The syntheses of [14C]BMS-823778 for use in a human ADME clinical study and of [13CD3 13CD2]BMT-094817, a stable-isotope labeled standard of a newly detected human metabolite

Article abstract of DOI:10.1002/jlcr.3383

Type 2 diabetes is a significant worldwide health problem. To support the development of BMS-823778 as an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 for type 2 diabetes, the synthesis of carbon-14-labeled material was required for use in a human adsorption, distribution, metabolism, and excretion (ADME) study. The HCl salt form of [¹⁴C]BMS-823778 was synthesized in two steps from commercially available [2-¹⁴C]acetone. The radiochemical purity of the synthesized [¹⁴C]BMS-823778 after dilution with unlabeled clinical-grade BMS-823778 was 99.5% having a specific activity of 7.379 μCi/mg. One result of the human ADME study was the detection of a new human metabolite, BMT-094817. To support the quantification of BMT-094817 in clinical samples, it was necessary to synthesize [¹³CD₃ ¹³CD₂]BMT-094817 for use as a liquid chromatography/mass spectrometry standard. [¹³CD₃ ¹³CD₂]BMT-094817 was prepared in five labeled steps from [¹³CD₃]iodomethane. To support the development of BMS-823778 as an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 for type 2 diabetes, the synthesis of [¹⁴C]BMS-823778 for use in a human adsorption, distribution, metabolism, and excretion (ADME) study was required. One result of the ADME study was the detection of a new human metabolite, BMT-094817. [¹³CD₃ ¹³CD₂]BMT-094817 was then prepared for use as a liquid chromatography/mass spectrometry standard.

Full text of DOI:10.1002/jlcr.3383

Special issue article
Received 16 December 2015,
Revised 20 January 2016,
Accepted 03 February 2016
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3383
14
The syntheses of [ C]BMS-823778 for use in a
13
human ADME clinical study and of [ CD3
13
CD2]BMT-094817, a stable-isotope labeled
standard of a newly detected human
metabolite
a
a
a
b
*
Brad D. Maxwell, Scott B. Tran, Michael Lago, Jun Li, and
Samuel J. Bonacorsi Jr.a
Type 2 diabetes is a significant worldwide health problem. To support the development of BMS-823778 as an inhibitor of
11β-hydroxysteroid dehydrogenase type 1 for type 2 diabetes, the synthesis of carbon-14-labeled material was required
for use in a human adsorption, distribution, metabolism, and excretion (ADME) study. The HCl salt form of [14C]BMS-
823778 was synthesized in two steps from commercially available [2-14C]acetone. The radiochemical purity of the
synthesized [14C]BMS-823778 after dilution with unlabeled clinical-grade BMS-823778 was 99.5% having a specific activity
of 7.379 μCi/mg. One result of the human ADME study was the detection of a new human metabolite, BMT-094817. To
support the quantification of BMT-094817 in clinical samples, it was necessary to synthesize [13CD3 13CD2]BMT-094817 for
use as a liquid chromatography/mass spectrometry standard. [13CD3 13CD2]BMT-094817 was prepared in five labeled steps
from [13CD3]iodomethane.
Keywords: type 2 diabetes; 11β-HSD1; human ADME; carbon-14; stable-isotope labeled metabolite synthesis
to quantify the amounts of BMT-094817, the stable-isotope
Introduction
labeled BMT-094817 needed to be prepared. This paper
describes the syntheses of [14C]BMS-823778 HCl salt, 7, and
Type 2 diabetes is a significant worldwide health problem afflicting
more than 300 million people worldwide.1,2 It is thought that
metabolic syndrome, a combination of insulin resistance, obesity,
dyslipidemia, hyperglycemia, and hypertension, is a major cause
of type 2 diabetes. Cortisol is a circulating glucocorticoid that
regulates carbohydrate, protein, and lipid metabolism as well
as modulates inflammatory and immune responses. Excess
glucocorticoids can cause increased glucose output, reduced
glucose-dependent insulin sensitivity in adipose tissue, and
reduced insulin secretion from the pancreas. 11β-Hydroxysteroid
dehydrogenase type 1 (11β-HSD1) is an enzyme that catalyzes
the conversion of inactive cortisone to cortisol. Transgenic mice
that overexpressed 11β-HSD1 in adipose tissue were found to
exhibit metabolic disorders including obesity, insulin resistance,
glucose intolerance, and hyperglycemia. 11β-HSD1 knockout mice
were found to be resistant to obesity and hyperglycemia.
Therefore, it would seem that an inhibitor of 11β-HSD1 could
possibly be an efficacious therapy for the treatment of
dysmetabolic syndrome and type 2 diabetes.3–5 BMS-823778 HCl
salt, as shown in Figure 1, represents such an 11β-HSD1
inhibitor.6–9 To further the development of BMS-823778, it was
necessary to prepare [14C]BMS-823778 HCl salt for use in a human
absorption, distribution, metabolism, and excretion (ADME) study.
One result of the human ADME clinical study was the discovery of a
previously undetected human metabolite, BMT-094817, 2. In order
[
13CD3, 13CD2]BMT-094817, 16.10
Experimental
Materials and methods
All reactions were run under an inert atmosphere of nitrogen and
stirred magnetically. Reactions were monitored by HPLC and/or
thin-layer chromatography with comparisons made to authentic
materials. All reagents and solvents were American Chemical Society grade
or better and used without further purification. [2-14C]Acetone (50 mCi,
specific activity 55 mCi/mmol, >97% radiochemical purity) was obtained
from ViTrax (Placentia, CA). [13CD3]Iodomethane (99 at.% 13C, 99.5 at.% D)
was obtained from Isotec (Miamisburg, Ohio). Clinical-grade BMS-823778
aDiscovery Chemistry Platforms-Radiochemistry, Research and Development,
Bristol-Myers Squibb, Route 206 and Province Line Road, Princeton, NJ 08540,
USA
bDiscovery Chemistry, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534,
USA
*Correspondence to: Brad D. Maxwell, Discovery Chemistry Platforms-
Radiochemistry, Research and Development, Bristol-Myers Squibb, Route 206
and Province Line Road, Princeton, NJ 08543, USA.
E-mail: brad.maxwell@bms.com
J. Label Compd. Radiopharm 2016, 59 255–259
Copyright © 2016 John Wiley & Sons, Ltd.

B. D. Maxwell et al.
followed by drying on a vacuum line to constant weight to give 78.55 mg
(0.238 mmol, 24% yield) of a viscous colorless film. The product analyzed
using HPLC method A showed it to be 99.8% chemically pure, retention
time (Rt) = 7.019 min, and 99.56% radiochemically pure. The material co-
eluted with an authentic sample. Analysis by LC/MS method A (ESI) showed
328.25 (6%)/329.25 (2%)/330.25 (100%)/331.25 (22%)/322.17 (34%)/333.17
(7%)/334.17 (1%).
Figure 1. Structures of BMS-823778 HCl salt, 1, and BMT-094817, 2.
[14C]2-(3-(1-(4-Chlorophenyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridin-
hydrochloride salt was obtained from the Process Research & Development
Department at Bristol-Myers Squibb (New Brunswick, NJ). All authentic
samples were obtained from the Process Research & Development
Department or the Medicinal Chemistry Department at Bristol-Myers
Squibb. Solvent removal under reduced pressure was accomplished using
a Büchi (Flawil, Switzerland) model 210 rotary evaporator. Column
chromatography was performed using an AnaLogix (Burlington, WI) BSR
Flash Chromatography system. Proton NMR spectra were recorded on
either a 300 MHz or 400 MHz Bruker (Billerica, MA) Avance spectrometer
as listed. Thin-layer chromatography analyses (EMD 60 (EMD Chemicals
Inc. Darmstadt, Germany), F254 silica gel-coated plates) were performed as
described using either UV (254 nm) or iodine to visualize. Liquid
chromatography/mass spectrometry (LC/MS) spectra were recorded on a
Finnigan LXQ (Thermo Fisher Scientific Inc. Waltham, MA USA) LC/MS
system with detection by ESI(+) ion. LC/MS method: column = Phenomenex
(Torrance, CA) Gemini 5 μm, C18, 50 × 3.0 mm, flow rate = 0.50 mL/min, UV
detection by PDA at 200–400 nm. Mobile phase A = 1000 water : 1 formic
acid, mobile phase B = 1000 MeCN : 1 formic acid; gradient, 0 min
10% B and 10 min 100% B. Specific activities were determined by
gravimetric analysis using liquid scintillation counting (PerkinElmer
(Waltham, MA) model 2900TR). HPLC analyses were performed on an
Agilent (Santa Clara, CA) 1200 HPLC system, with a diode array detector
8-yl)propan-2-ol hydrochloride or [14C]BMS-823778 HCl salt, 5
To [14C]BMS-823778, 4 (78.55 mg, 0.238 mmol), dissolved in isopropanol
(2.12 mL) and heptane (0.423 mL) at room temperature was added
concentrated HCl (0.020 mL, 0.238 mmol). This solution was stirred for
30 min, seeded with unlabeled clinical-grade BMS-823778 HCl salt, and stirred
overnight at room temperature. The solid product was collected by
centrifugation and then dried under vacuum to constant weight to give
65.77 mg of a white solid (0.180 mmol, 75% yield). Analysis by HPLC using
method B showed it to be 99.8 % chemically pure, RT = 21.96 min, and
98.4% radiochemically pure. The material co-eluted with an authentic sample.
Analysis by LC/MS showed 328.25 (6%)/329.25 (2%)/330.25 (100%)/331.25
(22%)/322.17 (34%)/333.17 (7%)/334.17 (1%). 1H-NMR (300 MHz, MeOH-d4) δ
8.43 (d, J = 6.7 Hz, 1H), 7.94 (d, J = 7.3 Hz, 1H), 7.49–7.18 (m, 5H), 1.90–1.61
(m, 10H). The 1H-NMR matched that of the unlabeled product. The specific
activity was measured to be 153.6 μCi/mg, 56.08 mCi/mmol, 10.10 mCi.
[14C]2-(3-(1-(4-Chlorophenyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridin-
8-yl)propan-2-ol hydrochloride or [14C]BMS-823778 HCl salt, 6
To [14C]BMS-8237788 HCl salt, 5 (55.90 mg, 0.171 mmol), was weighed
BMS-823778 HCl salt (55.90 mg, 0.171 mmol). To this was added absolute
ethyl alcohol (0.79 mL), and the suspension was heated to 75 °C until all
solid was dissolved. Heptane (2.52 mL) was slowly added with gentle
swirling. The mixture was allowed to cool slowly to room temperature
over 3 h. The solid was collected by filtration and then dried under
vacuum to constant weight to give 101.6 mg of white solid. Analysis by
HPLC using method B showed it to be 99.8 % chemically pure,
RT = 21.90 min, and 99.1% radiochemically pure. The material co-eluted
with an authentic sample. 1H-NMR (300 MHz, MeOH-d4) δ 8.41 (d,
J = 6.5 Hz, 1H), 7.91 (d, J = 7.0 Hz, 1H), 7.46–7.16 (m, 5H), 1.90–1.63 (m,
10H). The specific activity was measured to be 79.61 μCi/mg, 29.10 mCi/
mmol, 8.088 mCi.
for UV detection and an IN/US β-ram model
3 detector using
LAURALITE version 3.4.1.10 software (LabLogic Systems, Ltd., Sheffield,
England) for radiochemical detection. The following analytical
methods were used for in process reaction analyses and final purity
measurements. HPLC method A, column = YMC ODS AQ, 3 μm
(4.6 × 150 mm); mobile phase A, water with 0.05% trifluoroacetic acid;
mobile phase B, acetonitrile with 0.05% trifluoroacetic acid. Gradient:
0 min, 95% A; 12 min, 95% B; 16 min, 95% B; 20 min, 95% A, flow
rate = 1.0 mL/min; injection size, 10 μL. UV detection at 280 nm. HPLC
method B, column = YMC Pro C18, 3 μm (4.6 × 150 mm); mobile phase
A, 95% water : 5% MeOH with 0.10% trifluoroacetic acid; mobile
phase B, 10% water : 90% MeOH with 0.10% trifluoroacetic acid;
gradient, 0 min, 100% A; 1 min, 100% A; 6 min, 35% B; 25 min, 62%
B, 26 min 100% B, 28 min 100% B, 29 min 100% A, flow
rate = 1.0 mL/min; injection size, 10 μL. UV detection at 280 nm.
[14C]2-(3-(1-(4-Chlorophenyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridin-
8-yl)propan-2-ol hydrochloride or [14C]BMS-823778 HCl salt, 7
To [14C]BMS-8237788 HCl salt, 6 (69.48 mg, 0.191 mmol), was weighed
BMS-823778 HCl salt (697.5 mg, 1.915 mmol). To this was added
absolute ethyl alcohol (5.39 mL), and the suspension was heated to
75 °C until all solid was dissolved. Heptane (17.2 mL) was slowly
added with gentle swirling. The mixture was allowed to cool slowly
to room temperature over 3 h. The solid was collected by filtration
and then dried under vacuum to constant weight to give 677.8 mg
of white solid. Analysis by HPLC using method B showed it to be
99.9% chemically pure, RT = 21.90 min, and 99.5% radiochemically
pure. The material co-eluted with an authentic sample. Analysis by
LC/MS showed 328.17 (100%)/329.17 (21%)/330.17 (40%)/331.17
(8%)/322.08 (3%). 1H-NMR (300 MHz, MeOH-d4) δ 8.42 (dd, J = 7.0,
0.9 Hz, 1H), 7.93 (dd, J = 7.3, 0.9 Hz, 1H), 7.47–7.17 (m, 5H), 1.86–1.61
(m, 10H). The specific activity was measured to be 7.379 μCi/mg,
2.419 mCi/mmol, 5.001 mCi.
[14C]2-(3-(1-(4-Chlorophenyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridin-
8-yl)propan-2-ol or [14C]BMS-823778, 4
To 8-bromo-3-(1-(4-chlorophenyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridine
(0.349 g, 1.00 mmol), 3, in anhydrous THF (5.00 mL) under a nitrogen
atmosphere at À78 °C in a dry ice–acetone bath was added butyllithium
(2.5 M in hexane, 0.84 mL, 2.1 mmol) dropwise, and then the reaction was
stirred for 1 h. The reaction mixture was cooled in a liquid nitrogen bath,
and [2-14C]acetone (50.0 mCi, 55.0 mCi/mmol, 0.074 mL, 0.91 mmol) was
transferred by vacuum transfer. The reaction mixture was moved back to
the dry ice–acetone bath and was stirred for 2.5 h at À78 °C. After warming
to room temperature overnight, the reaction was quenched with a mixture
of 0.140 mL glacial acetic acid in methyl tert-butyl ether (2.5 mL). The
volatiles were removed under vacuum, and the residue was dissolved in
EtOAc (12 mL). The organic layer was washed with saturated ammonium
chloride (5.0 mL), with brine (3.0 mL), dried over anhydrous MgSO4, filtered,
and the solvent was removed by rotovap to give 0.3732 g of the crude
product as a yellow foam. The crude product was purified by flash
2-(3-(1-(4-Chlorophenyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)
propane-1,3-13C2-1,1,3,3,3-d5-1,2-diol, 16
chromatography (Teledyne (Thousand Oaks, CA) Isco RediSep Rf 24 g silica See the work of Cheng et al.10 for the complete experimental details for
cartridge) eluted with 35% EtOAc in hexane to 50% EtOAc in hexane. Pure the preparation of 2-(3-(1-(4-chlorophenyl)cyclopropyl)-[1,2,4]triazolo
product fractions were pooled, and the solvent was removed by rotovap [4,3-a]pyridin-8-yl)propane-1,3-13C2-1,1,3,3,3-d5-1,2-diol, 16.
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Copyright © 2016 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2016, 59 255–259

B. D. Maxwell et al.
HCl salt with a specific activity of 7.379 μCi/mg that was 99%
chemically pure and 99.5% radiochemically pure. This material
was fully tested and released for use in the human ADME study.
Results and discussion
The current Good Manufacturing Practice (cGMP) synthesis of
[14C]BMS-823778, 5, was completed in two synthetic steps as
shown in Scheme
1
from clinical-grade 8-bromo-3-(1-(4-
One purpose of the human ADME clinical study is to
chlorophenyl)cyclopropyl)-[1,2,4]triazolo-[4,3-a]pyridine, 3, and investigate the formation of new previously undetected
[2-14C]acetone in 18% overall yield after purification by flash metabolites.11 Samples analyzed from the human ADME clinical
chromatography and preparation of the hydrochloride salt form. study revealed the formation of a new metabolite, BMT-094817.
The drug substance was determined to be 99.8% chemically pure To fully analyze BMT-094817 in future clinical samples, it was
and 98.4% radiochemically pure, and the specific activity was necessary to prepare a stable-isotope labeled version of it for use
measured at 153.6 μCi/mg. To complete the ADME clinical study, as an LC/MS standard. Typically for LC/MS standards, it is necessary
it was necessary to reduce the specific activity of a portion of the to synthesize material with a molecular weight that is a minimum
high specific activity drug substance with clinical-grade of at least three mass units higher than the naturally occurring
unlabeled BMS-823788 HCl salt by a two-step dilution process molecular weight of the material of interest. As BMT-094817
in ethanol and heptane to generate 5.0 mCi of [14C]BMS-823778 contained a chlorine atom, it was necessary to prepare material
Scheme 1. Human ADME synthesis of [14C]BMS-823778 HCl salt, 7.
Scheme 2. Synthesis of [13CD3 13CD2]BMT-094817, 16.
J. Label Compd. Radiopharm 2016, 59 255–259
Copyright © 2016 John Wiley & Sons, Ltd.
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B. D. Maxwell et al.
that was at least five mass units higher than that of the unlabeled hydrazide 10.10 Compound 10 was cyclized with phosphorous
BMT-094817 to avoid interference from molecules that contained trichloride to generate the [1,2,4]triazolo[4,3-a]pyridine ring system
naturally occurring chlorine-37. We had previously prepared in 41% yield. Aromatic bromide, 3, was carbonylated followed by
[(13CD3)2]BMS-823778, 12, from the Grignard addition of two esterification using 1,3-bis(diphenylphosphino)propane, palladium
equivalents of 13CD3MgI to methyl 3-(1-(4-chlorophenyl) acetate, and 25 psi of carbon monoxide in MeOH at room
cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate,
11, temperature to give an 86% yield of ester, 11. Methyl ester 11 was
and felt that the route shown in Scheme 2 would not only reacted with two equivalents of 13CD3MgI to give the labeled parent
allow us to prepare the M + 7 isotopologue, [13CD3 13CD2] compound, BMS-823778, 12, in 49% yield. The proton of the tertiary
BMT-094817, but also have the additional advantage of alcohol was exchanged to a deuterium using deuterated MeOH in
preparing additional supplies of the parent compound 94% yield. Dehydration product, 15, was formed in 16% yield along
[(13CD3)2]BMS-823778, 12. 3-Bromo-2-hydrazinyl-pyridine
8
with a large amount (48%) of a very polar side product. The desired
was reacted with aromatic acid 9 with isobutyl-chloroformate product was purified by flash chromatography, and the polar side
and N-methylmorpholine in THF to give an 82% yield of product was eluted by flushing the flash column with 10%
Scheme 3. Possible E2 mechanism for the formation of product 19.
Scheme 4. Possible E1/SN1 mechanism for the formation of pyridine adduct, 14.
Scheme 5. Possible E1 mechanism for the formation of product 19.
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J. Label Compd. Radiopharm 2016, 59 255–259

B. D. Maxwell et al.
MeOH : 90% Dichloromethane. The polar side product was identified
by LC/MS and H-NMR to be the pyridine adduct, 14. Fortunately,
Acknowledgements
1
pyridine adduct 14 could be reacted with Hunig’s base in toluene
The authors would like to thank members of the Bristol-Myers
at 100 °C overnight to form 15 in 76% yield. Unsaturated product Squibb Process Research Development Department for supplies
of clinical-grade starting material 3 and unlabeled clinical-grade
BMS-823778 HCl salt. We would also like to thank Sharon Gong
of the Bristol-Myers Squibb DCP-Radiochemistry for HPLC and
LC/MS analysis of the final products.
15 was then hydroxylated with osmic acid to prepare racemic
[13CD3 13CD2]BMT-094817, 16 in 65% yield. No attempt was made
to resolve the enantiomers of [13CD3 13CD2]BMT-094817 because
the LC/MS analysis did not involve a chiral method and the results
from the in vivo study did not show a preference for the formation
of one enantiomer over the other.
Conflict of interest
During unlabeled practice reactions, dehydration of BMS-
823778 with POCl3 in pyridine produced the desired alkene,
19, in 60% isolated yield with only a trace amount of the
pyridine adduct being generated. The formation of the
pyridine adduct is likely the result of a deuterium kinetic
isotope effect. One possible explanation for the difference
in the product ratios of the POCl3 dehydration reaction for
the labeled tertiary alcohol compared with the unlabeled
tertiary alcohol is that unlabeled material, 17, can react
through an E2 mechanism of intermediate 18 to give the
desired product, 19, as shown in Scheme 3.
However, for the labeled chemistry, the C–D bond strength is
stronger than the C–H bond, which requires more energy for it to
be cleaved. Owing to this increased energy requirement, the
mechanism shifts to an E1 mechanism, and the C–O bond is
cleaved in preference to the loss of a proton to generate
carbocation 21 as shown in Scheme 4. Carbocation 21 is tertiary,
benzylic, and stabilized by the presence of the six deuteriums.12
It can then be attacked by pyridine through an SN1 mechanism
to form pyridine adduct 14.
The authors did not report any conflict of interest.
References
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stabilized by the presence of deuteriums as in intermediate 21,
one of the six C–H bonds cleaves to form product 19 as shown
in Scheme 5.
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Conclusions
We successfully prepared a total of 10.10 mCi of [14C]BMS-
823778 HCl salt having a specific activity of 153.6 μCi/mg, a
chemical purity of 99.0%, and a radiochemical purity of
98.4%. A portion of this product was mixed with unlabeled
clinical-grade BMS-823788 HCl salt in two steps to reduce
the specific activity to 7.379 μCi/mg to give a total of
[10] Y. Cheng, W. Chen, B. D. Maxwell, B. D. Tran, J. Li, “Isotopically labeled
5.001 mCi of
[
14C]BMS-823778 HCl salt that was 99.9%
triazolopyridine 11-beta hydroxysteroid dehydrogenase type
1
inhibitors”, WO 2015061272 A1.
chemically pure and 99.5% radiochemically pure. All material
met release specifications for use in a human clinical study
and was successfully used in the human ADME study. One
result of the human ADME study was the discovery of a
new previously undetected human metabolite, BMT-094817.
The synthesis of 280.8 mg of [13CD3 13CD2]BMT-094817 was
completed for use as an LC/MS standard for clinical samples.
[11] B. D. Maxwell, C. S. Elmore, Chapter 30 “Radiosynthesis for ADME
studies”. In ADME-Enabling Technologies in Drug Design and
Development (Eds.: D. Zhang, S. Surapaneni), John Wiley and Sons,
Inc.: Hoboken, NJ USA, 2012, pp. 461–472.
[12] D. E. Sunko, W. J. Hehre, Secondary deuterium isotope effects on
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Organic Chemistry (Ed.: R. W. Taft), Vol 14, John Wiley and Sons,
Inc.: Hoboken, NJ USA, 1983, pp. 205–246.
J. Label Compd. Radiopharm 2016, 59 255–259
Copyright © 2016 John Wiley & Sons, Ltd.
www.jlcr.org