Synthesis of [14C]omarigliptin

Article abstract of DOI:10.1002/jlcr.3421

An efficient synthesis for [¹⁴C]Omarigliptin (MK-3102) is described. The initial synthesis of a key ¹⁴C-pyrazole moiety did not work due to the lack of stability of ¹⁴C-DMF-DMA reagent. Thus, a new radiolabeled synthon, ¹⁴C-biphenylmethylformate, was synthesized from ¹⁴C-sodium formate in one step in 92% yield and successfully used in construction of the key ¹⁴C-pyrazole moiety. Regioselective N-sulfonation of the pyrazole moiety was achieved through a dehydration-sulfonation-isomerization sequence. [¹⁴C]MK 3102 was synthesized in five steps from ¹⁴C-biphenylmethylformate with 25% overall yield.

Full text of DOI:10.1002/jlcr.3421

Research article
Received 03 March 2016,
Revised 28 April 2016,
Accepted 28 May 2016
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3421
1
4
Synthesis of [ C]omarigliptin
Sumei Ren,* Donald Gauthier, Rosemary Marques, Roy Helmy and
David Hesk
1
4
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An efficient synthesis for [ C]Omarigliptin (MK-3102) is described. The initial synthesis of a key C-pyrazole moiety did not
1
4
14
work due to the lack of stability of C-DMF-DMA reagent. Thus, a new radiolabeled synthon, C-biphenylmethylformate, was
synthesized from C-sodium formate in one step in 92% yield and successfully used in construction of the key C-pyrazole
moiety. Regioselective N-sulfonation of the pyrazole moiety was achieved through a dehydration-sulfonation-isomerization
1
4
14
1
4
14
sequence. [ C]MK 3102 was synthesized in five steps from C-biphenylmethylformate with 25% overall yield.
14
Keywords: omarigliptin; DPP-4; sulfonation/isomerization; C-pyrazole; human AME; MK-3102
Introduction
Unlabeled ketone 10 is a key intermediate in this strategy and
was synthesized from Boc-pyranone 7 through reductive
Type 2 diabetes mellitus (T2DM) is a chronic, progressive disease
that affects about 387 million people globally. The dipeptidyl
peptidase 4 (DPP-4) inhibitors, such as Merck’s Sitagliptin,
once-daily antidiabetic agent, have been widely used to treat
T2DM. In an effort to identify other DPP-4 inhibitors with long
half-lives and the potential for once-weekly dosing, Merck teams
amination followed by Swern oxidation. The next step towards
1
14
[
C]MK 3102 was the synthesis of enamine 11 which turned
2
a
out to be a major unexpected challenge. Although the treatment
of Boc-protected ketone 10 with 3 equivalents unlabeled
14
DMF-DMA gave the enamine 11 in 54% isolated yield, no
C
labeled enamine 11 was obtained when using the commercially
3
–6
developed Omarigliptin (MK-3102).
14
available C-DMF-DMA from two different vendors. Further
Omarigliptin (MK-3102) is a potent and selective DPP-4 inhibitor
with an excellent pharmacokinetic profile. The compound is
currently in Phase 3 clinical development in the US as an oral,
once-weekly DPP-4 inhibitor indicated for the treatment of adults
with type 2 diabetes. Omarigliptin was approved as MARIZEV® in
GCMS analysis revealed that the major component of both
14
14
batches of C-DMF-DMA was C-DMF which does not react with
the ketone under these conditions. It highly suggests that the
14
14
C-DMF-DMA is not stable and an alternative C-reagent had
to be explored for the synthesis of the pyrazole moiety.
Fischer and coworkers synthesized the steroidal E-ring
pyrazoles by formylating at C16 with ethyl formate followed by
14
Japan in August 2015. During the drug development, [ C]MK
102 was requested to support the Quantitative Whole-Body
3
Autoradiography (QWBA), human Absorption, Metabolism and
Excretion (AME) studies and Environmental Fate studies.
7
a condensation with hydrazine as shown in Scheme 3.
14
[
C]ethyl formate is commercially available and can
potentially be used as the C-source for the synthesis of
C]MK 3102. However, [ C]ethyl formate is difficult to
14
The dosimetry calculation based on the C-QWBA study
14
14
revealed that the conventional approach for C-human AME study
with 50–200 microCurie (uCi) radioactivity doses combined with
Liquid Scintillation Counting analysis could cause unacceptable
14
14
[
handle because of its high volatility (bp: 54 °C), and in
addition long lead-times to obtain this material from CROs
are common which taken together make this a less attractive
option. Hence, synthesis of an alternative easy to handle
14
radiation exposure with [ C]MK 3102. Based on this finding, the
team decided to use a tracer labeling approach combined with
Accelerator Mass-Spectrometry (AMS) for analysis with a lower
targeted oral dose of 1.0 uCi/10 mg/person.
14
14
C-formate source from readily available [ C]sodium formate
was explored. Thus, benzyl formate, biphenylmethylformate
and octadecyl formate were synthesized from sodium formate
and evaluated in the formylating reaction. The non-volatile
biphenylmethylformate was chosen for ease of handling and
Results and discussion
The Medicinal Chemistry synthetic route for unlabeled MK-3102
shown in Scheme 1 served as the basis for the initial labeling
14
higher observed yields. The C-biphenylmethylformate was
14
synthesized from biphenylmethylbromide and
C-sodium
3
,4
approach.
N, N-dimethylformamide-[carbonyl- C]-dimethylacetal ( C-
14
14
14
DMF-DMA) is commercially available. Introduction of a C label
14
in the pyrazole ring of Omarigliptin using C-DMF-DMA seemed
Merck Research Laboratories, Labeled Compound Synthesis Group, Department
to be the best option based on the initial metabolism data and of Process and Analytical Chemistry Rahway, NJ, USA
the suitability of the chemistry. To reduce the radiosynthetic
*
Correspondence to: Sumei Ren, Merck Research Laboratories, Labeled
steps, ketone 10 was synthesized and used as the unlabeled
Compound Synthesis Group, Department of Process and Analytical Chemistry,
1
E-mail: sumei.ren@merck.com.
14
starting material. The proposed synthesis of [ C]MK 3102 is as
shown in Scheme 2.
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S. Ren et al.
Scheme 1. Medicinal Chemistry synthetic route for unlabeled MK-3102.
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Scheme 2. Proposed synthetic route for [ C]MK 3102 using C-DMF-DMA.
Scheme 3. Synthesis of steroidal E-ring pyrazole by Fischer.
1
4
formate. The first generation synthesis of [ C]MK 3102 using two-step dehydration-regioselective sulfonation sequence with
1
4
14
the C-biphenylmethylformate as the C source is shown in sodium hexamethyldisilazide (NaHMDS) and mesylate chloride
Scheme 4.
(MsCl) in 75 and 79% yield, respectively. However, applying this
1
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14
The
C-vinylogous acid 181 was obtained by Claisen approach to
C-pyrazole alcohol only gave the desired
4
14
condensation of ketone 10 with C-biphenylmethylformate 17
in the presence of potassium tert-butoxide (KOtBu) in 65% yield. Regioselective sulfonation of the C-pyrazole 13 with MsCl and
Condensation of the C-vinylogous acid 18 with hydrazine gave NaHMDS stalled at ~50% conversion with a 75:25 mixture of
the C-pyrazole alcohol 12 in 94% yield. Unlabeled alcohol 12 desired:undesired regioisomer of C-sulfonylated pyrazole 8.
was readily converted to sulfonylated pyrazole 8 through a After
tedious purification by RP-HPLC, only 22% of
C-pyrazole 13 in 30% yield1 in the dehydration step.
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14
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14
a
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S. Ren et al.
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Scheme 4. First generation synthesis of [ C]MK 3102 for supporting the QWBA study.
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14
C-sulfonylated pyrazole 8 was isolated. A total of 0.90 mCi of [ C] the concentration of the reaction is a key factor to drive the
MK 3102 was generated after deprotection of sulfonylated isomerization to completion. Indeed, after increasing the
pyrazole 8 which was sufficient to support the QWBA study.
Although we gratified that our early work afforded the initial
amount of [ C]MK 3102, it was clear that additional 74% of desired isomer
concentration of the reaction, the isomerization of the recovered
14
C-8a reached 99: 1 desired: undesired isomer within 3 h, and
1
4
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C-sulfonylated pyrazole 8 was
improvements would be required, especially to address the lack isolated. Des-SO Me pyrazole 13 is always observed under
2
of regiochemical control over the N-sulfonation of the pyrazole the reaction conditions by HPLC, and as such is consistent
moiety. To this end, we were inspired by progress on the parent with the proposed mechanism that the isomerization occurs
development program whereby alcohol 12 was readily through mesyl group cleavage of the undesired 8a to the
converted to sulfonylated pyrazole 8 through a two-step potassium anion of 13, which then allows for mesylation to
3
,6
3
sulfonation–isomerization sequence. Application of this approach desired 8. The proposed isomerization mechanism was shown
1
4
14
with C-alcohol 12 in the synthesis of [ C]MK 3102 is shown in in Scheme 6.
Scheme 5. The Boc protected C-sulfonylated pyrazole 8 was treated
Treatment of C-alcohol 12 with Hünig’s base and MsCl gave with acid to give the final high specific activity (SA) [ C]MK
a mixture of C-sulfonylated pyrazole 8 and 8a (15: 85) in 3102 in 94% yield. The final dilution with unlabeled MK-3102
9% isolated yield. The initial isomerization of C-8a to C-8 and recrystallization in dichloromethane (DCM)/isopropyl
1
4
1
4
14
1
4
14
14
5
stalled and generated 43% desired isomer 8, 23% undesired acetate (IPAc)/heptane led to the final crystalline API in
1
4
isomer 8a and 17% des-SO Me pyrazole 13. The solubility polymorphic form I in 91% yield. C-alcohol 12 was chosen
2
difference between the two isomers in THF was found to be as the GMP starting material and all steps thereafter were
the driving force for the isomerization. Therefore controlling performed under GMP conditions.
1
4
Scheme 5. Second generation synthesis of [ C]MK 3102 for supporting human AME study.
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S. Ren et al.
Scheme 6. Proposed isomerization mechanism of compound 8a.
3
1
.15–3.13 (m, 1H), 2.73–2.64 (m, 2H), 2.51–2.41 (m, 2H), 2.12–2.08 (m,
Experimental
H), 1.94–1.93 (m, 1H), 1.55–1.53 (m, 2H), 1.19 (s, 9H); LC-MS m/z: 399
+
General
[M + H] .
All commercially available reagents and solvents were used as received
14
Synthesis of ketone 10
without further purification. Sodium C-formate was purchased from
Quotient Bioresearch (Cardiff, UK). Compound 7 was obtained from
Merck Process Chemistry (Rahway, NJ). All HPLC analyses were
conducted using an Agilent 1200 HPLC with an attached PerkinElmer
Dimethyl sulfoxide (4.01 ml, 56.5 mmol) was added to a solution of
oxalyl chloride (1.98 ml, 22.6 mmol) in DCM (80 ml) dropwise over
1
5 min at À78 °C. After 5 min at À78 °C, alcohol 9 (4.50 g, 11.3 mmol)
(Waltham, MA, USA) Radiomatic 625TR flow scintillation analyzer.
in DCM (30 ml) was added over 10 min. The reaction was aged for
HPLC-MS analyses were performed on an Agilent 1100 HPLC-MSD
instrument in API-ES positive ionization mode using an Ascentis® Express
C18 column (2.7 μm, 4.6 × 100 mm, 5% to 95% acetonitrile (ACN)/0.1%
fomic acid aqueous solution, 1.0 ml/min). HPLC columns were purchased
from one of the following vendors: Phenomenex (Torrance, CA, USA),
Sigma Aldrich (St. Louis, MO, USA) and Advanced Chromatography
3
1
0 min, triethylamine (Et
0 min and the reaction allowed to warm to 0 °C over 15 min. The
3
N, 15.7 ml, 113 mmol) was added over
reaction was held at 0 °C for an additional 10 min and then quenched
with sat’d NH Cl solution (100 ml). The product was extracted with
DCM (2 × 30 ml) and the combined organic layers were dried over
Na SO , filtered and concentrated. The crude product was purified
via Biotage (100 g SNAP column 0-100% EtOAc/hexane gradient) to
give 3.50 g of ketone 10 as a tan solid in 78% yield. H NMR
500 MHz, DMSO-d , ppm) δ 7.20–7.13 (m, 3H), 6.91(d, J = 9.7 Hz,
H), 4.25 (d, J = 9.9 Hz, 1H), 4.18–4.11 (m, 1H), 3.68–3.58 (m, 1H),
.19 (t, J = 10.7, 1H), 3.04–2.95 (m, 3H), 2.89–2.85 (m, 1H), 2.61–2.57
4
1
2
4
Technologies Ltd (Aberdeen, Scotland). H NMR (500 MHz) was obtained
,
on a Bruker Ultrashield 500-MHz magnet with an AVIII console using
1
™
TopSpin 3.0 in CDCl
3
or DMSO-d
6
. Radioactivity was counted on a
(
1
3
6
calibrated PerkinElmer Tri-Carb® liquid scintillation counter using
TM
UltimaGold cocktail (PerkinElmer).
(
1
m, 1H), 2.32 (t, J = 6.9, 2H), 2.19–2.17 (m, 1H), 1.55 (q, J = 12.0, 1H),
.23 (s, 9H); LC-MS m/z: 397 [M + H] .
RP-HPLC1: ACE 3, C18, 150 × 3.0 mm, 30 °C, 0.75 ml/min,
Gradient 95 to 0% pH 3.5 aqueous ammonium
formate (5.0 mM) over 100% MeCN for 5 min
followed by equilibration, 220 nm.
+
14
Synthesis of C-biphenylmethylformate 17
14
RP-HPLC2: Ascentis Express C18, 150 × 3.0 mm, 2.7 um, 40 °C, A solid mixture of [ C]sodium formate (190 mCi, 55.0 mCi/mmol, 238 mg,
3
.45 mmol), tetrabutylammonium bromide (n-Bu NBr, 222 mg, 0.690 mmol),
4
0.8 ml/min, 95% to 0% C over 13 min, and hold
and biphenylmethyl bromide (1.70 g, 6.90 mmol) was heated in a reaction
vial to 150 °C for 1 h. The reaction was then allowed to cool to RT and diluted
with DCM (3.0 ml). The resulting slurry was purified via Biotage (50 g SNAP
column, 0–100% EtOAc/hexane, gradient) to give 0.68 g of
C-biphenylmethylformate as a white solid in 92% yield. The radiochemical
purity (RCP) was 100% by RP-HPLC1.
for 2 min. C: 0.1% aqueous formic acid, D: 0.1%
formic acid in MeCN, 210 nm.
RP-HPLC3: Ascentis Express C18, 100 × 4.6 mm, 2.7 μm, 35 °C,
1
.8 ml/min, 95 to 20% 5 mM potassium phosphate
buffer pH 7.0 over MeCN in 15 min, hold for 2 min,
20 nm.
14
2
1
4
Synthesis of C-vinylogous acid 18
Synthesis of alcohol 9
To
a
solution of the ketone (10) (228 mg, 0.575 mmol) and
C-biphenylmethylformate (55.0 mCi/mmol, 160 mg, 0.748 mmol) in
THF (0.75 ml, anhydrous) was added KOtBu (1.73 ml, 1.0 M in THF,
1.73 mmol) dropwise over 5 min at RT under N . The reaction was stirred
for 30 min, quenched with EtOAc (30 ml) and H O (10 ml), then HCl
(1.0 N) was added to adjust the pH to approximately 7. The organic layer
1
4
To a solution of Boc-pyranone (7, 4.39 g, 13.4 mmol) in MeOH (40 ml) was
added 3-pyrrolidinol (2.14 ml, 26.8 mmol) and the solution was aged at
RT for 1 h. Decaborane (0.49 g, 4.02 mmol) was added and aged at RT
overnight. After 20 h, the solution was concentrated and the crude
2
2
product was purified via Biotage (100 g SNAP column, DCM: EtOH:
1
14
NH
4
OH – 90: 10: 1) to give 4.80 g of alcohol 9 in 90% yield. H NMR was concentrated to give the C-vinylogous acid 18 as oil in 77.6% RCP
(
500 MHz, DMSO-d
6
, ppm) δ 7.14–7.10 (m, 3H), 6.89 (d, J = 8.6 Hz, 1H),
by RP-HPLC1 (160 mg, 65% yield). The crude product was directly used in
4.70 (brs, 1H), 4.35–4.32 (m, 2H), 4.22–4.05 (m, 1H), 3.64–3.53 (m, 1H), next step without further purification.
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S. Ren et al.
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3
silica column, 0–10% CH OH/DCM) to give the high SA [ C]MK 3102 as
Synthesis of C-pyrazole alcohol 12
a white solid (37 mg, 6.6 mCi) in 94% yield. The RCP was 99.7% by HPLC3.
The product was dissolved in 20.0 ml of MeCN solution and used in the
next step.
1
4
To a solution of C-vinylogous acid 18 (160 mg, 0.375 mmol) in EtOH
4.0 ml) was added hydrazine hydrate (91 μl, 1.88 mmol) at RT. The reaction
(
was heated to 55 °C for 10 min then cooled to RT and stored in À20 °C
freezer over 2 days. The crude product was warmed to RT and concentrated
to oil. Purification via Biotage (10 g SNAP column, 1–15% MeOH/DCM) led
to 155 mg of C-pyrazole alcohol 12 as light yellow oil with 98.7% RCP
by RP-HPLC1 in 94% yield.
14
Synthesis of [ C]MK 3102 API (low SA)
14
1
4
[
C]MK 3102 high SA (0.30 ml, 0.099 mCi, 0.33 mCi/ml in MeCN) was
concentrated under reduced pressure and mixed with unlabeled
MK-3102 (999 mg). The mixed solid was co-evaporated with DCM
(5.0 ml) under reduced pressure then dissolved in DCM (5.80 ml) at 30 °
1
4
Synthesis of C-sulfonylated pyrazole 8 and 8a
C under N
2
. Isopropyl acetate (9.60 ml) was added dropwise in 15 min.
for
h. Heptane (2.90 ml) was added over 10 min and stirred at 25 °C under
2
for 1 h. The suspension was filtered and the solid was washed with
1
4
To a solution of C-pyrazole alcohol 12 (155 mg, 0.35 mmol, 19.4 mCi) in
DCM (5.0 ml) was added Hünig’s base (184 μl, 1.06 mmol) and cooled to
The suspension was gradually cooled to 25 °C and stirred under N
2
N
2
0
2
°C under N . MsCl (69 μl, 0.88 mmol) was added dropwise and the
reaction was allowed to warm to RT. Analysis by HPLC1 after 30 min
showed ~70% conversion to the sulfonylated pyrazole 8a and 8. Hence
additional Hünig’s base (61 μl) and MsCl (14 μl) were added and stirred
in the same condition. After >90% conversion was achieved, the reaction
was concentrated and purified via Biotage (10 g SNAP column, 1–15%
MeOH/DCM, gradient) to give 183 mg (11.5 mCi, 59% yield) mixture of
heptane (2 × 3 ml). The solid was dried under vacuum to generate the
final product, [ C]MK 3102 API (912 mg, 0.0841 uCi/mg, 76.7 Ci) in 91%
yield. The purity of the final API is 99.3% RCP by HPLC3.
The batch was fully released and successfully used in a human AME
clinical study.
14
1
4
C-sulfonylated pyrazole 8a and 8 (8: 8a = 15:85) as a yellow solid with
+
Conclusion
9
7.0% RCP of (8a + 8) by RP-HPLC2. LC-MS m/z: 501 [M + H] .
14
A new radiolabeled synthon C-biphenylmethylformate was
synthesized from readily available biphenylmethyl bromide and
1
4
Synthesis of C-sulfonylated pyrazole 8 through
isomerization
14
14
C-sodium formate in one step in 92% yield. The [ C]MK 3102
high specific activity batch was synthesized in five steps from
14
To the flask containing the mixture of C-sulfonylated pyrazole 8a and 8
183 mg, 11.5 mCi) was added 1.0 ml of THF (anhydrous). The resulting
cloudy yellow suspension was cooled to 0 °C and KOtBu (0.12 ml, 1.0 M
in THF) was added over 5 min. The slurry was stirred at 0 °C under N
1
4
C-biphenylmethylformate with 25% overall yield through a
dehydration/sulfonation–isomerization sequence. The batch was
(
14
used to prepare the clinical [ C]MK 3102 API and successfully used
2
for 2 h, then warmed to RT and stirred for an additional 2 h. Analysis by for the human AME study with the tracer labeling approach
HPLC2 showed that the reaction had stalled. The suspension was combined with AMS for analysis.
quenched with EtOAc (30 ml) and H
of sat’d NaHCO to adjust the pH to ~7. The mixture was extracted with
DCM (3 × 30 ml). The combined organic phase was dried over Na SO
filtered and concentrated. The crude product was purified by Teledyne
Isco CombiFlash® systems (40 g Gold silica column, 0-10% CH OH/
DCM), 5.0 mCi of the desired regioisomer 8, 2.7 mCi of the undesired
regioisomer 8a and 2.0 mCi of the des-SO Me 13 were isolated. The
2
O (10 ml), followed by the addition
3
Acknowledgements
2
4
,
The authors are grateful to Dr. Ingrid Mergelsberg and Mr. Nelo
Rivera for helpful discussions and proofreading of the paper.
3
2
recovered undesired isomer 8a (2.7 mCi) was recycled. The reaction References
was set up as described above but a volume of only 0.10 ml THF was
used, which is 57% less volume compared to the above procedure. The
reaction reached 99% conversion within 3 h, and an additional 2.0 mCi
[
[
[
1] M. Thomas, M. Cooper, P. Zimmet, Nat. Rev. Nephrol. 2016, 12, 73–81.
2] http://www.januvia.com/sitagliptin/januvia/consumer/index.xhtml
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R. Dunn, A. Kassim, D. Lieberman, A. Moment, F. Sheen, M. Zacuto,
Org. Process Res. Dev. 2015, 19, 1760–1768.
(
74% yield) of desired regioisomer 8 was isolated after purification. A
14
total of 7.0 mCi of the desired product C-sulfonylated pyrazole 8 with
9
+
7.6% RCP by HPLC2 was obtained. LC-MS m/z: 501 [M + H] .
[4] T. Biftu, R. Sinha-Roy, P. Chen, X. Qian, D. Feng, J. Kuethe, G. Scapin,
Y. Gao, Y. Yan, D. Krueger, A. Bak, G. Eiermann, J. He, J. Cox, J. Hicks,
K. Lyons, H. He, G. Salituro, S. Tong, S. Patel, G. Doss, A. Petrov, J. Wu,
S. Xu, C. Sewall, X. Zhang, B. Zhang, N. Thornberry, A. Weber, J. Med.
Chem. 2014, 57, 3205–3212.
1
4
Synthesis of [ C]MK 3102 (high SA)
1
4
To
.144 mmol) in MeCN (1.8 ml, anhydrous) at À5 °C was added H
concentrated, 34 μl, 0.65 mmol) over 5 min. The mixture was aged 2 h
at À5 °C and quenched with water (8 ml) and EtOAc (30 ml). The aqueous
layer was basified with saturated Na CO solution to pH 8 and extracted
with 2 × 20 ml of EtOAc, then DCM (4 × 15 ml). The combined organic
layer was washed with brine (10 ml), dried over Na SO , filtered and
concentrated to oil. The crude product was purified by Isco (40 g Gold
a
suspension of
C-sulfonylated pyrazole
8
(7.0 mCi, 72 mg,
[
5] T. Biftu, P. Chen, J. Cox, A. Weber, U.S. Pat. Appl. Publ. 2010 US
0100120863 A1 20100513.
0
(
2
SO
4
2
[
6] M. Zacuto, R. Dunn, A. Moment, J. Janey, D. Lieberman, F. Sheen,
N. Bremeyer, J. Scott, J. Kuethe, L. Tan, Q. Chen, PCT Int. Appl.
2
3
2
013 WO 2013003250 A1 20130103.
[
7] D. Fischer, G. Allan, C. Bubert, N. Vicker, A. Smith, H. Tutill, A. Purohit,
L. Wood, G. Packham, M. Mahon, M. Reed, B. Potter, J. Med. Chem.
2005, 48, 5749–5770.
2
4
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Copyright © 2016 John Wiley & Sons, Ltd.
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