The syntheses of [14C] and [13C2, 15N3]aprepitant

Article abstract of DOI:10.1002/jlcr.872

In support of a program to develop a treatment for chemotherapy-induced nausea and vomiting, two isotopically labeled forms of neurokinin-1 receptor antagonist aprepitant have been synthesized. A [¹⁴C]-labeled version was synthesized for use in metabolism studies, while a [¹³C ₂, ¹⁵N₃]-labeled version was synthesized for use in a study to determine the bioavailability of the final market image. Both syntheses utilized labeled chloroacetonitrile which was synthesized in two steps from labeled potassium cyanide. Copyright

Full text of DOI:10.1002/jlcr.872

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2004; 47: 837–846.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.872
Research Article
The syntheses of [14C] and [13C2,15N3]aprepitant
Charles S. Elmore*, Dennis C. Dean, Yong Zhang and David G. Mellilo
Merck Research Laboratories, Department of Drug Metabolism, RY80R-104, P.O. Box
2000, Rahway, NJ 07065, USA
Summary
In support of a program to develop a treatment for chemotherapy-induced nausea and
vomiting, two isotopically labeled forms of neurokinin-1 receptor antagonist
aprepitant have been synthesized. A [l4C]-labeled version was synthesized for use in
metabolism studies, while a [13C2,15N3]-labeled version was synthesized for use in a
study to determine the bioavailability of the final market image. Both syntheses
utilized labeled chloroacetonitrile which was synthesized in two steps from labeled
potassium cyanide. Copyright # 2004 John Wiley & Sons, Ltd.
Key Words: substance P; hydroxyacetonitrile; chloroacetonitrile; NK1
Introduction
Neurokinin 1 (NK1) receptor is a G-coupled protein which has the highest
binding affinity for substance P among the endogenous neurokinins.1 The
release of substance P has been linked to inflammation and transmission of
pain.2 As a potential drug target, inhibition of substance P binding to the NK1
receptor has received significant attention over the last decade as a possible
treatment for pain, migraines, chemotherapy-induced nausea and vomiting
(CINV), and depression.3 Recently, Merck’s lead NK1 antagonist, aprepitant
(1),4 was approved for treatment of CINV.
During the course of development, several isotopically labeled aprepitant
tracers were prepared to address a range of drug metabolism and receptor
pharmacology issues. The primary tracer used for metabolism and distribution
studies contained the C-14 label in the morpholine ring, and it showed
aprepitant to be extensively metabolized.5 Since N-dealkylation of the
triazolone ring is a major metabolic pathway in all animal models studied, a
tracer with a C-14 label in the triazolone ring was desired to study the
metabolic fate of this fragment. Additionally, a stable isotope labeled form of
*Correspondence to: C. S. Elmore, R&D Discovery, AstraZeneca Pharmaceuticals LP, B-398A, 1800
Concord Pike, P.O. Box 15437, Wilmington, DE 19850-5437, USA. E-mail: chad.elmore@astrazeneca.com
Copyright # 2004 John Wiley & Sons, Ltd.
Received 17 December 2003
Revised 22 April 2004
Accepted 14 May 2004

838
C. S. ELMORE ET AL.
aprepitant, 1.
aprepitant with a minimum mass increase of 4 was required as a clinical tracer
to determine the human bioavailability of the final market image (for an
example of this type of application; see Reference6). Based on the synthesis of
the above C-14-labeled tracer, incorporation of C-13 and N-15 could be
readily accomplished to provide stable isotope labeled tracer with a mass
increase of 5 amu.
Results and discussion
A retrosynthetic analysis for the C-14-labeled version of NK1 antagonist
tracer [14C]-1 based on the previously reported synthesis of aprepitant7 led to
the logical disconnection into amidrizone [14C]-2 and amine 3 (Scheme 1).
Amine 3 was available internally8 while [14C]-2 could be synthesized from
[14C]chloroacetonitrile by reaction with hydrazine 4. Previous syntheses of
labeled chloroacetonitrile have relied upon the dehydration of labeled
chloroacetamide which necessitated harsh reaction conditions, the incon-
venient and costly preparation of [14C]chloroacetamide, and final purification
by inefficient small-scale distillation.9 We envisioned an alternative prepara-
tion of [l4C]chloroacetonitrile from [l4C]hydroxyacetonitrile which could be
produced by the coupling of K14CN and paraformaldehyde.10
Scheme 1. Retrosynthetic analysis of [14C]aprepitant
Copyright # 2004 John Wiley & Sons, Ltd.
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THE SYNTHESIS OF LABELED APREPITANT
839
The reaction of Kl4CN and paraformaldehyde in water followed by
continuous extraction for 12 h with Et2O gave [l4C]hydroxyacetonitrile in 75%
yield and high radiochemical purity (Scheme 2). The ethereal solution was
reacted directly with SOCl2 to afford [14C]chloroacetonitrile in 64% yield.
Maintaining the temperature at approximately 08C was critical to minimize
the by-product formation. The [14C]chloroacetonitrile was then treated with
NaOMe in MeOH followed by hydrazinocarboxylate 4 to give amidrizone
[14C]-2 in a 67% radiochemical yield. The camphorsulfonic acid salt of
morpholine 3 was coupled with [14C]-2 to give a 55% yield of [14C]-8 which
was cyclized in hot xylene to give [l4C]aprepitant in 74% radiochemical yield
(8.1 mCi, 94% radiochemical purity). Purification by preparative HPLC
followed by crystallization gave 4.6 mCi of [14C]-1 with 99.8% radiochemical
purity.
Scheme 2. Synthesis of [14C]aprepitant, [14C]-1
Our approach to [13C2,15N3]aprepitant was similar to that of the C-14 tracer
except that the synthesis of [l5N2]-4 was also required. While the synthesis of
[15N2]-4 appeared trivial, attempts at mono-acylation of [15N2]hydrazine with
methyl chloroformate using a variety of conditions gave substantial amounts
of the bis-adduct unless a large excess of [15N2]hydrazine was utilized.11 While
the mono-adduct could be separated from the bis-adduct by column
chromatography, other minor impurities were not separated and gave rise to
impurities in subsequent reactions that were difficult to remove. As an
alternative, a three-step procedure which provided [l5N2]-4 as a crystalline solid
in high purity was used instead (Scheme 3). [15N2]Hydrazine was reacted with
Copyright # 2004 John Wiley & Sons, Ltd.
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840
C. S. ELMORE ET AL.
Scheme 3. Synthesis of [l3C2,l5N3]aprepitant
benzil12 to give the corresponding hydrazone, 6, in 80% yield. Acylation of 6
with methyl chloroformate afforded 7 in 38% yield, and 7 was hydrolyzed in
concentrated HCl to give carbamate [l5N2]-4 as the HCl salt in 66% yield and
>95% purity.
The remaining steps in the synthesis of [l3C2,l5N]aprepitant were accom-
plished as previously described for [l4C]aprepitant. Since both [l3C2, 15N]-
hydroxyacetonitrile and [13C2,l5N]chloroacetonitrile are volatile, the quantity
1
of compound present in the ethereal solutions was determined by H NMR
using naphthalene as an internal standard. Purification of the final compound
was effected by preparative HPLC followed by crystallization to give 569 mg
l5
of [13C2, N3]aprepitant with 99.7% UV purity (238 nm).
In summary, we have reported the syntheses of [14C] and [13C2,15N3]apre-
pitant which served as important tracers for obtaining detailed late-stage drug
metabolism information. Both syntheses benefitted from the use of an
improved synthesis of labeled chloroacetonitrile from readily available labeled
precursors.
Copyright # 2004 John Wiley & Sons, Ltd.
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THE SYNTHESIS OF LABELED APREPITANT
841
Experimental
General
[l5N2]hydrazine hydrogen sulfate, potassium [13C,l5N]cyanide, and [13C]
paraformaldehyde were obtained from Cambridge Isotope Laboratories,
and 3 was obtained from Merck Process Research. Anhydrous solvents
(
were obtained from Aldrich and were dried over 4 A molecular sieves for at
least 24 h prior to use. Analytical HPLC was performed using a Shimadzu
HPLC system with LC-10ATVP pumps, a SPD-10AVP UV detector, a
1
CTO-10ASVP column oven heated to 308C, and a SCL-10A controller. H
NMR and C NMR spectra were recorded on a Varian U-400 spectrometer
l3
and were referenced to the residual solvent peak (7.26 and 77.00 ppm
for CDCl3, 3.30 and 49.2 ppm for CD3OD, and 2.49 and 39.5 ppm for
2H6-DMSO). LC/MS analyses were performed on an HP MSD-100 using
a XDB-C8 column, with 5–95% gradient over 15 min with MeCN-2 mM
ammonium formate buffer (pH=3.5) and electrospray ionization. The
reaction products were identified by HPLC comparison with the com-
mercially available materials or Merck Process Chemistry intermediates
when available using either method A (40/60 to 60/40 MeCN/0.1%
aqueous HClO4 gradient elution over 30 min, Zorbax RX C-8); method
B (35/65 to 80/20 MeCN/0.1% H3PO4 over 20 min, YMC ODS-AQ);
method C (20% MeCN–0.1% H3PO4 for 30 min, Zorbax RX C-8); method
D (0–5% MeCN–0.1% phosphoric acid over 30 min, Phenomenex Aqua
C-18); or method E (45% MeCN/0.1% aqueous HClO4 for 30 min,
Zorbax RX C-8). All HPLC analyses were conducted using a flow rate
of 1 ml/min on 4.6 mm ꢀ 250 mm columns heated to 308C and concluded with
a 10 min wash of 100% MeCN. Preparative HPLC conditions are described
separately.
Benzil [15N2]hydrazone ([15N2]-6)
The procedure of Nenitzescu was modified as follows.12 A solution of
15.5 g (117 mmol) of [l5N2]hydrazine sulfate and 39.6 g (483 mmol) of
NaOAc in 100 ml of water was heated for 30 min at 608C under N2. The
solution was diluted with 80 ml of MeOH and was cooled to room tempe-
rature (rt). The resulting precipitate was removed by filtration, and
20.0 g (95.2 mmol) of benzil was added to the solution. The resulting slurry
was heated at 608C for 2 h with vigorous stirring. The solution was
cooled to rt, and the precipitate removed by filtration to give 17.2 g (80%)
of [l5N2]-6 as a yellow solid. LC/MS (M/Z (abundance)): 227.1 (100), 228.1
(15), 249.1(13). 1H NMR (400 MHz, CDCl3) d 7.95 (m, 2H), 7.53 (m, 3H), 7.47
(m, 3H), 7.35 (m, 2H).
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C. S. ELMORE ET AL.
N-(1-[15N]-1-aza-3-oxo-2,3-diphenylprop-1-enyl)[15N]methoxycarboxamide
([15N2]-7)
A solution of 15.5 g (68.5 mmol) of hydrazone [l5N2]-6 in 400 ml of MeCN and
19 ml (240 mmol) of pyridine was stirred rapidly at rt as 21 ml (270 mmol) of
methylchloroformate was added in 2 ml aliquots over 1h. The reaction mixture
was stirred overnight at rt, and the precipitate was removed by filtration. The
solution was concentrated to dryness at reduced pressure to give 23.1 g of a
yellow solid which was purified by flash column chromatography on neutral
alumina (100% hexane to 25% EtOAc in hexane). Product containing
fractions were combined to give 7.40 g (26.1 mmol, 38%) of [15N2]-7 as a
yellow solid. LC/MS (M/Z (abundance)): 285.1 (100), 286.1 (18), 307 (15). 1H
NMR (400 MHz, CDCl3) d 8.60 (t, J=80 Hz, 1H), 8.16 (d, J=7.2 Hz, 1H),
7.86 (d, J=7.1 Hz, 1H), 7.60 (m, 2H), 7.45 (m, 3H), 7.33 (m, 3H), 3.81 (s, 3H).
Methyl [15N2]hydrazinocarbamate hydrochloride ([15N2]-4)
A biphasic solution of 3.33 g (11.7 mmol) of [15N2]-7 in 30 ml of CH2Cl2 and
15 ml of conc. HCl was stirred and heated at 708C under N2, and the reaction
followed by TLC (4:1 Hex:EtOAc) during which time a white precipitate
formed. After 3 h, the solid was removed by filtration through a glass frit to
give 998 mg (7.77 mmol, 66%) of [15N2]-4, as a white solid. 1H NMR (400 MHz,
D6-DMSO) d 3.66 (s). 13C NMR (100 MHz, D6-DMSO) d 156.2 (br), 53.0.
[13C2,15N]Hydroxyacetonitrile
A solution of 4.33 g (64.6 mmol) of K13C15N in 15 ml of water was cooled and
stirred at 08C as 1.96 g (42 mmol) of [13C]paraformaldehyde was added. The
solution was stirred for 35 min at which time the pH was adjusted to 2.5 with
conc. H2SO4. The solution was transferred to a liquid–liquid continuous
extraction apparatus and was extracted with 120 ml Et2O for 48 h. Midway
1
through the extraction an additional 50 ml of ether was added. H NMR
analysis of the ethereal solution using naphthalene as an internal standard
showed a total of 2.50 g (64%) of [l3C2,15N]hydroxyacetonitrile to be present in
30.4 g (ca. 43 ml) of ether. 1H NMR (400 MHz, CDCl3) d 4.78 (br s, 1H), 4.24
(ddd, J=151.2, 6.1, 1.1 Hz, 2H) spectrum also shows two 6 line multiplets at
7.44 (4.5 H), 7.80 (4.5H) for naphthalene and peaks at 3.44 (q, J=7.0 Hz,
33.4H) and 1.17 (t, 50H, J=7.0 Hz) for diethyl ether. 13C NMR (100 MHz,
CDCl3) d 118.0 (dd, J=60, 16 Hz), 48.2 (d, J=58 Hz); the spectrum also
contains H13C15N at 109.1 (d, J=18 Hz) and diethyl ether at 65.7,15.1.
[13C2,l5N]Chloroacetonitrile
A solution of ca. 1.39 g (23.1 mmol) [13C2,l5N]hydroxyacetonitrile in 33 ml of
Et2O and 4.l ml (79 mmol) of pyridine was stirred and cooled at 08C as 4.0 ml
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THE SYNTHESIS OF LABELED APREPITANT
843
(55 mmol) of SOCl2 was added over 45 min. After complete addition, the
reaction was stirred at 08C for 1 h and at rt for 3 h, and 10 ml of a solution of
saturated aq. NaCl was added. The aqueous layer was removed and the
organic layer was extracted with 5 ml of saturated aq. NaCl. The organic
layer was dried (MgSO4) and filtered to give 23.7 g of an ethereal solution.
1H NMR analysis using naphthalene as an internal standard showed
the yield to be 1.20 g (14.9 mmol, 65%) of [13C2,l5N]chloroacetonitrile.
1H NMR (400 MHz, CDCl3) d 4.03 (ddd, J=80, 7.8, 1.7 Hz). 13C
NMR(100 MHz, CDCl3) d 114.3 (dd, J=66, 18 Hz), 24.5 (dd, J=66,
2.5 Hz). The spectrum also shows peaks for naphthalene at 133.4, 127.8,
125.8, diethyl ether at 65.8 and 15.2, and a [13C2,15N] containing by-product at
113 (dd) and 48.2 (d).
N-((1Z)-2-[15N]amino-1-[15N]aza-3-chloro-[1-15N,2,3-13C2]prop-1-enyl)-
methoxycarboxamide ([13C2, 15N3]-2)
A solution of ca. 680 mg (8.51 mmol) of Cl13CH213C15N in 64 ml of ether was
cooled to 08C as 17 ml of a 0.33 M solution (5.64 mmol) of NaOMe in MeOH
was added. The solution was warmed to rt and stirred for 1 h, and 0.50 ml of
HOAc (8.74 mmol) and 984 mg (7.6 mmol) of methyl [l5N2]hydrazinocarba-
mate hydrochloride were added sequentially. The reaction was stirred under
N2 overnight, and the solvent was removed under a stream of N2 to give 1.43 g
1
of [13C2,15N3]-2 as a brown oil. H NMR (D6-DMSO, 400 MHz) d 4.05 (d,
J=76 Hz, 2H), 3.58 (d, J=4.3 Hz, 3H).
N-[3-(2-f(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxyg(3S,2R)-3-(4-fluoro-
phenyl)morpholin-4-yl)(1Z)-2-[15N]amino-1-[15N,13C2]azaprop-1-enyl]-
methoxy-carbox[15N]amide ([13C2, 15N3]-8)
A slurry of 1.15 g (6.7 mmol) of chloroamidrizone [13C2,15N3]-2, 1.72 g
(2.82 mmol) of p-toluenesulfonic acid salt 3, and 2.14 g (15.4 mmol) of
K2CO3 in 7 ml of DMSO was stirred at rt for 2 h at which time HPLC
analysis (method A) showed the reaction to be complete. The reaction mixture
was diluted with 100 ml of water and extracted with EtOAc (4 ꢀ 20 ml). The
combined organic layers were dried (MgSO4), filtered, and concentrated to
dryness to give 4.7 g of a brown oil. The oil was purified by flash column
chromatography on silica gel (20:1:2 PhCH3:EtOAc:MeOH), and product
containing fractions were combined and concentrated to give 2.7 g of a yellow
oil. 1H NMR (400 MHz, CDCl3) d 7.65 (s, 1H), 7.35 (m, 2H), 7.16 (s, 2H), 7.04
(t, J=8.6 Hz, 2H), 4.89 (q, J=6.5 Hz, 1H), 4.34 (d, J=2.8 Hz, 1H), 4.24 (td,
J=11.7, 2.1 Hz, 1H), 3.77 (s, 3H), 3.66 (dd, J=1.9, 11.2 Hz, 1H), 3.50 (m, 1H),
3.47 (s, 1H), 2.97 (d, J=11.7 Hz, 1H), 2.92 (d, J=17, 136 Hz, 1H), 2.51
(t, J=11.8 Hz, 1H), 1.47(d, J=6.6 Hz, 3H).
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[13C2,15N3]aprepitant ([13C2,15N3]-1)
A solution of 2.37 g (4.20 mmol) of [13C2,15N3]-8 in 50 ml of xylene and 15 ml
of diisopropylethylamine was purged with N2 and heated at 1508C for 3 h.
HPLC analysis (method A) showed the reaction to be complete. The solvents
were then removed at reduced pressure to afford 2.471 g of an orange oil. The
compound was taken up in PhCH3 and purified by flash column
chromatography on silica gel (10:1:1 PhCH3:MeOH:EtOAc). Product contain-
ing fractions were combined and concentrated to give 1.34 g of an off white
solid, and HPLC analysis (method A) showed the compound to be 89% pure
by UV analysis at 220 nm. The solid was dissolved in 5 ml of MeOH and 2 ml
of 0.1% H3PO4 and was purified in four portions by preparative HPLC
(Zorbax RX C-8, 50:50 MeCN:0.1% aq. H3PO4, 20 ml/min). The fractions
were analyzed by HPLC (method A) and pure fractions were pooled. The
combined fractions were concentrated at reduced pressure until H2O began
condensing, neutralized to pH>8 with Na2CO3, and extracted with EtOAc
(5 ꢀ 50 ml). The combined organic extracts were dried (MgSO4), filtered, and
concentrated, at reduced pressure to give 839 mg of a white solid. The solid
was dissolved in 5 ml of MeOH and was heated at 308C as 3 ml of water was
added over 1 h by syringe pump. The slurry was heated at 508C and was then
cooled to rt. The solid was removed by filtration through a glass frit and was
washed with 2 ml of water. The solid was dried under vacuum for 3 h to give
569 mg of [13C2,l5N3]aprepitant. HPLC analysis (method B) showed the UV
purity (220 nm) to be 99.6%. LC/MS (M/Z (abundance)): 534.1 (0.63) 535.0
l
(100), 536 (22.1), 537 (3.3), 538 (0.1). H NMR (400 MHz, CD3OD) d 7.71 (s,
1H), 7.52 (t, J=6.5 Hz, 2H), 7.32 (s, 2H), 7.05 (t, J=8.9 Hz, 2H), 4.95 (q,
J=6.6 Hz, 1H), 4.35 (d, J=2.8 Hz, 1H), 4.28 (td, J=11.7, 2.4 Hz, 1H), 3.66
(dq, J=11.4, 1.9 Hz, 1H), 3.56 (dm, J=140 Hz, 1H), 3.49 (t, J=2.4 Hz, 1H),
2.87 (d, J=11.9 Hz, 1H), 2.85 (ddm, J=135, 14.2 Hz, 1H), 2.49 (tt, J=11.5,
2.7 Hz, 1H), 1.44 (d, J=6.7 Hz, 3H).
[l4C]Hydroxyacetonitrile
The previously described route for [l3C2,l5N]hydroxyacetonitrile was followed
using 114 mg (1.75 mmol, 57 mCi/mmol) of K14CN, 4 ml of water, and 56 mg
(1.87 mmol) of paraformaldehyde. Liquid–liquid continuous extraction for
12 h gave 77 ml of an ethereal solution that contained 86 mCi of the desired
1
product. H NMR and HPLC (method C) analysis showed the compound to
be of >95% radiochemical purity.
[l4C]Chloroacetonitrile
The previously described route for [13C2,15N]chloroacetonitrile was followed
using 63 mCi (1.1 mmol, 57 mCi/mmol) of [14C]hydroxyacetonitrile in 51 ml of
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THE SYNTHESIS OF LABELED APREPITANT
845
Et2O, 140 mg (1.7 mmol) of pyridine, and 223 mg (1.9 mmol) of SOCl2 to give
52 mCi in 23 ml of ether. HPLC analysis (method C) showed the product to
have a purity of 82% with 18% [l4C]hydroxyacetonitrile present.
N-((1Z)-2-amino-1-aza-3-chloro-[3-14C]prop-1-enyl)methoxycarbox-amide
([l4C]-2)
The previously described route for [13C2,15N3]-2 was followed using 24.3 mCi
(0.43 mmol, 82% purity, 57 mCi/mmol) of ClCH2 14CN, 98.3 mg (1.3 mmol) of
ClCH2CN, 7 ml of MeOH, 89 mg (1.66 mmol) NaOMe, 100 mg (1.66 mmol) of
HOAc, and 137 mg (1.52 mmol) of methyl hydrazinocarbamate hydrochloride
to give 20 mCi of a methanol solution which contained 63% [l4C]-2, 16%
[l4C]hydroxyacetonitrile, and 10% chloroacetonitrile by HPLC analysis
(method D).
[14C]aprepitant, ([14C]-1)
The previously described route for [13C2,15N3]-1 was followed using 20 mCi
(1.83 mmol, 11 mCi/mmol, 63% radiochemical purity) of chloroamidrizone
[14C]-2, 1.4 g (2.0 mmol) of (R)-camphorsulfonic acid salt 3, and 632 mg
(5.6 mmol) of K2CO3 in 15 ml of DMSO. Product isolation was performed as
described previously to give 11 mCi of [14C]-8. The crude reaction extract was
then refluxed in 30 ml Xylene overnight to give 10 mCi [14C]-1. Prep-HPLC
(Zorbax RX C-8, 45% MeCN–0.1% phosphoric acid, 20 ml/min) gave 5.1 mCi
of [14C]-1 which was crystallized from 2.5 ml MeOH and 1 ml of H2O as
previously described to give 190 mg (4.6 mCi, 23% yield) of [14C]aprepitant
with a radiochemical purity of 99.8% (method E) and a specific activity of
13 mCi/mmol.
Acknowledgements
We would like to thank Dr Allen N. Jones, Steven J. Staskiewicz, and Noel
Byrne for analytical support and Dong-Wei Cai for supplying starting amine 3
and reference samples for synthetic intermediates.
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