The synthesis and analysis of [phenyl-14C(U)]BMS-770767 and [13C6]BMS-770767 for use in discovery biotransformation, human ADME and bioanalytical studies

Article abstract of DOI:10.1002/jlcr.3428

Type 2 diabetes is a significant worldwide health problem. To support the development of BMS-770767 as an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) for type 2 diabetes was required the synthesis of carbon-14-labelled material for use in metabolic profiling and for the human adsorption, distribution, metabolism and excretion (ADME) study. Initially, [phenyl-¹⁴C(U)]BMS-770767 was synthesized in two steps from a late-stage intermediate and [¹⁴C(U)]2-chlorophenol to give the desired final product in 18% yield. Later, the synthesis was completed for the human ADME clinical study using a combination of the discovery and process chemistry routes under cGMP to prepare [phenyl-¹⁴C(U)]BMS-770767. The radiochemical purity of the synthesized [phenyl-¹⁴C(U)]BMS-770767 after dilution with unlabelled clinical grade BMS-770767 was 99.1% having a specific activity of 1.61 μCi/mg. In addition, to support the quantification of BMS-770767 in LC/MS analyses, [¹³C₆]BMT-770767 was prepared in two steps from a late-stage intermediate and [¹³C₆]2-chlorophenol.

Full text of DOI:10.1002/jlcr.3428

Special issue article
Received 11 April 2016,
Revised 16 June 2016,
Accepted 22 June 2016
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3428
1
4
The synthesis and analysis of [phenyl- C(U)]
1
3
BMS-770767 and [ C ]BMS-770767 for use in
6
discovery biotransformation, human ADME
and bioanalytical studies
Brad D. Maxwell* and Samuel J. Bonacorsi Jr
Type 2 diabetes is a significant worldwide health problem. To support the development of BMS-770767 as an inhibitor of
1
1β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) for type 2 diabetes was required the synthesis of carbon-14-labelled
material for use in metabolic profiling and for the human adsorption, distribution, metabolism and excretion (ADME) study.
Initially, [phenyl- C(U)]BMS-770767 was synthesized in two steps from a late-stage intermediate and [ C(U)]2-chlorophenol
1
4
14
to give the desired final product in 18% yield. Later, the synthesis was completed for the human ADME clinical study using a
1
4
combination of the discovery and process chemistry routes under cGMP to prepare [phenyl- C(U)]BMS-770767. The
1
4
radiochemical purity of the synthesized [phenyl- C(U)]BMS-770767 after dilution with unlabelled clinical grade
BMS-770767 was 99.1% having a specific activity of 1.61 μCi/mg. In addition, to support the quantification of BMS-770767
1
3
13
6 6
in LC/MS analyses, [ C ]BMT-770767 was prepared in two steps from a late-stage intermediate and [ C ]2-chlorophenol.
Keywords: type 2 diabetes; 11β-HSD1; human ADME; carbon-14; stable isotope-labelled synthesis
Introduction
Type 2 diabetes is a significant worldwide health problem
1,2
afflicting more than 300 million people worldwide.
thought that metabolic syndrome, a combination of insulin
resistance, obesity, dyslipidemia, hyperglycemia and
It is
Figure 1. Structure of BMS-770767, 1.
hypertension, may be a major cause of type 2 diabetes. Cortisol
is a circulating glucocorticoid that regulates carbohydrate,
protein and lipid metabolism as well as modulates inflammatory Experimental
and immune responses. Excess glucocorticoids can cause
increased glucose output, reduced glucose-dependent insulin
Materials and methods
sensitivity in adipose tissue and reduced insulin secretion from
All reactions were conducted under an inert atmosphere of nitrogen and
stirred magnetically. Microwave reactions were carried out in a CEM
the pancreas. 11β-Hydroxysteroid dehydrogenase type
1
(
11β-HSD1) is an enzyme that catalyzes the conversion of (Matthews, NC) Discover microwave system at 200 W with cooling. All
3
inactive cortisone to cortisol.
overexpressed 11β-HSD1 in adipose tissue were found to exhibit and used without further purification. [ C(U)]2-Chlorophenol for the
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.
Figure 1, represents such an 11β-HSD1 inhibitor.
the development of BMS-770767, it was necessary to prepare
Transgenic mice that reagents and solvents were American Chemical Society grade or better
14
discovery synthesis (100 mCi, specific activity 78 mCi/mmol, >98.8%
3
radiochemical purity) and for the current good manufacturing practice
(cGMP) synthesis (97.2 mCi, specific activity 53.4 mCi/mmol, >98.8%
radiochemical purity) were obtained from PerkinElmer Life Sciences
3
13
13
(
6
Boston, MA). [ C ]2-Chlorophenol (99.1 atom% C) was obtained from
IsoSciences (King of Prussia, PA). Clinical grade BMS-770767 was
obtained from the Process Research and Development Department at
3
–5
BMS-770767, as shown in
6
–9
To further
1
4
[
phenyl- C(U)]BMS-770767,
5
early on for discovery
Bristol-Myers Squibb Research and Development, Discovery Chemistry Platforms-
biotransformation studies, and then later, 25 was prepared at a Radiochemistry, Route 206 and Province Line Road, Princeton, NJ 08540, USA
different specific activity for use in a human absorption,
1
0
*Correspondence to: Brad D. Maxwell, Bristol-Myers Squibb Research and
Development, Discovery Chemistry Platforms-Radiochemistry, Route 206 and
Province Line Road, Princeton, NJ 08540, USA.
distribution, metabolism and excretion (ADME) study. This
paper also describes the synthesis of [ C
use as an LC/MS standard.
13
6
]BMS-770767, 8 for
E-mail: brad.maxwell@bms.com
J. Label Compd. Radiopharm 2016
Copyright © 2016 John Wiley & Sons, Ltd.

B. D. Maxwell and S. J. Bonacorsi
Bristol-Myers Squibb (New Brunswick, NJ). All authentic samples were
obtained from either the Process Research and Development
Department, the Discovery Chemical Synthesis Group (Princeton, NJ) or
the Medicinal Chemistry Department (Pennington, NJ) at Bristol-Myers
Squibb. Solvent removal under reduced pressure was accomplished
ion. LC/MS method: column = Phenomenex 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, 10 min 100% B.
14
using a Büchi (Flawil, Switzerland) model 200 rotary evaporator. Specific Discovery synthesis of [ C(U)]BMS-770767
activities were determined by gravimetric analysis using liquid
scintillation counting on a Perkin Elmer (Waltham, MA) model 2900TR
Liquid Scintillation Counter.
14
8
1
-([Phenyl- C(U)]-2-chlorophenoxy)-3-(4-methoxybicyclo[2.2.1]heptan-
-yl)-[1,2,4]triazolo[4,3-a]pyridine, 4. To a dry microwave vial with stir bar
was weighed 8-bromo-3-(4-methoxybicyclo[2.2.1]-heptan-1-yl)-[1,2,4]triazolo
4,3-a]pyridine, 3 (248 mg, 0.768 mmol) and Cs CO (249 mg, 0.763 mmol).
To this was added DMF (1.0 mL) and [ C(U)]2-chlorophenol, 2 (66.4 μL,
2.4 mg, 0.641 mmol, specific activity = 78 mCi/mmol, 50 mCi). The reaction
was heated to 160°C under microwave radiation at 200 W for 3.5 h. After
cooling to room temperature, the reaction mixture was diluted with EtOAc
[
2
3
14
Chromatography systems
8
Column chromatography was performed using an AnaLogix (Burlington,
WI) BSR Flash Chromatography system using Teledyne Isco (Lincoln, NB)
Redi-Sep R
f
silica cartridges. TLC analyses (EMD (Darmstadt, Germany) 60,
(
10 mL), washed with 1 N NaOH (3 × 2 mL) and water (3 × 2 mL), dried over
Na SO and filtered, and the solvent was removed under reduced pressure
F
254 silica gel coated plates) were performed using either UV (254 nm) or
2
4
iodine to visualize. HPLC analyses were performed on an Agilent (Santa
Clara, CA) 1200 HPLC system, with a diode array detector for UV
detection and an IN/US, now LabLogic, (Tampa, FL) Beta-Ram model 3
detector using LauraLite Version 3.4.1.10 software for radiochemical
detection. The following analytical methods were used for in process
analyses and final purity measurements. HPLC method A: Agilent Eclipse
XDB C18, 5 μm, 4.6 × 150 mm, mobile phase A: water with 0.1%
trifluoroacetic acid (TFA), mobile phase B: acetonitrile (MeCN) with 0.1%
TFA. Gradient: 0 min, 90% A; 10 min, 90% B; 12 min, 90% B; 13 min,
to give 169 mg of crude product. The crude product was combined with that
from another reaction on a similar scale. The combined material was purified
by flash chromatography using a Redi-Sep R 40 g silica cartridge and eluting
f
with 20% EtOAc : 80% hexane to 80% EtOAc : 20% hexane. Pure product
fractions were pooled, and the solvent was removed under reduced pressure
followed by drying on a vacuum line to constant weight to give 158 mg of a
white solid, 4 (33% yield). The product was analyzed using HPLC method A
which showed it to be 99% chemically pure with a retention time of
7.33 min and 99.6% radiochemically pure. The labelled product co-eluted
90% A, flow rate = 1.0 mL/min. UV detection at 254 nm. HPLC method
with an authentic sample. The product was used in the next step of the
synthesis without further purification.
B: Phenomenex (Torrance, CA) Luna C18, 3 μm, 4.6 × 50 mm mobile
phase A = 95% water : 5% MeCN : 0.05% TFA, mobile phase B = 95%
MeCN : 5% water : 0.05% TFA, 0 min 15% B, 8 min 15% B, 18 min 100%
B, 20 min 100% B, 22 min 15% B, flow rate = 2.0 mL/min, UV detection
at 220 nm. HPLC method C: Agilent Technologies Zorbax SB-C18,
14
4
3
8
-(8-([Phenyl- C(U)]2-chlorophenoxy)-[1,2,4]triazolo[4,3-a]pyridin-
14
-yl)bicyclo[2.2.1]heptan-1-ol, [phenyl- C(U)]BMS-770767, 5. To
-([phenyl- C]-2-chlorophenoxy)-3-(4-methoxybicyclo[2.2.1]heptan-1-yl)-
1
4
3
.5 μm, 4.6 × 150 mm mobile phase A = 10 mM NH
to pH = 4.5 with AcOH, mobile phase B = MeCN, gradient: 0 min 20% B,
min 20% B, 26 min 28% B, 41 min 80% B, 45 min 80% B, 45.5 min 20%
4
OAc in water adjusted
[
1,2,4]triazolo[4,3-a]pyridine, 4 (67 mg, 0.18 mmol) dissolved in acetic
anhydride (0.5 mL) at 0°C was added 48% HBr (0.50 mL, 9.2 mmol). After
addition, the solution was stirred at room temperature for 10 min and
then warmed to 100°C for 1.5 h. The reaction was cooled to room
temperature, and the solvent was removed under reduced pressure. To
the resulting crude solid was added MeOH (0.8 mL) and 2.2 M NaOH
1
B, 50 min 20% B, flow rate = 1.0 mL/min, UV detection at 273 nm, column
temperature = 40°C. Preparative HPLC was performed on a Varian, now
part of Agilent (Santa Clara, CA) PrepStar HPLC System with two Varian
PrepStar model 218 pumps with 25 mL heads and a Varian ProStar UV-
Vis model 320 detector. Preparative HPLC method A: Phenomenex Luna
C18, 5 μm, 250 × 21.2 mm. mobile phase A: water with 0.1% TFA, mobile
phase B: MeCN with 0.1% TFA, gradient: 0 min 30% B, 12 min 80% B,
(
aq) (0.33 mL, 0.72 mmol). The solution was warmed to 65°C for 1 h. After
cooling to room temperature, a solid formed. The solvent was removed
under reduced pressure, and water (5 mL) was added. The water layer
3 3
was extracted with CHCl (3 × 5 mL). The pooled CHCl extracts were
15 min 80% B, 17 min 30% B, flow rate = 10 mL/min, UV detection at
254 nm. Preparative HPLC method B: Phenomenex Gemini C18, 4 μm,
250 × 21.2 mm mobile phase A: 90% water : 10% MeCN with 0.1% TFA,
dried over MgSO and filtered, and the solvent was removed under
4
reduced pressure to give 54.7 mg of crude product. This crude product
was combined with the crude product from that of another reaction at
mobile phase B: 90% MeCN : 10% water with 0.1% TFA, gradient: 0 min
0% B, 12 min 90% B, 15 min 90% B, 17 min 20% B, flow rate = 10 mL/
1
.36 times the scale. The crude products were purified by preparative
2
HPLC using method A. Fractions containing the pure product were
pooled, and the solvent was removed under reduced pressure using
EtOH to azeotrope the last traces of water and then dried on a vacuum
line to consistent weight to give 84 mg of an off white solid,
min, UV detection at 254 nm. Preparative HPLC method C: Phenomenex
Luna 5 μm C18, 250 × 21.2 mm, mobile phase A = water with 0.5% TFA,
mobile phase B = MeCN with 0.05% TFA, gradient: 0 min 40% B, 15 min
77% B, 17 min 90% B, 20 min 90% B, 22 min 40% B, flow rate = 10 mL/
1
4
[
phenyl- C(U)]BMS-770767, 5 (55% yield). Analysis by HPLC using
min, UV detection at 220 nm. Preparative HPLC method D: Phenomenex
Luna C18, 5 μm, 250 × 21.2 mm mobile phase A: water with 0.5% TFA,
mobile phase B: MeCN with 0.05% TFA. Gradient: 0 min 90% A, 20 min
method A showed the product to be 99.9% chemically pure with a
retention time of 6.13 min and 99.6% radiochemically pure. The material
co-eluted with an authentic sample. Analysis by LC/MS showed m/z
90% B, 22 min 90% B, 25 min 90% A, flow rate = 10 mL/min, UV detection
(
(
(
+ ion) =356 (100%)/358 (41%)/360 (33%)/362 (19%)/364 (26%)/366
at 220 nm.
1
6
9%). H NMR (300 MHz, DMSO-d ) δ ppm 8.33 (d, J = 6.6 Hz, 1H), 7.65
d, J = 7.7 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.24–7.33 (m, 2H), 6.81 (t,
NMR
J = 7.1 Hz, 1H), 6.47 (d, J = 7.1 Hz, 1H), 5.14 (s, 1H), 2.03–2.18 (m, 4H),
.01 (s, 2H), 1.79–1.87 (m, 2H), 1.62–1.69 (m, 2H). The specific activity
was measured to be 216 μCi/mg, 76.8 mCi/mmol, to yield a total of
2
Proton NMR spectra were recorded on either a 300 or 400 MHz Bruker
(Billirica, MA) Avance spectrometer or a JEOL (Tokyo, Japan) EC+ 500
1
8.2 mCi of product.
MHz spectrometer as listed. For stable isotope-labelled products, only
13
carbon-13 enriched positions are reported for C NMR characterization
purposes.
13
Synthesis of [ C ]BMS-770767
6
13
8
-([ C ]2-Chlorophenoxy)-3-(4-methoxybicyclo[2.2.1]heptan-1-yl)-
6
[
1,2,4]triazolo[4,3-a] pyridine, 7. To a dry microwave vial with stir
MS
bar was weighed 8-bromo-3-(4-methoxybicyclo [2.2.1]-heptan-1-yl)-
LC/MS spectra were recorded on a Finnigan LXQ (Thermo Fisher
Scientific Inc., Waltham, MA) LC/MS System with detection by ESI (+)
[1,2,4]triazolo[4,3-a]pyridine,
(253 mg, 0.78 mmol). To this was added DMF (1.0 mL) and [
3
(250 mg, 0.78 mmol) and Cs
2
CO
3
13
C
6
]2-
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Copyright © 2016 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2016

B. D. Maxwell and S. J. Bonacorsi
chlorophenol, 6 (77 μL, 95 mg, 0.71 mmol). The reaction was heated to 4-(2-(3-Bromopyridin-2-yl)hydrazine-1-carbonyl)bicyclo[2.2.1]heptan-1-
1
60°C under microwave radiation for 3 h. After cooling to room
yl 3,5-difluorobenzoate, 19. To a new dry 100 mL round bottom flask
with stir bar under nitrogen was weighed 4-((3,5-difluorobenzoyl)oxy)
bicyclo[2.2.1]heptane-1-carboxylic acid, 14 (5.00 g, 16.9 mmol). To this
was added toluene (25.4 mL) and one drop of DMF. The suspension was
stirred for 5 min, and oxalyl chloride (1.5 mL, 17 mmol) was added
dropwise over 10 min. The reaction was stirred for 45 min, and the
suspension became a clear solution. In a separate new 250 mL round
bottom flask with stir bar was weighed 3-bromo-2-hydrazinylpyridine, 18
temperature, the reaction mixture was diluted with EtOAc (10 mL),
washed with 1 N NaOH (3 × 2 mL) and water (3 × 2 mL), dried over
Na SO and filtered, and the solvent was removed under reduced
2 4
pressure to give the crude product. The crude product was combined
with that from another reaction on a similar scale. The combined crude
f
product was purified by flash chromatography using a Redi-Sep R 40 g
silica cartridge and eluted with 20% EtOAc : 80% hexane to 80%
EtOAc : 20% hexane. Pure product fractions were pooled, and the
solvent was removed under reduced pressure followed by drying on a
vacuum line to constant weight to give 118 mg of a white solid, 7
(
2.89 g, 15.4 mmol) and K
THF (34 mL). The solution was cooled to 0–5°C in an ice-water bath. Water
25 mL) was added, and the suspension was stirred for 15 min until two
2 3
CO (2.48 g, 17.9 mmol). To this was added
(
(
44% yield). The product was analyzed using HPLC method A which
showed it to be 97.1% chemically pure with a retention time of
.09 min. The labelled product co-eluted with an authentic sample.
layers formed. To this was added the acid chloride solution over 15 min
while stirring slowly. The reaction was stirred at 3–5°C for 3 h and then
warmed to room temperature and stirred for 2.5 h. The bottom aqueous
layer was removed. The organic layer was washed with 5% brine solution
7
The product was used in the next step of the synthesis without further
purification.
(
(
25 mL). The solvent was removed under reduced pressure. Hot toluene
25 mL) was added to completely dissolve the solid. Upon cooling,
13
4
-(8-([ C ]2-Chlorophenoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)bicyclo
6
13
crystallization occurred and heptane (10 mL) was added to complete the
crystallization. The crystals were collected and dried on a vacuum line to
give 4.40 g of off white solid, 19 (61.3% yield). HPLC analysis using
analytical method B showed the material to be 100% pure with a retention
13
[
3
(
2.2.1]heptan-1-ol,[ C ]BMS-770767, 8. To 8-([ C
6
]2-chlorophenoxy)-
-(4-methoxybicyclo[2.2.1]heptan-1-yl)-[1,2,4]triazolo[4,3-a]pyridine,
60 mg, 0.16 mmol) dissolved in acetic anhydride (0.44 mL) at 0°C was
6
7
added 48% HBr (0.44 mL, 8.1 mmol). After addition of HBr, the solution
was stirred at room temperature for 10 min and then warmed to 100°C
for 1 h. The reaction was cooled to room temperature, and the solvent
was removed under reduced pressure. To the resulting crude oil was
added MeOH (0.73 mL) and 2.2 M NaOH (aq) (0.29 mL, 0.64 mmol). The
solution was warmed to 65°C for 1 h. After cooling to room temperature,
time of 12.45 min. LC/MS analysis showed m/z (+ ion) = 466.17 (100%)/
1
4
68.17 (97%) with a retention time of 6.15 min. H NMR (300 MHz,
DMSO-d
J = 7.8, 1.5 Hz, 1H), 7.53–7.69 (m, 3H), 6.69 (dd, J = 7.6, 4.8 Hz, 1H), 1.78–
.23 (m, 10H).
6
) δ ppm 9.61 (d, J = 2.1 Hz, 1H), 8.04–8.13 (m, 2H), 7.83 (dd,
2
a solid formed. This crude product was combined with the crude product 4-(8-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)bicyclo[2.2.1]heptan-1-
from that of another reaction at nearly the same scale. To the crude
yl 3,5-difluorobenzoate, 20. To a new dry 250 mL round bottom flask
products was added water (5 mL). The water layer was extracted with
CHCl (5 × 4 mL). The pooled CHCl extracts were dried over Na SO and
filtered, and the solvent was removed under reduced pressure to give
5 mg of crude product. The crude product was purified by preparative
with stir bar under nitrogen was weighed 3.96 g of 4-(2-(3-
bromopyridin-2-yl)hydrazine-1-carbonyl)bicyclo[2.2.1]heptan-1-yl 3,5-
difluorobenzoate, 19 (8.49 mmol). To this was added anhydrous toluene
58 mL). The suspension was stirred for 5–10 min at 75°C until the solid
completely dissolved. POCl (4.40 mL, 47.2 mmol) was added dropwise
3
3
2
4
9
(
HPLC using method B. Fractions containing the pure product were pooled,
and the solvent was removed under reduced pressure using EtOH to
remove the last traces of water by azeotrope and then dried on a vacuum
line to consistent weight to give 77 mg of a white solid (68% yield).
Analysis by HPLC using method A showed the product to be 99.6%
chemically pure with a retention time of 6.18 min. The material co-eluted
3
over 5 min, and the solution was warmed to 92°C. After 43 h, the solvent
was removed by under reduced pressure. MeCN (54 mL) was added. The
suspension was cooled to 0–5°C, and 18% aqueous potassium phosphate
(
44 mL) was added and additional solid formed. The solid was collected
by filtration and washed with cold water (100 mL). The solid was
transferred to a flask and was dried on a vacuum line to give 3.18 g of
a white solid, 20 (84% yield). HPLC analysis using analytical method B
showed the product to be 100% chemically pure with a retention time
of 13.17 min. LC/MS analysis showed the product m/z (+ ion) = 448
with an authentic sample. Analysis by LC/MS showed m/z = 361 (2%)/362
1
(
100%)/363 (16%)/364 (34%)/365 (5%)/366 (0.6%). H NMR (300 MHz,
DMSO-d
6
) δ ppm 8.33 (d, J = 6.6 Hz, 1H), 7.92 (m, 1H), 7.60 (m, 1H), 7.40
m, 1H), 7.05 (m, 1H), 6.81 (t, J = 7.1 Hz, 1H), 6.47 (d, J = 7.1 Hz, 1H), 5.14
s, 1H), 2.03–2.18 (m, 4H), 2.01 (s, 2H), 1.79–1.87 (m, 2H), 1.62–1.69 (m,
(
(
(
95.9%)/449 (22.4%)/450 (100%)/451 (22.0%)/452 (2.9%) and eluted with
1
3
1
6
2H). C NMR (125.77 MHz, DMSO-d ) δ ppm 150.07 (dd, J = 68.6 and
a retention time of 6.07 min. H NMR (300 MHz, DMSO-d
J = 6.6 Hz, 1H), 7.73 (d, J = 6.8 Hz, 1H), 7.57–7.70 (m, 3H), 6.89 (t, J = 7.0 Hz,
H), 2.05–2.40 (m, 10H).
6
) δ ppm 8.67 (d,
73.8 Hz), 130.88 (dd, J = 58.5 and 61 Hz), 129.05 (t, J = 56 Hz), 126.55
(
(
dd, J = 53.4 and 55.6 Hz), 124.71 (dd, J = 68.7 and 71.2 Hz), 121.76
dd, J = 66.1 and 56 Hz).
1
4
-(8-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)bicyclo[2.2.1]heptan-1-
1
4
ol, 21. To a new dry 100 mL recovery flask with stir bar under
nitrogen was weighed 4-(8-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)
cGMP synthesis of [phenyl- C(U)]BMS-770767
3
-Bromo-2-hydrazinylpyridine, 18. To a new round bottom flask with bicyclo[2.2.1]heptan-1-yl 3,5-difluorobenzoate, 20 (1.90 g, 4.24 mmol).
stir bar was weighed 3-bromo-2-chloropyridine, 17 (8.55 g, 44.4 mmol). To this was added methanol (19 mL) to form a thick suspension. To the
Absolute ethanol (85.5 mL) was added, and the solution was stirred for
min. To this solution was added hydrazine monohydrate (65 mL, 65%
in water, 0.86 mol) over 5 min. The solution was stirred for 5–10 min at
suspension was added 2.5 M NaOH (3.7 mL, 9.3 mmol). The suspension
was stirred at room temperature for 2.5 h after which it became a cloudy
solution. The methanol was removed under reduced pressure, and water
5
room temperature, and then, the flask was attached to a reflux (12 mL) was added to dissolve the solid. The aqueous layer was extracted
condenser and heated to 100°C overnight. The solution was cooled to with EtOAc (5 × 20 mL). The pooled EtOAc extracts were dried over
room temperature and large crystals formed. The reaction mixture was
2 4
Na SO and filtered, and the solvent was removed under reduced
filtered, and the crystals were washed with cold water. The material pressure. The product was further dried on a vacuum line to give 1.49 g
was transferred to a round bottom flask and was dried under vacuum of an off white solid composed of 1.19 g of the desired product, 21
1
to give 7.10 g of white crystals, 18 (85% yield). HPLC analysis using and 0.30 g of 3,5-difluorobenzoic acid as determined by H NMR (88%
analytical method B showed the product to be 100% chemically pure
yield). HPLC analysis using analytical method A showed the product to
with a retention time of 0.285 min. LC/MS analysis showed m/z = 188 be 67% chemically pure with a retention time of 5.96 min. LC/MS analysis
1
(
1
(
100%)/190 (98%). H NMR (300 MHz, CDCl
.4 Hz 1H), 7.66 (dd, J = 7.6, 1.5 Hz, 1H), 6.60 (d, J = 7.6, 4.8 Hz, 1H), 6.25
br. s. 1H), 4.00 (br. s. 2H).
3
) δ ppm 8.15 (dd, J = 4.9, showed the product with m/z (+ ion) = 308.25 (100%)/310.25 (97%) with
1
a retention time of 2.18 min. H NMR (300 MHz, DMSO-d
6
) δ ppm 8.60
(dd, J = 7.0, 0.6 Hz, 1H), 7.69 (dd, J = 7.1, 0.5 Hz, 1H), 6.84 (t, J = 7.0 Hz,
J. Label Compd. Radiopharm 2016
Copyright © 2016 John Wiley & Sons, Ltd.
www.jlcr.org

B. D. Maxwell and S. J. Bonacorsi
1
4
1H), 5.17 (s, 1H), 1.97–2.19 (m, 6H), 1.76–1.92 (m, 2H), 1.59–1.73 (m, 2H).
new dry 10 mL recovery flask with stir bar was weighed 8-([phenyl- C
Integration shows approximately 0.5 equivalents of 3,5-difluorobenzoic (U)]2-chlorophenoxy)-3-(4-methoxybicyclo[2.2.1]heptan-1-yl)-[1,2,4]
acid to one equivalent of the desired product, 21. The mixture of
products was used in next reaction without additional purification.
triazolo[4,3-a]pyridine, 24 (41.7 mg, 0.113 mmol). To this was added
glacial acetic acid (0.36 mL), and the solution was cooled to 0–5°C with
an ice-water bath. To this solution was added 48% HBr (0.36 mL,
8
-Bromo-3-(4-methoxybicyclo[2.2.1]heptan-1-yl)-[1,2,4]triazolo[4,3-
3
5
.2 mmol) dropwise over 5 min. The solution was stirred for 5 min at 0–
°C and then placed in an oil bath at 100°C for 2 h. The solution was
a]pyridine, 3. To a new dry round bottom flask with stir bar under
nitrogen was weighed 4-(8-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)
bicyclo[2.2.1]heptan-1-ol, 21 (1.00 g, 3.24 mmol) and sodium amide
cooled to room temperature, and the solvent was removed under
reduced pressure. Methanol (0.5 mL) and 2.2 M NaOH (0.20 mL) was
added, and the solution was placed in oil bath at 65°C for 1 h. The
reaction was cooled to room temperature, and the solvent was removed
under reduced pressure. To the crude product was added water (0.5 mL).
The aqueous layer was extracted with EtOAc (5 × 1.5 mL). The pooled
(140 mg, 3.60 mmol). To this was syringed DMF (30 mL) to form a yellow
suspension. The suspension was stirred for 30 min, and then, a solution of
iodomethane (0.23 mL, 3.6 mmol) in DMF (1.0 mL) was added, and the
suspension was stirred at room temperature overnight. The solvent was
removed under reduced pressure leaving a light yellow solid. The crude
2 4
EtOAc extracts were dried over anhydrous Na SO and filtered, and
product was purified by flash chromatography using a 120 g Redi-Sep R
2
cartridge and a gradient of 100% CH Cl to 10% methanol/90% CH Cl .
Pure fractions were pooled, and the solvent was removed by under
reduced pressure and then dried on a vacuum line to constant weight
to give 269 mg of a white solid, 3 (26% yield). HPLC analysis using
analytical method B showed the product to be 100% chemically pure
f
the solvent was removed under reduced pressure to give a semisolid
that was purified by preparative HPLC using method D. Pure fractions
were pooled, and the solvent was removed under reduced pressure
2
2
2
14
and then dried under vacuum to give 32 mg of white solid, [phenyl-
U)]BMS-770767, 25 (4.7 mCi, 78% yield). HPLC analysis using method C
showed the product to be 99.5% chemically pure with a retention time
C
(
14
with a retention time of 2.18 min. LC/MS analysis showed m/z (+ ion)
of 22.48 min and 99.2% radiochemically pure. LC/MS of [phenyl- C(U)]
1
=
322.25 (100%)/324.17 (97%) with a retention time of 2.43 min.
NMR (400 MHz, DMSO-d
J = 7.2, 0.6 Hz. 1H), 6.87 (t, J = 7.0 Hz, 1H), 3.31 (s, 3H), 2.10–2.21 (m, 6H),
.91–2.02 (m, 2H), 1.70 (dt, J = 13.7, 5.1 Hz, 2H).
H
BMS-770767 showed m/z (+ ion) = 356 (100%)/357 (22.4%)/358 (37.3%)/
6
) δ ppm 8.67 (d, J = 6.4 Hz, 1H), 7.72 (dd,
3
3
59 (7.5%)/360 (26.1%)/361 (5%)/362 (10.8%)/363 (2.1%)/364 (15.8%)/
1
65 (2.5%)/366 (5.8%)/368 (3.3%) with a retention time of 3.84 min.
H
1
NMR (300 MHz, DMSO-d
6
) δ ppm 8.35 (d, J = 6.6 Hz, 1H), 7.68 (dd,
1
4
J = 7.8, 1.5 Hz, 1H), 7.38–7.48 (m, 1H), 7.27–7.37 (m, 2H), 6.84 (t,
J = 7.2 Hz, 1H), 6.51 (d, J = 7.3 Hz, 1H, 1.98–2.20 (m, 6H), 1.78–1.92 (m,
Cesium [phenyl- C(U)]2-chlorophenolate, 23. To a new dry 25 mL
round bottom flask with stir bar under nitrogen was weighed Cs CO
272 mg, 0.833 mmol). To this was syringed ethyl ether (7.0 mL) to form
a white suspension. The suspension was cooled to 3°C in an ice-water
2
3
2
H), 1.60–1.74 (m, 2H). The specifc activity was measured to be 149 μCi/
(
mg or 53.3 mCi/mmol.
14
bath, and
a
solution of
[
C(U)]2-chlorophenol (0.19 mL, specific
14
[
Phenyl- C(U)]BMS-770767, 26, intermediate specific activity
activity = 53.4 mCi/mmol, 1.82 mmol, 97.2 mCi) in ether (0.83 mL) was
added dropwise over 3 min with vigorous stirring keeping the
14
product. To the 50 mL recovery flask containing [phenyl- C(U)]BMS-
770767, 25 (28.7 mg, specific activity = 149 μCi/mg, 4.28 mCi,
14
temperature below 4°C. The vial containing the [ C(U)]2-chlorophenol
was rinsed with ether (1.3 mL), and this was added to the reaction flask.
The light yellow suspension was stirred at 3–5°C for 15 min and then
warmed to room temperature overnight. The suspension was filtered,
and the off white solid was washed with ether (20 mL), air dried and then
dried on a vacuum line until constant weight was achieved to give
08 mg of a white solid, 23 (43% yield). H NMR (300 MHz, DMSO-d
ppm 6.84 (dd, J = 7.7, 1.9 Hz, 1H), 6.60 (ddd, J = 8.4, 6.8, 2.0 Hz, 1H), 6.08
dd, J = 8.1, 1.2 Hz, 1H), 5.71 (td, J = 7.3, 1.0 Hz, 1H).
0
0
.080 mmol) was weighed clinical grade BMS-770767 (103 mg.
.290 mmol). To this was added absolute ethanol (25 mL), and the
mixture was warmed to 40°C for 5–10 min in a water bath to completely
dissolve all of the solids. The ethanol was removed under reduced
pressure to give a white solid that was further dried on a vacuum line
to constant weight to give 132 mg of product, 26 (100% yield). HPLC
analysis using analytical method C showed the material to be 99.6%
1
2
6
) δ
chemically pure with
radiochemically pure. LC/MS analysis of [phenyl- C(U)]BMS-770767
a retention time of 22.63 min and 99.4%
(
14
14
8
1
-([Phenyl- C(U)]2-chlorophenoxy)-3-(4-methoxybicyclo[2.2.1]heptan- showed m/z (+ ion) = 356 (100%)/357 (22.4%)/358 (36.1%)/359
1
(
(
1
6
7.9%)/360 (5.4%)/364 (2.9%) with a retention time of 3.79 min. H NMR
300 MHz, DMSO-d ) δ ppm 8.35 (d, J = 6.8 Hz, 1H), 7.67 (dd, J = 7.8,
.4 Hz, 1H), 7.38–7.48 (m, 1H), 7.26–7.38 (m, 2H), 6.83 (t, J = 7.2 Hz, 1H),
.50 (d, J = 7.3 Hz, 1H), 1.99–2.21 (m, 6H), 1.77–1.93 (m, 2H), 1.60–1.75
-yl)-[1,2,4]triazolo[4,3-a]pyridine, 24. To a new dry glass test tube
with stir bar under nitrogen was weighed 8-bromo-3-(4-methoxybicyclo
6
[
2.2.1]heptan-1-yl)-[1,2,4]triazolo[4,3-a]pyridine, 3 (185 mg, 0.574 mmol) and
1
4
the cesium salt of [ C(U)]2-chlorophenol, 23 (148 mg, 0.567 mmol.) The test
tube was placed in an oil bath at 220–225°C and stirred under nitrogen for
(
1
m, 2H). The specific activity was measured to be 32.9 μCi/mg or
1.7 mCi/mmol.
1
h. To the black solid was added water (1.8 mL), and the mixture was
heated to 135°C for 20 min. After cooling to room temperature, 1 M NaOH
1.0 mL, 1.0 mmol) was added. The aqueous layer was extracted with CH Cl
7 × 2.5 mL). The combined CH Cl layers were washed with saturated NH Cl
5.0 mL), brine (5.0 mL), dried over anhydrous Na SO and filtered, and the
solvent was removed under reduced pressure to give a black semisolid.
The crude product was purified by preparative HPLC using method C. Pure
fractions were pooled. The solvent was removed under reduced pressure,
and then, the product was dried under vacuum to constant weight to give
4 mg of an off white solid, 24 (26% yield). HPLC analysis using method B
showed the product to be 99.5% chemically pure with a retention time of
1.22 min and 99.4% radiochemically pure. LC/MS of the product showed
m/z (+ ion) = 370.25 (100%)/372. 25 (36%)/374.33 (25%)/376.25 (10%)/
1
4
[
Phenyl- C(U)]BMS-770767, 27, low specific activity final product.
(
2 2
14
To a new dry recovery flask was weighed [phenyl- C(U)]BMS-770767,
(
2
2
4
2
6 (69.7 mg, specific activity = 32.9 μCi/mg, 2.29 mCi, 0.195 mmol) and
(
2
4
clinical grade BMS-770767 (1.36 g, 3.82 mmol). To this was added
absolute ethanol (200 mL), and the mixture was warmed to 40–45°C for
2
0–30 min in a water bath to completely dissolve all of the solids. The
ethanol was removed under reduced pressure to give a white solid that
was further dried on a vacuum line to constant weight to give 1.44 g of
product. To the white solid was added glacial acetic acid (6.8 mL) and
sterile water (1.7 mL). The mixture was heated to 65°C in a water bath.
The hot solution was filtered, and the flask was rinsed with 4:1 AcOH :
water (3 × 0.5 mL) solution, and these rinsings were also filtered. To the
filtrate was added sterile water (8.0 mL) at 65°C, and the solution
was cooled to room temperature overnight. The solution was cooled to
5
1
1
3
78.25 (15%) and 380.25 (5%) with a retention time of 4.90 min. H NMR
(
300 MHz, CDCl
3
) δ ppm 7.72 (d, J = 6.8 Hz, 1H), 7.40–7.48 (m, 1H), 7.21–
.30 (m, 1H), 7.12–7.21 (m, 2H), 6.57 (t, J = 7.2 Hz, 1H), 6.12 (d, J = 7.4 Hz,
H), 3.33 (s, 3H), 2.05–2.32 (m, 6H), 1.89–2.05 (m, 2H), 1.69–1.83 (m, 2H).
7
1
1
5–20°C with an ice-water bath, and the solid was collected by filtration.
The solid was rinsed with cold water, air dried for 45 min and then
14
4
3
-(8-([Phenyl- C(U)]2-chlorophenoxy)-[1,2,4]triazolo[4,3-a]pyridin-
dried under vacuum at 60–65°C for 3 h to give 1.28 g of white
1
4
14
-yl)bicyclo[2.2.1]heptan-1-ol, [phenyl- C(U)]BMS-770767, 25. To a solid [phenyl- C(U)]BMS-770767, 27 (90% yield). HPLC analysis
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Copyright © 2016 John Wiley & Sons, Ltd.
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B. D. Maxwell and S. J. Bonacorsi
usinganalytical method C showed the material to be 99.9% chemically synthesis of [ C ]BMS-770767, 8 was completed in three steps
13
6
1
4
pure with a retention time of 22.62 min and 99.1% radiochemically pure.
using the same synthetic route as that for [phenyl- C(U)]BMS-
1
4
LC/MS of [phenyl- C(U)]BMS-770767 showed m/z (+ ion) = 356
13
7
70767, except that [ C
6
]2-chlorophenol, 6 was used in place
of [ C(U)]2-chlorophenol and the overall yield was higher at
0%. Both of these syntheses were able to be completed quickly
because of the incorporation of the labelled reagents late in the
syntheses, the use of the same synthetic routes for both labelled
products and the availability of intermediate 3.
1
(
100%)/357 (21.5%)/358 (36%)/359 (7.1%)/360 (0.8%). H NMR (300 MHz,
DMSO-d ) δ ppm 8.34 (d, J = 6.8 Hz, 1H), 7.67 (dd, J = 7.8, 1.7 Hz, 1H),
.38–7.47 (m, 1H), 7.26–7.37 (m, 2H), 6.82 (t, J = 7.2 Hz, 1H), 6.49
d, J = 7.3 Hz, 1H), 5.14 (s, 1H), 1.99–2.21 (m, 6H), 1.77–1.93 (m, 2H),
14
6
3
7
(
1
1
.60–1.73 (m, 2H). The specific activity was measured to be
.61 μCi/mg or 0.57 mCi/mmol.
Between the time when the discovery syntheses of
1
4
13
[
phenyl- C(U)]BMS-770767, 5 and [ C
completed and the need for the synthesis of [phenyl- C(U)]
The discovery phase synthesis of [phenyl- C(U)]BMS-770767 BMS-770767 for use in the human ADME clinical study, the
6
]BMS-770767, 8 were
Results and discussion
14
14
14
was completed in three steps by reacting [ C(U)]2- Bristol-Myers Squibb Process Research Group developed a
chlorophenol,
with 8-bromo-3-(4-methoxybicyclo-[2.2.1] completely new synthetic route to BMS-770767 as shown in
heptan-1-yl)-[1,2,4]triazolo[4,3-a]pyridine, 3 and Cs
under microwave heating to give the desired ether product in synthetic route for the cGMP synthesis of [phenyl- C(U)]BMS-
3% yield. The demethylation of the methyl ether with 48% 770767 for use in the human ADME clinical study. Two
2
8,9
2
CO
3
in DMF Scheme 2.
Naturally, we were eager to utilize the new
14
3
HBr and acetic anhydride gave the desired labelled product, 5 advantages to following the process chemistry route was the
as shown in Scheme 1 in 55% yield or 18% overall. Although this high yielding and dependable procedures and the availability
yield appears to be low, this route was advantageous in that the of large supplies of cGMP produced intermediate, 14.
desired labelled product was prepared in only three steps and in Unfortunately, the process route involved the reaction of five
two flasks in a short amount of time to meet the timeline for the equivalents of 2-chlorophenol, 9, with 3-chloro-2-nitropyridine,
necessary biotransformation studies to be initiated. Likewise, the 10 in the first step of the synthesis which would mean that our
1
4
13
Scheme 1. Discovery syntheses of [phenyl- C(U)]BMS-770767, 5 and [
6
C ]BMS-770767, 8.
Scheme 2. Bristol-Myers Squibb Process Research synthesis of BMS-770767, 1.
J. Label Compd. Radiopharm 2016
Copyright © 2016 John Wiley & Sons, Ltd.
www.jlcr.org

B. D. Maxwell and S. J. Bonacorsi
labelled reagent would need to be used in large excess in the excess of 10 did not improve the production of 11 as shown in
first step of the synthesis and would be carried through all entries 5 and 6.
six steps of the synthesis leading to low overall radiochemical
Because the first step of the process chemistry route was
1
4
yields of [phenyl- C(U)]BMS-770767. This left us with three becoming challenging to repeat and we were short on time,
possible options for completing the cGMP synthesis of we decided to reconsider the very short discovery chemistry
1
4
[
phenyl- C(U)]BMS-770767 for use in the human ADME clinical route that we have previously used with success. However, there
study. Option 1 would be to use the process chemistry route were no supplies of the critical intermediate aromatic bromide,
and try to modify it slightly by lowering the number of 3, that had been prepared under cGMP and was suitable for
1
4
equivalents of [ C(U)]2-chlorophenol to make it more efficient use in the human ADME synthesis. As such, we shifted to option
14
with regards to the labelled reagent. Option 2 would be to use 3 and developed a new route to [phenyl- C(U)]BMS-770767
the discovery chemistry route that we were already familiar with, taking advantage of the availability of intermediate 14 prepared
but this would also require the synthesis of aromatic bromide, 3 under cGMP to prepare 3 in five steps with approval of our
under cGMP conditions to meet the requirements of our quality quality assurance group who were concerned with the possibility
assurance group. Option 3 would be to develop a completely of generating a different impurity profile than that which was
new route and incorporate the best of both the discovery known from the process chemistry cGMP route. Even though
chemistry and process chemistry routes. This would also need some new impurities could be formed with the new route, we
to be conducted under cGMP to gain the approval of our quality were able to convince our quality assurance colleagues that
assurance group.
the presence of the carbon-14 label later in the synthesis
Initially, we decided to follow the process route to take gave us the ability to detect and identify them in smaller
advantage of the availability of intermediate 14. During the first quantities, as well as show that they were not carried through
practice chemistry attempt, 5 equivalents of 2-chloro-phenol, 9, to the final labelled API. They agreed, but insisted on the
were reacted with 3-chloro-2-nitropyridine, 10, and K CO3 in steps leading up to the incorporation of the carbon-14 be
2
toluene at 70°C which resulted in a mixture of 41.5% of desired conducted under cGMP just as would be expected if our
product 11, 28.3% of product 11a resulting from displacement colleagues in process chemistry were to have prepare
of the nitro group by the phenol and 30.2% of product 11b by compound 3 for us to use in our human ADME synthesis.
14
the double displacement of the chloride and nitro groups by This also allowed for the late-stage incorporation of [ C(U)]2-
phenol as shown in Scheme 3 and as reported as entry 1 of chlorophenol as shown in Scheme 4 and as was done in the
Table 1. Process chemists at Bristol-Myers Squibb reported the discovery chemistry route.
ratio of products to be 80% of product 11, 15% of product 11a
3-Bromo-2-chloropyridine, 17 was reacted with hydrazine in
and 5% of product 11b under the same conditions, but on a water at 100°C to give 3-bromo-2-hydrazinylpyridine, 18 in
larger scale. As expected, reducing the number equivalents of 85% yield. Oxalyl chloride was reacted with clinical grade acid
2
-chlorophenol from five to one and increasing the number of intermediate 14 to generate the acid chloride that was directly
equivalents of 10 to 1.1 slightly increased the yield of 11 and reacted with hydrazine 18 to give hydrazide 19 in 61% yield.
nearly eliminated the production of diether product, 11b, as Cyclization of 19 with phosphorous oxychloride at 92°C
shown in entry 2. Encouraged by this result, increasing the produced compound 20 in 84% yield. Product 20 was saponified
number of equivalents of 10 to 1.2 did not improve the yield with 2.5 M sodium hydroxide to generate alcohol 21 in 88%
of 11 but instead decreased it and resulted in the formation of yield. The alcohol was protected as the methyl ether by reacting
other unidentifiable products as shown in entry 3. Changing with sodium amide and iodomethane to generate intermediate
the solvent from toluene to acetonitrile and using 3 equivalents 3 in 26% yield. Intermediate 3 was thermally reacted at
14
of 10 in entry 4 resulted in the exclusive formation of 11a. 220–225°C with the cesium salt of [ C(U)]2-chlorophenol, 23
14
2 3 2 3 2 3
Replacement of K CO with Cs CO as the base using a large prepared from Cs CO and [ C(U)]2-chlorophenol, 22 in ether
Scheme 3. Practice chemistry of first step of process chemistry route to BMS-770767.
Table 1. Effect of reaction parameters on the ratio of products as determined by HPLC.
Entry
9 (eq)
10 (eq)
Base
Solvent
%11
%11a
%11b
1
2
3
4
5
6
5
1
1
1
1
1
1.0
1.1
1.2
3.0
4.4
3.0
K2CO3
K2CO3
K2CO3
K2CO3
Toluene
Toluene
Toluene
MeCN
DMF
41.5
47.8
8.1
0
25
25
28.3
52.2
47.4
100
75
30.2
Trace
4.5
0
Cs CO3
Trace
Trace
2
Cs CO3
2
DMF
75
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J. Label Compd. Radiopharm 2016

B. D. Maxwell and S. J. Bonacorsi
1
4
Scheme 4. cGMP synthetic route to [phenyl- C(U)BMS-770767.
to give product 24 in 26% yield. During the discovery synthesis was necessary to reduce the specific activity of this material by
14
shown in Scheme 1, the cesium salt of [ C(U)]2-chlorophenol sequentially mixing the radiolabelled material with clinical grade
was prepared in situ and reacted directly with intermediate 3 unlabelled BMS-770767 in ethanol and recrystallizing to give
to produce 4 under microwave heating in 33% yield. During 2.07 mCi of the final drug substance that was 99.9% chemically
practice reactions with unlabelled material, we found that pure, 99.1% radiochemically pure and had a specific activity of
the yield of product 4 was improved to approximately 65% 1.61 μCi/mg. We typically dilute the high specific activity product
when the cesium salt was isolated and then reacted thermally to the low specific activity product over more than one step in
with intermediate
3 in a two-step sequence. However, order to give us another two opportunities to make corrections
during the labelled chemistry run, we experienced lower yields to the amount of unlabelled material that needs to be mixed
than expected because of the smaller scale on which with the labelled material. Completing the dilution in this fashion
the reaction was conducted as well as suffering large losses also gives us another chance to measure radiochemical purities
incurred during purification by preparative HPLC because of and specific activities on material that contains enough
the removal of impurities that eluted close to the retention time radioactivity to measure it reliably. The target specific activity
of the desired product. These impurities were not detected required for the human ADME clinical study was 1.6 μCi/mg. This
during the unlabelled practice reactions. The methyl ether was material was fully tested and met the release criteria for use in
converted to the desired high specific activity product, the human ADME study.
1
4
[
phenyl- C(U)]BMS-770767, 25, with 48% hydrogen bromide in
acetic acid followed by treatment with NaOH (aq) at 65°C. The
Conclusions
crude product was purified by preparative HPLC to give 32 mg
1
4
14
of [phenyl- C(U)]BMS-770767 that was 99.5% chemically pure We initially prepared [phenyl- C(U)]BMS-770767 in 18% yield for
13
and 99.2% radiochemically pure with a specific activity of use in metabolic profiling and [ C ]BMS-770767 in 30% yield to
6
1
49 μCi/mg. To complete the human ADME clinical study, it serve as an standard for LC/MS analysis. Both of these syntheses
J. Label Compd. Radiopharm 2016
Copyright © 2016 John Wiley & Sons, Ltd.
www.jlcr.org

B. D. Maxwell and S. J. Bonacorsi
were completed in three steps in two pots from appropriately
labelled 2-chlorophenol and a late-stage intermediate. For the
human ADME clinical study, we successfully prepared 4.73 mCi
of [phenyl- C(U)]BMS-770767 by developing a new synthetic
route that was a combination of the discovery chemistry and
the process chemistry routes. The product specific activity was
measured at 149 μCi/mg and was 99.5% chemically pure and
[5] J. Li, L. J. Kennedy, H. Wang, J. J. Li, S. J. Walker, Z. Hong, S. P.
O’Connor, A. Nayeem, D. M. Camac, P. E. Morin, S. Sheriff, M. Wang,
T. Harper, R. Golla, R. Seethala, T. Harrity, R. P. Ponticiello, N. N.
Morgan, J. R. Taylor, R. Zebo, D. A. Gordon, J. A. Robl, Chem. Lett
1
4
2
014, 5, 803–808.
[6] J. Li, L. J. Kennedy, H. Wang, J. J. Li, S. J. Walker, Z. Hong, S. P.
O’Connor, X-Y. Ye, S. Chem, S. Wu, D. Yoon, A. Nayeem, D. M. Camac,
P. E. Morin, S. Sheriff, M. Wang, T. Harper, R. Golla, R. Seethala,
T. Harrity, R. P. Ponticiello, N. M. Morgan, J. R. Taylor, R. Zebo, D. A.
Gordon and J. A. Robl. “Optimization of 1,2,4-Triazolopyridines as
Inhibitors of Human 11β-Hydroxysteroid dehydrogenase Type 1:
9
9.2% radiochemically pure. A portion of this product was mixed
with unlabelled clinical grade BMS-770767 in two steps to
reduce the specific activity to 1.61 μCi/mg to give a total of
Discovery of Clinical Candidate BMS-823778” Oral presentation
made at Division of Medicinal Chemistry Session at the 250
American Chemical Society Meeting, Boston, MA, USA August
th
14
2
.07 mCi of [phenyl- C(U)]BMS-770767 that was 99.9%
chemically pure and 99.1% radiochemically pure. All material
met release specifications for use in a human clinical study and
was successfully used in the human ADME study.
1
6-20, 2015.
[
7] J. A. Robl, H. Wang, J. J. Li, L. G. Hamann, L. Simpkins, R. Golla, Y-X. Li,
R. Seethala, T. Zvyaga, T. Harper, M. Hsueh, M. Wang, L. Hansen,
C. Patel, A. Azzara, S. Roonely, S. Sheriff, P. E. Morin, D. M. Camac,
T. W. Harrity, R. Zebo, R. Ponticiello, N. Morgan, J. Taylor and
D. A. Gordon. “Optimization of triazolopyridine based
Acknowledgements
1
1β-hydroxysteroid dehydrogenase type-1 (11βHSD-1) inhibitors
The authors would like to thank members of the Bristol-Myers
Squibb Process Research Development Department for supplies
of clinical grade intermediate 14 and unlabelled clinical grade
BMS-770767. We would also like to thank Sharon Gong of
Bristol-Myers Squibb DCP-Radiochemistry for LC/MS analysis of
leading to the discovery of the clinical candidate BMS-770767”
th
244
American Chemical Society Meeting and Exposition,
Philadelphia, PA, USA August 19-23, 2012, MEDI-217.
8] X. Qian, W. Yang, K. Yamamoto, R. O. Cann, M. Hickey, M. Schmidt,
L. Kolla, J. Li, J. Nye, J. Sawyer, D. Hsieh, F. Buono, N. Strotman and
[
13
M. Lindrud. “Highly efficient synthesis of a potent 11beta-HSD-1
[
C6]BMS-770767.
th
inhibitor containing a [2.2.1]bicyclic functionality” 248 American
Chemical Society Meeting and Exposition, San Francisco, CA, USA
August 10-14, 2014.
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