Synthesis of the NK3 receptor antagonist AZD2624 in C-14-, H-3- and C-13-labeled forms

Article abstract of DOI:10.1002/jlcr.1858

In support of a program to develop an antipsychotic treatment for schizophrenia, three labeled forms of the NK3 receptor antagonist AZD2624 have been prepared. [³H₂]AZD2624 was synthesized by tritiodehalogenation for use in receptor

Full text of DOI:10.1002/jlcr.1858

Research Article
Received 20 September 2010,
Accepted 22 October 2010
Published online 17 February 2011 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1858
Synthesis of the NK3 receptor antagonist
AZD2624 in C-14-, H-3- and C-13-labeled forms
Ã
Charles S. Elmore, Peter N. Dorff, Mark E. Powell, James E. Hall, and
Thomas R. Simpson
In support of a program to develop an antipsychotic treatment for schizophrenia, three labeled forms of the NK3 receptor
antagonist AZD2624 have been prepared. [3H2]AZD2624 was synthesized by tritiodehalogenation for use in receptor
occupancy and autoradiographic studies. [13C6]AZD2624 was prepared for use as an internal standard through the
intermediacy of [13C6]isatin, and two C-14 isotopomers of AZD2624 were prepared from [14C]benzoic acid and [14C]isatin for
a variety of DMPK studies.
Keywords: NK3 receptor antagonist; isatin; AZD2624
considerable debate regarding the therapeutic value of NK3
receptor antagonists in treating schizophrenia.
Introduction
Schizophrenia is a serious psychiatric illness characterized by
positive symptoms such as distorted perception of reality,
hallucinations, delusions, disordered thinking, and paranoia;
negative symptoms such as anergia (lack of energy), anhedonia
(lack of joy in life), and avolition (lack of desire); and cognitive
symptoms such as attention and memory deficits.1,2 Schizo-
phrenia often leads to social isolation or withdrawal. Approxi-
mately 1% of the population develops schizophrenia during
their lifetime and while it affects both genders in equal
proportions, it has an earlier onset age in males. Many
treatments are currently marketed that provide some efficacy
versus the positive symptoms of schizophrenia. Unfortunately,
current therapies, including second generation antipsychotics,
do not have much efficacy in treating the negative or cognitive
symptoms and are sometimes associated with side effects
including: weight gain, extrapyamidal effects, CV effects, and
liability for type II diabetes.2 These treatments are generally
thought to function by reducing dopamine neurotransmission
through modulation of D2 receptors and tend to possess
activity at multiple other targets including adrenergic, muscar-
To address these questions, we developed AZD2624 as a
selective, high-affinity NK3 receptor antagonist. In support of
the pre-clinical and clinical studies, we isotopically labeled this
compound with tritium, C-14, and C-13, and these syntheses will
be detailed herein.
Experimental
General
(1R,2S)1-phenyl-2-hydroxy-propylamine was prepared in two
steps according to the method of Russell.7 [Carbonyl-14C]ben-
zoic acid and methyl [carbonyl-14C]benzoate were prepared
3
from Ba14CO3 using standard methodology.8,9 Handling of H2
was done on a RC Tritec tritium gas manifold.10 AZD2624 was
provided by AstraZeneca CNS-Chemistry. [13C6]aniline was
obtained from Cambridge Isotopes Laboratories, and K14CN
(54 mCi/mmol) and Ba14CO3 (54 mCi/mmol) were obtained from
American Radiolabeled Chemicals, Inc. All other reagents were
obtained from Acros and Sigma-Aldrich and were used without
purification. 1H NMR and 13C NMR spectra were recorded on
Bruker Avance 500 spectrometer and/or an Avance 600 with a
1H, 13C Dual Cryoprobe spectrometer in DMSO, CDCl3, or CD3OD
and were referenced to the residual solvent peak. Assignment of
the protons of AZD2624 and 1 was done using a combination of
COSY, NOESY, and HMBC. LC/MS analyses were performed on an
HP MSD-1100 using a 4.6 ꢀ 100 mm Luna-C18(2) column, with a
10–100% gradient of MeCN-0.1% aq formic acid over 10 min and
electrospray ionization. HPLC analyses were performed using a
inergic, histaminergic, and serotonergic (in particular 5-HT2A
)
receptors.3,4 Because of this lack of efficacy especially in treating
the negative and cognitive aspects of the disease and because
of the side effect liabilities of these substances, considerable
research effort has been focused on the discovery of alternative
therapeutic targets beyond D2 receptor modulators.5 One such
mechanistic alternative is the NK3 receptor. Extensive preclinical
evidence exists to show that NK3 activity modulates mono-
aminergic and amino acid neurotransmission and furthermore,
that NK3 receptor antagonists are active in a range of animal
models.6 Two chemically distinct, high-affinity, selective NK3
receptor antagonists have been evaluated clinically and have
been claimed to show efficacy in Phase II trials. However, both
compounds have been dropped from development and there is
Isotope Chemistry, CNS Chemistry, AstraZeneca Pharmaceuticals LP, Wilmington,
DE 19850, USA
*Correspondence to: Charles S. Elmore, 911 Barley Ct. Landenberg, PA 19350, USA.
E-mail: chad_elmore@yahoo.com
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Copyright r 2011 John Wiley & Sons, Ltd.

C. S. Elmore et al.
Agilent 1100 series HPLC system using either: method A (2.4 mmol, 54 mCi/mmol) of methyl [14C]benzoate was added in
(4.6 ꢀ 100 mm Phenomenex Luna C-18(2), 10–100% MeCN- 5 mL of THF and the solution was stirred overnight. The reaction
0.1% TFA over 20 min), method B (4.6 ꢀ 100 mm Phenomenex mixture was diluted with 50 mL of EtOAc and 50 mL of water
Luna C-18(2), 30–50% MeCN-0.1% TFA over 20 min), method C and the layers separated. The aqueous layer was then extracted
(4.6 ꢀ 100 mm Phenomenex Luna C-18(2), 10–100% MeCN-0.1% twice with 25 mL of EtOAc and the organic extracts were
TFA over 10 min), or method D (2.1 ꢀ 50 mm Zorbax C-8, 5–85% combined to give 94 mCi. HPLC assay (method C) showed a 50%
MeCN-0.1% formic acid over 12 min). All HPLC analyses were radiochemical purity with 37% of residual methyl [14C]benzoate.
conducted using a flow rate of 1 mL/min on columns heated to The volatiles were removed via vacuum distillation and the
301C and concluded with a 5 min wash of 100% MeCN. residue was taken up in 10 mL of THF to give 32 mCi (23%
Preparative HPLC was performed using the following methodol- radiochemical yield) of [14C]-4 (purity of 95%, method C). The
ogy: method E (21.2 ꢀ 250 mm Phenomenex Luna C-18(2), volatiles contained 25 mCi (19%) of methyl [carbonyl-14C]benzo-
50–100% MeOH-0.1% TFA over 40 min, 15 mL/min), method F ate which was of sufficient quality to be recycled in this
(10 ꢀ 250 mm Phenomenex Luna C-18(2), 30–90% MeCN-0.1% procedure without further purification.
TFA over 40 min, 3 mL/min), method G (30 ꢀ 100 mm Pheno-
[1-14C]2-chloroacetophenone ([14C]-5): A solution of 5.7 mCi
menex Gemini C18, 15–42% over 7 min then 42–90% over 5 min (0.11 mmol, 54 mCi/mmol) of [14C]-4 in 0.5 mL of THF was stirred
MeCN-5 mM NH4HCO3, 51 mL/min,), method H (21.2 ꢀ 250 mm at room temperature as 30 mL (0.12 mmol) of 4 M HCl in dioxane
Phenomenex Luna C-18(2), 20–30% MeCN-0.1% TFA over was added and then the solution was heated at 901C for 2 h.
40 min, 15 mL/min), or method I (21.2 ꢀ 250 mm Phenomenex The solvent was removed by distillation at reduced pressure and
Luna C-18(2), 25–70% MeCN-0.1% TFA over 40 min, 15 mL/min). the residue was partitioned between 5 mL of water and 5 mL of
GC/MS analyses were conducted with a Hewlett Packard 6890 MTBE. The layers were separated and the aqueous layer was
GC system and 5973 Mass Selective Detector using a tempera- extracted two additional times with 5 mL of MTBE. The organic
ture gradient of 70–2601C over 20 min. layers were combined to give 5.2 mCi and the solvent was
(S)-N-(1-(3,4-diiodophenyl)propyl)-3-(methylsulfonamido)-2-phe- removed by distillation. HPLC analysis showed a radiochemical
nylquinoline-4-carboxamide (1): A solution of 5 mg (0.011 mmol) purity of 35% (method C).
of AZD2624 in 0.5 mL of TFA was degassed by bubbling
(1H-imidazol-1-yl) [carbonyl-14C]benzoate ([14C]-7): A solution
Ar through the solution and then 10 mg (0.044 mmol) of of 12.5 mCi (0.23 mmol) of [carbonyl-14C]benzoic acid in 2 mL of
N-iodosuccinimide was added and the solution stirred under CH2Cl2 was stirred as 0.10 mL (1.2 mmol) of oxalyl chloride and
Ar overnight. The solution was then concentrated to dryness 0.01 mL of DMF were added sequentially and the resulting
and the residue purified by preparative HPLC (method E) to give solution was stirred for 3 h. The solution was concentrated to
4 mg of a white solid (52%). LC/MS: 712 (100%), 713 (29.8%), 714 dryness under a stream of N2, and the residue was dissolved in
(9.0%). 1H NMR (600 MHz, CDCl3)dppm 0.96 (t, J = 7.2 Hz, 3 H), 2 mL of CH2Cl2 and was then added to a solution of 76 mg
1.89 (m, 1 H), 2.07 (d, J = 5.7 Hz, 1 H), 2.18 (s, 3 H), 5.01 (q, (1.1 mmol) of imidazole in 1 mL of THF. The reaction mixture was
J = 6.4 Hz, 1 H), 7.17 (br. s., 1 H), 7.34 (m, 3 H), 7.67 (br. s., 3 H), stirred for 16 h at room temperature and was then washed four
7.79 (t, J = 7.4 Hz, 3 H), 7.88 (d, J = 7.9 Hz, 1 H), 8.00 (br. s., 1 H), times with 2 mL of water. The organic layer was then dried
8.18 (d, J = 6.0 Hz, 1 H).
(MgSO4) and filtered to give 12.1 mCi of [14C]-7 (97%, radio-
(S)-N-(1-([3,4-3H2]phenyl)propyl)-3-(methylsulfonamido)-2-phenyl- chemical purity 95.5%, method C).
quinoline-4-carboxamide ([3H2]AZD2624): A slurry of 0.35mg
[1-14C]2-nitro-acetophenone ([14C]-8): To a stirred solution of
(0.60 mmol) of iodide 1, 10mL (0.072mmol) of NEt3 and 0.45mg 12.1 mCi (0.22 mmol) of [14C]-7 in 2 mL of THF was added
of 5% Pd/C in 0.5 mL of DMF was degassed using freeze–thaw NaCH2NO2 (formed from 86 mg (1.4 mmol) of MeNO2 and 96 mg
methodology and then 38mBar (0.011mmol, 624 mCi) of 3H2 was (1.4 mmol) of NaOEt in 0.5 mL of EtOH). The resulting slurry was
added to the N2(l)-cooled solution. The solution was warmed to warmed to 751C and stirred overnight. The reaction mixture was
room temperature and was stirred for 2 h. The remaining 3H2 was diluted with 15 mL of water and was acidified to pH 1 with conc
recovered and the volatiles were transferred into a waste HCl. The resulting solution was extracted three times with 20 mL
container. The residue was taken up in 1 mL of EtOH and this of EtOAc. The combined organic layers were dried (MgSO4),
slurry was filtered through a syringe filter to afford 10mCi of filtered, and concentrated to give 10.8 mCi (56% radiochemical
[3H2]AZD2624 with a radiochemical purity of 94.5% (method A). yield) of [14C]-8 with a radiochemical purity of 63% (method C,
Purification of 2.5 mCi of the crude material by semi-preparative assay showed 35% of residual starting material).
HPLC (method F) and isolation by Oasis HLB SepPak gave
[1-14C]2-amino-acetophenone ([14C]-6): A solution of 155 mg
1.67mCi at a radiochemical purity of499.5% (method B) and a (0.69 mmol) of stannous chloride dihydrate in 0.23 mL of conc
specific activity of 37Ci/mmol. LC/MS: 462 (100%), 464 (99%), HCl and 0.18 mL of EtOH was added to 10.8 mCi (0.13 mmol, 63%
460 (26%). 1H NMR (500MHz, CD3OD)dppm 7.31 (m, 0.21 H), 7.40 radiochemical purity) of [14C]-8 under N2 and the resulting
(dt, J = 7.8, 3.8 Hz, 1.5 H), 7.47 (d, J = 7.7 Hz, 2 H), 7.55 (m, 4 H), 7.68 solution was stirred at 701C for 2 h. The solution was diluted
(d, J = 8.2 Hz, 1 H), 7.74 (dd, J = 7.9, 1.4 Hz, 2 H), 7.81 (m, 1 H), 8.09 with 5 mL of water and was then extracted five times with 1 mL
3
(d, J = 8.4 Hz, 1 H). H NMR (534MHz, CD3OD)dppm 7.32 (m, 1 H) of CH2Cl2. The organic extracts were discarded. The aqueous
7.40 (m, 1 H) 7.46 (s, 0.03 H). 3H fproton decoupledgNMR solution was then basified with NaOH and was extracted five
(534MHz, CD3OD)dppm 7.31 (s, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.40 times with 2 mL of CH2Cl2. The combined organic layers were
(d, J = 8.0 Hz, 1 H), 7.40 (s, 1 H), 7.47 (s, 0.13 H).
dried (Na2SO4), filtered, and concentrated to approximately 2 mL
Dimethylsulfoxonium [2-14C]2-phenyl-2-oxoethylide ([14C]-4): to give 5.3 mCi (78% radiochemcial yield) of [14C]-6 (99.5%
solution of 1.54 g (12.0 mmol) of trimethylsulfoxonium radiochemical purity, method C). LC/MS: 138 (100%), 136
A
chloride in 12 mL of THF was stirred as 12.2 mL of 1 M (15.5%), 137 (7.7%).
(12.2 mmol) KOtBu in THF was added. The solution was then
[2-14C]N-(2-oxo-2-phenylethyl)methanesulfonamide
warmed to 701C for 2 h under N2. After cooling to rt, 130 mCi A stirred solution of 5.3 mCi (0.10 mmol) of [14C]-6 in 2 mL of
([14C]-2):
www.jlcr.org
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C. S. Elmore et al.
CH2Cl2 was cooled to 01C and 0.07 mL (0.5 mmol) of NEt3 was 01C and the layers were then separated. The aqueous layer was
added followed by dropwise addition of 0.2 mL (2.5 mmol) of extracted twice with 0.5 mL of CH2Cl2 and the combined organic
methanesulfonyl chloride over 5 min. The solution was stirred at layers were dried (MgSO4). The drying agent was removed by
01C for 1 h and then at room temperature for 1 h. After cooling filtration to give 60 mCi (61%) of ethyl [14C]cyanoformate in
to 01C, the solution was diluted with 3 mL of water and the CH2Cl2 which was used directly in the next reaction without
layers were separated. The aqueous layer was extracted five further characterization.
times with 10 mL of CH2Cl2. The combined organic layers were
Diethyl [14C]oxalate: A solution of 60 mCi (1.1 mmol) of ethyl
washed with 5 mL of saturated aq NaCl and were then dried [14C]cyanoformate in 1.5 mL of CH2Cl2 was added to 0.6 mL
(Na2SO4). The drying agent was removed by filtration to give a (10 mmol) of EtOH and HCl(g) was bubbled through the solution
solution containing 3.8 mCi (64% radiochemical yield) of ([14C]-3 for 30 min. The solvent was then carefully removed under
(90% radiochemical purity, method C).
3-(Methylsulfonamido)-2-phenyl[2-14C]quinoline-4-carboxylic
vacuum. The residue was taken up in 1 mL of water and the
resulting solution was extracted five times with 1 mL of CH2Cl2.
([2-14C]-9): A solution of 22mg (0.15 mmol) of isatin and 60mg The combined organic layers were dried (Polycarbonate-MgSO4)
(1.5mmol) of NaOH in 0.50mL of water was stirred at room and the solution was then purified by silica gel (100% CH2Cl2) to
temperature as 1.65mCi (0.031mmol) of [14C]-2 in 1.25mL of give 45 mCi (75% radiochemical yield) of diethyl [14C]oxalate
EtOH, 0.25mL of THF and 1.25mL of water was added dropwise (91% radiochemical purity, method C).
over 30min. The resulting solution was heated at 851C for 16h.
[Carbonyl-14C]ethyl 2-(2-(tert-butoxycarbonylamino)phenyl)-2-oxoa-
The organics were removed under a stream of N2 and the cetate ([14C]-10): A solution of 280 mg (1.03 mmol) of t-butyl
solution was applied to an Oasis HLB SepPak. The compound was 2-bromophenylcarbamate in 2 mL of Et2O and 2 mL of THF under
eluted from the seppak with MeCN to give 1.5 mCi (42% Ar was stirred as 0.06 mL (0.09 mmol) of 1.6 M MeLi in Et2O was
radiochemical purity) which was purified by Silica Gel chromato- added dropwise. The solution was stirred for 30 min at room
graphy (1–10% MeOH-CH2Cl2) to give 0.65mCi (39% radio- temperature and was then cooled to ꢁ781C as 1.24mL (2.1mmol)
chemical yield) of [2-14C]-9 (97% radiochemical purity, method C). of 1.7 M t-butyllithium in pentane was added dropwise and the
(S)-3-(Methylsulfonamido)-2-phenyl-N-(1-phenylpropyl)[2-14C]-
resulting solution was stirred for 90 min. To this solution was added
quinoline-4-carboxamide ([2-14C]AZD2624): A solution of 0.7 mCi 13 mg (0.09 mmol, 5 mCi) of diethyl [14C]oxalate in 2 mL of Et2O and
(0.013 mmol) [2-14C]-9,15 mg (0.11 mmol) of HOBT and 0.040 mL the solution was stirred for 0.5 h. The reaction was then diluted
(0.36 mmol) of N-methylmorpholine in 1 mL of CH2Cl2 was with 10 mL of Et2O and 5 mL of water and the layers were
stirred as 21 mg (0.11 mmol) of 1-ethyl-3-(3-dimethylaminopro- separated. The organic layer was extracted four times with 1 M
pyl) carbodiimide and 15 mg (0.11 mmol) of (S)-1-phenyl NaOH and the combined aqueous layers were acidified with 5 M
propylamine were added sequentially. After 22 h, the material HCl. The resulting solution was extracted five times with 10 mL of
was diluted with 0.1% aqueous TFA and purified by preparative CH2Cl2. The combined organic layers were dried (Na2SO4) and the
HPLC (method I) to give 0.12 mCi (17% radiochemical yield) of drying reagent removed by filtration to give 3.0 Ci (87%
[14C]AZD2624 (97.3% radiochemical purity, method C) with a radiochemical purity, method C) of [14C]-10.
specific activity of 54 mCi/mmol. LC/MS (M11): 462 (100%), 463
(29.8%), 460 (13.9%).
[Carbonyl-14C]Isatin ([14C]-3): A solution of 21 mg (3.6 mCi,
0.071 mmol) of [14C]-10 in 1 mL of dimethoxyethane was stirred
t-Butyl 2-bromophenylcarbamate: A slurry of 512mg (12.8mmol) as 0.35 mL of conc. HCl was added and the resulting solutiuon
of 60% NaH in oil and 70 mL of THF was stirred as 2.0 g (11.6 mmol) was stirred at 801C for 2 h. The solvent was removed and the
of 2-bromoaniline was added. The solution was heated at reflux for residue taken up in 5 mL of water. The aqueous solution was
1h and after cooling to room temperature, 3.04g (14mmol) di- applied to a 1 g Oasis HLB SepPak column and was washed with
t-butyl carbonate was added. The resulting slurry was stirred for 10 mL of 5% NaHCO3 and 20 mL of water prior to eluting the
30 min and another 512 mg (12.8 mmol) of 60% NaH in oil was compound with 20 mL of MeCN to give 2.9 mCi (74%) of [14C]-3
added. The slurry was heated at reflux for 2 h and at 501C for 72h. (90% radiochemical purity, method C).
Then the reaction mixture was partitioned between 50 mL of water
3-(Methylsulfonamido)-2-phenyl[4-14C]quinoline-4-[14C]carboxylic
and 75mL of Et2O. The layers were separated and the aqueous acid, ([carbonyl, 4-14C]-9): A solution of 2.9 mCi (0.071 mmol) of
layer was extracted twice with 75 mL of Et2O. The combined isatin and 15mg (0.070 mmol) of N-(2-oxo-2-phenylethyl)metha-
organic layers were washed with 50 mL of saturated aqueous nesulfonamide in 0.1 mL of EtOH was heated for 3 min with a
NH4Cl and 50 mL of saturated aq. NaHCO3 and were then dried heat gun. The red gum was diluted with 0.8mL of water and
(Na2SO4). The drying agent was removed by filtration and the 0.2 mL of MeCN and the resulting solution purified by preparative
solvent removed at reduced pressure. The residue was purified by HPLC (method H). Product containing fractions were concen-
silica gel chromatography (5% Et2O in hexane) and the product trated to remove the MeCN and then applied to Oasis SepPak to
containing fractions were combined to give 1.1 g (36%) of t-butyl afford 2.3 mCi (79% radiochemical yield) of [carbonyl, 4-14C]-9
2-bromophenylcarbamate (498% UV area % purity, method C). (95% radiochemical purity, method C) in EtOH. LC/MS (M11): 345
LC/MS(M11-56): 215.9(100%), 217.9 (92%). 1H NMR (500 MHz, (100%), 343 (15.6%), 346 (18.0%).
CDCl3)dppm 1.54 (m, 9 H), 6.89 (td, J=7.6, 1.5Hz, 1 H), 6.98 (br. s.,
(S)-3-(Methylsulfonamido)-2-phenyl-N-(1-phenylpropyl) [4-14C]qui-
1 H), 7.28 (ddd, J=8.5, 7.1, 1.5 Hz, 1 H), 7.49 (dd, J= 7.9, 1.5 Hz, 1 H), noline-4-14C]carboxamide ([carbonyl, 4-14C]AZD2624): A solution of
8.14 (d, J= 7.3 Hz, 1 H). 13C NMR (126 MHz, CDCl3)dppm 28.3, 81.1, 2.3 mCi (0.043 mmol) of [carbonyl, 4-14C]-9, 12 mg (0.082 mmol) of
112.4, 120.1, 123.8, 128.3, 132.2, 136.3, 152.4.
HOBT, and 0.022 mL (0.20 mmol) of N-methylmorpholine in 1.5 mL
Ethyl [14C]cyanoformate:
A
solution of 119 mg (99 mCi, of CH2Cl2 was stirred for 5 min and then 15 mg (0.081 mmol) of
1.77 mmol) of K14CN in 0.8 mL of water was cooled to 01C as (S)-1-phenylpropylamine was added. After stirring 10 min, 11 mg
0.22 mL (0.22 mmol) of 1 M NH4OH in MeOH and 288 mg (0.081 mmol) of (S)-1-phenylpropan-1-amine was added and the
(2.65 mmol) of ethyl chloroformate in 0.8 mL of CH2Cl2 were solution was stirred overnight at room temperature. The solution
added. The bi-phasic mixture was stirred vigorously for 45 min at was concentrated to near dryness and was then purified by
J. Label Compd. Radiopharm 2011, 54 239–246
Copyright r 2011 John Wiley & Sons, Ltd.
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C. S. Elmore et al.
preparative HPLC (method I). The product containing fractions of 100 mg (0.29 mmol) of [13C6]-9 and 70 mg (0.52 mmol) of
were pooled, concentrated to remove the MeCN, and applied to HOBT in 0.2 mL (1.8 mmol) of N-methylmorpholine and 5 mL of
an Oasis HLB SepPak. Elution with 10 mL of EtOH afforded 1.8 mCi CH2Cl2 was stirred under N2 as 84 mg (0.54 mmol) of 1-ethyl-3-
(78% radiochemical yield) of [carbonyl, 4-14C]AZD2426 with a (3-dimethylaminopropyl) carbodiimide was added. After 5 min,
specific acidity of 53 mCi/mmol and radiochemical purity of 99.5% 55 mg (0.41 mmol) of (S)-1-phenylpropylamine was added and
(method C). LC/MS (M11): 462 (100%), 463 (28%), 460 (15%), 463 the solution was stirred overnight. The solution was diluted with
(8.7%). 1H NMR (500 MHz, CDCl3)dppm 0.94 (t, J= 7.4 Hz, 3 H), 1.95 10 mL of CH2Cl2 and was washed with 10 mL of water, 5 mL of
(d of quintet, J = 13.7, 7.8, 7.8, 7.8, 7.8 Hz, 1 H), 2.14 (s, 1 H), 2.17 (m, 0.5 M HCl, and 10 mL of sat. aq. NaHCO3. The organic layer was
3 H), 5.18 (m, 1 H), 7.03 (d, J=7.6 Hz, 1 H), 7.19 (s, 1 H), 7.31 (m, 1 dried (MgSO4) and the drying agent removed by filtration. The
H), 7.39 (m, 4 H), 7.47 (m, 3 H), 7.53 (t, J = 7.6 Hz, 1 H), 7.68 (dd, organic solution was then concentrated to dryness and purified
J=7.8, 1.4Hz, 2 H), 7.74 (m, 2 H), 8.13 (d, J= 8.4 Hz, 1 H). 13C NMR by preparative HPLC (method G) to give 51 mg (38 %) of
(126 MHz, CDCl3)dppm 10.6, 28.8, 41.8, 56.7, 123.4, 124.4, 125.1, [13C6]AZD2624 (99.5% UV area%, method D) as a white solid. LC/
1
127.1, 127.7, 128.1, 128.7, 128.8, 129.2, 129.8, 129.9, 130.7, 138.8, MS (M11): 465 (5.6%), 466 (100%), 467 (24.7%), 468 (7.9%). H
141.1, 143.2, 147.2, 158.1, 165.0.
NMR (500 MHz, DMSO-d6)dppm 0.92 (t, J = 7.3 Hz, 3 H), 1.84 (d of
2-(Hydroxyimino)-N-[13C6]phenylacetamide ([13C6]-11): A solu- septet, J = 65, 6.8 Hz, 2 H), 2.37 (s, 3 H), 5.01 (q, J = 7.5 Hz, 1 H),
tion of 1.00 g (10.1 mmol) of [13C6]aniline in 10 mL of water and 7.29 (m, 1 H), 7.38 (t, J = 7.6 Hz, 2 H), 7.48 (m, 5 H), 7.78 (d,
1 mL of concentrated HCl was stirred as 2.01 g (13.7 mmol) of J = 6.7 Hz, 3 H), 7.81 (d, J = 155 Hz, 1 H), 8.06 (d, J = 161 Hz, 1 H),
chloral in 30 mL of water and 30 g (211 mmol) of Na2SO4 in 9.16 (d, J = 7.3 Hz, 1 H), 9.31 (s, 1 H). 13C NMR (126 MHz, DMSO-
80 mL of water were added sequentially. After stirring 20 min, d6)dppm 124.2 (t, J = 56 Hz), 125.2 (t, J = 55 Hz), 127.2 (t,
2.40 g (72.7 mmol) of hydroxylamine in 10 mL of water was J = 55 Hz), 128.8 (t, J = 59 Hz), 130.3 (t, J = 54 Hz), 146 (t, J = 58 Hz).
added and the solution warmed to 1051C. After 2 h, the solution
N-((1R,2S)-2-hydroxy-1-phenylpropyl)-3-(methylsulfonamido)-2-
was cooled to 01C and the resulting precipitate was removed by phenyl[4a, 5, 6, 7, 8, 8a-13C6]quinoline-4-carboxamide ([13C6]-12):
filtration and was allowed to air dry for 12 h to give 2 g (133%) of A solution of 100 mg (0.29 mmol) of [13C6]-9 and 70 mg
[
13C6]-11 as white solid.
(0.52 mmol) of HOBT in 0.2 mL (1.8 mmol) of N-methylmorpho-
[13C6]Isatin ([13C6]-3): A solution of 1.0 g (5.1 mmol, containing line and 5 mL of CH2Cl2 was stirred under N2 as 84 mg
33% water) of [13C6]-11 in 2 mL of concentrated H2SO4 was (0.54 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
heated at 651C for 1 h. The solution was poured slowly into was added. After 5 min, 54 mg (0.36 mmol) of (R)-1-amino-1-
100 mL of ice and the orange solid removed by filtration. The phenylpropan-2-ol was added and the solution was stirred
solid was dissolved in EtOAc and the resulting solution was overnight. LC/MS assay indicated substantial starting material
dried (MgSO4). The dying agent was removed by filtration and remaining; therefore, 70 mg (0.52 mmol) of HOBT, 0.2 mL
the solvent was removed at reduced pressure to give 0.42 g (1.8 mmol) of N-methylmorpholine, 84 mg (0.54 mmol) of 1-
(56% yield from [13C6]aniline) of [13C6]-3 as an orange solid. LC/ ethyl-3-(3-dimethylaminopropyl) carbodiimide and 54 mg
MS (M11): 154 (100%), 153 (5.6%), 155 (5.5%). 1H NMR (500 MHz, (0.36 mmol) of (R)-1-amino-1-phenylpropan-2-ol were added
CDCl3)dppm 6.91 (dq, J = 164, 6.7 Hz, 1 H), 7.13 (dq, J = 165, and the solution was stirred 3 h longer. The solution was diluted
7.6 Hz, 1 H), 7.56 (dquin, J = 162, 9.2 Hz, 1 H), 7.62 (dq, J = 166, with 10 mL of CH2Cl2 and was washed with 10 mL of water, 5 mL
8.2 Hz, 1 H), 8.01 (br. s., 4 H). 13C NMR (126 MHz, CDCl3)dppm of 0.5 M HCl, and 10 mL of sat. aq. NaHCO3. The organic layer
112.2 (dddd, J = 67, 57, 6.4, 2.7 Hz), 118.2 (ddd, J = 62, 58, 8.5 Hz), was dried (MgSO4) and the drying agent removed by filtration.
124.0 (tdd, J = 56, 9.1, 1.8 Hz), 125.8 (ddd, J = 64, 56, 5.5 Hz), 138.6 The solution was concentrated to dryness to give 130 mg (94%)
(td, J = 57, 8.2 Hz), 149.0 (ddd, J = 67, 58, 10 Hz).
3-(Methylsulfonamido)-2-phenyl[4a, 5, 6, 7, 8, 8a-13C6]quinoline-4- LC/MS (M11): 482 (100%), 483 (24.6%), 481 (7.8%), 480 (0.1%).
carboxylic acid ([13C6]-9): A solution of 0.57 g (3.35 mmol) of
(R)-3-(methylsulfonamido)-N-(2-oxo-1-phenylpropyl)-2-phenyl
of [13C6]-12 which was carried directly into the next reaction.
[13C6]isatin, 1.54 g (37.5 mmol) of NaOH and 3 mL of water was [4a, 5, 6, 7, 8, 8a-13C6]quinoline-4-carboxamide ([13C6]-13): A
stirred at 851C for 20 min. A solution of 0.90 g (4.1 mmol) of N-(2- solution of ca 130 mg (0.29 mmol) of [13C6]-12 in 5 mL of CH2Cl2
oxo-2-phenylethyl)methanesulfonamide in 20 mL of EtOH, 20 mL of was stirred as 220 mg (1.0 mmol) of pyridium chlorochromate
water, and 10mL of THF was added dropwise and was stirred was added. After 1 h, the reaction was concentrated to dryness
overnight. The organic solvents were removed under reduced and then taken up in 5 mL of CH2Cl2. The resulting solution was
pressure and the aqueous solution was washed twice with 20 mL of filtered. Purification by preparative HPLC (method G) afforded
ether. The aqueous layer was acidified to pH 1 with concentrated 21 mg (15% yield from [13C6]-9) of [13C6]-13 (96.5% UV area%
HCl and was then extracted twice with 100 mL of EtOAc. The purity, method D) as a white solid. LC./MS: 480 (100%), 481
organic layer was dried (MgSO4) and then filtered. The organic (24%), 479 (8.4%), 478 (0.3%). 1H NMR (500 MHz, DMSO-d6)dppm
solution was concentrated to dryness and was then recrystallized 2.20 (s, 3 H), 2.42 (s, 3 H), 5.86 (d, J = 6.1 Hz, 1 H), 7.45 (m, 8 H),
from a minimum of MeCN to give 0.67 g (52%) of [13C6]-9 as a 7.82 (d, J = 155.0 Hz, 1 H), 7.80 (d, J = 6.7 Hz, 3 H), 8.06 (d,
yellow solid. LC/MS (M11): 349 (100%), 350 (14.2%), 348 (5.7%). 1H J = 155.0 Hz, 1 H), 7.96 (d, J = 145.0 Hz, 1 H), 9.43 (d, J = 6.1 Hz, 1
NMR (500 MHz, CD3OD)dppm 2.51 (s, 3 H), 7.53 (m, 4 H), 7.71 (dm, H). 13C NMR (126 MHz, DMSO-d6)dppm 124.2 (t, J = 52 Hz), 125.5
J= 165 Hz, 1 H), 7.76 (m, 1 H), 7.86 (dm, J= 165 Hz, 1 H), 8.07 (d, (td, J = 56, 3.6 Hz), 127.3 (ddd, J = 56, 52, 8.0 Hz), 128.7 (t, J = 60 Hz),
J= 163.0 Hz, 1 H), 8.12 (d, J= 165 Hz, 1 H). 1H fC-13 decoupledg NMR 130.3 (t, J= 53 Hz), 145.9 (t, J=59Hz).
(500 MHz, CD3OD)dppm 2.51 (s, 3 H), 7.54 (m, 3 H), 7.71 (t, J=7.8Hz,
1 H), 7.76 (d, J= 6.7 Hz, 1 H), 7.86 (t, J= 7.0 Hz, 1 H), 8.07 (d, J=8.5Hz,
1 H), 8.12 (d, J=8.5Hz, 1 H). 13C NMR (126 MHz, CD3OD)dppm 123.8
(m), 125.5 (m), 127.8 (m), 128.0 (m), 130.7 (m), 145.9 (m).
Results
[3H2]AZD2624 was required for use in receptor occupancy and
(S)-3-(Methylsulfonamido)-2-phenyl-N-(1-phenylpropyl)[4a, 5, 6, autoradiographic studies. The site of labeling was not critical so
7, 8, 8a-13C6]quinoline-4-carboxamide ([13C6]AZD2624): A solution long as the tritium label was in a non-exchangable location with
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Copyright r 2011 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2011, 54 239–246

C. S. Elmore et al.
a specific activity of430 Ci/mmol. Unlabeled AZD2624 was fragments that were considered for C-14 labeling: methanesul-
iodinated with N-iodosuccinimide in TFA and the iodide fonamide 2 and isatin, 3 (Scheme 2). We investigated two routes
(1) subjected to tritiodehalogenation (Scheme 1). Purification leading to [14C]sulfonamide 2 both of which originated from
by semi-preparative HPLC gave [3H2]AZD2624 with a specific [14C]benzoic acid. In route A, benzoic acid would be converted
activity of 37 Ci/mmol. The sites of tritiation were confirmed by to an a-chloroketone via the sulfur ylide and subsequently to
3H NMR. As can be seen from the 3H NMR (Figure 1), the ratio of
[
14C]-2 via nucleophilic displacement. In route B, benzoic acid
tritium is an approximately 1:1 split between the para and meta would be coupled with nitromethane (offering an alternative
positions of the phenylpropyl ring. The proton decoupled 3H site of label incorporation) to give the a-nitroketone which could
NMR shows a mixture of two singlets and two doublet in be reduced and then converted to [14C]-2. Route C which
approximately 1:1:1:1 ratio which correspond to meta and para targeted label incorporation in isatin was envisioned as
monotritiated AZD2624 and meta and para ditritiated AZD2624. consisting of the coupling of aniline and [14C]diethyloxalate.
We next turned our efforts to the synthesis of C-14-labeled
AZD2624. The medicinal chemistry approach offered two benzoate was reacted with trimethylsulfoxonium chloride to
We chose to first investigate Route A. Methyl [carbonyl-14C]-
3H
I
3H
I
3H2, Pd/C,
O
NH
O
S
O
NIS, TFA
O
NH
H
O
NH
H
O
O
S
O
N
H
NEt3, DMF
N S
O
N
N
N
N
[3H2]AZD2624
1
AZD2624
Scheme 1. Preparation of [3H2]AZD2624.
Figure 1. A stacked plot of (A) 1H NMR of unlabeled AZD2624 (B) 1H NMR of [3H2]AZD2624 (C) 3H NMR of [3H2]AZD2624 (D) proton decoupled 3H NMR of [3H2]AZD2624.
J. Label Compd. Radiopharm 2011, 54 239–246
Copyright r 2011 John Wiley & Sons, Ltd.
www.jlcr.org

C. S. Elmore et al.
O
O
Route A
Route B
O
SOMe2
Cl
NHSO2Me
2
O
O
H
NO2
O
O
OH
O
NH
O
H
O
S
O
H
N S
O
N
N
N
AZD2624
Route C
H
O
OEt
O
O
N
H2N
O
O
O
O
O
3
Scheme 2. Retrosynthetic analysis of C-14-labeled AZD2624.
O
14C
performed on the same day. Careful temperature control was
required during the sulfonylation to minimize decomposition and
provided the target compound in 64% radiochemical yield.
Sulfonamide [14C]-2 was then reacted with isatin to give acid
O
14C
SOMe2
Me3SCl, KOtBu,
HCl
O
Dioxane
35%
THF
23%
14C]-9 in 39% radiochemical yield. Peptide coupling of [14C]-9 to
[
14C]-4
[
give [2-14C]AZD2624 occurred in low yield but provided an initial
batch of [2-14C]AZD2624 for DMPK studies. The difficulties
encountered in the handling of [14C]-6 made Route B unattrac-
tive. Therefore, we turned our attention to Route C.
N
O
N
N
O
N
14C
NH2
14C
Cl
NaI, HCl, EtOH, H2O
low yield
Lastly we investigated Route C which goes via [14C]isatin.
14C]-5
[
14C]-6
[
There are multiple reports of labeled isatins in the literature16–18
;
three of these procedures couple an aniline or Boc-protected
aniline with chloral or ethyl oxalate. Diethyl [14C]oxylate was
prepared in two steps using a modification of the procedure
Scheme 3. Investigation of Route A towards C-14-labeled AZD2624.
give b-keto sulfur ylide [14C]-4, albeit in poor yield (Scheme 3).11 reported by Wilmes (Scheme 5).19 K14CN was coupled with ethyl
A considerable amount of methyl [carbonyl-14C]benzoate was chloroformate in a biphasic mixture of dichloromethane and
recovered during the reaction, accounting for the poor yield. water to afford the ethyl [14C]cyanoformate in 60% yield.
Ylide [14C]-4 was then reacted with anhydrous HCl in dioxane to Ethanolysis of the cyanoformate to diethyl [14C]oxylate pro-
give the corresponding chloride [14C]-5 in 35% yield.11 The ceeded in 75% radiochemical yield after purification by silica gel
reaction produced many radiochemical impurities and purifica- chromatography. Ortho lithiation of Boc-protected aniline
tion was difficult due to the impurity profile and the reactivity of followed by reaction with diethyl oxylate gave poor results in
20–22
[
14C]-5. Conversion of [14C]-5 to amine [14C]-6 was attempted our hands,17,
but halogen-metal exchange of t-butyl
on the crude reaction mixture using hexamine in EtOH,12 but a carbamate protected 2-bromoaniline with t-butyllithium to
low yield was observed likely due to the low purity of the generate the anion followed by coupling with diethyl [14C]oxy-
starting material. As the radiochemical yields of this route were late afford diketone [14C]-10 in 60% yield on a small scale
low and the purifications difficult, we sought an alternate route. (Scheme 6). The yield of the reaction dropped to 20% when the
Next we investigated Route B. [Carbonyl-14C]benzoic acid reaction scale was increased from 5 mCi to 50 mCi perhaps due
was activated as the imidazole amide ([14C]-7)13 and sub- to loss of temperature control. The diketone was then cyclized
sequently reacted with nitromethane to give nitro adduct [14C]-8 to [14C]isatin [14C]-3 in 74% radiochemical yield. Coupling with
(Scheme 4).14 Reduction of the nitro to give amine [14C]-6 with N-(2-oxo-2-phenylethyl)methanesulfonamide afforded acid [car-
SnCl2 in concentrated HCl proceeded in modest yield,15 but bonyl, 4-14C]-9 in 79% radiochemical yield. This time the final
isolation of the amine proved to be problematic. Multiple peptide coupling was smoothly accomplished to give a 78%
extractions were required to remove the majority of the radiochemical yield of the target compound after HPLC
compound from the aqueous layer, and if the compound was purification.
warmed above room temperature or concentrated to near
Finally we turned our attention to the preparation of stable
dryness it decomposed, presumably via self condensation. To isotope-labeled AZD2624 which was required for use as an
minimize the decomposition of amine [14C]-6, the isolation and internal standard for mass spectrometry to allow quanititation of
subsequent conversion of [14C]-6 to the sulfonamide [14C]-2 were AZD2624 in biological samples. A minimum mass increase of
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Copyright r 2011 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2011, 54 239–246

C. S. Elmore et al.
O
O
14C
1. Oxalyl Chloride, CH2Cl2
2. imidazole, THF
97%
14C
MeNO2, NaOEt,
THF, 75 ˚C
63%
H
O
N
N
[
14C]-7
O
O
14C
NH2
14C
NO2
SnCl2, HCl,
EtOH, H2O, 70 ˚C
69%
MeSO2Cl, NEt3,
CH2Cl2, 0 ˚C
64%
[
14C]-6
[
14C]-8
H
N
O
OH
O
S
O
H
N
O
14C
O
O
NHSO2Me
14C
N
NaOH, H2O, EtOH,
THF, 85 ˚C
[
14C]-2
[2-14C]-9
39%
NH2
O
NH
O
S
O
H
NMM, HOBT,
EDC, CH2Cl2
N
14C
N
17%
[2-14C]AZD2624
Scheme 4. Synthesis of [2-14C]AZD2624 via Route B.
O
O
O
HCl, EtOH,
O
Cl
N
14C K
O
14C
O
14C N
O
NH4OH, MeOH,
CH2Cl2, water, 0 ˚C
CH2Cl2, 50 ˚C
75%
O
60%
Scheme 5. Preparation of diethyl [14C]oxylate using a modification of the procedure reported by Wilmes.15
1. MeLi, Et2O, THF,
H
H
N
H
N
2. t-BuLi, -78 ˚C
N
O
HCl,
DME, 80 ˚C
74%
O
14C
O
14C
O
3.
O
O
O
14C
O
14C
O
O
Br
O
O
14C
O
14C]-10
[
14C]-3
[
20 to 60%
14CO2H
O
Ph
O
S
H
O
14C
N
NHSO2Me
NH
14C
O
S
O
Ph
NH2
H
O
14C
N
HOBT, NMM,
CH2Cl2
EtOH
79%
N
N
78%
[carbonyl, 4-14C]-9
[carbonyl, 4-14C]AZD2624
Scheme 6. Preparation of [carbonyl, 4-14C]AZD2624 via [14C]isatin (Route C).
four daltons and no detectable amount of the unlabeled
[
13C6]-9 as previously described. At this point the material
material was needed. Based on our previous experience, we was split: a portion being converted to [13C6]AZD2624 as
elected to target the isatin portion for label incorporation. Isatin previously described for the C-14-labeled material and a
has been labeled with N-15,23 and deuterium18 previously and portion being converted to the ketone metabolite of AZD2624
our selected route was very similar to those reports. The reaction (Scheme 8). The metabolite was prepared by peptide coupling
of [13C6]aniline with chloral gave acetanilide
[
13C6]-11 of acid [13C6]-9 to give alcohol [13C6]-12 which was reacted with
which was converted to [13C6]isatin by heating in sulfuric PCC to give ketone [13C6]-13 in 15% isolated yield after
acid (Scheme 7). Isatin ([13C6]-3 was then converted to acid preparative HPLC.
J. Label Compd. Radiopharm 2011, 54 239–246
Copyright r 2011 John Wiley & Sons, Ltd.
www.jlcr.org

C. S. Elmore et al.
O
O
NOH
NH2
*
HN
*
H
Cl3C
H
H2SO4
65 ˚ C
N
O
*
HCl, Na2SO4,
water, NH2OH
O
[
13C6]-11
[
13C6]-3
O
O
H
Ph
N
S
O
OH
O
S
H
O
O
NH
H
N
NH2
N
O
S
O
O
*
HOBT, NMM,
CH2Cl2
NaOH, Water, 85 ˚C
Et OH, THF
N
*
N
78%
95%
[
13C6]-9
[
13C6]AZD2624
*denotes 13C6 labeled aromatic ring
Scheme 7. Preparation of [13C6]AZD2624.
OH
OH
O
Ph
O
OH
H
O
NH2
O
NH
O
NH
N S
O
PCC, CH2Cl2
O
S
O
O
S
O
H
H
*
N
N
HOBT, NMM,
CH2Cl2
N
*
*
N
N
[
13C6]-9
[
13C6]-9
15% from
[
13C6]-12
[
13C6]-13
*denotes 13C6 labeled aromatic ring
Scheme 8. Preparartion of [13C6]-13.
[8] C. S. Elmore, J. E. Hall, X. Ye, J. R. Heys, J. Label. Compd.
Radiopharm. 2007, 50, 412–413.
Conclusion
`
[9] W. Shieh, S. Dell, O. RepicIŒ, J. Org. Chem. 2002, 67, 2188–2191.
In support of the AZD2624 program, we synthesized three
different labeled forms of AZD2624: 3H2, 13C6 and two 14C
isotopomers. The tritiation was accomplished in a straighfor-
ward manner as was the C-13 labeling. The C-14 labeling,
however, required considerable development and ultimately
three routes to arrive at a sufficient amount of material and to
progress the project were developed.
[10] R. L. Crumbie, J. S. Nimitz, H. S. Mosher, J. Org. Chem. 1982, 47,
4040–4045.
[11] D. Wang, M. D. Schwinden, L. Radesca, B. Patel, D. Kronenthal,
M. Huang, W. A. Nugent, J. Org. Chem. 2004, 69, 1629–1633.
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J. M. Tesorero, J. Org. Chem. 1989, 54, 5620–5623.
[14] C. S. Elmore, The use of isotopically labeled compounds in drug
discovery. In Annual Reports in Medicinal Chemistry (Eds.: John E.
Macor), Academic Press, Oxford, UK, 2009, pp. 515–534.
[15] L. M. Long, H. D. Troutman, J. Am. Chem. Soc. 1949, 71,
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J. Label Compd. Radiopharm 2011, 54 239–246