Process development of a dual MMP/TNF inhibitor (SDZ 242-484)

Article abstract of DOI:10.1021/op025536e

The compound (2R,3S)-N-4-((S)-2,2-Dimethyl-1-methylcarbamoyl-propyl)-N-1-hydroxy-2- hydroxymethyl-3-(4-methoxy-phenyl)-succinamide (1; SDZ 242-484) shows antiinflammatory effects due to inhibition of matrix metalloproteases (MMP) and tumor necrosis factor

Full text of DOI:10.1021/op025536e

Organic Process Research & Development 2002, 6, 652−659
Technical Notes
Process Development of a Dual MMP/TNF Inhibitor (SDZ 242-484)
Guido Koch,* Georg Kottirsch, Bernhard Wietfeld, and Ernst Ku¨sters
Process Research and DeVelopment, Chemical and Analytical DeVelopment, NoVartis Pharma AG,
CH 4002, Basel, Switzerland
Abstract:
The compound (2R,3S)-N-4-((S)-2,2-Dimethyl-1-methylcarbam-
oyl-propyl)-N-1-hydroxy-2-hydroxymethyl-3-(4-methoxy-phenyl)-
succinamide (1; SDZ 242-484) shows antiinflammatory effects
due to inhibition of matrix metalloproteases (MMP) and tumor
necrosis factor-r activity (TNF). We describe the development
of a chromatography-free process for a multikilogram-scale
pilot-plant production. Two of the three chiral centers are
introduced in a diastereoselective Claisen-Ireland rearrange-
ment. It was found that the selectivity of this step was
significantly enhanced by the addition of catalytic amounts of
Lewis acids. The resulting enantiomeric carboxylic acids were
resolved with (S)-(-)-phenylethylamine. The use of osmi-
umtetroxide was considered to be problematic for pilot-plant
use. Therefore, it was necessary to find an alternative method
for the oxidative cleavage of the terminal olefin functionality.
For the last chemical transformation, a hydrogenolytic cleavage
of a benzyl group in the presence of a hydroxamate, a selective
hydrogenation protocol was developed. To improve drug
substance properties a series of hydroxamic acid salts were
synthesized, and their physical behaviors were investigated.
Figure 1.
dibromobutene (2) which was used in excess to alkylate
benzyl alcohol. After chromatographic separation the allyl-
bromide 3 and p-methoxyphenyl acetic acid were treated with
DBU in dichloromethane followed by silica gel chromatog-
raphy to give allylic ester 4. The silyl enol ether was
generated in situ at -78 °C by deprotonation of the ester 4
with LDA followed by TMSCl quench. If the solution was
warmed quickly to reflux, the rearrangement product 5 could
be isolated as a 2.8-9/1 mixture of racemic erythro-/threo-
isomers in variable 60-80% yield. However, these conditions
were not suitable for scale-up, most likely due to the limited
thermal stability of the silyl ketene acetal intermediate. The
resulting isomeric mixture of 5 was coupled to L-tert-leucine-
N-methylamide under standard peptide coupling conditions
(EDC, DMAP) to form a mixture of four diastereomeric acids
6 in 4/4/1/1 ratio. A three-step oxidation protocol was used
for the cleavage of the terminal olefin. Osmylation, followed
by periodate cleavage and chlorite oxidation of the resulting
aldehyde, gave the corresponding carboxylic acid 7 in high
yield. The benzyl-protected hydroxamate was obtained after
coupling of N-benzylhydroxylamine hydrochloride to acid
7 in the presence of EDC, HOBT, and triethylamine. After
chromatographic purification, the final debenzylation was
achieved by catalytic hydrogenation (Pd-BaSO4). The
mixture of four diastereomeric hydroxamates was subjected
to reverse phase chromatography, providing the desired
product in moderate yield (1% over nine steps).
Introduction
SDZ 242-484 (1) (Figure 1) was discovered by Kottirsch
et al. at Novartis Pharmaceuticals Corporation. It is a direct
inhibitor of the release of tumor necrosis factor-R (TNF) from
the cells. TNF triggers a variety of proinflammatory events
in rheumatoid arthritis; its inhibition (by antibodies of
receptor constructs) has been shown to be beneficial for
rheumatoid arthritis patients. In addition, SDZ 242-484 (1)
is a direct and potent inhibitor of matrix metalloproteinases
(MMP), the enzymes that are largely responsible for the
destruction of cartilage and bone in rheumatoid arthritis and
osteoarthritis.1 The dual TNF/MMP inhibitor SDZ 242-484
(1) is therefore expected to have combined antiinflammatory
and joint-protective effects.
Results and Discussion
(a) The Medicinal Chemistry Synthesis. The original
nine-step synthesis of 1 (Scheme 1)1 started from trans-1,4-
(b) Process R&D (Scheme 2). Due to the limited
availability of trans-dibromobutene (2) an alternative syn-
thesis for the construction of ester 4, the precursor for the
Claisen-Ireland rearrangement, had to be established. Pro-
pargylic alcohol (10) was chosen as starting material. After
alkylation in a biphasic system under phase-transfer condi-
* Corresponding author: Dr. Guido Koch, Novartis Pharma AG, WSJ-
507.704, Postfach, CH-4002 Basel, Switzerland, Telephone: ++41 61 324 42
38. Fax: ++41 61 324 42 36. E-mail: guido.koch@pharma.novartis.com.
(1) (a) Kottirsch, G.; Neumann, U.; Feifel, R.; Koch, G. J. Med. Chem. 2002.
In press. (b) Kottirsch, G.; Neumann, U. WO 9814424 A1.
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Vol. 6, No. 5, 2002 / Organic Process Research & Development
10.1021/op025536e CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/16/2002

Scheme 1. Medicinal chemistry synthesisa
a Reagents and conditions: a) BnOH, Bu4NHSO4, NaOH, H2O, CH2Cl2, 23 °C, flash chromatography, 50%; b) p-methoxyphenylacetic acid, DBU, CH2Cl2, 23 °C,
flash chromatography, 82%; c) LDA, TMSCl, THF, -78 °C-66 °C, 80%; d) EDC, DMAP, L-tert-leucine-N-methylamide, CH2Cl2, 23 °C, flash chromatography,
60%; e) OsO4, NMO, acetone, H2O, tert-butyl alcohol, 23 °C, 90%, f) NaIO4, acetone, H2O, 23 °C, 90%; g) NaClO2, HaH2PO4, 2-methyl-2-butene, H2O, tert-butyl
alcohol, 23 °C, 80%; h) O-benzylhydroxylamine hydrochloride, EDC, HOBt, Et3N, DMF, 23 °C, flash chromatography, 60%; i) 1 bar H2, Pd/BaSO4, MeOH, 23 °C,
reverse phase chromatography, 30%.
tions, prop-2-ynyloxymethyl-benzene (11)2 was subjected to
deprotonation with hexyllithium followed by reaction with
paraformaldehyde to give monobenzylated butynediol (12)3a
in a clean reaction. The resulting alkyne is selectively reduced
to the trans-allylic alcohol 133 with RedAl in THF at 0 °C.
The mono-benzyl-protected butenediol can be purified by
distillation under reduced pressure. Esterification with p-
methoxyphenylacetic acid was achieved using dicyclohexyl-
carbodiimid as coupling reagent in the presence of catalytic
amounts of DMAP4 in toluene. Addition of heptane forced
the urea byproduct to precipitate from the reaction mixture.
After a simple filtration and evaporation of the solvents, the
allylic ester could be used for the Claisen-Ireland5 rear-
rangement without further purification.
There was some evidence that the conditions previously
described for the rearrangement reaction were suitable for
scale-up. However, most likely due to the thermal instability
of the silylketene acetal intermediate first scale-up experi-
ments were not reproducible. In regard to achieving a highly
selective, robust process, this step was closely investigated.
The addition of catalytic amounts of Lewis acids was
beneficial in terms of both yield and selectivity.6
Due to the thermal instability of the intermediate silyl-
ketene acetal reaction monitoring is rather difficult using
conventional methods. However, when using online FT-IR
spectroscopy the process could be followed step-by-step.
When generating the enolate with LiHMDS the expected
E-enolate is formed selectively, clearly identified by a single
IR absorption band 1598 cm-1. Treatment with TMSCl gave
the corresponding (Z)-silylenolether as a single isomer (1656
cm-1). In the presence of a catalytic amount of TiCl4 the
diastereoselective rearrangement starts at about 0 °C. The
IR spectrum clearly shows the expected carbonyl absorption
at 1718 cm-1 (Figure 2) for the resulting carboxylic acid
silylester. A highly diastereoselective titaniumtetrachloride-
catalyzed Ireland-Claisen rearrangement was developed,
which yields the racemic diastereomeric carboxylic acids
(erythro/threo)13:1) in high yield.
The racemic acid can be effectively resolved with (S)-
(-)-phenylethylamine.7 (one recrystallization: 88.0% ee,
yield: 32%; two recrystallizations: 98.5% ee, yield: 90%).
The application of such a chiral resolution process prior to
the peptide-coupling step allowed us to minimize the amount
of rather expensive L-tert-leucine-N-methylamide. The free
(2) Boger, D. L.; Palanki, M. S. S. J. Am. Chem. Soc. 1992, 114, 9318.
(3) (a) Harding, K. E.; Hollingsworth, D. R. Tetrahedron Lett. 1988, 29, 3789.
(b) Kurth, M. J.; Decker, O. H. W. J. Org. Chem. 1985, 50, 5769. (c)
Kizil, M.; Murpy, J. A. Tetrahedron 1997, 53, 16847.
(4) Neises, B.; Steglich, W. Angew. Chem. 1978, 90, 556.
(5) For reviews see: (a) Fraenrath, H. Methods of Organic Chemistry (Houben-
Weyl), 4th ed.; G. Thieme: Stuttgart, 1952 and 1995; Vol. E21d, p 3301.
(b) Schubert, P.; Srebnik, M. Aldrichimica Acta 1993, 26, 17. (c) Wipf, P.
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: New York, 1991, Vol. 5, 827.
(6) Koch, G.; Kottirsch, G.; Wietfeld, B.; Ku¨sters, E. Tetrahedron Lett. 2002,
in press.
(7) For a review see: Juaristi, E.; Escalante, E.; Leo´n-Romo, J. L.; Reyes, A.
Tetrahedron: Asymmetry 1998, 9, 715.
Vol. 6, No. 5, 2002 / Organic Process Research & Development
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653

Scheme 2: Manufacturing process of SDZ 242-484a
a Reagents and conditions: a) BnBr, NaOH, Bu4NBr, H2O, toluene, 50 °C, 98%; b) Hexyl-Li, THF, paraformaldehyde, -78 °C-23 °C, 96%; c) Red-Al, THF, 0
°C, distillation, 80%; d) DCC, DMAP, p-methoxyphenylacetic acid, toluene, 23 °C, 88%; e) LHMDS, TMSCl, TiCl4, THF, -78 °C-23 °C, 77%; f)
(S)-(-)-phenylethylamine, EtOAc; g) 1 N HCl, toluene, 23 °C; h) Vilsmeier reagent, N-methylmorpholine, L-tert-leucine-N-methylamide, THF, 23 °C, 98%; i) O3,
MeOH, -78 °C; j) (CH3)2S, MeOH, -78 °C-23 °C; k) NaClO2, NaH2PO4, 2-methyl-2-butene, tert-butanol, H2O, 23 °C, crystallization, 62%; l) DIC, HOBt, H2NOH,
H2O, TBME, DMF, 23 °C, crystallization, 64%; m) H2, Pd/C, MeOH, 23 °C, crystallization, 74%.
Figure 2. FT-IR monitoring of the rearrangement of ester 4. Reaction profile from React-IR.
acid was generated by treating a suspension of the phenyl-
ethylamine salt in toluene with aqueous HCl (1.0 N). In the
medicinal chemistry synthesis the coupling with L-tert-
leucine-N-methylamide was performed under standard pep-
tide chemistry conditions using EDC, DMAP.1 Careful HPLC
and NMR analysis indicated that significant epimerization
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Vol. 6, No. 5, 2002 / Organic Process Research & Development

Table 1. Dihydroxylation: catalyst screening
Table 2. Osmium balancea
volume Os-content Os-amount
layer
[ml]
[ppm]
[mg]
distilled acetone
225
<0.1
205
35
0
46
4
sodiumsulfite layer (pH 9)
first HCl layer (pH 1)
second HCl layer (pH 1)
227
110
54
12
1
sodium bicarbonate layer (pH 8) 150
22
3
0
0
0
first brine layer (pH 8)
second brine layer (pH 7)
distilled isopropyl acetate
crude diol
105
100
375
<1
<1
<1
320
K2OsO4
entry (mol %)
reaction
time (h)
ligand
solvent
50.42 g
16
1
2
3
4
5
6
7
8
9
1
1
1
0.5
0.5
0.5
-
acetone/H2O
acetone/H2O
>15
15
15
20
20
4
a Batch: 0.1 mol of alkene 6 (44 g). Total amount of osmium used: 74 mg
DABCO (5 mol %)
found: 70 mg.
(DHQD)2PHAL (2.5 mol %) acetone/H2O
DABCO (5 mol %)
quinuclidine (5 mol %)
(DHQD)2PHAL (2.5 mol %) Acetone/H2O
acetone/H2O
Acetone/H2O
Table 3. Osmium reduction
0.25 (DHQD)2PHAL (1 mol %) Acetone/H2O
0.4 (DHQD)2PHAL (2 mol %) t-BuOH/H2O
0.25 (DHQD)2PHAL (1 mol %) t-BuOH/H2O >24
15
18
Os-content
of diol [ppm]
entry
resin
1
2
3
4
5
6
367
363
240
217
237
273
PureLite S930
PureLite S920
IONAC SR-3
IONAC SR-4
(>5%) occurred under the employed reaction conditions.
Therefore, and also because of the significant cost factor of
EDC, we were looking for alternative coupling procedures.
The use of isobutylchloroformate8 to form a mixed anhydride
intermediate was not successful. The formation of the
anhydride was found to be clean and complete; however,
competitive nucleophilic attack to the carbonate carbon
resulted in regeneration of significant amounts of starting
material. Carbonyldiimidazole9 and dimethoxychlorotriaz-
ine10 gave unsatisfactory results as well. A very clean reaction
without any detectable epimerization was observed when
using the commercially available Vilsmeier reagent11 for the
activation of the carboxylic acid functionality. The desired
product (6) was isolated in quantitative yield and could be
used in the following step without further purification.
The terminal olefin was cleaved to the carboxylic acid in
a three-step procedure.1 Osmium catalyzed dihydroxylation
using NMO as cooxidant (Upjohn process),12 followed by
periodate cleavage and NaClO2 oxidation. The use of highly
toxic osmium compounds in the pilot-plant environment was
accompanied with safety and environmental issues. We
therefore made an effort to reduce the amount of osmium
catalyst as much as possible. It is well-known that the
dihydroxylation process can be significantly accelerated by
amine ligands coordinating to the catalytically active osmium
species.13 Results with some ligands investigated are sum-
marized in Table 1.
Na2SO3-wash (5 times)
of the corresponding isolated diol. Surprisingly, the diaste-
reoselectivity of the process was very low for both the
mismatched and the matched ligand enantiomers. The process
was very carefully investigated for environmental reasons.
The osmium flow was monitored (Table 2). In total, 95% of
the osmium introduced in the reaction could be found and
localized. Unfortunately it was found that even after extensive
wash of the product layer and treatment of the crude diol
with ion-exchange resins (Table 3), significant amounts of
the heavy metal was still found in the diol after recrystal-
lization. Not surprisingly the molecule acts as an excellent
chelating ligand for metal ions such as osmium.
Therefore, we decided to look for other possibilities to
achieve double bond cleavage. In a first attempt we applied
von Rudloff-Lemieux conditions.15 The reaction with
catalytic amounts of KMnO4 in the presence of HIO4 offers
a one-step transformation to the corresponding carboxylic
acid. However, the reaction proceeded with low yield most
likely due to undesired aromatic ring cleavage reactions and
product isomerization. After crystallization the acid 7 was
isolated in 20% yield (Table 4).
A very efficient and clean reaction was obtained when
treating the alkene with ozone in methanol. After reduction
with dimethyl sulfide the resulting aldehyde was directly
oxidized without any purification. The carboxylic acid was
effectively purified by crystallization from ethyl acetate in
62% overall yield over the three steps. The coupling with
N-benzylhydroxylamine using a standard protocol (EDC,
HOBt) resulted in smooth formation of the benzylhydrox-
amate 8. However, selective debenzylation proved to be
Under Sharpless asymmetric dihydroxylation conditions14
osmium loading as low as 0.25 mol % still gave high yields
(8) (a) Boissonnas, R. A. HelV. Chim. Acta 1951, 34, 874; HelV. Chim. Acta
1952, 35, 2229 and 2237. (b) Wieland, T.; Bernhard, H. Liebigs Ann. 1951,
572, 190.
(9) (a) Staab, H. A.; Lu¨king, M.; Du¨rr, F. H. Chem. Ber. 1962, 95, 1275. (b)
Staab, H. A. Angew. Chem. 1962, 74, 407.
(10) Kaminsky, Z. J.; Paneth, P.; Rudzinsky, J. J. Org. Chem. 1998, 63, 4248.
(11) Bosshard, H. H.; Zollinger, H. C. H. Angew. Chem. 1959, 71, 375.
(12) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17,
1973.
(14) For a review see: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. ReV. 1994, 94, 2483.
(13) (a) Erdik, E.; Kahya, D.; Daskapan, T. Synth. Commun. 1998, 28, 1. (b)
Oishi, T.; Hirama, M. Tetrahedron Lett. 1992, 33, 639.
(15) Lemieux, R. U.; von Rudloff, E. Can. J. Chem. 1955, 33, 1701, 1710. von
Rudloff, E. Can. J. Chem. 1965, 43, 1784.
Vol. 6, No. 5, 2002 / Organic Process Research & Development
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655

Table 4. von Rudloff-Lemieux reaction conditionsa
Table 5. Crystal modifications of SDZ 242-484
(manufacturing conditions and analytical characterisation)
KMnO4 temperature time yield
entry solvent (v/v) [eq]
[°C]
[h]b (7) [%]
remarks
cryst.
temp
[°C]
DSC TG
1
2
3
4
5
6
7
8
9
t-BuOH/H2O 0.16
(1:2)
t-BuOH/H2O 0.48
(1:3)
t-BuOH/H2O 0.48
(1:3)
t-BuOH/H2O 0.48
(1:3)
t-BuOH/H2O 0.16
(1:3.5)
t-BuOH/H2O 0.48
(1:3.5)
t-BuOH/H2O 0.48
(1:3.5)
acetone/H2O 0.16
(1:3.5)
50
50
50
50
0
1
1
7.8
36
solvent
XRPD
[°C] [%]
20% isolated yield
after crystallization
reaction at pH 8-8.5
by adding NaOH
reaction in buffer
at pH 7
water
(melt)
60 modification A 88.2 15.5
123 modification B 150.7 6.5
60 modification C 67.7 0.5
1
29
19
17
22
34
0
tetrahydrofuran/methanol )
10/1 (V/V)
1
methanol/toluene )
1.5/10 (V/V)
methanol/ethyl acetate )
0.5/20 (V/V)
tetrahydrofuran/water )
100/2 (V/V)
65 modification D 82.5 3.0
65 modification E 66.2 2.8
70 modification F 107.5 2.0
24
24
48
24
24
0
-6
0
methanol/2-propanol )
1/10 (V/V)
65 modification G 96
1.1
acetone/H2O 0.48
(1:3.5)
0
0
a 6 equiv of NaIO4 and 1.3 equiv of K2CO3 were used. bConversation of
(between 150 and 190 °C). Nevertheless, all salts were again
solvates that exhibited a strong tendency to take up water
and to become amorphous under drying conditions. It should
be mentioned that until now the preparation of a solvent-
free crystal modification has not been accomplished.
starting material 6 was in all cases greater than 95% for that time.
rather difficult. Significant N-O-reduction was observed.
To avoid these selectivity problems in the bis-debenzylation
step a new synthetic strategy was chosen. Instead of
introducing O-benzylhydroxylamine the free hydroxamate
was synthesized using simply aqueous hydroxylamine solu-
tion in the presence of DIC, HOBt. The highly crystalline
hydroxamic acid derivative could be effectively purified by
a simple recrystallization. The debenzylation step was carried
out on 5% Pd/C in methanol at atmospheric hydrogen
pressure providing the drug substance (1) in quantitative yield
and high purity. Selectivity problems, for example hydro-
genolytic cleavage of the N-O bond vs benzyl hydrogena-
tion, were not detected upon applying these conditions. The
final synthetic route is shown in Scheme 2.
(c) Drug Substance Properties. The drug substance SDZ
242-484 crystallizes from water as tetra-hydrate (15.5 wt %)
which is in agreement with the theoretical amount (15.4 wt
%). This crystal modification, further mentioned as modifica-
tion A, melts at 88.2 °C and is characterised by single X-ray
powder diffraction (XRPD), thermogravimetry (TG), and
differential scanning calorimetry (DSC). Strong drying of
the tetra-hydrate leads to amorphous material. The water
sorption isotherm of the amorphous form resembled that of
modification A which shows that under humid conditions
the amorphous form can recrystallize into the tetra-hydrate.
Crystallization of amorphous material (from the melt at 123
°C) yielded modification B with a melting point of 150.7
°C and a water content of only 6.5 wt %. The water content
corresponds to a 1.5-hydrate and is constant between 30 and
95% relative humidity Unfortunately, modification B, which
exhibits better physicochemical properties, could not be
obtained in conventional crystallization experiments.
Conclusions
In summary, a robust process for a large-scale, chroma-
tography-free preparation of 1 was developed. The key step
in the reaction sequence utilized a Lewis acid-mediated
diastereoselective Claisen-Ireland rearrangement followed
by a chiral resolution. One batch of 4.5 kg of drug substance
(1) was produced in pilot-plant equipment. The physico-
chemical properties of the drug substance were optimized.
Experimental Section
Starting materials, reagents, and solvents were obtained
from commercial suppliers and were used without further
purification. All the melting points are uncorrected and
1
determined on a Bu¨chi apparatus. H NMR spectra were
recorded at 300 MHz, and 13C NMR spectra were recorded
at 75 MHz on a Bruker DPX 300 instrument. IR spectra
were measured on a Bruker IFS660 spectrometer. The
enantiopurity of 5 was determined on a Hewlett-Packard
Series 1100 HPLC system using a Daicel Chiralcel OD
column.
Prop-2-ynyloxymethylbenzene (11).2 To a solution of
propargylic alcohol 10 (22.1 mL, 0.37 mol) in 170 mL of
toluene was added a solution of NaOH (10.0 M, 37.5
mL,0.37 mol) followed by the addition of 11.93 g (37 mmol)
Bu4NBr. The resulting mixture was heated to 50 °C and
treated with benzylbromide (40.0 mL, 0.34 mol) over 1 h.
The biphasic solution was stirred for additional 14 h at 50
°C and then cooled to 23 °C. The two layers were separated,
and the organic phase was washed three times with brine.
After evaporation of the solvent 47.6 g (98%) of a pale
yellow oil was obtained. Purity: 97% (GC). Rf ) 0.82
(EtOAc/heptane ) 1:1); 1H NMR (300 MHz, CDCl3) δ 2.49
(t, J ) 2.4 Hz, 1 H), 4.20 (d, J ) 2.4 Hz, 2 H), 4.64 (s, 2
H), 7.30-7.39 (m, 5 H).
All crystallization experiments with other solvents to
obtain a solvent and water-free crystal form failed so far.
As illustrated in Table 5, at least five additional crystalline
forms have been identified which all present solvate forms
and which are all characterised by a strong water uptake.
Transformation of SDZ 242-484 into its sodium, calcium,
and magnesium salts yielded higher-melting compounds
4-Benzyloxy-but-2-yn-1-ol (12).3a In a 1.5-L flask equipped
with a mechanical stirrer, prop-2-ynyloxymethylbenzene (11)
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Vol. 6, No. 5, 2002 / Organic Process Research & Development

(39.3 g, 0.27 mol) was dissolved in 220 mL of THF and
cooled to -78 °C. n-Hexyllithium (33% in hexanes, 118 mL,
0.30 mol) was added over a period of 1 h. The resulting
yellow solution was stirred for 2 h. Paraformaldehyde (9.73
g, 0.32 mol) was added in one portion, and the yellow
suspension was warmed to 23 °C over 2 h. The reaction
mixture was stirred for 16 h and then quenched with aqueous
NH4Cl solution (20%, 175 mL). TBME (260 mL) was added,
and the two layers were separated. After extraction of the
aqueous layer with TBME (80 mL) the organic phases were
combined and washed three times with 170 mL of brine.
Concentration and azeotropic removal of water with toluene
(2 times 60 mL) afforded 45.54 g (96%) of crude alcohol
55.2, 64.6, 69.7, 72.3, 114.0, 126.0, 126.6, 127.0, 127.7,
127.8, 128.4, 130.3, 130.9, 138.1, 158.7, 171.6. MS (EI) m/z
326 (M+), 166, 148, 121, 91, 65.
(()-3-Benzyloxymethyl-2-(4-methoxy-phenyl)-pent-4-
enoic Acid ((-5). A solution of 38.4 mL (184.3 mmol)
1,1,1,3,3,3-hexamethyldisilazane in 100 mL of THF was
treated with n-hexyllithium (63.65 g, 184.0 mmol, 26.6% in
hexanes) at 0 °C over a period of 14 min. The LHMDS
solution was stirred for 5 min and cooled to -78 °C. Then
chlorotrimethylsilane (23.3 mL, 184.0 mmol) was added over
15 min. To the resulting mixture a solution of ester 4 (50.0
g, 153.2 mmol) in 50 mL of THF was slowly added (43
min). The reaction mixture was treated with 0.31 mL (0.31
mmol) of a TiCl4 solution (1.0 M in toluene), warmed to 23
°C over 90 min, and stirred at room temperature for 1 h.
The reaction was quenched by the addition of a 1.0 M
solution of NaOH (400 mL). The layers were separated, and
the organic layer was extracted once with 72 mL of 1.0 M
NaOH. The combined aqueous solutions were acidified to
pH 1.0 by slow addition of 5% HCl (390 mL) at 0 °C. Then
286 mL of toluene were added, the layers were separated,
and the organic solution was concentrated in vacuo to afford
38.35 g (77%) of a yellow oil (anti/syn ) 13:1 (HPLC)).
The crude mixture was subjected to the resolution with L-
1
12 as a yellow oil. Rf ) 0.44 (EtOAc/heptane ) 1:1); H
NMR (300 MHz, CDCl3) δ 1.69 (s, br, 1 H), 4.24 (t, J )
1.6 Hz, 2 H), 4.35 (t, J ) 1.6 Hz, 2 H), 4.62 (s, 2 H), 7.32-
7.39 (m, 5 H).
(E)-4-Benzyloxy-but-2-en-1-ol (13).3 A solution of alkyne
12 (40 g, 0.23 mol) in 185 mL of THF was cooled to 0 °C.
RedAl (70% in toluene, 85.2 g, 0.30 mol) was slowly added
over 1 h. After complete addition the reaction mixture was
immediately transferred into a solution of aqueous H2SO4
(20%, 300 mL) at 0 °C. Toluene was added (260 mL), and
the biphasic system was vigorously stirred for 5 min. The
two phases were separated, and the aqueous layer was
extracted with 40 mL of toluene. The combined organic
layers were washed with aqueous NaHCO3 (8%, 150 mL)
and brine (150 mL), concentrated, and dried by azeotropic
distillation of toluene to afford 36.40 g (90%) of crude trans-
alcohol 13. The product was purified by distillation (110 °C,
0.3 mbar) to yield 80% of a yellow oil. Purity: 83% (GC).
(-)-R-methylbenzylamine. HPLC tR (anti-isomer)
)
17.3/22.7 min/tR (syn-isomer) ) 15.4/20.1 min (Chiralcel
OD n-hexanes/i-PrOH/TFA ) 95:5:0.1).
(2S,3R)-3-Benzyloxymethyl-2-(4-methoxyphenyl)-pent-
4-enoic Acid L-(-)-r-Methylbenzylammonium salt (5a).
Crude racemic acid 5 (45.17 g, 138.3 mmol) was dissolved
in 1760 mL of ethyl acetate and treated with 19.4 mL (152.2
mmol) of L-(-)-R-methylbenzylamine. The resulting suspen-
sion was heated to reflux. A clear solution was obtained,
from which upon cooling to 20 °C over a period of 2 h
crystallization occurred (seeding if necessary). After ad-
ditional stirring of the suspension for 2 h the mixture was
filtered, and the white crystals were washed with 90 mL of
cold (-20 °C) ethyl acetate in two portions. The product
was dried under vacuum (50 mbar) at 50 °C for 8 h to afford
25.35 g (41%) of the L-(-)-R-methylbenzylammonium salt
(86% ee; HPLC). Recrystallization from 1075 mL of ethyl
acetate yielded 15.5 g (62%) of enantiomerically pure (98.5%
ee) white crystals. Mp ) 177 °C.
(2S,3R)-3-Benzyloxymethyl-2-(4-methoxyphenyl)-pent-
4-enoic Acid (5). A 2-L flask equipped with a mechanical
stirrer was charged with 34.2 g (76.4 mmol) of L-(-)-R-
methylbenzylammonium salt (5a) and suspended in 780 mL
of toluene. HCl (240 mL of a 1.0 M solution, 240 mmol)
was added. Stirring was continued until a clear biphasic
solution was observed (0.5-3.0 h). The two layers were
separated, the aqueous phase was subjected to reextraction
(vigorous stirring for 25 min) with 250 mL of toluene, and
the combined toluene layers were washed with 400 mL of
water followed by a second wash with 200 mL of water.
After concentration in vacuo 25.73 g (100%) of a colorless
oil was obtained. Rf ) 0.49 (heptane/EtOAc/AcOH ) 60:
40:2). HPLC tR ) 22.7 min (Chiralcel OD n-hexanes/
i-PrOH/TFA ) 95:5:0.1). IR (film, cm-1) 2935m, 1704s,
1
Rf ) 0.37 (EtOAc/heptane ) 1:1); H NMR (300 MHz,
CDCl3) δ 1.36 (s, br, 1 H), 3.97 (d, J ) 5.3 Hz, 2 H), 4.09-
4.10 (m, 2 H), 4.46 (s, 2 H), 5.73-5.90 (m, 2 H), 7.32-
7.39 (m, 5 H).
(4-Methoxyphenyl)acetic Acid (E)-4-Benzyloxy-but-2-
enyl ester (4). A 2.5-L flask was charged with a solution of
(E)-4-benzyloxy-but-2-en-1-ol (13) (100 g, 0.56 mol), 4-meth-
oxyphenylacetic acid (93.03 g, 0.56 mol) and 4-DMAP
(3.425 g, 28 mmol) in 550 mL of toluene. Dicyclohexyl-
carbodiimide (50% in DMF, 222.6 mL, 0.56 mol) was added
slowly. The reaction temperature was kept between 23 and
27 °C. When the addition was finished, heptane (225 mL)
was added. The resulting suspension was cooled to -10 °C,
stirred for 10 min, and filtered. The filter cake was washed
with 300 mL of heptane. Water (1275 mL) was added to
the filtrate, the layers were separated, and the organic phase
was washed with an additional 640 mL of water. Filtration
of the organic solution through a pad of aluminum oxide
(500 g), elution with toluene/heptane (1:1, 1110 mL), and
concentration of the filtrate afforded 161.41 g (88%) of a
yellowish oil. Rf ) 0.38 (heptane/EtOAc ) 50:25). IR (film,
cm-1) 2930m, 1736s, 1613w, 1514s, 1454m, 1302m, 1249s,
1
1152m, 1034m, 976m, 821w, 739w, 699w. H NMR (300
MHz, CDCl3) δ 3.57 (s, 2 H), 3.77 (s, 3 H), 3.99-4.03 (m,
2 H), 4.50 (s, 2 H), 4.57-4.62 (m, 2 H), 5.82-5.86 (m, 2
H), 6.84 (d, J ) 8.6 Hz, 2 H), 7.19 (d, J ) 8.6 Hz, 2 H),
7.28-7.39 (m, 5 H). 13C NMR (75 MHz, CDCl3) δ 40.4,
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657

1611m, 1512s, 1454m, 1363w, 1251s, 1179m, 1105m,
1034m, 922w, 828w, 738w, 699w. H NMR (300 MHz,
180 mL of NaHCO3 (8%) and twice with 100 mL of NaCl
(20%). The organic layer was concentrated to give a
diastereomeric mixture of crude diol (50.42 g, 106%) which
was subjected directly to the next step.
1
CDCl3) δ 3.13-3.18 (m, 1H), 3.43 (dd, J ) 9.4, 6.2 Hz, 1
H), 3.56 (dd, J ) 9.4, 5.3 Hz, 1 H), 3.72-3.78 (m, 1H),
3.75 (s, 3 H), 4.47 (s, 2 H), 4.94 (dd, J ) 15.5, 12.3 Hz, 2
H), 5.48 (ddd, J ) 15.5, 12.3, 8.8 Hz, 1 H), 6.81 (d, J ) 8.8
Hz, 2 H), 7.19 (d, J ) 8.8 Hz, 2 H), 7.27-7.30 (m, 5 H),
8.60-9.80 (s, br, 1 H). 13C NMR (75 MHz, CDCl3) δ 46.1,
52.1, 55.2, 72.0, 73.1, 113.8, 117.8, 127.5, 127.6, 128.3,
130.3, 136.1, 138.1, 158.9, 179.4. MS (EI) m/z 326 (M+),
282, 217, 165, 137, 121, 91.
(2S,3R)-N-((S)-2,2-Dimethyl-1-methylcarbamoyl-
propyl)-3-hydroxymethyl-2-(4-hydroxy-phenyl)-4-oxobutyr-
amide. A solution of 16.33 g (33.6 mmol) of crude diol was
dissolved in 160 mL of acetone and treated with a solution
of 7.89 g (36.9 mmol) of NaIO4 in 80 mL of H2O. The
reaction mixture was stirred for 3 h at 23 °C, diluted with
200 mL of isopropyl acetate and 200 mL of H2O, and the
resulting layers were separated. The aqueous phase was
extracted with 120 mL of isopropyl acetate, and the combined
organic phases were washed with 160 mL of NaCl (20%).
Concentration in vacuo afforded 14.52 g (95%) of a
yellowish foam, which was directly further oxidized with
sodium chlorite to the corresponding carboxylic acid as
described in the following procedure.
(2S,3R)-3-Benzyloxymethyl-2-(4-methoxy-phenyl)pent-
4-enoic Acid ((S)-2,2-Dimethyl-1-methylcarbamoylprop-
yl)amide (6). To a suspension of (chloromethylene)di-
methylammonium chloride (21.4 g, 167 mmol) in 156 mL
of THF was added a solution of 36.2 g (111 mmol) of
carboxylic acid 5 in 144 mL of THF at 0 °C. The slurry
was stirred at 0 °C for 1 h before N-methylmorpholine (49.1
mL, 445 mmol) was added, followed by the addition of a
solution of L-tert-leucine-N-methylamide (17.7 g, 122 mmol)
in 100 mL of THF and 4 mL of DMF over 15 min. The
reaction mixture was warmed to 23 °C over 25 min and
stirred for additional 2 h. A 1.0 M solution of HCl (180 mL)
was added. After dilution with 120 mL of isopropyl acetate
the two layers were separated, and the aqueous phase was
extracted with ethyl acetate. The combined organic extracts
were washed once with 120 mL of 1.0 M NaOH and three
times with brine (120 mL). The solvent was removed, and
49.1 g (98%) of a yellow foam was obtained. Rf ) 0.33
(heptane/EtOAc/AcOH ) 60:40:2). IR (KBr, cm-1) 3307s,
2955m, 1634s, 1569m, 1538m, 1511s, 1454w, 1384w,
1249m, 1179w, 1100w, 1036w, 698w. 1H NMR (300 MHz,
CDCl3) δ 0.97 (s, 9 H), 2.52 (d, J ) 4.7 Hz, 3 H), 3.12-
3.16 (m, 1 H), 3.44-3.48 (m, 1 H), 3.59-3.67 (m, 1 H),
3.69-3.77 (m, 1 H), 3.73 (s, 3 H), 4.33 (d, J ) 9.4 Hz, 1
H), 4.48 (dd, J ) 21.9, 12.0 Hz, 2 H), 4.94 (dd, J ) 19.7,
10.6 Hz 2 H), 5.56-5.68 (m, 1 H), 6.60-6.63 (m, 2 H),
6.75 (d, J ) 8.7 Hz, 2 H), 7.16 (d, J ) 8.7 Hz, 2 H), 7.25-
7.33 (m, 5 H). 13C NMR (75 MHz, CDCl3) δ 26.7, 34.6,
46.3, 53.1, 55.1, 60.5, 71.8, 73.3, 113.7, 117.3, 127.6, 127.7,
128.3, 129.4, 129.6, 130.1, 137.2, 138.3, 158.7, 170.8, 172.9.
MS (ESI) m/z 475 (M + Na+), 453, 422, 366, 290, 200.
(2S,3R)-4,5-Dihydroxy-3-hydroxymethyl-2-(4-hydroxy-
phenyl)pentanoic Acid ((S)-2,2-Dimethyl-1-methylcar-
bamoylpropyl)amide. To a solution of 143.7 mg (0.39
mmol) K2OsO4 in 220 mL of H2O was added a solution of
760 mg (0.98 mmol) of (DHQ)2PHAL in 20 mL of acetone,
followed by the addition of a solution of 44.14 g (97.5 mmol)
alkene 6 in 200 mL of acetone. The resulting mixture was
treated slowly with an aqueous solution (50%) of N-
methylmorpholine-N-oxide (27.0 mL, 127 mmol) at 23 °C.
Stirring was contiued for 17 h. For the workup, a solution
of 2.2 g of sodium hydrogen sulfite (38-40%) was dissolved
in 11 mL of H2O and added to the reaction mixture. After 3
h the solution was concentrated in vacuo to a total volume
of 340 mL. The residue was extracted with 150, 100, and
75 mL of isopropyl acetate. The combined organic layers
were washed with 100 mL of 1 N HCl (100 and 50 mL),
(2R,3S)-2-Benzyloxymethyl-N-((S)-2,2-dimethyl-1-me-
thylcarbamoylpropyl)-3-(4-methoxy-phenyl)succinamic
Acid (7). Alkene 6 (6.0 g, 11.3 mmol) was dissolved in 230
mL of methanol and cooled to -78 °C. The solution was
treated with a stream of ozone for 1 h until a blue-coloured
solution was obtained. The reaction mixture was purged with
nitrogen for 5 min to remove the excess of O3. To the clear,
colourless solution was added dimethyl sulfide (4.9 mL, 66.8
mmol). The reaction mixture was warmed to 23 °C over 1
h and stirred for additional 14 h. After concentration under
reduced pressure 8.20 g of crude aldehyde were obtained,
which was subsequently dissolved in 80 mL of tert-butanol
and treated with 3.83 g (46.6 mmol) of 2-methyl-2-butene
(85%) and a solution of 3.61 g (39.9 mmol) of sodium
chlorite and 3.51 g (29.3 mmol) sodium dihydrogenphosphate
in 35 mL of water at 0 °C. The reaction mixture was stirred
for 30 min at 0 °C and for 2 h at 23 °C. Sodium hydrogen
sulfite solution (10%, 98 mL) was slowly added, and the
pH was adjusted to 3.0 by the addition of 1 N HCl (15 mL).
The mixture was extracted three times with ethyl acetate (50
mL each). Concentration of the combined organic extracts
afforded 6.61 g (72%) of crude acid 7. Purity: 69% (HPLC).
Crystallization: Crude acid 7 (55 g, 118 mmol) was disolved
in 400 mL of refluxing ethyl acetate. Cooling to 0 °C over
4 h and stirring at 0 °C for 2 h followed by filtration afforded
crystalline product. The cake was washed with cold ethyl
acetate (50 mL) and dried for 15 h at 50 °C at 10 mbar.
White crystals (34.63 g, 62%) were obtained. Purity: 93%
(HPLC). Rf ) 0.30 (heptane fractions/EtOAc/AcOH ) 20:
80:1). Mp ) 201 °C. IR (KBr, cm-1) 3305m, 2963m, 1712m,
1638s, 1545m, 1513s, 1369m, 1253m, 1180m, 110w, 1030w.
1H NMR (300 MHz, DMSO) δ 0.86 (s, 9 H), 2.45 (s, 3 H),
3.28-3.35 (m, 1 H), 3.48-3.52 (m, 1 H), 3.61 (t, J ) 9.5
Hz, 1 H), 3.70 (s, 3 H), 3.90 (d, J ) 11.5 Hz, 1 H), 4.15 (d,
J ) 9.6 Hz, 1 H), 4.45 (s, 2 H), 6.08 (d, J ) 8.5 Hz, 2 H),
7.28-7.36 (m, 7 H), 7.84 (d, br, J ) 4.3 Hz, 1 H), 8.14 (d,
J ) 9.4 Hz, 1 H), 11.98 (s, br, 1 H). 13C NMR (75 MHz,
DMSO) δ 23.7, 25.4, 32.9, 47.5, 48.2, 53.6, 58.4, 68.9,
70.8, 112.0, 126.15, 126.21, 126.9, 128.1, 128.8, 136.6,
658
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Vol. 6, No. 5, 2002 / Organic Process Research & Development

156.9, 168.7, 169.6, 172.3. MS (ES) m/z 469 (M - H)-,
235.
dissolved. The layers were separated, and the organic phase
was washed twice with 100 mL of 0.1 N HCl. The organic
layer was concentrated to a total volume of 700 mL. The
resulting suspension was heated to reflux and cooled to 0
°C over 2 h. Crystallization was initiated by seeding at 45-
50 °C. The white crystals were filtered and washed twice
with cold ethyl acetate (100 mL). Drying under vacuum (10
mbar) at 50 °C for 15 h afforded 10.42 g (64%) of
hydroxamic acid 9. Additional 8% yield could be recovered
by washing the mother liquor with 0.1 N HCl and recrys-
tallization following the described procedure. Rf ) 0.33
(EtOAc/AcOH ) 100:1). Mp ) 209 °C. IR (KBr, cm-1)
3339m, 3277s, 2963m, 1705m, 1678m, 1628s, 1512s, 1455w,
(2R,3S)-2-Benzyloxymethyl-N-((S)-2,2-dimethyl-1-me-
thylcarbamoylpropyl)-3-(4-methoxy-phenyl)succinamic
Acid (7) (von Rudloff-Lemieux Conditions). Alkene 6 (3.6
g, 8.0 mmol) was dissolved in 45 mL of tert-butanol at room
temperature. Potassium carbonate (1.4 g, 10.4 mmol) dis-
solved in water (40 mL) was added, and the mixture was
heated to 50 °C (pH 13). To this mixture a solution of sodium
periodate (10.2 g, 47.8 mmol) in water (55 mL) was added
followed by the additon of a solution of potassium perman-
ganate (0.6 g, 3.8 mmol) in water (40 mL). Thereafter, the
reaction mixture was stirred for 1 h until no alkene 6 was
detectable (TLC: EtOAc/heptane/AcOH ) 60:40:2 v/v). The
red-brown solution (pH 6) was cooled to room temperature,
sodium sulfite solution (20%, 100 mL) was added, and the
two-phase mixture was concentrated under reduced pressure
until no tert-butanol distilled. Ethyl acetate (200 mL) was
added, and the pH was adjusted to 3.0 by the addition of 1
N HCl (110 mL). After phase separation, the ethyl acetate
layer was washed one time with sodium sulfite solution
(20%, 40 mL) and two times with brine (20%, 75 mL each).
Concentration of the ethyl acetate phase afforded 3.2 g (84%)
of the crude acid 7 as a yellow foam. Purity: 37% (HPLC).
The foam was dissolved in toluene (150 mL) and extracted
twice with 1 N NaOH (50 mL each). The combined alkaline
phases were adjusted to pH 1 by the additon of HCl (10%,
30 mL) and extracted two times with ethyl acetate (150 mL
each). The combined ethyl acetate extracts were washed three
times with brine (10%, 100 mL each). Concentration in vacuo
afforded 2.2 g (57%) of a yellowish foam. Purity: 44%
(HPLC). Crystallisation: Crude acid 7 (2.2 g) was dissolved
in 100 mL of refluxing ethyl acetate. The solution was
concentrated to 11 mL and cooled to 0 °C over 4 h. At this
temperature the slurry was stirred overnight. Filtration
afforded a crystalline product, which was washed with cold
ethyl acetate (20 mL) and dried for 15 h at 50 °C at 10 mbar.
White crystals (0.7 g, 20%) were obtained. Purity: 87%
(HPLC).
(2R,3S)-2-Benzyloxymethyl-N-4-((S)-2,2-dimethyl-1-
methylcarbamoylpropyl)-N-1-hydroxy-3-(4-methoxy-
phenyl)succinamide (9). A solution of carboxylic acid 7
(15.62 g, 33.2 mmol) in 66 mL of DMF was cooled to 0 °C,
treated with 1-hydroxybenzotriazole (6.73 g, 49.8 mmol),
followed by the addition of diisopropylcarbodiimide (12.57
g, 126.2 mmol). Stirring was continued for 2 h at 0 °C and
for 1 h at 23 °C. The mixture was diluted with TBME (330
mL) and reacted with a hydroxylamine solution (50% in
water) (4.39 g, 66.4 mmol). The resulting suspension was
stirred for 1 h and filtered. The product was washed twice
with 50 mL of TBME each. The crude product was dried in
vacuo at 50 °C overnight to give 27.40 g of a white solid.
This was added to 1350 mL of ethyl acetate and 1350 mL
of 0.1 N HCl and stirred for 1 h until all solids completely
1
1407w, 1367m, 1250m, 1179w, 1105m, 1036m, 747. H
NMR (300 MHz, DMSO) δ 0.85 (s, 9 H), 2.45 (s, 3 H),
3.16 (t, J ) 10.6 Hz, 1 H), 3.29-3.31 (m, 1 H), 3.60 (t, J )
9.9 Hz, 1 H), 3.70 (s, 3 H), 3.88 (d, J ) 11.5 Hz, 1 H), 4.10
(d, J ) 9.4 Hz, 1 H), 4.42 (s, 2 H), 6.78 (d, J ) 8.5 Hz, 2
H), 7.28-7.36 (m, 7 H), 7.78 (d, br, J ) 4.3 Hz, 1 H), 8.08
(d, J ) 9.4 Hz, 1 H), 8.61 (s, 1 H), 10.35 (s, 1 H). 13C NMR
(75 MHz, DMSO) δ 25.0, 26.6, 34.0, 45.9, 48.7, 54.8, 59.7,
67.0, 71.9, 113.1, 127.3, 127.4, 128.1, 129.4, 130.1, 138.0,
158.0, 167.6, 168.0, 171.3. MS (ESI) m/z 486 (MH+), 470,
453.
(2R,3S)-N-4-((S)-2,2-Dimethyl-1-methylcarbamoyl-
propyl)-N-1-hydroxy-2-hydroxymethyl-3-(4-methoxy-phenyl)-
succinamide (1). The benzyl ether 9 (25.0 g, 51.5 mmol)
was dissolved in 125 mL of methanol and hydrogenated over
2.5 g of Pd/C (5%) at 1.1 bar and 22 °C for 1.25 h. The
catalyst was removed by filtration over Celite and was
washed with MeOH. Concentration of the filtrate resulted
in 19.66 g (97%) of crude drug substance. Recrystallization
from 72 mL of water afforded the desired tetrahydrate (17.80
g) in 74% yield. Rf ) 0.14 (toluene/EtOAc/AcOH )
50:50:10). Mp ) 88.2 °C, IR (KBr, cm-1) 3583m, 3243s,
3099m, 2965m, 1658s, 1635s, 1536m, 1513s, 1372w, 1253m,
1235m, 1086m, 1040m. 1H NMR (300 MHz, DMSO) δ 0.91
(s, 9 H), 2.45 (2, J ) 4.5 Hz, 3 H), 2.88-2.96 (m, 1 H),
3.40 (s, 1 H), 3.45-3.60 (m, 1 H), 3.70 (s, 3 H), 3.84 (d, J
) 11.5 Hz 1 H), 4.13 (d, J ) 9.4 Hz 1 H), 4.64 (s, br, 1 H),
6.77 (d, J ) 8.7 Hz, 2 H), 7.26 (d, J ) 8.7 Hz, 2 H), 7.75
(d, J ) 4.5 Hz, 1 H), 8.01 (d, J ) 9.4 Hz, 1 H), 8.47 (s, 1
H), 10.20 (s, 1 H). 13C NMR (75 MHz, DMSO) δ 25.4, 27.1,
34.5, 48.9, 49.2, 60.2, 62.0, 113.5, 129.8, 130.9, 158.3, 168.8,
170.5, 172.0. MS (ES) m/z 394 (M - H)-, 367, 209.
Acknowledgment
We acknowledge the support of Dr. W. Prikoszovich for
FT-IR studies, H. Steiner for the hydrogenation experiments,
E. Schmid for the crystallisation experiments, and Dr. M.
Mutz for the analytical drug substance characterisation.
Received for review April 2, 2002.
OP025536E
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