. Rev. Cancer 2005, 5, 761–772.
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Acknowledgements
The authors are grateful to the Takeda San Diego Process
Chemistry Research Group for their support. We wish also to
thank Dr Mark Milton for the H-NMR acquisition spectra of the
1
radiolabeled compound.
[7] M. A. Gray, L. Konopski, Y. Langlois, Synth. Commun. 1994, 24(10),
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Conflict of Interest
[8] T. Nguyen, M. A. Wicki, V. Snieckus, J. Org. Chem. 2004, 69, 7816–7821.
[9] T. M. Raynham, T. R. Hammonds, M. D. Charles, G. A. Pave, C. H.
Foxton, W. P. Blackaby, A. P. Stevens, C. T. Ekwuru, PCT 2008, WO
2008/074997 A1.
The authors did not report any conflict of interest.
[10] Report from Asymchem Laboratories Inc., 2008.
[11] T. D. Machajewski, C. M. Shafer, C. McBride, W. Antonios-McCrea, B.
M. Doughan, B. H. Levine, Y. Xia, M. McKenna, X. M. Wang, K.
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J. Label Compd. Radiopharm 2014, 57 574–578