Synthesis of carbon-14-labeled isotopomer of 6-(4-methanesulfonylphenyl)-5- [4-(2-piperidin-1-yl-ethoxy)phenoxy]-naphthalen-2-ol HCL salt (LY2066948-[ 14C] HCL salt)

Article abstract of DOI:10.1002/jlcr.1403

Carbon-14-labeled 6-(4-methanesulfonylphenyl)-5-[4-(2-piperidin-1-yl- ethoxy)phenoxy]naphthalen-2-ol, a novel selective estrogen receptor modulator (SERM) was synthesized. The key component, 6-methoxy-1-tetralone-[carbonyl- ¹⁴C], was synthesize

Full text of DOI:10.1002/jlcr.1403

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 706–710.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1403
Research Article
Synthesis of carbon-14-labeled isotopomer of 6-(4-
methanesulfonylphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)
phenoxy]-naphthalen-2-ol HCL salt (LY2066948-[14C]
HCL salt)
FENGJIUN KUO*, DEAN K. CLODFELTER and TAMARA R. PRIEST
Lilly Research Laboratories, Division of Eli Lilly and Company Lilly Corporate Center, Indianapolis, IN 46285, USA
Received 12 January 2007; Accepted 12 May 2007
Abstract: Carbon-14-labeled 6-(4-methanesulfonylphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)phenoxy]naphthalen-2-ol,
a novel selective estrogen receptor modulator (SERM) was synthesized. The key component, 6-methoxy-1-
tetralone-[carbonyl-14C], was synthesized from 3-(3-methoxyphenyl)-propionic acid via an intra-molecular
Friedel–Crafts acylation of 4-(3-methoxyphenyl)butanoic acid-[carboxy-14C]. A palladium catalyzed alpha-keto
arylation of 6-methoxy-1-tetralone with 4-methanesulfonyl-phenyl bromide, followed by a sequence of bromination,
DDQ dehydrogenation, aryl Ullmann reaction, and demethylation with BBr3 gave the desired product LY2066948-
[
14C]. Copyright # 2007 John Wiley & Sons, Ltd.
Keywords: 6-methoxy-1-tetralone-[1-14C]; LY2066948-[14C]; SERM GYN
Introduction
Scheme 1
The HCl salt of compound 6-(4-methanesulfonylphe-
nyl)-5-[4-(2-piperidin-1-yl-ethoxy)phenoxy]naphtha-
len-2-ol (1, LY2066948 HCl) is a novel selective
estrogen receptor modulator (SERM) for the potential
treatment of uterine leiomyoma. It binds with high
affinity to estrogen receptors a and b (ERa and ERb,
respectively) and is a potent uterine antagonist with
minimal effects on the ovaries as determined by serum
biomarkers and histologic evaluation.1 To support the
studies on metabolism and disposition of the com-
pound in a number of animal species it was necessary
to have its carbon-14-labeled isotopomer synthesized.
The chemistry for the preparation of this compound will
be presented here.
A route to label the carbon-14 on the 4-[2-piperidiny-
lethoxy]phenol 3 was ruled out considering the cost
and the possible metabolic instability of the molecule at
that location. In order to put the labeling on inter-
mediate 4, two possible approaches, path A and B,
were considered. Methylation of a commercially avail-
able 4-bromobenzenethiol 7 with a volatile carbon-14-
labeled methyliodide, followed by an oxidation of the
thiol ether will give the corresponding methylsulfone, 5.
Alternatively, the carbon chain on a commercially
available 3-[3-methoxylphenyl]propionic acid, 8, can
be extended by one carbon unit using a carbon-14-
labeled potassium cyanide. Hydrolysis of the nitrile to
the corresponding carboxylic acid, followed by an
intramolecular Friedel–Crafts acylation should give
the desired compound 6-methoxy-1-tetralone, 6.
Although route B will take three radiosynthetic steps
to give the desired intermediate, considering the cost
and the availability of the reagents, it was decided to
take route B to pursuit the synthesis.
Discussion
Retrosynthetic analysis of the target compound 12 gave
two possible approaches to introduce the carbon-14
labeling (Scheme 1).
A
tosylate 9 was prepared in two steps from
carboxylic acid 8 by a borane reduction followed by a
tosylation of the resulting alcohol. Treatment of the
tosylate 9 with a carbon-14-labeled potassium cyanide,
*Correspondence to: Fengjiun Kuo, Eli Lilly and Company, Lilly
Corporate Center, DC0734, Indianapolis, IN 46285, USA.
E-mail: kuo fengjiun@lilly.com
Copyright # 2007 John Wiley & Sons, Ltd.

SYNTHESIS OF CARBON-14-LABELED ISOTOPOMER 707
Scheme 1
followed by a hydrolysis in 1 N NaOH gave a carbon-14-
labeled carboxylic acid 11. Conversion of the acid 11 to
the corresponding acyl chloride followed by an intra-
molecular Friedel–Crafts acylation with AlCl3 in
benzene gave the key intermediate 6-methoxy-1-tetralone-
[carbonyl-14C], 6 (Scheme 2).
novel selective estrogen receptor modulator (SERM).
The key component, 6-methoxy-1-tetralone-[1-14C]
6-[14C] was synthesized by intramolecular Friedel–
Crafts acylation on 4-[3-methoxyphenyl]butanoic acyl
chloride-[carboxy-14C], which was synthesized in five
steps (three radioactive steps) from 3-[3-methoxylphe-
nyl]propionic acid using potassium cyanide-[14C] to
introduce the labeling.
The coupling of keto-enolates with aryl halides is a
very important and useful transformation in organic
synthesis, but has been difficult to achieve until
recently when Hartwig and Buchwald3,4 discovered
the highly active and selective palladium catalysts for
the formation of a-aryl ketones. Thus, the treatment of
6-methoxy-1-tetralone 6 with 4-methanesulfonylphe-
nyl bromide 5 under the conditions described by
Buchward gave a coupling product 4.2 This aryl ketone
4 was then converted to a vinyl bromide 12 with
phosphorus tribromide5 in toluene, followed by dehy-
drogenation with DDQ6 to give the 2-aryl-1-bromo-
naphthalene 2.
Experimental
The H-NMR spectra were obtained on a Varian Mer-
cury-400 spectrometer at 400 (1H). Chemical shifts are
reported in parts per million (ppm) downfield from
tetramethylsilane. Electrospray mass spectra were
obtained on a Waters Micromass ZQ single quadro-
pole mass spectrometer. Flash chromatography was
performed on BiotageTM system. Unless otherwise
noted, the organic extracts were dried over anhydrous
magnesium sulfate. Thin-layer chromatography was
performed on E. Merck silica gel F-254 plates. All
carbon-14-labeled compounds were identified by TLC
and or radio-HPLC comparison with the corresponding
non-labeled isotopomers. Radiochemical purity (RCP)
was assessed by radio-HPLC.
Scheme 2
An Ullmann diaryl ether formation7 was carried out by
heating a degassed solution of aryl bromide 2 and 4-(2-
piperidinylethoxy)phenol 14 in diglyme in the presence
of cuprous chloride and cesium carbonate2 to afford a
free base of compound 13. The free base was then
converted to its hydrochloric acid salt 13 before it was
demethylated with boron trichloride8 to give the desired
final product 1, LY2066948 HCl salt.
Synthesis of 6-methoxy-1-tetralone-[carbonyl-14C], 6
To the solution of a compound tosylate 9 (1.25 g, 4 mmol,
prepared from the corresponding alcohol, which was
prepared from the corresponding acid 9 by borane
reduction) in 5 mL of anhydrous DMF was added
potassium cyanide (143 mg, 2.2 mmol) and carbon-14-
labeled potassium cyanide (1.71 mmol, 94.6 mCi at
55.1 mCi/mmol) with stirring. The resulting mixture was
Conclusions
A general and simple method has been developed for
the synthesis of a carbon-14-labeled LY2066948, a
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 706–710
DOI: 10.1002.jlcr

708 F. KUO ET AL.
O
S
O
Pd(OAc)2, DPEPOS
NaOBu, Toluenet
O
*
O
*
O
MeO
S
O
MeO
8. R=CO2H
9.R=CH2OT
R
MeO
6
4
Br
s
5
10. R=CH2CN-[14C]
11.R=CH2CO2H-[14C]
O
S
O
S
DDQ
Acetonitrile
Br
*
Br
*
O
PBr3
O
Toluene
MeO
MeO
2
12
O
N
OH
14
HCl
O
N
O
1) CuCl, Cs2CO3
S
O
2-methoxyethyl ether,
O
*
2) EtOH/HCl in dioxane
MeO
O
13
HCl
N
O
S
O
BCl3
O
*
HO
1, LY2066948 HCl
Scheme 2
heated gradually to about 808C, and was stirred at that
temperature for about 22 h under argon atmosphere.
After cooling to room temperature, the solution was
diluted with 100 mL of water, and the resulting aqueous
solution was extracted three times with EtOAc/hexanes
(3:1). The combined extracts were washed twice with
water and concentrated with ethanol to give a light brown
residue. After briefly drying in vacuo, this light brown
residue was taken into 10 mL of ethanol and 10 mL of 1 N
NaOH solution. To the solution was added 0.5 mL of 30%
H2O2, and the resulting solution was stirred at 40–508C
for about 2.5 h. The color faded and the solution turned
colorless. This clear colorless solution was then heated to
reflux overnight (about 17 h). TLC (SiO2, 1:1 hexanes/
CH2Cl2) indicated no starting material remained. After
cooling to room temperature, the ethanol was removed
under reduced pressure. The remaining aqueous solution
was diluted with 10 mL of 1 N NaOH, and extracted twice
with ethyl ether to remove any remaining neutral
components. The solution was then adjusted to about
pH 1.0 by adding 6 mL of 5 N HCl, and extracted once with
ethyl acetate. The extract was washed twice with water,
concentrated with ethanol, and then with toluene/EtOAc,
to give the desired acid 11 as a light brown viscous oil
(636 mg, 3.24 mmol, 80.9% from tosylate 9).
This acid 11 was dissolved in 15 mL of anhydrous
benzene to give a clear pale yellow solution, to which
was added 1.5 mL of oxalyl chloride quickly using a
syringe. The reaction flask was equipped with a drying
tube filled with Drierite1, and the solution was stirred
at room temperature overnight. The solution was
concentrated under reduced pressure; the residue
was taken into 10 mL of anhydrous benzene, and the
solution was concentrated again to remove residual
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 706–710
DOI: 10.1002.jlcr

SYNTHESIS OF CARBON-14-LABELED ISOTOPOMER 709
oxalyl chloride. The residue was taken into 16 mL of
anhydrous benzene, and cooled in an ice bath. To the
solution was added 750 mg of anhydrous AlCl3 powder
in one portion with stirring. The solution turned
reddish brown immediately and started to freeze after
stirring in the ice bath for about 45 min. The cooling
bath was removed, and the solution was stirred at room
temperature for about 5 h. TLC (SiO2, 1:1 CH2Cl2/
EtOAc) indicated that most of the starting material was
consumed. The solution was cooled in an ice bath, and
the reaction was quenched by adding 10 mL of ethyl
ether and 15 mL of 1 N HCl. The color of the solution
faded to light greenish yellow. The solution was further
diluted with 25 mL of EtOAc to give clear two layers.
The organic layer was separated, washed twice with
water, and concentrated with ethanol to give a light
yellowish solid. The crude material was purified by the
Biotage1 system eluting with CH2Cl2 to give the desired
product 6-methoxy-1-tetralone-[14C], 6 as a white solid
(493 mg, 2.77 mmol). H-NMR (CDCl3, ppm) of non-
labeled analog: 8.0 (d, 1H), 6.81 (d, 1), 6.70 (s, 1H),
3.82 (s, 3H), 2.90 (t, 2H), 2.60 (t, 2H), 2.10 (m, 2H).
and combined with the crude product from filtrate. The
combined solution was concentrated to give crude 12
as a light yellowish solid. (956 mg, 2.43 mmol). H-NMR
(CDCl3, ppm) of non-labeled analog: 7.98 (d, 2H), 7.66
(d, 2H), 7.58 (d, 1H), 6.80 (d, 1H), 6.72 (br 1H), 3.83 (s,
3H), 3.09 (s, 3H), 2.94 (t, 2H), 2.70 (t, 2H).
The crude solid was suspended in 10 mL of anhy-
drous acetonitrile, and the solution was heated to
reflux to give a clear light brown solution. After slightly
cooling, DDQ (717 mg, 1.3 eq.) was added as a powder
in one portion to the solution. The solution turned dark
immediately, and was heated at reflux for about 6 h
(1108C bath). After cooling to room temperature, a
solution of 10 mL of 1 N NaOH was added, and the
resulting mixture, containing some yellowish solid, was
stirred for 2.5 h. The solid was filtered off, washed with
50% acetonitrile in water in the funnel until no color
was observed in the filtrate. The white solid left in the
funnel was dried in vacuo for about 3 h. The solid was
then dissolved in CH2Cl2, and the solution was
concentrated with EtOAc to give a beige solid. Further
drying in a vacuum oven at 408C overnight gave a crude
desired product 2 (682 mg, 1.73 mmol). Only one spot
was observed on TLC (SiO2, CH2Cl2), and the material
was used in the next step without further purification.
H-NMR (CD3OD, ppm) of non-labeled analog: 8.24
(d, 1H), 8.04 (d, 2H), 7.85 (d, 1H), 7.70 (d, 2H), 7.35
(d, 1H), 7.30 (m, 2H), 3.95 (s, 3H), 3.18 (s, 3H).
Synthesis of 1-bromo-2-(4-methanesulfonyl-phenyl)-
6-methoxy-naphthalene-[14C], 2
To a solution of 6 mL of anhydrous toluene containing
6-methoxy-1-tetralone-[14C], 6, (493 mg, 2.77 mmol)
was added in sequence 690 mg of 14, 35 mg of
Pd(OAc)2, and 80 mg of bis[(2-diphenylphosphino)phe-
nyl] ether (DPEPOS) followed by adding 700 mg of
t-BuONa as a powder in one portion to give a yellow
slurry. The flask was rinsed with 1 mL of anhydrous
toluene, and the slurry was stirred in an oil bath (80–
908C) for about 90 min. TLC (SiO2, 1:1 CH2Cl2/EtOAc)
indicated the disappearance of 1-tetralone 6. The
solution was cooled to room temperature. To this
solution was added 1 mL of PBr3, and the solution
was heated at reflux overnight (about 17 h at 1358C)
with the condenser equipped with a drying tube filled
with Drierite1. After cooling to room temperature,
15 mL of CH2Cl2 was added to this dark brown
heterogeneous mixture with vigorous stirring. The
mixture was filtered, and the solid in the funnel was
rinsed with CH2Cl2. The combined filtrates were
concentrated to remove CH2Cl2, and the remaining
toluene (heterogeneous) solution was diluted with some
ethyl acetate. Some white solid remained, to which
about 25 mL of water was added, and the solution was
stirred for 2 h. Some of the product, 12, remained as a
white solid in the solution, and was filtered off. The
organic layer of the filtrate was separated, washed
twice with water, and concentrated with ethanol. The
white solid left in the funnel was dissolved in CH2Cl2
Synthesis of 1-(2-{4-[2-(4-methanesulfonyl-phenyl)-
6-methoxyl-naphthalen-1-yloxy]-phenoxy}-ethyl)pi-
peridine-[14C] Hydrochloride salt, 13
A heterogeneous solution of 10 mL of diglyme (2-
methoxyethyl ether) containing the crude bromide 2
(682 mg, 1.73 mmol), 14 (765 mg, 2 eq.), CuCl (65 mg)
and Cs2CO3 (2 g, 3.5 eq.) was degassed and flushed
with argon gas five times at room temperature. The
resulting solution was then heated to 1408C for about
48 h as the reaction was monitored by TLC (SiO2,
CH2Cl2, then 10:1 CH2Cl2/MeOH or 10:1 CH2Cl2/
EtOAc). After cooling to room temperature, the brown
heterogeneous solution was purified directly by chro-
matography by loading and eluting the column initially
with CH2Cl2, then with 20:1 CH2Cl2/MeOH. The
desired fractions were collected and concentrated in
vacuo to give a desired product (a free base of 13) as a
white solid (696 mg, 1.3 mmol). H-NMR (CD3OD, ppm)
of non-labeled analog: 7.88 (m, 3H), 7.78 (m, 3H), 7.55
(d, 1H), 7.35 (s, 1H), 7.10 (d, 1H), 6.68 (d, 2H), 6.52 (d,
2H), 3.92 (t, 2H), 3.90 (s, 3H), 3.70 (s, 3H), 2.65 (t, 2H),
2.50 (br, 4H), 1.58 (m, 4H), 1.45 (br, 2H). The solid was
dissolved in a mixed solvent of CH2Cl2 and EtOH, to
which 0.9 mL of 4 N HCl in dioxane was added. The
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 706–710
DOI: 10.1002.jlcr

710 F. KUO ET AL.
resulting clear yellowish solution was concentrated in
vacuo to give a solid residue. This solid was further
dried in vacuo at 408C overnight to give the desired
product 13 as a HCl salt (740 mg). H-NMR (CD3OD,
ppm) of non-labeled analog: 7.85 (m, 6H), 7.78 (d, 1H),
7.55 (s, 1H), 7.12 (d, 1H), 6.76 (d, 2H), 6.60 (d, 2H),
4.20 (m, 2H), 3.92 (s, 3H), 3.45 (m, 4H), 3.30 (br, 2H),
3.10 (s, 3H), 1.7–2.0 (br, 6H). Mass: ½M þ Hꢀþ ¼ 532:3.
The material was dissolved in 8 mL of anhydrous
CH2Cl2, and the resulting solution was divided into
two flasks, concentrated, and dried in vacuo to give two
lots (385 mg in Lot A and 355 mg in Lot B).
at 0.6 and 1.0%. To further purify the product, the
material was suspended in 4 mL of absolute EtOH and
0.55 mL of water, and the slurry was heated in an oil
bath at about 898C for 30 min to give a yellowish clear
solution. After cooling to room temperature, a white
crystalline solid formed. The solution was stirred for
another 30 min. The white solid was filtered off, rinsed
with 95% EtOH, and dried in vacuo at room tempera-
ture overnight to give the desired product 1,
LY2066948-[14C] (191 mg, 0.344 mmol) as an off-white
powder. RCP ¼ 98:8%. Specific activity ¼ 43:1 mCi=mg.
H-NMR (CD3OD, ppm) of free base of non-labeled
analog: 7.78–7.90 (m, 5H), 7.69 (d, 1H), 7.52 (d, 1H),
7.20 (s, 1H), 7.05 (d, 1H), 6.70 (d, 2H), 6.55 (d, 2H),
3.96 (t, 2H), 3.10 (s, 3H), 2.70 (t, 2H), 2.50 (br, 4H),
1.60 (Br, 4H), 1.45 (br, 2H). Mass: ½M þ Hꢀþ ¼ 518:20.
Synthesis of 6-(4-methanesulfonyl-phenyl)-5-[4-(2-
piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol-
[
14C] HCl Salt, 1. LY2066948-[14C] HCl Salt
The aryl methyl ether 13 (Lot A 385 mg, 0.67 mmol) in
the flask was cooled in a dry ice/acetone bath (about
ꢁ508C), to which 4 mL of 1 M solution of BCl3 in CH2Cl2
was quickly added using a syringe. The solution turned
dark brown quickly and was warmed up slowly to room
temperature. The reaction was monitored by TLC (SiO2,
6:1 CH2Cl2/MeOH). After stirring for about 64 h, the
solution was cooled to 58C in an ice bath, and the
reaction was quenched by adding 4 mL of anhydrous
MeOH using a syringe. The solution turned light brown
and was concentrated in vacuo to give a residue as a
yellowish solid. The solid residue was suspended in
CH2Cl2, to which a saturated solution of NaHCO3 wad
added slowly with stirring. The solid dissolved slowly to
give a clear two-layer solution. The organic layer was
separated and concentrated in vacuo. The resulting
residue was purified by the Biotage1 system (SiO2,
CH2Cl2, then 10:1 CH2Cl2/MeOH) to give the desired
product as a free base (290 mg, 0.56 mmol). The free
base was suspended in 5 mL of absolute EtOH and
cooled in an ice bath. To this solution was added
dropwise a solution of 0.25 mL of 4 N HCl in dioxane.
The solid dissolved initially to give a clear solution and
then more solid formed again while stirring in the ice
bath. To the heterogeneous solution was added 9 mL of
MTBE to cause the precipitation of the product. After
stirring in an ice bath for about 30 min and at room
temperature for additional 90 min, the solution was
filtered, and the solid was rinsed with MTBE. Further
drying in vacuo at room temperature gave a product
(293 mg) as a milk-white solid. Analysis by radio-HPLC
indicated RCP ¼ 97:5%, but containing two impurities
Acknowledgements
The authors would like to thank the support from the
colleagues of Department of Isotopic Chemistry and
the colleagues from CPR&D of LRL for providing
compound 14.
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Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 706–710
DOI: 10.1002.jlcr