Synthesis of stable isotope-labeled metabolites of asenapine

Article abstract of DOI:10.1002/jlcr.2924

The stable isotope-labeled synthesis of four of the major metabolites of asenapine is described. The synthesis of [¹³CD₃]-asenapine N-oxide proceeded in two synthetic steps. Preparation of [¹³CD ₃]-asenapine 11-

Full text of DOI:10.1002/jlcr.2924

Research Article
Received 27 January 2012,
Revised 22 March 2012,
Accepted 27 March 2012
Published online 20 April 2012 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.2924
Synthesis of stable isotope-labeled
metabolites of asenapine
*
Jeffrey T. Kuethe
The stable isotope-labeled synthesis of four of the major metabolites of asenapine is described. The synthesis of [13CD3]-
asenapine N-oxide proceeded in two synthetic steps. Preparation of [13CD3]-asenapine 11-hydroxysulfate and [13C6]-N-
desmethylasenapine paralleled established synthetic protocols with effective utilization of labeled precursors. The synthesis
of [13CD3]-asenapine N+-glucuronide was achieved in three chemical steps followed by purification.
Keywords: asenapine; metabolites; [13CD3]-asenapine N-oxide; [13CD3]-asenapine 11-hydroxysulfate; [13C6]-N-desmethylasenapine;
and [13CD3]-asenapine N+-glucuronide
of [13CD3]-asenapine N-oxide 7, perhaps the simplest of the
Introduction
required metabolites, is outlined in Scheme 1 and began with
desmethylasenapine 4.5 Methylation of 4 was accomplished
Belonging to potent class of dibenzoxepinopyrrolidine com-
pounds, asenapine 1 is currently marketed as a novel antipsychotic
agent for the treatment of schizophrenia and for manic episodes
associated with bipolar disorders. Trade names for asenapine
include Saphris and Sycrest. Asenapine is a multireceptor
antagonist and has a high affinity for a-adrenergic receptors
via an Eschweiler–Clark reductive amination using [13C,D2]
formaldehyde and [D2]-formic acid to give [13CD3]-asenapine 7
in 85% yield.7 Treatment of 6 with meta-chloroperbenzoic
acid (MCPBA) afforded [13CD3]-asenapine N-oxide 7 in 67%
isolated yield.
(a1A, a2A, a2B, a2C), dopamine (D1, D3, D4), histamine (H1, H2) and
serotonin (5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6, 5-HT7).1 The
[13CD3]-asenapine 11-hydroxysulfate 13
clinical efficacy, kinetics, safety, pharmacological profile, metabolism
and excretion for asenapine have recently been reported.2,3 The
major metabolites of asenapine detected in human clinical trials
include, asenapine 11-hydroxysulfate 3, N-desmethylasenapine
4 and asenapine N+-glucuronide 5 (Figure 1).3 Also detected
bioanalytically in certain plasma samples was asenapine N-oxide 2.
These metabolites were observed in both preclinical species and
in humans. The predominant metabolite in plasma of asenapine is
direct N-glucuronidation. Generally considered as a pathway of
detoxification, the formation of N+-glucuronides is a biological
process whereby lipophilic compounds are transformed into
hydrophilic metabolites. Asenapine N+-glucuronide is not believed
to be associated with any adverse effects and only the partent
compound is considered to be responsible for the effects of
asenapine.2 To fully support evaluation of clinical samples, stable
isotope-labeled variants of each of the four major metabolites
were required. Herein, we report the synthesis of [13CD3]-asenapine
N-oxide 7, [13CD3]-asenapine 11-hydroxysulfate 13, [13C6]-N-
desmethylasenapine 24 and [13CD3]-asenapine N+-glucuronide 28.
The preparation of [13CD3]-asenapine 11-hydroxysulfate 13 began
with asenapine
(Scheme 2).8 [13C]-Ethyl chloroformate,
1
generated in situ from [13C]-phosgene and EtOH, was allowed to
react with 1 in refluxing benzene/toluene and provided carbamate
8 in 44% isolated yield. The mass balance was unreacted 1,
presumably due to unproductive formation of [13C]-ethyl
chloroformate. Friedel–Crafts acylation with acetyl chloride in the
presence of AlCl3 furnished acetate 9 in quantitative yield.
Baeyer–Villiger oxidation of 9 with MCPBA (92%) was followed by
hydrolysis with K2CO3/MeOH and provided phenol 11 in 91%
overall yield for the two steps. Reduction of the carbamate with
LiAlD4 in THF gave [13CD3]-11-hydroxyasenapine 12 in 94% yield.
The sulfonylation of 12 proved problematic because of the
insoluble nature of 12 in the reaction solvent (pyridine), and
complete conversion to [13CD3]-asenapine 11-hydroxysulfate 13
was never achieved. Despite the limited conversion, the reaction
proceeded to produce sufficient quantities of 13, which were
purified by reverse phase HPLC to give 13 in 12% unoptimized
yield. The mass balance of the reaction was unreacted 12, which
was recovered in 60% yield.
Results and discussion
[13CD3]-asenapine N-oxide 7
Department of Process Research, Labeled Compound Synthesis Group, Merck &
Co., Inc., Rahway, NJ 08065, USA
The original synthesis of asenapine, the radiochemical syntheses
(including both 3H and 14C) and an improved manufacturing
process have been reported.4–6 Because asenapine is marketed
*Correspondence to: Jeffrey T. Kuethe, Department of Process Research, Labeled
Compound Synthesis Group, Merck & Co., Inc., Rahway, NJ 08065, USA.
as a racemate, each of these syntheses are racemic. The synthesis E-mail: Jeffrey_Kuethe@merck.com
J. Label Compd. Radiopharm 2012, 55 180–185
Copyright © 2012 John Wiley & Sons, Ltd.

J. T. Kuethe
N-desmethylasenapine 4. Because of the potential of transacyla-
tion with acylated hemiacetals, glucuronidation of 4 was best
accomplished with triisobutyl hemiacetal 26.11 Reaction of 26 in
toluene at 50ꢀC for 18 h gave 27 in near quantitative yield.
Methylation of 27 with 13CD3OTf, prepared by reaction of 13CD3I
with silver triflate, proceeded smoothly in dichloroethane at
50ꢀC. The intermediate quaternary ammonium glucuronide was
hydrolyzed directly after concentration of the crude reaction
mixture. Hydrolysis of the isobutyl groups and the methyl ester
with 10% aqueous Na2CO3 in MeOH gave a mixture of the desired
zwitterionic [13CD3]-N+-asenapine glucuronide 28 and minor
amounts (~ 15%) of the eliminated by-product 29, which was
detected by liquid chromatography–mass spectrometry (LC-MS)
in the crude reaction mixture.11 Reverse phase purification
effectively removed all traces of 29 and gave 28 as an inseparable
mixture of all four possible diastereomers in 20% yield from 27.
The formation of all four possible diastereomers was an expected
result as asenapine is racemic and had no detrimental effect on
evaluation of clinical supplies.
In conclusion, the stable isotope-labeled synthesis of the four
major metabolites of asenapine in support evaluation of clinical
samples has been achieved. The preparation of [13CD3]-asenapine
N-oxide 7 proceeded in two chemical steps and in 57% overall
yield. The preparation of [13CD3]-asenapine 11-hydroxysulfate 13
and [13CD3]-desmethylasenapine 24 required incorporation of
the labels at an early stage in the synthesis. An effective labeling
strategy for the preparation of the quaternary ammonium
N-glucuronidation of asenapine allowed for the synthesis of
[13CD3]-asenapine N+-glucuronide 28 in three linear chemical
steps followed by purification by HPLC.
Figure 1. Asenapine and its major metabolites.
[13C6]-N-desmethylasenapine 24
The preparation of a labeled version of N-desmethylasenapine
with >M + 4 necessitated the incorporation of the label within
the carbon framework of the core molecule. To circumvent to
synthesis of a labeled version of sarcosine 17 and provide for a
reasonably straight forward synthesis of a labeled version of
N-desmethylasenapine 4, our efforts focused on starting with
readily available [13C-6]-phenol 14 (Scheme 3). Conversion of 14
to [13C6]-asenapine 23 was straight forward and followed the
published protocol.5 Finally, demethylation was accomplished by
reaction of 23 with a-chloroethyl chloroformate followed by
ethanol hydrolysis to provide [13C6]-N-desmethylasenapine 24 in
60% yield.9
Acknowledgements
The author thanks Dr. David Schenk, Ms. Van Trong and Dr. Eric
Streckfuss of Merck & Co., Inc. for valuable analytical assistance.
In addition, the author thanks Dr. Peter Wiegerinch for helpful
discussions during the synthesis and for providing analytical
samples of unlabeled metabolites of asenapine.
Experimental
[13CD3]-asenapine N+-glucuronide 28
General
To prepare zwitterionic [13CD3]-asenapine N+-glucuronide 28, we
first investigated the direct glucuronidation of [13CD3]-asenapine
by examining the established procedure for glucuronidation of
mirtazapine.10 For example, reaction of 6 with epoxide 25 in the
presence of anhydrous ZnCl2 was investigated under a variety of
conditions (Scheme 4). Unfortunately, no detectable reaction was
observed in all attempts, and this approach was abandoned.
The successful preparation of zwitterionic [13CD3]-asenapine
N+-glucuronide 28 is shown in Scheme 5 and began with
All reactions were carried out under an atmosphere of nitrogen.
Purifications were carried out by using flash column chromatography
on a Teledyne Isco CombiFlash Rf using a mixture of EtOAc and hexanes
unless otherwise stated. All commercially available reagents and sol-
vents were purchased from Aldrich and were used without purification.
Samples were analyzed on an Agilent 1100 CDMSD instrument in API-ES
positive ionization mode. All unlabeled products have previously been
fully characterized elsewhere, where noted in the succeeding
paragraphs.
Scheme 1. Preparation of [13CD3]-asenapine 7.
J. Label Compd. Radiopharm 2012, 55 180–185
Copyright © 2012 John Wiley & Sons, Ltd.
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J. T. Kuethe
Scheme 2. Preparation of [13CD3]-asenapine 11-hydroxysulfate 13.
Scheme 3. Preparation of [13C6]-N-desmethylasenapine 24.
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Copyright © 2012 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2012, 55 180–185

J. T. Kuethe
elute was identified as 8 (1.00 g, 44%) as a colorless oil. The second
product to elute from the column was recovered asenapine 1 (0.95g, 50%).
To a solution of 0.50 g (1.45mmol) of 8 in 10 mL of CH2Cl2 was added
0.52 g (3.92 mmol) of AlCl3 as a solid followed by 0.16ml (2.18 mmol) of
acetyl chloride. The resulting mixture was stirred at room temperature for
1 h and quenched with 20mL of water. The layers were separated, and
the aqueous layer was back extracted with 10mL of CH2Cl2. The combined
organic extracts were washed with 15mL of saturated NaHCO3 and then
15 mL of brine, dried over MgSO4. After filtration of the MgSO4, the solvent
was removed under reduced pressure to afford 0.56 g (99%) of 9, which was
used in the next reaction without further purification.
Scheme 4. Attempted preparation of [13CD3]-asenapine N+-glucuronide 28.
To a solution of 0.50 g (1.29mmol) of 9 in 10 mL of CH2Cl2 was added
1.65 g (7.37 mmol) of MCPBA followed by 0.25 g (1.32 mmol) of TsOH. The
mixture was warmed to 35ꢀC for 6 h, cooled to room temperature and
quenched with 20 mL of water. The layers were separated, and the aqueous
layer was back extracted with 15 mL of CH2Cl2. The combined extracts were
washed with 15mL of 25% Na2S2O3, dried over MgSO4. After filtration of
the MgSO4, the solvent was concentrated under reduced pressure to
give 480 mg (92%) of 10, which was used in the next step without
further purification.
To a solution of 180mg (0.45 mmol) of 10 in 10mL of EtOH was added
185 mg (1.34 mmol) of solid K2CO3. The mixture was stirred at room
temperature for 5h, diluted with 15mL of water and 20 mL of EtOAc. The
layers were separated, and the organic layer was washed with brine, dried
over MgSO4, filtered and concentrated under reduced pressure to give
159mg (99%) of 11.
Preparation of [13CD3]-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1-
H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole 2-oxide (7)
To a solution of 400 mg (1.38 mmol) of [13CD3]-asenapine 6 in 5 mL of
CH2Cl2 was added 445 mg (1.93 mmol) of MCPBA. The resulting mixture
was stirred at room temperature for 2 h. To the reaction mixture was
added 286 mg (2.07 mmol) of solid K2CO3, and the slurry was stirred for
30 min and was filtered eluting with CH2Cl2. The solvent was removed
under reduced pressure, and the residue was purified by silica gel
chromatography eluting with 5% to 12% MeOH/CH2Cl2 to give 283 mg
(67%) of 7 as a colorless foam. LC-MS (EI+) asenapine N-oxide 2: m/z
302.1 (M + H)+; [13CD3]-7 m/z 306.1 (M + H)+. The spectroscopic data
for 7 was in complete agreement with that reported in the literature.12
Preparation of [13CD3]-11-chloro-2-methyl-2,3,3a,12b-tetrahydro-1-
H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole-5-sulfonic acid (13)
To a solution of 39 mg (0.29 mmol) of AlCl3 in 10 mL of THF was added
dropwise 1.04 mL (1.04 mmol) of a 1-M solution of lithium aluminum
To a solution of 9.97 mL (9.97 mmol) of a 1-M solution of [13C]-phosgene deuteride. To the resulting mixture was added 150 mg (0.42 mmol) of
in benzene at 0 ꢀC was added 0.83 mL (10.31 mmol) of pyridine followed
by the dropwise addition of 0.58 mL (9.97 mmol) of ethanol. The reaction 30 min. To the reaction was added sequentially 44 mL of water, 44 mL of
11 in 5 mL of THF and the solution was stirred at room temperature for
mixture was allowed to warm to room temperature and stirred for 2 h
and filtered. To the filtrate was added 1.90 g (6.65 mmol) of asenapine
15% NaOH and 133 mL of water. The slurry was stirred for 15 min and
filtered eluting with EtOAc. The filtrate was dried over MgSO4, filtered
(1) in 10 mL of toluene. The mixture was heated to reflux for 4 h, cooled and concentrated under reduced pressure. The residue was slurried in
to room temperature and concentrated under reduced pressure. The 10 mL of methyl tert-butyl ether (MTBE) and filtered to give 120 mg
residue was purified by silica gel chromatography. The first product to (94%) of 12.
Scheme 5. Preparation of [13CD3]-asenapine N+-glucuronide 28.
J. Label Compd. Radiopharm 2012, 55 180–185
Copyright © 2012 John Wiley & Sons, Ltd.
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J. T. Kuethe
To a slurry of 65 mg (0.21 mmol) of 12 in 250 mL of pyridine was added
To a slurry of 119 mg (3.14 mmol) of lithium aluminium hydride in
37.2 mg (0.23 mmol) of sulfur trioxide-pyridine complex. The reaction 8 mL of MTBE was added 251 mg (1.88 mmol) of AlCl3. The mixture was
mixture was stirred at room temperature for 5 days where conversion cooled to À70 ꢀC, and 192 mg (0.63 mmol) of 21 in 2 mL of THF was
was 40%. The reaction mixture was concentrated under reduced added. The reaction mixture was allowed to warm to room temperature
pressure and the residue re-dissolved in dimethylsulfoxide and purified and stirred for 1 h. To the mixture was added sequentially 119 mL of
by reverse phase HPLC (Waters Xbridge C18, 19 Â 100 mm, 5 mm, linear water, 119 mL of 15% NaOH and 360 mL of water. The solids were filtered
gradient 10% MeCN/0.16% NH4OH in water to 66% MeCN/0.16% NH4OH and the filtrate was concentrated under reduced pressure. The residue
in water, 50 mL/min) to provide 10 mg (12%) of 13. LC-MS (EI+) was purified by silica gel chromatography eluting with 5% MeOH in
Asenapine 11-hydroxysulfate 3: m/z 380.0 (M + H)+; [13CD3]-13 m/z 384.0 CH2Cl2 to provide 165 mg (90%) of 23 as a clear oil.
(M + H)+. The spectroscopic data for 13 and all other intermediates was
To a solution of 150 mg (0.51 mmol) of 23 in 10 mL of dichloroethane
(DCE) was added 0.2mL (2.06 mmol) of a-chloroethyl chloroformate and
the mixture was heated to 100ꢀC for 1h. The solvent was removed under
reduced pressure, and the crude intermediate was dissolved in 4 mL of a
1:1 mixture of EtOH/DCE and heated to 75ꢀC for 2h. The solvent was
removed under reduced pressure, and the residue was purified by silica
gel chromatography eluting with 5% MeOH in CH2Cl2 to afford 85 mg
(59%) of 24. LC-MS (EI+) desmethylasenapine 4: m/z 272.1 (M + H)+; [13C6]-
24m/z 278.1 (M+ H)+. The spectroscopic data for 21 as well as all other
intermediates was in complete agreement with that reported in the
literature.5,6,12
in complete agreement with that reported in the literature.8,12
Preparation of [13C6]-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1-H-
dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole (24)
To solution of 4.50 g (23.80 mmol) of 2,5-dichloroacetophenone, 2.62 g
(26.20 mmol) of [13C6]-phenol 14, and 4.93 g (35.70 mmol) of powdered
K2CO3 in 7 mL of dimethylsulfoxide was added 227 mg (3.57 mmol) of
copper powder. The reaction mixture was heated to 130 ꢀC for 36 h,
cooled to room temperature and diluted with methyl tert-butylether
(MTBE). The resulting slurry was filtered through a pad of Celite eluting
with additional MTBE. The filtrate was washed with 10 mL of 1 N NaOH
and 10 mL of brine, dried of MgSO4, filtered and concentrated under
reduced pressure. The residue was purified by silica gel chromatography
Preparation of [13CD3]-2-((3R,4 S,5S,6 S)-6-carboxy-3,4,5-trihydroxy-
tetrahydro-2H-pyran-2-yl)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-
1-H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol (28)
to give 3.60 g (60%) of
[ A
13C6]-5-chloro-2-phenoxyacetophenone.
mixture of 2.98 g (11.80 mmol) of this material, 550 mg (17.10 mmol) of
sulfur in 5 mL of morpholine, was heated at reflux for 24 . The mixture
was cooled to room temperature and diluted with 25 mL of water and
35 mL of EtOAc. The layers were separated, and the aqueous layer was
back extracted with 20 mL of EtOAc. The combined extracts were washed
with brine, dried over MgSO4, filtered and concentrated under reduced
pressure. The crude product was then dissolved in 20 mL of MeOH and
5.29 g (94.5 mmol) of solid KOH was added, and the mixture was heated
to reflux for 24 h. The reaction mixture was concentrated under reduced
pressure and dissolved in 50 mL of water, washed with 25 mL of MTBE
and then made acidic (pH = 1–2) with 5 N HCl. The product was extracted
with EtOAc (2 Â 30 mL), washed with brine, dried over MgSO4, filtered
and concentrated to give 1.40 g (44%) of 16.
To a solution of 177 mg (0.65 mmol) of 4 in 3 mL of toluene was added
273 mg (0.65 mmol) of 26, and the mixture was warmed to 50 ꢀC for
18 h. The reaction mixture was cooled the room temperature and
concentrated under reduced pressure. The crude product was passed
through a short pad of silica gel eluting with CH2Cl2 to give 430 mg
(98%) of 27 as a mixture of diastereomers and as a colorless foam, which
was sufficiently pure for use in the next reaction.
To a slurry of 1.76 g (6.85 mmol) of silver triflate in 12 mL of CCl4 was
added 1.00 g (6.85 mmol) of 13CD3I, and the mixture was stirred at room
temperature for 18 h. The slurry was filtered through a small pad of Celite
eluting with 2 mL of CCl4 to give ~14 mL of a 6.85 mmol solution
(0.49 mmol)/mL) of 13CD3OTf stock solution, which was used directly in
the next reaction without purification.
To a solution of 1.38 g (5.14 mmol) of 16 in 15 mL of CH2Cl2 was added
0.63 mL (7.19 mmol) of oxalyl chloride followed by one drop of dimethylfor-
mamide. The mixture was stirred at room temperature for 3 h and concen-
trated under reduced pressure. The crude acid chloride was re-dissolved in
10 mL of CH2Cl2 and added to a solution of 0.93 g (6.68 mmol) of sarcosine
17 and 2.50 mL (17.98 mmol) of diisopropylethylamine. The resulting
mixture was stirred for 1 h, diluted with 30 mL of EtOAc and 20 mL of 1 M
H3PO4. The layers were separated, and the organic layer was washed with
brine, dried over MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by passing over a plug of silica gel eluting with
EtOAc to give 1.29 g (71%) of 18.
To a solution of 1.29 g (3.65 mmol) of 18 in 15 mL of toluene was
added 0.51 g (4.56 mmol) of solid KO-tBu. The reaction was stirred at
room temperature for 1 h, quenched by the addition of 10 mL of 6 N
HCl and extracted with EtOAc. The organic layer was dried over MgSO4,
filtered and concentrated to afford 0.90 g (77%) of 19 as a colorless solid.
A mixture of 0.88 g (2.74 mmol) of 19 and 3 g of polyphosphoric acid
was heated to 110 ꢀC for 3 h, cooled to room temperature and diluted
with 25 mL of water. The resulting slurry was filtered and washed with
water. The solid was dried under vacuum/nitrogen sweep for 12 h to give
575 mg (69%) of 20 as a colorless solid.
To a solution of 0.73 mL (0.39 mmol) of the previous stock solution of
13CD3OTf was added 219 mg (0.32 mmol) of 27 in 1 mL of DCE. The
resulting mixture was warmed to 50 ꢀC for 20 h and cooled to room
temperature. The mixture was concentrated under reduced pressure
and re-dissolved in 2 mL of MeOH. To this was then added 0.69 mL of a
10% aqueous solution of Na2CO3, and the mixture was aged at room
temperature for 18 h. The reaction mixture was then washed with 5 mL
of MTBE, and the aqueous phase was purified by reverse phase HPLC
(Restek Ultra II biphenyl 250 Â 30 mm, 5 mm isocratic elution 40%
MeCN/0.1% trifluoroacetic acid in water, 20 mL/min). The pure fractions
were combined and lyophilized to give 30 mg (20%) of 28. LC-MS (EI+)
Asenapine N+-glucuronide 5: m/z 462.2 (M + H)+; [13CD3]-28 m/z 466.2
(M + H)+. The spectroscopic data for 25 was in complete agreement with
that reported in the literature.12
Conflict of Interest
The authors have declared that there is no conflict of interest.
To a solution of 575 mg (1.89mmol) of 20 in 8 mL of MeOH was added
552mg (22.72 mmol) of magnesium metal. After 1-h stirring, the reaction
was quenched with 8 mL of 6 N HCl and extracted with CH2Cl2
(2Â 20 mL). The organic layer was washed with brine, dried over MgSO4,
filtered and concentrated under reduced pressure. The residue was purified
by silica gel chromatography to give 174 mg of 21 and 450mg of 22.
To a solution of 450 mg (1.47mmol) of 22 in 5mL of toluene was
added 0.33mL of DBU. The mixture was aged at room temperature for
2 h, concentrated under reduced pressure and purified by silica gel
chromatography. The process gave a combined total of 250 mg (43%) of 21.
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