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H.-U. Blaser et al.
PAPER
ing was 95–97%. To obtain analytically pure (S)-4·HCl, the isolated
solid was recrystallized from EtOAc in 81% yield (ee = 99.6%).
1H NMR (D2O): = 1.14–1.19 (t, J = 7 Hz, 3 H), 2.11–2.19 (m, 2
H), 2.49–2.70 (m, 2 H), 3.74–3.79 (t, J = 6.0 Hz, 1 H), 4.03–4.11 (q,
J = 7 Hz, 2 H), 4.12 (br s, 2 H), 7.07–7.38 (m, 10 H).
13C NMR (DMSO-d6): = 14.80 (CH3), 26.48 (2 CH2), 26.89
(CH2), 28.17 (CH2), 33.31 (2 CH2), 37.38 (CH2), 52.71 (CH), 52.93
(CH), 62.29 (CH), 169.97 (C=O).
(+)-Ethyl (S)-2-Hydroxy-4-cyclohexylbutyrate [(S)-7]
Compound (S)-3 (450 g) was dissolved in EtOH (4 L). After the ad-
dition of Nishimura catalyst (4.5 g, Degussa, 45.6% Rh and 18.8%
Pt by weight), the 6.3 L autoclave was closed and purged with N2
(3 ×) and H2 (3 ×). The hydrogenation was carried out for 4.25 h at
100 bar and r.t. After this, the H2 was replaced by N2 and the cata-
lysts were filtered off and the EtOH was evaporated to dryness.
Upon standing, small amounts of colorless crystals were formed.
Therefore, the product mixture was filtered for a second time and
the solvent was evaporated; yield 440 g (95%). The product was
>95% pure according to 1H NMR spectroscopy. To obtain analyti-
cally pure material, (S)-7 was vacuum distilled at 88 °C/1 Torr, after
addition of a small amount of a weakly basic ion exchange resin,
with a yield of >95% and a purity of >98% (ee = 99.6%).
1H NMR (CDCl3): = 0.74–0.81 (m, 2 H), 1.03–1.13 (m, 4 H),
1.15–1.20 (t, J = 7 Hz, 3 H), 1.19–1.24 (m, 2 H), 1.47–1.62 (m, 4
H), 1.60–1.70 (m, 1 H), 3.14 (br s, 1 H, OH), 4.00–4-05 (m, 1 H),
4.05–4.15 (m, 2 H).
13C NMR (CDCl3): = 14.44 (CH3), 26.55 (CH2), 26.57 (CH2),
26.88 (CH2), 32.04 (CH2), 32.52 (CH2), 33.36 (CH2), 33.60 (CH2),
37.70 (CH), 61.47 (CH2), 70.88 (CH), 175.27 (C=O).
13C NMR (D2O): = 13.64 (CH3), 30.54 (CH2), 30.93 (CH2), 50.34
(CH2), 58.28 (CH2), 64.06 (CHN), 126.93 (CH), 128.74 (CH),
129.00 (CH), 129.53 (CH), 129.75 (CH), 130.16 (CH), 130.38
(CH), 139.59 (C), 169.29 (C=O).
The benzylammonium 4-nitrobenzenesulfonate isolated above
could be reconverted to nosyl chloride and recycled.
(+)-Ethyl (S)-2-Amino-4-phenylbutyrate Hydrochloride [(S)-
5·HCl]
Compound (S)-4·HCl (286 g) was dissolved in absolute EtOH (2.6
L) in a 6 L shaker. After the addition of 5% Pd/C (58 g, Engelhard
4522), the shaker was evacuated and flushed with H2 (3 ×). The hy-
drogenation was carried out at 25 °C and 1.1 bar H2 pressure for
17.25 h. After pooling two identical batches, the catalyst was fil-
tered off and the EtOH was removed at reduced pressure. The white
product was dried at 10–2 bar; yield: 414.5 g (99%). 1H NMR anal-
ysis showed a purity of about 98% (ee 98.2%) (HPLC). To obtain
analytically pure (S)-5·HCl, the isolated solid was recrystallized
from i-PrOH in 80–82% yield (ee = 99.7%).
(+)-Ethyl (S)-2-Amino-4-cyclohexylbutyrate Hydrochloride
[(S)-6·HCl]
Acknowledgments
Compound (S)-5·HCl (144.2 g) was dissolved in H2O (2 L). After
the addition of 1 N HCl (15–20 mL), and Nishimura catalyst (1 g,
Degussa, 45.6% Rh and 18.8% Pt by weight), the 8 L autoclave was
closed and purged with N2 (3 ×) and H2 (3 ×). The hydrogenation
was carried out at 100 bar for 23 h at r.t. After 1 h, an additional
amount of catalyst (2 g) and 1 N HCl (20 mL) were added. After 18
h, another batch of catalyst (2 g) was added and the hydrogenation
was continued for 1 h. After this, the H2 was replaced by N2 and the
catalysts was filtered off. The filtrate was neutralized with a weakly
basic ion-exchanger Amberlite IRA93 to pH 7. The resulting solu-
tion was evaporated under reduced pressure and dried; yield: 132 g
(89%, some handling loss); purity 90% (1H NMR). To obtain ana-
lytically pure (S)-6·HCl, the isolated solid was recrystallized from
EtOAc–EtOH 10/:1 in 75–80% yield (ee = 99.8%).
The authors would like to thank the Syngenta Kilo lab (P. Riebli) for
the skillful experimental work.
References
(1) Garrett, C. E.; Jiang, X.; Prasad, K.; Repic, O. Tetrahedron
Lett. 2002, 43, 4161.
(2) (a) Herold, P.; Indolese, A. F.; Studer, M.; Jalett, H. P.;
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(b) Studer, M.; Herold, P.; Indolese, A.; Burkhardt, S. Ciba
Specialty Chemicals Holding, Inc., Switzerland, PCT Int.
Appl. WO 9950223, 1999; Chem. Abstr. 1999, 131, 243073.
(3) Studer, M.; Burkhardt, S.; Indolese, A. F.; Blaser, H.-U.
Chem. Commun. 2000, 1327.
(4) Exner, C.; Pfaltz, A.; Studer, M.; Blaser, H.-U. Adv. Synth.
Catal., submitted.
(5) Blaser, H.-U.; Jalett, H.-P.; Sedelmeier, G. Eur. Pat. Appl.
EP 206993 A1, 1986; Chem. Abstr. 1987, 107, 77434.
1H NMR (DMSO-d6) : = 0.75–0.88 (m, 2 H), 1.07–1.22 (m, 4 H),
1.19–1.23 (t, J = 7 Hz, 3 H), 1.25–1.33 (m, 2 H), 1.53–1.58 (m, 1
H), 1.57–1.65 (m, 4 H), 1.74–1.88 (m, 2 H), 3.35 (br s, 2 H, NH2),
3.84–3.88 (t, J = 6 Hz, 1 H), 4.09–4.26 (m, 2 H).
Synthesis 2003, No. 11, 1679–1682 © Thieme Stuttgart · New York