Synthesis of [3H]ABT-518, a matrix metalloproteinase inhibitor (MMPI) labeled in the phenyl rings

Article abstract of DOI:10.1002/jlcr.1574

A novel matrix metalloproteinase inhibitor, ABT-518, [S-(R*, R*)]-N-[1-(2, 2-dimethyl-1,3-dioxol-4-yl)-2-[[4-[4-(trifluoromethoxy)- phenoxy]phenyl]sulfonyl]ethyl]-N-hydroxyformamide, was labeled with tritium in two phenyl rings in a sevenstep synthesis. T

Full text of DOI:10.1002/jlcr.1574

Research Article
Received 24 September 2008,
Revised 17 November 2008,
Accepted 27 November 2008
Published online 8 January 2009 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1574
Synthesis of [3H]ABT-518, a matrix
metalloproteinase inhibitor (MMPI)
labeled in the phenyl rings
Ã
Shirish N. Raja,a Bruce W. Surber,a Jia Du,a and Jeffrey L. Crossb
A novel matrix metalloproteinase inhibitor, ABT-518, [S-(R*, R*)]-N-[1-(2, 2-dimethyl-1,3-dioxol-4-yl)-2-[[4-[4-(trifluoro-
methoxy)-phenoxy]phenyl]sulfonyl]ethyl]-N-hydroxyformamide, was labeled with tritium in two phenyl rings in a seven-
step synthesis. The overall radiochemical yield of [3H]ABT-518 in seven steps starting from 1-(methylsulfonyl)-4-[4-
(trifluoromethoxy)phenoxy]benzene was 6.2% with the radiochemical purity of 99.4%.
Keywords: matrix metalloproteinase inhibitors; MMPI; ABT-518; 1-(methylsulfonyl)-4-[4-(trifluoromethoxy)phenoxy]benzene
[14C]ABT-770.6 To support the pre-clinical evaluation of ABT-518,
ADME studies in laboratory animals were undertaken, which
Introduction
The matrix metalloproteinases (MMPs) also known as matrixins
play a vital role in remodeling and maintenance of normal
tissue in biological processes. These are the family of enzymes
containing zinc that degrade the extracellular matrix.1
The disruption in a balance between the active enzymes and their
natural inhibitors accelerates the destruction of the connective
tissue, which is associated with diseases such as arthritis, cancer,
required radiolabeled ABT-518. The seven-step synthesis of
[3H]ABT-518 starting from 1-(methylsulfonyl)-4-[4-(trifluoro-
methoxy)phenoxy]benzene (4) employed halogenation/tritiode-
halogenation to introduce tritium label into both aromatic rings.
Results and discussion
multiple sclerosis, and cardiovascular diseases.2 There are more Our initial attempts to make [3H]ABT-518 from unlabeled
than 20 different enzymes known to be in the MMP family and compound using Crabtree’s catalyst introduced tritium in the
more are being discovered and characterized as MMPs.1 The formyl group of 2, which was confirmed by tritium NMR. In vitro
potential therapeutic agents that inhibit the MMP activity are metabolism studies indicated that this label was labile. Crabtree
referred to as matrix metalloproteinase inhibitors (MMPIs). catalyst-mediated tritium/hydrogen exchange was attempted
Our cancer research team had discovered two MMPIs from on sulfone 4 and obtained the intermediate 3 with a poor yield
the retrohydroximate family, namely ABT-770 and ABT-518 of radioactivity.
OTC
OH
T
O
S
N
H3CO2S
T
OCF3
OCF3
O
O
O
O
O
2
3
(Figure 1). Both of these compounds are potent inhibitors of
MMP-2 (gelatinase A) and MMP-9 (gelatinase B), which are
involved in tumor growth and metastasis. The replacement of
the ether linkage of ABT-770 with a sulfone group led to a
substantial increase in the activity against MMP-2 and MMP-9.3
Furthermore, toxicity studies revealed that ABT-770 has a number
Parts of this work were presented at the 23rd Northeast US Chapter IIS
Symposium, Princeton, NJ, 25–26 October 2007.
aProcess Chemistry Department, R450, AP9, Abbott Laboratories, 100 Abbott
Park Road, Abbott Park, IL 60064-6114, U.S.A.
of adverse effects caused by metabolite accumulation in tissues.4 bStructural Chemistry, R418, AP9, Abbott Laboratories, 100 Abbott Park Road,
Abbott Park, IL 60064-6114, U.S.A.
It was found out that ABT-518 had 200-fold greater MMP-9
potency with a larger estimated therapeutic window and good
*Correspondence to: Shirish N. Raja, Process Chemistry Department, R450, AP9,
Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6114, U.S.A.
pharmacokinetic characteristics and was as efficacious as ABT-770
in pre-clinical models.5 We previously reported a radiosynthesis of E-mail: shirishn.raja@abbott.com
J. Label Compd. Radiopharm 2009, 52 98–102
Copyright r 2009 John Wiley & Sons, Ltd.

S. N. Raja et al.
OHC
OH
O
N
OHC
OH
N
N
O2
S
OCF3
O
NH
O
O
O
O
F3CO
ABT-770
ABT-518
Figure 1. Chemical structures of MMPIs: ABT-770 and ABT-518.
H3CO2S
OCF3
H5IO6 / I2 / H2SO4
AcOH
5a + 5b +5c
O
4
Scheme 1.
Our next approach was to prepare a halogenated precursor so chromatography (HPLC) and was N-formylated to provide
that dehalogenation with tritium gas would give us access to a [3H]ABT-518 (1). This was achieved by using 2,2,2-trifluoroethyl-
starting material with a tritium label in the aromatic core of the formate as a formylating agent.9 There is a kinetic competition
molecule. The halogenated precursor was prepared by the between formylation on oxygen and nitrogen. The N-formyl
reaction of 4 with H5IO6 and I2 in a mixture of AcOH and H2SO4 isomer is favored thermodynamically. To enhance the rate of the
(Scheme 1).7
interconversion of the O-formyl isomer to N-formyl isomer under
Proton NMR indicated that the major species, 5a, had iodine the reaction conditions, a small amount of formic acid was
meta to –OCF3 (44%). The second most plentiful species (5b) added. The reaction medium was buffered with sodium formate
contained two iodine atoms: the first iodine meta to the –OCF3 to avoid acetonide hydrolysis of 11 to form a diol. The yield for
group and the second iodine meta to the –SO2CH3 group (38%). this step was 54%. The overall radiochemical yield of [3H]ABT-
The minor, 5c, was a monoiodinated compound with the 518 (1) after the HPLC purification was 6.2% (Scheme 2).
halogen meta to the –SO2CH3 group (18%). The mixture of 5a–c
was the key intermediate in the radiosynthesis of [3H]ABT-518
(1). The general sequence of the synthesis is shown in the
scheme. Thus, [3H]ABT-518 (1) was synthesized by the catalytic
Experimental
All chemicals and solvents were reagent grade or better and
dehalogenation of the mixture of iodo compounds 5a–c in the
presence of tritium gas, 10% Pd/C, and triethylamine in ethyl
acetate to give 418 mCi of 7. Both 1H and 3H-NMR indicated
specific labeling consistent with reductive deiodination at the
expected positions. Initially, the specific activity was lowered to
approximately 800 mCi/mmol by mixing 7 with an unlabeled 7
in THF and was further lowered to approximately 500 mCi/mmol
by mixing 8 with an unlabeled 8 in THF. The conversion of 7 to 8
was achieved by treating 7 at–781C with 1.05 equivalents each
of LiHMDS and n-butyllithium to generate the lithium anion,
which was quenched with optically active 2,20-dimethyl-
[1,3]dioxolane-4-carboxylic acid methyl ester 6 in THF.8 To
minimize the acetonide hydrolysis of 8 to form the diol, the
reaction mixture was worked up with 10% CH3COOH to yield
68% of 8. Rapid reduction of 8 to alcohol 9 was achieved at
room temperature (RT) by using sodium borohydride in ethanol
and THF to give 85% of the alcohol 9. To accomplish the
dehydration of the alcohol 9 to vinyl sulfone 10, alcohol 9 was
treated with methanesulfonyl chloride and an excess of
triethylamine at 01C to give a 93% yield of vinyl sulfone
products with 10 as the predominant isomer in a 1:10 cis to
trans ratio. The 1,4-addition of hydroxylamine to the isomeric
mixture of vinyl sulfone products was accomplished at a lower
temperature by using 50% hydroxylamine solution, which
proceeded with 5:1 selectivity in favor of the desired
stereochemistry to give 58% of 11. The desired isomer of
11 was purified by preparative high-performance liquid
purchased from commercial suppliers. They were used without
further purification. Tritium gas was purchased from American
Radiolabeled Chemicals, St. Louis, MO. IN/US Systems, Inc. TRI-
SORBER (tritium manifold system) was used for the tritiation.
1-(Methylsulfonyl)-4-[4-(trifluoromethyl)phenoxy]benzene 4 was
obtained from the Abbott process chemistry group. The identity
of intermediates was confirmed by comparison with authentic
samples supplied by the Abbott process chemistry group. Liquid
scintillation counting was performed on LKB-Wallac 1214 Rack
Beta ‘Excel’ counter. TLC plates were coated with Kieselgel 60
(0.25 mm, Merck) and were scanned for radioactivity with a
Radiomatic RS chromatograph. The 3H-NMR spectrum was
recorded at 501 MHz and chemical shifts are reported in
ppm (d). Preparative HPLC on 11 was performed using
Shimadzu LC system consisting of
a Shimadzu SIL-10A
autosampler, Shimadzu FRC-10A fraction collector, and two
Shimadzu LC-8A pumps. Peak detection and chromatograms
were obtained with a Shimadzu SPD-10A VP variable wave-
length UV detector set at 210 nm and Shimadzu Ezchrom
software. The compound 11 was analyzed using Hitachi L-7000
series analytical HPLC system consisting of an autosampler, a
pump, a variable wavelength UV detector, and Packard A-500
liquid scintillation radioactivity flow detector (Packard Instru-
ments, 0.5 mL flow cell, 3:1 ratio of Packard Ultima-Flo M
scintillant to effluent). A Perkin Elmer 250 analytical HPLC system
(Zorbax Rx-C8 column, 4.6 ꢀ 250 mm, 5 mm, UV at 220 nm, flow
rate = 1 mL/min, 30% CH3CN/0.1% H3PO4 to 90% CH3CN/0.1%
J. Label Compd. Radiopharm 2009, 52 98–102
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org

S. N. Raja et al.
10
1
14
H3CO2S
OCF3
15
H3CO2S
OCF3
6
5
13
12
H5IO6 / I2 / H2SO4
AcOH
2
3
16
O
4
O
17
R2
R1
R1
R2
%
4
5a.
H
I
44
5b.
5c.
I
I
I
38
18
H
10
O
1
T
14
O2
S
H3CO2S
OCF3
15
6
5
13
12
n-BuLi / LiHMDS
OCF3
T2 / 10% Pd/C/TEA
EtOAc
2
3
16
O
O
O
O
O
O
4
17
T
O
OCH3
T
T
T
T
O
O
68%
8
7
6
OH
O2
S
O2
S
OCF3
OCF3
CH3SO2Cl
NaBH4 / EtOH
O
O
O
O
O
85%
Et3N/EtOAc
93%
T
T
T
9
10
OHC
OH
NHOH
N
O2
S
O2
S
OCF3
OCF3
50%NH2OH
CF3CH2OCHO
O
O
O
O
CH3-O-t-Bu
IPA
O
54%
T
T
58%
T
Prep HPLC
20%
11
1
[3H]ABT-518
Scheme 2.
H3PO4 over 15 min, hold at this concentration for 5 min, and
back to the initial concentration in 1 min), an Applied Biosystems
UV detector, and the same liquid scintillation radioactivity flow
detector as above were used to analyze 7, 9, 10, 11, and 1.
Preparative HPLC on [3H]ABT-518 (1) was performed using
an Agilent 1100 series HPLC system. Peak detection and
chromatograms were obtained with a Agilent variable wave-
length UV detector set at 210 nm and Agilent Chemstation
software. Fractions of the [3H]ABT-518 (1) peak were collected
using an Agilent fraction collector. [3H]ABT-518 (1) was analyzed
using an Agilent 1100 series HPLC system consisting of an
Agilent variable wavelength UV detector set at 210 nm,
Chemstation software, and the same Packard A-500 radio-
detector as above.
Iodination of 1-(methylsulfonyl)-4-[4-(trifluoromethoxy)phe-
noxy]benzene (5a–c)
Into a mixture containing 4 (0.156 g, 0.5 mmol), H5IO6 (0.025 g,
0.11 mmol), and iodine (0.051 g, 0.2 mmol) was added a solution
of concentrated sulfuric acid (0.5 mL) and water (0.3 mL) in acetic
acid (1.5 mL). The resulting solution was heated at 901C for 27 h.
The reaction mixture was diluted with water (5 mL) and
extracted with ethyl acetate (2 ꢀ 30 mL). The combined organic
layers were washed with water and brine solution (20 mL each).
The solvent was removed on a rotary evaporator. The crude
product obtained was purified by preparative silica gel plates
(2 ꢀ 2000 mm, 20 ꢀ 20 cm, 60% pentane in ethyl acetate). The
bands corresponding to the product were scraped and
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J. Label Compd. Radiopharm 2009, 52 98–102

S. N. Raja et al.
extracted with ethyl acetate (4 ꢀ 45 mL). The solvent was were washed with H2O (3 ꢀ 25 mL) and brine solution
(3 ꢀ 25 mL). The solvent was removed on a rotary evaporator
to give 131 mCi of 9. HPLC analysis (tR = 13 min) showed 96% of
9. The crude product was purified by preparative silica gel plates
(1000 mm, 20 ꢀ 20 cm, 60% pentane in ethyl acetate). The bands
corresponding to the product were scraped and extracted with
ethyl acetate (4 ꢀ 35 mL). The solvent was removed on the
rotary evaporator to give 120 mCi of 9 in 85% yield.
removed on a rotary evaporator to give approximately 50 mg
of a mixture of 5a–c containing mono- and di-iodo aromatic
1
substituted analogues as they were observed from H and 13C-
NMR spectra.10
[3H] - 1 - (methylsulfonyl) - 4 - [4 -(trifluoromethoxy)phenoxy]-
benzene (7)
[3H] - (S,E) - 2, 2 - dimethyl - 4 -(2-([3-3H]-4-([2-3H]-4-(trifluoro-
methoxy)phenylsulfonyl)vinyl)1,3-dioxolane (10)
A mixture of iodo compounds 5a–c (7.7 mg), 10% Pd/C
(10.9 mg), triethylamine (100 mL), and ethyl acetate (2 mL) was
placed in a 5 mL round-bottom flask. The flask was attached to
the tritium manifold (TRI-SORBER) and degassed by free-
ze–pump–thaw. Tritium gas (0.063 mmol, 3.65 Ci) was intro-
duced and the mixture was vigorously stirred at RT for 2.4 h. The
excess gas was removed to a charcoal trap cooled in a liquid
nitrogen bath, the catalyst was filtered, and the labile tritium
was removed by three evaporations of methanol (10 mL each) to
yield 418 mCi of 7. HPLC analysis (tR = 12.9 min) indicated the
presence of 7 in 97% radiochemical purity. 1H-NMR (501 MHz,
CD3OD): d 7.95 (d, J = 8.9 Hz, 2H, H(1), H(3)), 7.37 (d, J = 8.9 Hz, 2H,
H(14), H(16)), 7.20 (d, J = 8.9, 2H, H(13), H(17)), 7.17 (d, J = 8.9 Hz,
2H, H(4), H(6)), 3.11 (s, 3H, CH3). 3H-NMR (534 MHz, CD3OD): d
7.20 (3H(17)), 7.17 (3H(4)).
Into a solution of 9 (120 mCi, 0.111 g) in ethyl acetate (1.5mL)
under nitrogen was added Et3N (200 mL, 1.4 mmol). The reaction
mixture was cooled in an ice bath, methane sulfonyl chloride
(0.044 g, 0.38 mmol) was added slowly, and the mixture was
stirred for 45 min. The ice bath was removed and stirring
was continued at RT for 2.5 h. To complete the reaction, Et3N
(20 mL, 14 mmol) and methane sulfonyl chloride (0.010 g,
0.09 mmol) were added and the reaction mixture was stirred at
RT for 1.2 h. The reaction mixture was worked up by adding 10%
citric acid (2.5mL, pH =4), EtOAc (10 mL), and water (2mL). The
aqueous layer was separated and extracted with ethyl acetate
(20 mL). The combined organic layers were washed with 5%
NaHCO3 (2.5 mL) and brine solution (30 mL). The solvent was
removed on a rotary evaporator to give 120 mCi of 10. The crude
product was purified by preparative silica gel plates (2 ꢀ 1000 mm,
20 ꢀ 20 cm, 2% ethyl acetate in methylene chloride). The bands
corresponding to the product were scraped and extracted with
EtOAc (4 ꢀ 35 mL). The solvent was removed on a rotary
evaporator to yield 112 mCi of 10 in 93% yield. TLC analysis (silica
gel, 2% ethyl acetate in methylene chloride, Rfꢁ0.4) and HPLC
analysis (tR =14.8min) showed radiochemical purity 492%.
[3H] - 1 - (2,2 - dimethyl - [1,3]dioxolan - 4 - yl) - 2 -[4-(4-trifluor-
omethoxy-phenoxy)-benzenesulfonyl] ethanone (8)
Into a solution of [3H]-1-(methylsulfonyl)-4-[4-(trifluoromethoxy)-
phenoxy]benzene (7, 210 mCi, ꢁ1 mg) and unlabeled
7
(102 mg, 0.31 mmol to give a specific activity of ꢁ0.8 Ci/mmol)
in THF (3 mL) under N2 at ꢂ781C was added 1 M LiHMDS in THF
(0.33 mL, 0.33 mmol) followed by 1.55 M n-BuLi in hexanes
(0.22 mL, 0.33 mmol). The reaction mixture was stirred at ꢂ781C
for 2 h. A solution of 2,20-dimethyl-[1,3]dioxolane-4-carboxylic
acid methyl ester (6, 0.060 g, 0.37 mmol) in 60 mL of THF was
added to the reaction mixture and stirring was continued for 1 h.
The TLC analysis (silica gel, 10% acetic acid in ethyl acetate)
showed 60% of 8. Additional 2,20-dimethyl-[1,3]dioxolane-4-
carboxylic acid methyl ester (6, 0.01 g, 0.063 mmol) was added
and the mixture was stirred at ꢂ781C for 1.5 h. The reaction
mixture was diluted with 10% CH3COOH and extracted with
EtOAc (3 ꢀ 20 mL). The combined organic layers were washed
with H2O (3 ꢀ 20 mL) and brine solution (2 ꢀ 20 mL) and the
solvent was removed on a rotary evaporator. The crude product
was purified on preparative silica gel plates (2 ꢀ 2000 mm,
20 ꢀ 20 cm, 60% pentane in ethyl acetate). The bands corres-
ponding to the product were scraped and extracted with ethyl
acetate (4 ꢀ 45 mL). The solvent was removed on a rotary
evaporator to give 142 mCi of 8 in 68% yield. TLC analysis (silica
gel, 50% pentane in ethyl acetate, Rfꢁ0.5) indicated radio-
chemical purity 499%.
[3H] - N - 1 -(2,2-dimethyl-[1,3]dioxolan-4-yl)-2-[4-(4-trifluoro-
methoxy-phenoxy)-benzenesulfonyl]-ethyl-hydroxylamine (11)
A solution of 10 (60 mCi, 0.053 g) in methyl t-butyl ether (1.5 mL)
under N2 was cooled to ꢂ151C and 50% hydroxylamine (185 mL)
was added. The reaction mixture was stirred for 4 h. An aliquot was
analyzed by HPLC (tR = 11.9 min) showing 77% of 11. The reaction
mixture was diluted with EtOAc (40 mL) and brine solution (15 mL).
The organic layer was separated. The solvent was removed on a
rotary evaporator to give 56 mCi of 11 that was further purified by
preparative HPLC (Phenomenex Luna C8 column, 21.2 ꢀ 250 mm,
5mm, UV at 210 nm, flow rate = 20 mL/min, 65% CH3CN and 35%
water, isocratic tR = 8.7 min) to give 35 mCi of 11 in 58% yield with
radiochemical purity 499%.
[3H]ABT-518 (1)
A solution containing 11 (35 mCi, 0.045 g), 2,2,2-trifluoroethyl-
formate (135 mL), isopropyl acetate (500 mL), 96% formic acid
(12 mL), and sodium formate (0.005 g) was heated at 651C for 3 h.
The reaction mixture was diluted with 5% NaHCO3 solution
(5 mL) and extracted with EtOAc (30 mL). The organic layer was
[3H] - 1 -(2, 2 - dimethyl - [1, 3dioxolan - 4 - yl) - 2 - [4-(4-trifluor-
omethoxy-phenoxy)-benzenesulfonyl]-ethanol (9)
Into a solution of ketone (8, 140 mCi, ꢁ2 mg) and unlabeled 8 concentrated on a rotary evaporator to yield 28.5 mCi of 1. The
(114 mg, 0.247 mmol to give a specific activity of ꢁ0.5 Ci/mmol) crude product was purified by preparative silica gel plates (1000
in THF (0.5 mL) and EtOH (1.6 mL) was added sodium and 2000 mm, 20 ꢀ 20 cm, 55% methanol in methylene chloride).
borohydride (72 mg, 1.9 mmol). The reaction mixture was stirred The bands corresponding to the product were scraped and
at RT for 1.5 h, quenched with 10% CH3COOH (10 mL), and was extracted with ethyl acetate (4 ꢀ 30 mL). The solvent was
extracted with EtOAc (2 ꢀ 20 mL). The combined organic layers removed on the rotary evaporator to give 19 mCi of 1.
J. Label Compd. Radiopharm 2009, 52 98–102
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org

S. N. Raja et al.
HPLC analysis (tR = 12 min) and TLC analysis (silica gel, 5% in the second step. The radiochemical purity was 499% and the
methanol in methylene chloride, Rfꢁ0.1) showed radiochemical specific activity was 381.6 mCi/mmol. This material was suitable
purity of 94%.
for use in in vivo and in vitro metabolism studies.
Purification by preparative HPLC
Acknowledgement
Approximately 19 mCi of crude [3H]ABT-518 (1) was added to
1 mL of CH3CN and 0.5 mL of H2O. Each 0.1 mL of the sample
preparation was injected onto a Zorbax Rx-C8 column (5 mm,
250 ꢀ 4.6 mm ID) using an Agilent 1100 series HPLC system.
[3H]ABT-518 (1) was eluted at a flow rate of 1 mL/min with
isocratic elution of 50% acetonitrile. Peaks were detected and
chromatograms were obtained using an Agilent variable
wavelength UV detector set at 210 nm and Chemstation
software. The fractions containing [3H]ABT-518 (1) were
collected at approximately 11 min using an Agilent fraction
collector. Fractions were further purified using Phenomenex
Luna C18 (2) column (5 mm, 250 ꢀ 4.6 mm ID) and Agilent 1100
series HPLC system. [3H]ABT-518 (1) was eluted at a flow rate of
1 mL/min with isocratic elution of 65% MeOH. Peaks were
detected and chromatograms were obtained using an Agilent
UV detector set at 210 nm. The fractions containing [3H]ABT-518
(1) were collected at approximately 22 min using an Agilent
fraction collector. The product-containing fractions were pooled
and solvents were evaporated in vacuo to yield 7.1 mCi of 1.
The author would like to gratefully acknowledge the process
and discovery chemistry groups for starting materials, inter-
mediate samples, and experimental details.
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Purity and specific activity determination by HPLC
[3H]ABT-518 (1) was analyzed by reverse-phase HPLC and
compared with authentic ABT-518. Each sample was injected
onto a Zorbax Rx-C8 column, 4.6 ꢀ 250 mm, 5 mm, and eluted at
1 mL/min with mobile phase consisting of 0.1% trifluoroacetic
acid and 50% acetonitrile. Peaks were detected with a UV
detector at 210 nm and a liquid scintillation radioactivity flow
detector. Greater than 99% of radioactivity corresponded to the
UV peak of ABT-518 at 11.8 min. An assay of the effluent showed
that greater than 99% of the activity was recovered from the
column. The specific activity of the product was calculated by
relative proportions of UV-detected signal from the radioactive
product and an unlabeled reference. It was found to be
381.6 mCi/mmol.
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[10] For 5a: 1H-NMR (501 MHz, CDCl3): d 7.92 (d, J = 9.0 Hz, 2H, H(1),
H(3)), 7.79 (d, J = 2.6 Hz, 1H, H(16)), 7.29 (dd, J = 8.8, 2.6 Hz,
1H, H(14)), 7.05 (d, J = 9.0 Hz, 2H, H(4), H(6)), 7.02 (d, J = 8.8 Hz,
1H, H(13)), 3.07 (s, 3H, CH3). 13C-NMR (125.2 MHz, CDCl3): d 132.87
(C(16)), 129.98 (C(1), C(3)), 122.86 (C(14)), 121.41 (C(13)), 117.54
(C(4), C(6)), 44.78 (CH3). For 5b: 1H-NMR (501 MHz, CDCl3): d 8.45
(d, J = 2.4 Hz, 1H, H(3)), 7.83 (dd, J = 8.5, 2.4 Hz, 1H, H(1)), 7.77 (d,
J = 2.7 Hz, 1H, H(16)), 7.29 (ds, J = 8.9, 2.7 Hz, 1H, H(14)), 7.06 (d,
J = 8.9 Hz, 1H, H(13)), 6.68 (d, J = 8.5 Hz, 1H, H(6)), 3.06 (s, 3H, CH3).
13C-NMR (125.2 MHz, CDCl3): d 139.61 (C(3)), 132.87 (C(16)), 129.28
(C(1)), 122.86 (C(14)), 121.65 (C(13)), 115.92 (C(4)), 44.78 (CH3). For
5c: 1H-NMR (501 MHz, CDCl3): d 8.43 (d, J = 2.2 Hz, 1H, H(3)), 7.84
(dd, J = 8.6, 2.2 Hz, 1H, H(1)), 7.29 (d, J = 9.1 Hz, 2H, H(13), H(17)),
7.09 (d, J = 9.1 Hz, 2H, H(14), H(16)), 6.87 (d, J = 8.6 Hz, 1H, H(6)), 3.07
(s, 3H, CH3). 13C-NMR (125.2 MHz, CDCl3): d 139.45 (C(3)), 129.28
(C(1)), 122.86 (C(13), C(17)), 121.09 (C(14), C(16)), 117.01 (C(6)), 44.78
(CH3).
Conclusion
[3H]ABT-518 (1) was synthesized in seven steps from
1-(methylsulfonyl)-4-[4-(trifluoromethoxy)phenoxy]benzene (4)
in 6.2% radiochemical yield. The radioactivity was introduced
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Copyright r 2009 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2009, 52 98–102