A novel asymmetric synthesis of tritium and carbon-14 labeled (R)-ibuprofen

Article abstract of DOI:10.1002/jlcr.1040

An efficient asymmetric synthesis of tritium and carbon-14 labeled R-ibuprofen was achieved in good overall yield (15% and 47%, respectively) and excellent enantiomerical excess (>98% e.e.), using (4R, 5S)-4-methyl-5- phenyl-2-oxazolidinone as a chiral au

Full text of DOI:10.1002/jlcr.1040

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2006; 49: 237–244.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1040
Research Article
A novel asymmetric synthesis of tritium and carbon-14
labeled (R)-ibuprofen
Yinsheng Zhang1,*, Yang Hong2, Che C. Huang3 and Daniel Belmont1
1 Chemical R&D, Michigan Pharmaceutical Sciences, Pfizer Inc., 301 Henrietta St,
Kalamazoo, MI 49007, USA
2 Radiochemistry, Department of Chemical Synthesis, Pharmaceutical Research
Institute, One Squibb Drive, New Brunswick, NJ 08903, USA
3 3465 Narrow Gauge Way, Ann Arbor, MI 48105, USA
Summary
An efficient asymmetric synthesis of tritium and carbon-14 labeled R-ibuprofen was
achieved in good overall yield (15% and 47%, respectively) and excellent
enantiomerical excess (>98% e.e.), using (4R, 5S)-4-methyl-5-phenyl-2-oxazolidinone
as a chiral auxiliary. Copyright # 2006 John Wiley & Sons, Ltd.
Key Words: R-ibuprofen; radioactive labeling; tritium; carbon-14; asymmetric
synthesis; chiral auxiliary
Introduction
2-(4-isobutylphenyl)propionic acid (ibuprofen) is one of the most well-known
non-steroidal anti-inflammatory agents. The metabolic transformations of
ibuprofen include oxidation at both the methine and terminal methyl carbon
of the isobutyl side-chain to give the hydroxy metabolite and carboxy
metabolite. Most importantly, it has been also shown that ibuprofen
undergoes metabolic chiral inversion at the 2-position of the propionic acid
group from the R-enantiomer to the S-isomer.1–3 Evidently, this in vivo
bioactivation process leads to enhanced therapeutic and toxic effects of the
drug. As the metabolic chiral inversion is an important reaction in the
pharmacokinetics of some optically active drugs, the radioisotopic labeled
ibuprofen was needed for fatty acid CoA lipases inhibition studies. The
carbon-14 labeled (R)-ibuprofen was first synthesized, however, the specific
activity of [14C](R)-ibuprofen was not high enough for the assay, so tritium
*Correspondence to: Yinsheng Zhang, Chemical R&D, Michigan Pharmaceutical Sciences, Pfizer Inc.,
301 Henrietta St, Kalamazoo, MI 49007, USA. E-mail: Yinsheng.Zhang@pfizer.com
Copyright # 2006 John Wiley & Sons, Ltd.
Received 27 October 2005
Revised 21 November 2005
Accepted 28 November 2005

238
Y. ZHANG ET AL.
labeled ibuprofen was synthesized. In this paper, we would like to introduce a
novel asymmetric synthesis of radio-labeled (R)-ibuprofen.
Results and discussion
The synthesis of racemic stable-isotope labeled ibuprofen has been reported in
literatures.4–6 The known seven-step synthetic approach could be adapted to
prepare radiolabeled racemic ibuprofen. The desired R-enantiomer of
ibuprofen could then be separated by chiral prep. HPLC. However,
considering the long synthetic steps and the loss of half radioactive material,
a more efficient asymmetric synthesis needed to be developed.
Unlabeled S-ibuprofen was synthesized in 95–96% e.e. using homochiral
N-acylbornanesultam7 or 4-isopropyl-2-oxazolidinone8 as chiral auxiliaries. It
was reported that an asymmetric methylation of 4-methyl-5-phenyl-2-
oxazolidinone imide derivatives gave a higher diastereoselectivity (>95%
d.e.) than 4-substituted 2-oxazolidinone imides.9 Therefore, 4(R)-methyl-5(S)-
phenyl-2-oxazolidinone was applied as the chiral auxiliary to prepare both
[14C] and [3H](R)-ibuprofen.
Carbon-14 labeled (R)-ibuprofen was synthesized in three steps (see
Scheme 1) in an overall 47% yield (>98% e.e.). 4-Isobutylphenylacetic acid
1 was prepared from isobutylbenzene in two steps by adapting the known
procedure.4 Two methods, A and B, for the N-acylation of the oxazolidinone
were applied.8 Method B was preferred due to its higher yield and shorter
reaction time. As expected, the asymmetric methylation of imide 2 with
[14C]MeI in the presence of NaHDMS gave the desired methylated product 3
with high diastereoselectivity (98.2% d.e. based on a chiral HPLC assay).
Hydrolysis of the chiral auxiliary with standard reaction conditions (LiOH/
30% H2O2) furnished the desired [14C]R-ibuprofen 4 in 81%. The chemical
and radiochemical purities of 4 were found to be >98% and specific activity
was found to be 54.8 mCi/mmol by gravimetric assay.
O
NaHMDS/-78οC
14CH3I/THF/-78οC/5h
O
Method A or B
CH2CO2H
O
N
69%
Ph
1
Me
2
Method A: Me3CCOCl/Et3N/LiCl/24h; 45%
Method B: 1) SOCl2 /1h, 2) n-LiBu/-30οC/1h: 75%
O
O
LiOH/30% H2O2
THF/H2O/0οC/2h
HO
O
O
N
14CH3
90%
14CH3
Ph
Me
3
4
Scheme 1. Asymmetric synthesis of [14C]R-ibuprofen
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ASYMMETRIC SYNTHESIS OF TRITIUM AND CARBON-14 LABELED (R)-IBUPROFEN 239
The new synthetic approach was easily applied to the preparation of the
chiral unsaturated precursor 10 of R-ibuprofen. Thus, the treatment of
commercially available p-bromomethylphenylacetic acid with triethyl phos-
phine formed triethylphosphonium bromide 6. Wadsworth-Emmons olefina-
tion gave olefin 7 in the presence of 15-crown-5 in 62% yield, but only 32%
without the crown ether. Unsaturated phenylacetic acid 7 was converted to the
corresponding acryl chloride with SOCl2, followed by the N-acrylation of the
4-methyl-5-phenyl-2-oxazolidinone. The treatment of the chiral imide 8 with
NaHMDS in THF afforded the enolate which was stereoselectively alkylated
with methyl iodide to furnish the a-methyl intermediate 9 with >95% d.e.
Removal of the chiral auxiliary using LiOH-H2O2 in THF/H2O resulted in the
formation of desired unsaturated chiral acid 10. The enantiomeric excess (e.e.)
of 3, 4, 9 and 10 were determined to be more than 97% from their 400 MHz
1H-NMR and chiral HPLC analysis.
The tritiation of unsaturated precursor 10 of R-ibuprofen was completed in
presence of Wilkinson’s catalyst to form the desired [3H2] R-ibuprofen with
99.72% radiochemical purity and 98.5% enantiomeric purity. No racemiza-
tion was found during the Wilkinson’s catalytic reduction reaction (Scheme 2).
O
P
CH3COCH3
NaH/15-crown-5
P(OEt)3
80%
EtO
EtO
BrH2C
CH2CO2H
CH2CO2H
62%
5
6
NaHMDS/-78οC
CH3I/THF/-78οC/5h
1) SOCl2/1h
2) n-LiBu/-30οC/1h
O
O
CH2CO2H
O
N
O
73 %
70%
O
NH
Me
Ph
Me
7
Ph
8
3H2(gas)
Wilkinson catalyst
O
O
O
LiOH/30% H2O2
THF/H2O/0οC/2h
O
HO
N
92 %
CH3
CH3
Ph
Me
9
10
T
T
O
HO
CH3
11
Scheme 2. Asymmetric synthesis of [3H2](R)-ibuprofen 11
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Y. ZHANG ET AL.
Experimental
All reactions were carried out under an atmosphere of nitrogen unless
otherwise stated. 1H and 13C NMR spectra were recorded on a Varian Gemini
200 or 400 MHz. Mass spectra was recorded on Waters Micromass ZQ 2050.
Chemical purity of all labeled compounds was determined by HPLC and
GC-MS or LC-MS. Purifications were done by flash column chromatography
on a Biotage Flash 40 system. [14C]CH3I (100 mCi, 55 mCi/mmol) was
purchased from American Radiolabeled Chemicals Inc (ARC). Tritium gas
was purchased from ARC. Acid 1 was prepared by following Capponi’s
procedure starting with isobutylbenzene.4
(4R, 5S)-N-(4-isobutylphenyl acetyl)-4-methyl-5-phenyl-2-oxazolidinone 2
A solution of 4-isobutylphenyl acetic acid 1 (1.55 g, 8.1 mmol) in SOCl2
(1.5 ml, 17.3 mmol) was stirred at 1008C for 1 h. The excess SOCl2 was
removed with THF (2 ꢀ 5 ml) under reduced pressure. The residue was
dissolved in THF (3 ml) to form solution A. To a solution of (4R, 5S)-4-
methyl-5-phenyl-2-oxazolidinone (1.5 g, 8.5 mmol) in THF (5 ml) was added a
solution of n-BuLi (2.5 M, 3.4 ml, 8.5 mmol) at ꢁ408C. The mixture was stirred
for 30 min at the same temperature. To this solution was added solution A at
ꢁ408C (CH3CN/dry ice). The mixture was stirred at ꢁ408C for 1.5 h, and then
quenched with 1 N NaHSO4 (60 ml). The aqueous layer was extracted with
CH2Cl2 (4 ꢀ 20 ml). The combined organic layers were washed with water
(20 ml) and brine (20 ml), dried over MgSO4, and concentrated to give crude 2,
which was purified by flash chromatography (silica gel, 5% EtOAc/hexane).
1
The titled compound was obtained as a colorless oil (2.13 g, 75%). H NMR
(CDCl3) d 0.894 (d, J ¼ 6:59 Hz, 6H), 0.883 (d, J ¼ 6:59 Hz, 3H), 1.848
(m, 1H), 2.45 (d, J ¼ 7:24 Hz, 2H), 4.27 (dd, J ¼ 5:82 Hz, 2H), 4.754 (m, 1H),
5.65 (d, J ¼ 7:248 Hz, 1H), 7.10 (d, J ¼ 7:90 Hz, 2H), 7.22 (d, J ¼ 7:90 Hz,
2H), 7.27–7.29 (m, 2H), 7.36–7.42 (m, 3H); 13C NMR (CDCl3) d 172.1, 171.5,
138.2, 135.6, 132.3, 131.0, 129.6, 129.2, 129.0, 128.9, 125.9, 124.5, 78.7, 55.5,
43.4, 42.7, 30.1, 22.9, 18.3, 14.6; MS (CI) ½M þ Hþꢂ: 352.
(4R, 5S)-N-(4-isobutylphenyl-a-[14C]methylacetyl)-4-methyl-5-phenyl-2-oxa-
zolidinone 3
To a solution of compound 2 (0.60 g, 1.68 mmol) in THF (15 ml) was added a
solution of 1 M NaHMDS in THF (2.0 ml, 2 mmol) at ꢁ788C over 15 min. The
resulting red yellow solution was stirred for 1 h. To this solution was added
[14C]CH3I (100 mCi, 55 mCi/mmol, 1.8 mmol) at ꢁ788C. The mixture was
stirred at ꢁ788C for 1 h and then at ꢁ408C for 2 h which produced a cloudy
mixture. The mixture was quenched with a solution of AcOH (0.40 g) in ether
(15 ml). After stirring for 15 min, the mixture was filtered and the filtrate was
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ASYMMETRIC SYNTHESIS OF TRITIUM AND CARBON-14 LABELED (R)-IBUPROFEN 241
concentrated by distillation. Purification by flash chromatography (silica gel,
5% EtOAc/hexane) gave the title compound 3 (0.460 g, 69 mCi, 69%).
1H NMR (CDCl3) d 0.88 (s, 3H), 0.89 (d, J ¼ 6:59 Hz, 6H), 1.49
(d, J ¼ 6:81 Hz, 2H), 1.84 (m, 1H), 2.43 (d, J ¼ 7:15 Hz, 2H), 4.67 (m, 1H),
5.10 (q, J ¼ 7:01 Hz, 1H), 5.50 (d, J ¼ 7:02 Hz, 1H), 7.09 (d, J ¼ 7:91 Hz, 2H),
7.26–7.28 (m, 5H), 7.34–7.41 (m, 2H); 13C NMR (CDCl3) d 174.6, 174.4,
138.1, 129.6, 128.9, 127.7, 125.8, 78.8, 55.6, 43.5, 42.8, 30.3, 22.7, 19.5, 18.5,
14.7. MS (CI) ½M þ Hþꢂ: 366.
[14C] (R)-ibuprofen 4
To a solution of compound 3 (0.45 g, 67.5 mCi, 1.23 mmol) in THF (6 ml) and
water (2.2 ml) was added a solution of LiOH (0.088 mg, 3.7 mmol) in water
(2.3 ml) and H2O2 (30%, 1.65 ml) at 08C. The resulting mixture was stirred at
08C for 3 h. To this cold solution was added a solution of NaHSO3 (0.35 g),
Na2SO3 (0.62 g) in water (2.5 ml). The mixture was extracted with CH2Cl2
ð5 ꢀ 20 mlÞ. The combined organic layers were washed with brine (15 ml),
dried over MgSO4, and then concentrated to give an oily residue, which was
purified by flash chromatography (silica gel MeOH/Et2O/hexane=5/30/65).
Compound 4 was obtained as colorless oil (0.231 g, 61 mCi, 90%). Specific
activity ðSAÞ ¼ 54:8 mCi=mmol; radiochemical purity: 98.7%; chiral purity:
98.1%; reverse phase HPLC conditions: column: Phenomenex LUNA C18(2),
3 mm, 4:6 ꢀ 150 mm; mobile phase: A ¼ 0:01 M TEA, pH ¼ 2:5 w/HClO4,
B ¼ CH3CN, 80% A linear gradient to 30% A over 10 min, hold at
A:B=30:70 for 10 min, flow rate: 1.0 ml/min, UV detection: 220 nm, retention
time: 12.3 min; chiral HPLC conditions: column: Chiralcel OH-RH, 3 mm,
4:6 ꢀ 150 mm, mobile phase: Premix 25% H2O, 75% MeOH þ 0:1% acetic
acid, flow rate: 1.0 ml/min, UV: 220 nm, retention time: 10.1 min.
[4-(Diethoxyphosphinyl)methyl]-phenylacetic acid 6
A suspension of p-bromomethylphenylacetic acid 5 (5.0 g, 21.9 mmol) in
triethylphosphite (20 ml, 117 mmol) was heated at 1208C for 18 h. After
cooling to room temperature, the mixture was quenched with water
(38 ml) and 2 N NaOH (48 ml). The aqueous layer was washed with EtOAc
ð5 ꢀ 25 mlÞ and then acidified with 1 N HCl (20 ml). The acidic solution
was extracted with EtOAc ð3 ꢀ 100 mlÞ. The combined organic layers
were washed with water (25 ml) and brine (20 ml), dried over MgSO4,
and concentrated by rotovap to give 6 as a colorless oil which solidified
1
after stirring (5.0 g, 80%). H NMR (CDCl3) d 7.25–7.23 (m, 4H), 4.03–3.96
(m, 4H), 3.59 (s, 2H), 3.13 (d, J ¼ 21:7 Hz, 2H), 1.25–1.19 (m, 6H); MS (CI)
½M þ Hþꢂ: 287.
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Y. ZHANG ET AL.
4-Isobuteneyl-phenylacetic acid 7
To a solution of compound 6 (4.1 g, 14.2 mmol) in THF (80 ml) and 15-crown-
5 (3.6 g) at 58C, was added NaH (60%, 2.3 g) in three portions. Then to this
suspension was added acetone (10 ml). The resulting mixture was stirred at RT
for 48 h. To the reaction mixture was added cold water (200 ml). The mixture
was extracted with CH2Cl2 ð3 ꢀ 80 mlÞ. The aqueous layer was acidified with
1 N HCl (50 ml), extracted with CH2Cl2 ð4 ꢀ 80 mlÞ, washed with brine, and
dried over MgSO4. Concentration by rotovap gave crude product 7, which was
purified by flash chromatography (silica gel, MeOH/Et2O/hexane/AcOH=
1
5/30/65/0.5). Compound 7 was obtained as a white solid (1.68 g, 62%). H
NMR (CDCl3) d 11.3 (bs, 1H), 2.25–7.17 (m, 4H), 6.24 (s, 1H), 3.62 (s, 2H),
1.89 (d, J ¼ 1:32 Hz, 3H), 1.85 (d, J ¼ 1:31 Hz, 3H). 13C NMR (CDC13) d
178.1, 135.1, 129.2, 127.3, 45.6, 41.5, 30.1, 19.3; MS (CI) ½M þ Hþꢂ: 191.
(4R, 5S)-N-(4-isobutenylphenylacetyl)-4-methyl-5-phenyl-2-oxazolidinone 8
A solution of compound 7 (1.55 g, 8.15 mmol) in SOCl2 (1.5 ml, 17.3 mmol)
was stirred at 1008C for 1 h. The excess SOCl2 was removed with THF
ð2 ꢀ 5 mlÞ under reduced pressure. The residue was dissolved in THF (3 ml) to
form solution A. To a solution of 4-methyl-5-phenyl-2-oxazolidinone (1.5 g,
8.5 mmol) in THF (5 ml) was added a solution of n-BuLi (2.5 M, 3.4 ml,
8.5 mmol) at ꢁ408C. The mixture was stirred for 30 min at the same
temperature. To this solution was added the solution A at ꢁ408C (CH3CN/
dry ice). The mixture was stirred at ꢁ408C for 1.5 h and then quenched with
1 N NaHSO4 (60 ml). The aqueous layer was extracted with CH2Cl2
ð4 ꢀ 20 mlÞ. The combined organic layers were washed with water (20 ml)
and brine (20 ml), dried over MgSO4, and concentrated to give a crude
product, which was purified to flash chromatography (silica gel, 5% EtOAc/
hexane). Compound 8 was obtained as a colorless oil (1.99 g, 70%). 1H NMR
(CDCl3) d 0.89 (d, J ¼ 7:59 Hz, 3H), 1.85 (d, J ¼ 1:09 Hz, 3H), 1.89
(d, J ¼ 1:09 Hz, 3H), 4.28 (dd, J ¼ 5:6 Hz, 2H), 4.75 (m, 1H), 5.65
(d, J ¼ 7:25 Hz, 1H), 6.24 (s, 1H), 7.19 (d, J ¼ 7:12 Hz, 2H), 7.28 (d, J ¼
7:12 Hz, 2H), 7.34–7.67 (m, 2H), 7.37–7.42 (m, 3H); 13C NMR (CDCl3)
d 171.5, 153.1, 138.1, 135.8, 132.5, 131.2, 129.5, 129.1, 129.0, 128.9, 125.8,
124.9, 79.2, 55.3, 41.6, 27.1, 19.7, 14.7; MS (CI) ½M þ Hþꢂ: 350.
(4R, 5S)-N-[(4-(isobutenylphenyl)-a-methylacetyl]-4-methyl-5-phenyl-2-oxa-
zolidinone 9
To a solution of compound 8 (0.8 g, 2.3 mmol) in THF (12 ml) was added 1 M
NaHMDS in THF (2.53 ml, 2.53 mmol) at ꢁ788C to form a yellow solution,
which was stirred for 1 h at ꢁ788C. To this cold solution was added MeI
(1.76 g, 12.5 mmol) at ꢁ788C. The resulting mixture was stirred at ꢁ788C for
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ASYMMETRIC SYNTHESIS OF TRITIUM AND CARBON-14 LABELED (R)-IBUPROFEN 243
1.5 h, then at ꢁ408C for 2 h. The mixture was quenched with AcOH (0.41 g,
6.8 mmol) in ether (10 ml), and filtered through a Celite bed. The filtrate was
concentrated by rotovap to give an oily residue, which was apurified by flash
chromatography (silica gel, 3% EtOAc/hexane).
1
Compound 9 was obtained as a colorless oil (0.61 g, 73%). H NMR
(CDCl3) d 0.93 (d, J ¼ 6:59 Hz, 3H), 1.50 (d, J ¼ 7:03 Hz, 3H), 1.86
(d, J ¼ 1:09 Hz, 3H), 1.88 (d, J ¼ 1:09 Hz, 3H), 4.67 (m, 1H), 5.12
(q, J ¼ 6:80 Hz, 1H), 5.50 (d, J ¼ 7:03 Hz, 1H), 6.22 (s, 1H), 7.18 (d, J ¼
8:34 Hz, 2H), 7.26 (d, J ¼ 8:34 Hz, 2H), 7.27–7.42 (m, 5H); 13C NMR (CDCl3)
d 171.6, 152.8, 138.0, 133.6, 130.4, 129.2, 128.9, 127.9, 126.9, 125.8, 78.9, 55.6,
44.1, 27.2, 24.9, 19.5, 14.7; MS (CI) ½M þ Hþꢂ: 364.
4-(Isobutenylphenyl)-a-methylacetic acid 10
To a solution of compound 9 (0.3 g, 0.83 mmol) in THF (4 ml) and water
(1.5 ml) was added a solution of LiOH (60 mg, 2.5 mmol) in water (1.5 ml) and
H2O2 (30%, 1.1 ml) at 08C. The resulting mixture was stirred at 08C for 3 h. To
this cold solution was added a solution of NaHSO3 (0.235 g), Na2SO3 (0.416 g)
in water (1.5 ml). The mixture was extracted with CH2Cl2 ð15 ml ꢀ 5Þ. The
combined organic layers were washed with brine (15 ml), dried over MgSO4,
and then concentrated by rotovap to give an oily residue, which was purified
by flash chromatography (silica gel, MeOH/Et2O/hexane=5/30/65). Com-
1
pound 10 was obtained as colorless oil (0.156 g, 92%). H NMR (CDCl3)
d 1.50 (d, J ¼ 7:25 Hz, 3H), 1.84 (d, J ¼ 1:09 Hz, 3H), 1.88 (d, J ¼ 1:09 Hz,
3H), 3.71 (q, J ¼ 6:93 Hz, 1H), 6.22 (s, 1H), 7.17 (d, J ¼ 8:34 Hz, 2H), 7.25
(d, J ¼ 8:34 Hz, 2H); 13C NMR (CDCl3) d 179.9, 138.1, 137.3, 135.9, 130.8,
130.4, 129.2, 128.6, 128.1, 127.7, 124.8, 45.1, 27.1, 19.6, 18.3; MS (CI)
½M þ Hþꢂ: 205.
[3H2]R-2-(4-Isobutylphenyl)propionic acid (R-ibuprofen) 11
Compound 10 (1 mg, 4.9 mmol) was reduced with 600 mCi carrier free tritium
gas and 1 mg Wilkinson’s catalyst in 0.5 ml EtOH on a commercial tritiation
manifold (TRI-SORBER 1 Tritiation Manifold, IN/US Systems, Inc.) for 4 h.
Labile products were removed by distillation in ethanol and the crude product
was subjected to the reverse phase HPLC purification. The fractions
containing pure product were pooled and reconstituted in ethanol to give
11 mCi of final product with the following specifications: specific activity
(SA)=54 Ci/mmol (by MS); radiochemical purity: 99.72%; chiral
purity ¼ 99:92%; reverse phase HPLC conditions: column: Phenomenex
LUNA C18(2), 3 mm, 4:6 ꢀ 150 mm; mobile phase: A ¼ 0:01 M TEA,
pH ¼ 2:5 w/HClO4, B ¼ CH3CN, 80% A linear gradient to 30% A over
10 min, hold at A:B=30:70 for 10 min, flow rate: 1.0 ml/min, UV detection:
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Y. ZHANG ET AL.
220 nm, retention time: 12.1 min; chiral HPLC conditions: column: Chiralcel
OH-RH, 3 mm, 4:6 ꢀ 150 mm, mobile phase: Premix 25% H2O, 75% MeOH þ
0:1% acetic acid, flow rate: 1.0 ml/min, UV: 220 nm, retention time: 10.0 min.
Conclusion
In conclusion, we have developed an efficient asymmetric synthesis of tritium
and carbon-14 labeled (R)-ibuprofen with excellent enantiomeric excess and
good overall yields.
Acknowledgement
The author thanks Mr Yun Huang for his analytic support and valuable
remarks concerning this work.
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Copyright # 2006 John Wiley & Sons, Ltd.
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