The synthesis of a chiral fluoxetine intermediate by catalytic enantioselective hydrogenation of benzoylacetamide

Article abstract of DOI:10.1016/S0957-4166(98)00158-X

In the presence of a chiral BINAP-ruthenium(II) catalyst, asymmetric hydrogenation of β-keto propanoic acid N-methyl amide under 200 psi of hydrogen pressure furnished the corresponding 3-hydroxypropanoic acid N- methyl amide as the single enantiomer. The

Full text of DOI:10.1016/S0957-4166(98)00158-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1637–1640
The synthesis of a chiral fluoxetine intermediate by catalytic
enantioselective hydrogenation of benzoylacetamide
∗
Hsiang-Ling Huang, Lee Tai Liu, Shyh-Fong Chen and Hao Ku
Development Center for Biotechnology, 102, Lane 169, Kang-Ning St., Hsi-Chih, Taipei, Taiwan, ROC Taiwan
Received 18 February 1998; accepted 13 April 1998
Abstract
In the presence of a chiral BINAP–ruthenium(II) catalyst, asymmetric hydrogenation of β-keto propanoic acid
N-methyl amide under 200 psi of hydrogen pressure furnished the corresponding 3-hydroxypropanoic acid N-
methyl amide as the single enantiomer. The product can be used as an intermediate for chiral fluoxetine. © 1998
Published by Elsevier Science Ltd. All rights reserved.
1. Introduction
Fluoxetine and analogues belong to a class of selective serotonin (5-HT) reuptake inhibitors (SSRI),
1
and have been widely used as antidepressants. Although fluoxetine hydrochloride is currently sold as the
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racemate (Prozac), related studies showed that the two enantiomers have different activities and rates
3
of metabolism. In recent years, non-racemic fluoxetine and its intermediates have been prepared by
4
–6
7
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chemical, enzymatic, and microbiological methods. Recently, Lily submitted an approval applica-
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tion for (R)-fluoxetine in the US for the treatment of bulimia. Due to its medical potential, non-racemic
fluoxetine still attracts considerable interest for organic and medicinal chemists. In this paper, we describe
a convenient procedure for the preparation of a homochiral β-hydroxy amide as an intermediate for
fluoxetine by asymmetric hydrogenation of a β-keto amide.
2. Results and discussion
Hydrogenation of β-keto carboxylates aided by chiral catalysts affords the corresponding enantiomer-
ically pure 3-hydroxy esters with high enantioselectivity.9,10 However, hydrogenation of β-keto amides
and the application of this methodology for the synthesis of chiral compounds have not been reported in
∗
Corresponding author. E-mail: ltliu@dcbnotes.dcb.org.tw
0957-4166/98/$19.00 © 1998 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00158-X

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H.-L. Huang et al. / Tetrahedron: Asymmetry 9 (1998) 1637–1640
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literature. In fact, asymmetric hydrogenation of a β-keto amide followed by reduction of the amide to
an amine should be a good pathway for the preparation of chiral 3-amino alcohols. In addition, because
most primary and secondary amides are solid, these amides can be conveniently purified by a simple
crystallization. Herein, we report our preliminary study on the asymmetric hydrogenation of a β-keto
amide with a chiral catalyst.
The β-keto amide 2 was prepared from the reaction of N-methylamine and β-keto methyl ester 1
Scheme 1). The crude solid was recrystallized several times until a colorless compound 2 was obtained.
(
Asymmetric hydrogenation of the β-keto amide 2 in the presence of (R)-BINAP–RuCl under 200 psi
2
of hydrogen at 100°C (in a sealed reaction vessel) gave 3a. The reaction mixture was chromatographed
over silica gel to afford a crude chiral alcohol 3a. After repeated recrystallization to remove colored
impurities, (S)-alcohol 3a was obtained as white needles in 50% yield. Analysis by chiral HPLC (Daicel
Chiralcel OD column, iso-propanol:hexanes, 9:1) showed that this (S)-alcohol 3a is a single enantiomer
and is not contaminated by the other enantiomer 3b. The high purity of this chiral alcohol 3a was also
confirmed by its specific rotation value (−29.1, see Table 1), which was higher than that of the literature
8
value (−25.5). We observed that the stereoselectivity in the enantioselective hydrogenation of the β-
keto amide 2 and the configuration of the β-hydroxy amide 3 in this reaction are similar to those in the
reduction of β-keto esters to the corresponding β-hydroxy esters. (R)-Alcohol 3b was also prepared in
an enantiomerically pure form when an (S)-BINAP–RuCl complex was used as the catalyst. In a test
2
experiment, we found that the enantioselectivity of this asymmetric hydrogenation was still very high
(>99.9% ee) if this reaction was performed in a Parr shaker at 80°C and under 60 psi of hydrogen, but
the yield of the product was not satisfactory.
Scheme 1.
3. Experimental section
3.1. General
All reactions were carried under nitrogen unless otherwise stated. Thin layer chromatography (TLC)
was performed on 0.2 mm aluminum sheets precoated with silica gel 60 (Kieselgel-60 F254, E. Merck
Art. 5554). Visualization was performed with UV light, 5% ninhydrin, or 5% vanillin ethanolic solution.
Table 1
Asymmetric hydrogenation of β-keto amide 2 to chiral alcohol 3

H.-L. Huang et al. / Tetrahedron: Asymmetry 9 (1998) 1637–1640
1639
Flash chromatography was carried out using 0.040–0.063 mm (230–400 mesh) silica gel 60 (Kieselgel-
0, E. Merck Art. 9385). High-performance liquid chromatography (HPLC) analysis was performed on
a Shimadzu LC-10At solvent delivery system equipped with an SPD-10A UV–Vis detector and an IT-
00 integrator. Proton and carbon-13 NMR spectra were recorded using a Bruker AC-200 or AVANCE
DRX-500 spectrometer at room temperature. Chemical shifts are reported in ppm relative to Si(CH ) .
6
5
3
4
Coupling constants are reported in hertz. The specific rotation value was measured at the sodium D-line
589 nm) using a Dr. Kernchen’s Propol automatic polarimeter.
(
3.2. 3-Oxo-3-phenylpropanoic acid N-methyl amide 2
A mixture of 10 mL of methyl benzoylacetate and 50 mL of aqueous 40% methylamine solution was
refluxed for 72 h. The solution was extracted with ethyl acetate several times. The organic layer was
washed with a brine solution and dried over magnesium sulfate. After evaporation of ethyl acetate, the
viscous liquid was diluted with ethyl acetate/hexanes and stored in the freezer overnight. The solid was
1
collected, and recrystallized from ethyl acetate and hexanes (50% yield): mp 80.8–81.0°C; H NMR (200
MHz, CDCl ) δ 8.05–7.95 (m, 2H), 7.70–7.30 (m, 3H), 7.16 (br s, 1H), 3.97 (s, 2H), 2.87 (d, J=4.8 Hz,
3
3H).
3.3. (3S)-(−)-3-Hydroxy-3-phenylpropanoic acid N-methyl amide 3a
To a 400 mL reaction vessel in an AtmosBag under argon was added 2 g of compound 2, 100 mg
10b
of (R)-BINAP–RuCl complex, and 100 mL of dry methanol. The reaction vessel was tightly sealed,
2
and hydrogen was filled to about 30 psi and then released after shaking. This process was repeated
three times, then hydrogen was introduced into the reaction vessel until the pressure reached about
200 psi. The solution was stirred at 100°C for 18 h. The reaction vessel was allowed to cool to room
temperature and excess hydrogen was carefully bled off. The solvent was evaporated and the residue
was chromatographed over silica gel. After evaporation, the crude product was recrystallized from ethyl
acetate and hexanes several times until colorless needles were obtained (50% yield): mp 125.8–126.0°C;
2
5
1
[
(
α]D =−29.1 (c 1.25, CH OH); H NMR (200 MHz, CDCl ) δ 7.25–7.17 (m, 5H), 5.81 (br s, 1H), 5.11
3
3
dd, J=4.9, 7.5 Hz, 1H), 2.82 (d, J=4.8 Hz, 3H), 2.56 (m, 2H).
3.4. (3R)-(+)-3-Hydroxy-3-phenylpropanoic acid N-methyl amide 3b
The procedure was similar to that of compound 3a except the (S)-BINAP–RuCl complex was used
2
25
1
as the catalyst: mp 126.0–126.2°C; [α]D =+28.3 (c 1.25, CH OH); H NMR (200 MHz, CDCl ) δ
.25–7.17 (m, 5H), 5.81 (br s, 1H), 5.11 (dd, J=4.9, 7.5 Hz, 1H), 2.82 (d, J=4.8 Hz, 3H), 2.56 (m, 2H).
3
3
7
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