New technical synthesis of ethyl (R)-2-hydroxy-4-phenylbutyrate of high enantiomeric purity

Article abstract of DOI:10.1016/S0040-4020(00)00617-7

A new technical synthesis to produce ethyl (R)-2-hydroxy-4-phenylbutyrate (5), an important intermediate for several ACE inhibitors with >99% ee in an over-all yield of 50-60% is described starting from acetophenone and diethyl oxalate. Key step is the chemo- and enantioselective hydrogenation of ethyl 2,4-dioxo-4-phenylbutyrate (6) (ee up to 86%) catalyzed by a heterogeneous Pt catalyst modified with dihydrocinchonidine, followed by crystallization of the 2-hydroxy-4-oxo ester 7 and hydrogenolysis of the 4-keto group. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00617-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 6497±6499
New Technical Synthesis of Ethyl
(R)-2-Hydroxy-4-phenylbutyrate of High Enantiomeric Purity
*
P. Herold, A. F. Indolese, M. Studer, H. P. Jalett, U. Siegrist and H. U. Blaser
Solvias AG, P.O. Box, CH-4002 Basel, Switzerland
Received 12 May 2000; revised 4 July 2000; accepted 11 July 2000
AbstractÐA new technical synthesis to produce ethyl (R)-2-hydroxy-4-phenylbutyrate (5), an important intermediate for several ACE
inhibitors with .99% ee in an over-all yield of 50±60% is described starting from acetophenone and diethyl oxalate. Key step is the chemo-
and enantioselective hydrogenation of ethyl 2,4-dioxo-4-phenylbutyrate (6) (ee up to 86%) catalyzed by a heterogeneous Pt catalyst modi®ed
with dihydrocinchonidine, followed by crystallization of the 2-hydroxy-4-oxo ester 7 and hydrogenolysis of the 4-keto group. q 2000
Elsevier Science Ltd. All rights reserved.
A variety of commercially important Angiotensin-Convert-
ing Enzyme (ACE) inhibitors contain an (S)-homophenyl-
alanine moiety which can be introduced starting from
various building blocks.1 One of the most useful is enantio-
merically pure ethyl (R)-2-hydroxy-4-phenylbutyrate (5)
which after introduction of a leaving group can be coupled
with inversion with the respective amino moiety. Key
transformations of existing technical processes to 5 are
summarized in Scheme 1: (i) classical racemate resolution
of the hydroxy acid 1,2 (ii) enantioselective reduction of the
3,4-unsaturated 2-keto acid 2 and esteri®cation,3,4 (iii)
enantioselective reduction of the 2-keto acid 4 and esteri-
®cation,3,5 (iv) enantioselective hydrogenation or reduction
of the 2-keto ester 4.3 However, all four routes have one or
more weak points: (i) at best 50% yield, cost of pyruvic acid,
(ii, iii) cost of pyruvic acid and dif®culties with one or both
Scheme 1. Structures of ethyl (R)-2-hydroxy-4-phenylbutyrate (5), important intermediates and selected ACE inhibitors.
Keywords: HPB ester synthesis; enantioselective hydrogenation; cinchona modi®ed platinum catalysts; ACE inhibitor; chiral intermediate; technical synthesis.
* Corresponding author. Tel.: 141-61-686-6426; fax: 141-61-686-6311; e-mail: adriano.indolese@solvias.com
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00617-7

6498
P. Herold et al. / Tetrahedron 56 (2000) 6497±6499
Scheme 2. New total synthesis of ethyl (R)-2-hydroxy-4-phenylbutyrate (5).
Table 1. Hydrogenation of ethyl 2,4-dioxo-phenylbutyrate (6): screening of catalyst and solvent
Entry
Catalyst
Typea,b
Modi®erc
Solvent
ee (%)
Rate (mmol/g min)
1.1
1.2
1.3
1.4
1.5
1.6
5%Pt/Al2O3
5%Pt/Al2O3
5%Pt/Al2O3
5%Pt/Al2O3
5%Pt/SiO2
5%Pt/SiO2
JMC 94
JMC 94
JMC 94
E 4759
D TKS I
D F340
HCd
HCd
HCd
HCd
HCd
HCd
Toluene
AcOH
EtOH
Toluene
Toluene
Toluene
86
45
40
86
60
74
6.4
3.6
5.2
3.4
6.8
1.9
a Reaction conditions see Experimental (ee optimized procedure): 258C, 60 bar.
b JMC Johnson Matthey, E Engelhard, D Degussa-HuÈls.
c HCd: dihydrocinchonidine.
reduction steps (selectivity and/or catalyst activity), (iv)
stability of keto ester (high puri®cation losses), sensitivity
of enantioselective hydrogenation to substrate quality.
heterogeneous cinchona modi®ed Pt catalysts were favored
because both homogeneous and bio catalysts exhibited
either too low activity or were dif®cult to scale up and/or
to handle on a technical level.3,8 However, the ®nding that
the 2-keto group was fully enolized according to the NMR
spectrum made predictions more dif®cult. With an extensive
catalyst, modi®er and solvent screening (for selected results
see Table 1), followed by a careful parameter optimization
we succeeded to develop a catalyst system that gave (R)-2-
hydroxy-4-oxo ester 7 as a viscous oil with high chemical
yield, up to 86% ee and a reasonable catalyst activity.9 As
already observed for the hydrogenation of 2-keto esters,8 the
quality of 6 was of special concern to get good ee's.
Because many of these drugs either have lost patent protec-
tion or will soon do so, the cost of the required building
blocks has become a major issue. Herein we describe a new
cost ef®cient technical synthesis of 5 (ee.99%) with an
over-all yield of 50±60%, starting from acetophenone and
diethyl oxalate.6
For our re-engineering task we de®ned the following goals
and prerequisites: (i) .99% chemical and enantiomeric
purity; (ii) not more than four steps starting from low cost
starting materials; (iii) enantioselective, high yield,
preferentially catalytic transformations; (iv) easy puri®ca-
tion. After assessing a variety of synthetic routes, we
focused on the one depicted in Scheme 2: Claisen con-
densation, followed by chemo- and enantioselective
hydrogenation of the resulting diketo ester 6, and
hydrogenolysis to 5.
In order to reach the necessary enantiomeric purity of
.99%, enrichment was obviously required. It turned out
that the partially enriched 2-hydroxy-4-oxo ester 7 was
well suited for this purpose. DSC experiments indicated a
melting point between 20 and 408C and a solvent screening
Table 2. Hydrogenolysis of ethyl (R)-2-hydroxy-4-oxo-phenylbutyrate (7)
Claisen condensation7 of acetophenone with diethyl oxalate
5% Pd/C
Solvent
Acid
Conditions
5a
proved to be straightforward. A quantitative yield of the 2,4-
dioxo ester 6 was obtained by adding diethyl oxalate
followed by acetophenone to a suspension of NaOEt in
toluene, reacting at 8±108C and work up (ice/acetic acid)
and extraction.
b
b
10% (w/w) AcOH
EtOH
±
±
r.t.; 1.1 bar; 11 h
r.t.; 1.1 bar; 20 h
±
±
5% (w/w)
EtOH
HCl r.t.; 1.1 bar; 4 h
H3PO4 558C; 4 bar; 21 h
.95%
±
b
Toluene
EtOH
Toluene/EtOH H2SO4 508C; 21 bar; 1.5 h
H2SO4 508C; 21 bar; 1.25 h Quant.
Quant.
The key step of the new synthesis was undoubtedly
the chemo- and enantioselective hydrogenation of the
2,4-dioxo ester 6. Based on our experience with the
enantioselective hydrogenation of 2-keto acid derivatives,
a No racemization but traces of the hydroxy acid were observed.
b Ethyl (2R, 4R/S))-2,4-dihydroxy-buyrate and not identi®ed side-
products were formed.

P. Herold et al. / Tetrahedron 56 (2000) 6497±6499
6499
program enabled us to ®nd suitable crystallization condi-
tions where 7 of .72% ee was enriched to .99% ee in
one crystallization step with yields between 50 and 70%,
depending on the starting ee.
Crystallization of ethyl (R)-2-hydroxy-4-oxo-phenyl-
butyrate (7). 74 g (0.332 mol) of the residue of the hydro-
genation was dissolved in 220 ml diisopropyl ether. Seeding
crystals of enantiomerically pure (R)-2-hydroxy-4-oxo ester
7 were added and the solution was slowly cooled to 58C.
Yield of (R)-2-hydroxy-4-oxo ester 7: 47 g, 64%, product
content .99%, ee 99% (hplc, for method see 6), mp 36±
388C. The 1H NMR and the 13C NMR spectra were identical
with the one described above. [a]2D5ˆ111.5 (cˆ10, EtOH).
It is well known that aromatic ketones can be hydrogenated
to the corresponding hydrocarbons in the presence of Pd
catalysts.10 However, catalyst activity is often low requiring
high catalyst loadings and/or acidic conditions. As shown in
Table 2, reasonable reaction times and very high chemo-
selectivity for the removal of the 4-keto group in 7 were
indeed only achieved in the presence of a strong acid. Based
on these results and further optimization of catalyst type and
reaction conditions, a technical process was established
operating at 1.1 bar at 408C with a reaction time of ,6 h
giving .98% 5 with .99% ee containing ca. 1% (R)-2-
hydroxy acid.
Typical hydrogenolysis procedure of ethyl (R)-2-
hydroxy-4-oxo-phenylbutyrate (7). 46 g crystallized
(R)-2-hydroxy-4-oxo ester 7 (ee .99%) was hydrogenated
in 170 ml ethanol at 208C and 1.1 bar hydrogen pressure in a
glass autoclave in the presence of 1.0 wt% of a 5% Pd/C
(460 mg) catalyst and 5 wt% HCl. After hydrogen uptake
had stopped (5±6 h), the catalyst was ®ltered off and the
solvent was evaporated in vacuo. Yield of 5: 42 g, 98%,
1
In conclusion, the new route described above gives an
ef®cient and cost effective access to 5 that is now developed
further in collaboration with the Life Science Molecules
group of Ciba Specialty Chemicals (Ciba LSM) in order
to produce t/y quantities for commercialization.
product content .98% according to H NMR (1H NMR
(CDCl3): 7.15±7.35 (m, 5H), 4.15±4.25 (m, 3H), 2.70±
2.90 (m, 3H), 2.05±2.20 (m, 2H), 1.90±2.00 (m, 2H), 1.30
(t, 3H), ee .99% (hplc, OD±H, hexane/ethanol/TFAˆ970/
30/0.4):); byproduct: ,0.1% (R)-2-hydroxy-4-phenyl-
butyric acid.
Experimental
All reagents and solvents were purchased from Fluka and
Acknowledgements
1
used as received. H an 13C NMR spectra were recorded in
CDCl3 using a Bruker dpx 400 Fourier transform NMR
spectrometer and data reported using the chemical shift
scale in units of ppm relative to SiMe4. Mass Spec analysis
was carried out on a MAT 212 Finnigan apparatus, with EI
ionization. HPLC analysis was carried out on a HP 1100
apparatus. Ethyl 2,4-dioxo-phenylbutyrate was synthesized
according to the literature.11
This project was carried out for and in collaboration with the
Life Science Molecules group of Ciba Specialty Chemicals
(Ciba LSM). We would like to thank F. Spindler, A. Hafner,
H. Probst and R. Sommerlade for valuable discussions
and A. Boos, S. Burkhardt, A. Tarman and W. Schmidt
for careful experimental work.
Hydrogenation of ethyl 2,4-dioxo-phenylbutyrate (6), ee
optimized procedure. 2.0 g diketo ester 6 in 30 ml toluene
were hydrogenated at 258C and 60 bar hydrogen pressure in
a 50 ml stainless steel autoclave in the presence of 50 mg
5% Pt/Al2O3 (pretreated for 2 h in H2 at 4008C) and 5 mg
10,11-dihydrocinchonidine. After hydrogen uptake had
stopped (ca. 160 min), the catalyst was ®ltered off and the
solution was evaporated to dryness at reduced pressure.
Yield of 7: 1.97 g, 98%, product content .97% (NMR),
ee 86% (hplc, OD±H, hexane/EtOH 98.5/1.5, ¯ow 0.7 ml/
min; retention time: (S)-enantiomer 46.0 min, (R)-enantio-
References
1. Sheldon, R. A. Chimica Oggi 1991 (May), 35.
È
2. Attwood, M. R.; Hassall, C. H.; Krohn, A.; Lawton, G.;
Redshaw, S. J. Chem. Soc. Perkin Trans. I 1986, 1011.
3. Schmidt, E.; Blaser, H. U.; Fauquex, P. F.; Sedelmeier, G.;
Spindler, F. Microbial Reagents in Organic Synthesis; Servi, S.,
Ed.; Kluwer: Dordrecht, 1992, p 377.
4. Schmid, R.; Broger, E. A. Proceedings of the ChiralEurope'94
Symposium, Spring Innovation: Stockport, UK, 1994 (pp 79).
5. Blaser, H. U.; Jalett, H. P. Stud. Surf. Sci. Catal. 1993, 78, 139.
6. Studer, M.; Herold, P.; Indolese, A.; Burkhardt, S. WO 9950223
(31.03.1998, assigned to Ciba LSM), CAN 1999:640817.
7. Beyer, C.; Claisen, L. Ber. Dtsch. Chem. Ges. 1887, 20, 2178.
8. Blaser, H. U.; Jalett, H. P.; Spindler, F. J. Mol. Catal. A:
Chemical 1996, 107, 85.
1
mer 49.6 min). MS M1: 222. H NMR (CDCl3): 7.95 (d,
2H), 7.60 (dd, 1H), 7.45 (dd, 2H), 4.65 (m, 1H), 4.25 (q,
2H), 3.30±3.60 (m, 3H), 1.30 (t, 3H). 13C NMR (CDCl3),
198, 174, 136, 134, 129, 128, 67, 62, 42, 14 ppm.
Hydrogenation of 6, volume yield optimized procedure.
80.0 g diketo ester 6 in 120 ml toluene were hydrogenated at
258C and 58 bar hydrogen pressure in a 300 ml stainless
steel autoclave in the presence of 2.00 g 5% Pt/Al2O3
(pretreated for 2 h in H2 at 4008C) and 200 mg 10,11-
dihydrocinchonidine. After hydrogen uptake had stopped
(ca. 140 min), the catalyst was ®ltered off and the solution
was evaporated to dryness at reduced pressure. Yield of 7:
76.0 g, 94%, product content .97% (NMR), ee 76% (hplc).
9. For a detailed description see Studer, M.; Burkhardt, S.;
Indolese, A.; Blaser, H. U.; Solvias A. G. Chem. Commun. 2000
p 1327.
10. Rylander, P. Catalytic Hydrogenation in Organic Synthesis,
Academic Press: London, 1979 (pp 103).
11. Wakabayashi, Y.; Miyata, A.; Sato, H. JP 4149154
(22.5.1992), CAN 117:170989.