New asymmetric synthesis of dexecadotril and ecadotril starting from a single precursor

Article abstract of DOI:10.1081/SCC-100000201

We describe herein a method providing access to both enantiomers of 3-acetylthio-2-benzylpropionic acid via enzymatic desymmetrization of 2-benzyl-1,3-propanediol. These compounds are respectively the starting materials for the synthesis of ecadotril, and dexecadotril, which are powerful inhibitors of NEP (EC 3.4.24.11) and have been developed as therapeutic agents.

Full text of DOI:10.1081/SCC-100000201

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NEW ASYMMETRIC SYNTHESIS OF DEXECADOTRIL AND
ECADOTRIL STARTING FROM A SINGLE PRECURSOR
Thierry Monteil , Denis Danvy , Jean-Christophe Plaquevent a , Lucette Duhamel a
,
Pierre Duhamel a , Claude Gros b , Jean-Charles Schwartz b & Jeanne-Marie Lecomte
a Institut de Recherche en Chimie Organique Fine , Université de Rouen , UPRES-A 6014,
Mont-Saint-Aignan, F-76181, France
b Centre Paul Broca , U109, INSERM, 2ter rue d'Alésia, Paris, F-75014, France
Published online: 16 Aug 2006.
To cite this article: Thierry Monteil , Denis Danvy , Jean-Christophe Plaquevent , Lucette Duhamel , Pierre Duhamel ,
Claude Gros , Jean-Charles Schwartz & Jeanne-Marie Lecomte (2001) NEW ASYMMETRIC SYNTHESIS OF DEXECADOTRIL
AND ECADOTRIL STARTING FROM A SINGLE PRECURSOR, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:2, 211-218, DOI: 10.1081/SCC-100000201
To link to this article: http://dx.doi.org/10.1081/SCC-100000201
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SYNTHETIC COMMUNICATIONS, 31(2), 211–218 (2001)
NEW ASYMMETRIC SYNTHESIS
OF DEXECADOTRIL AND ECADOTRIL
STARTING FROM A SINGLE PRECURSOR
Thierry Monteil,1 Denis Danvy,1 Jean-Christophe
Plaquevent,2,∗ Lucette Duhamel,2 Pierre Duhamel,2
Claude Gros,3 Jean-Charles Schwartz,3
and Jeanne-Marie Lecomte1
1Bioprojet, 30 rue des Francs Bourgeois, F-75003
Paris, France
2Institut de Recherche en Chimie Organique Fine,
UPRES-A 6014, Universite´ de Rouen, F-76181
Mont-Saint-Aignan, France
3U109, Centre Paul Broca, INSERM, 2ter rue d’Ale´sia,
F-75014 Paris, France
ABSTRACT
We describe herein a method providing access to both enan-
tiomers of 3-acetylthio-2-benzylpropionic acid via enzymatic
desymmetrization of 2-benzyl-1,3-propanediol. These compounds
are respectively the starting materials for the synthesis of ecadotril,
and dexecadotril, which are powerful inhibitors of NEP
(EC 3.4.24.11) and have been developed as therapeutic agents.
∗ To whom correspondence should be addressed.
211
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

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MONTEIL ET AL.
Figure 1.
Racecadotril (RS)-1 (previously named acetorphan) is used as a therapeutic
agent against diarrhea, and was launched in France in 1993 (1–3). Actually, it
plays the role of a prodrug of thiorphan (N-[(RS)-1-oxo-2-(mercaptomethyl)-3-
phenypropyl]-glycine), whichactsasapowerfulinhibitorofNEP(EC3.4.24.11). It
has been shown that the two enantiomers of thiorphan have a strong and equipotent
in vitro affinity on the considered enzyme (4). However, the corresponding pro-
drugs display different pharmaceutical profiles. Indeed, the (R) enantiomer (dexe-
cadotril (R)-1) is under phase 3 clinical evaluation as an intestinal antisecretatory
agent, while the (S) enantiomer (ecadotril (S)-1) is useful in the cardiovascular
field (6) (Fig. 1).
The industrial synthesis of both enantiomers of racecadotril relies on the pep-
tidic coupling of benzyl glycinate with the optically pure 3-acetylthio-2-benzylpro-
pionic acid 2 of the required configuration, which thus constitutes the key inter-
mediate for the synthesis of (S) and (R)-1. Presently, the only described entries
to the enantiomers are based either on a resolution process (4,5,7), or a catalytic
asymmetric synthesis by means of an enantioselective hydrogenation of a prochi-
ral precursor (8). Alternatively, the Evans oxazolidinone method leads to a closely
related precursor in which the sulfur atom is benzylated instead of acetylated (9).
In this paper we describe our results in the preparation of both enantiomers starting
from the same prochiral precursor. The key step of the present work was the desym-
metrization of 2-benzyl-1,3-propanediol 3 by means of a lipase catalyzed transes-
terification (Scheme 1). Indeed, the known (R)-2-benzyl-1-hydroxypropylacetate
(R)-4 (10–13) was readily prepared from the prochiral compound 3 using either
the lipase PS Amano or the lipase P Fluka.
The optimal conditions for the use of both enzymes were realized after a
systematic study (see Table 1).
Varying the source of the enzyme and experimental conditions allowed us to
improve the transformation up to 91% (LPF, entry 5) and 86% yield (PS, entry 9),
respectively. Comparison of the optical rotations of the obtained product with the
highest reported value indicated that compound (R)-4 was generated in high ee

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DEXECADOTRIL AND ECADOTRIL
213
Scheme 1.
(>94%) (10–13). We observed that the lipase PS allowed us to carry out the trans-
esterification at RT with good yield and a reasonable reaction time (entry 9). After
Jones oxidation, hydrolysis by means of aqueous lithium hydroxide provided the
corresponding hydroxy acid (S)-5. Thioacetylation of this compound was carried
Table 1. Monoacetylation of 2-Benzyl-1,3-Propanediol 3 into (R)-4
d
Entry
Lipasea (%)b
Reaction Temp. (◦C)
Reaction Time
Yield (%)c
[α]D
1
2
3
4
5
6
7
8
9
LPF (2.5)
LPF (1)
23
23
25
37
40
45
20
21
25
29
29
17 h
73 h
11 d
44 h
72 h
11 d
24 h
21 h
42 h
4 h
83
85
88
89
91
86
64
78
86
43
0e
+27.6
+28.9
+26.7
+27.6
+27.7
+20.7
+28.0
+26.8
+28.5
+2.2
LPF (0.5)
LPF (0.5)
LPF (0.25)
LPF (0.1)
PS (1)
PS (0.5)
PS (0.25)
LCA (0.5)
LCA (10)
10
11
20 h
—
aLPF: lipase P from Pseudomonas fluorescens (31.5 U/mg) purchased from Fluka; PS: lipase
PS Amano kindly provided to us by Amano; LCA: lipase Novozym 435 from Candida
antartica (7 U/mg) kindly provided to us by Novo Nordisk.
bThe indicated % represents the massic amount of enzyme with respect to the substrate 3
(entries 1–7: 0.36 M in vinyl acetate; entries 8–11: 0.56 M in vinyl acetate).
cAfter purification by flash chromatography.
d20◦C, c = 1, CHCl3, lit. +28.6 (>94% ee) (11).
eIn this experiment, only the corresponding diacetate 6 was obtained in a quantitative yield.

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MONTEIL ET AL.
out by dropwise addition of thioacetic acid (1.5 equiv.) and of (S)-5 (1 equiv.) in
THF at -10◦C to the preformed salt of triphenylphosphine and DIAD (1.5 equiv.)
in THF (14). This one-step substitution provided simple access with high yield to
(R)-2, directly starting from the parent β-hydroxyacid.
For the access to (S)-2, we first tried to achieve the monoacetylation of the
same precursor 3 using lipase LCA, because this enzyme had been reported to give
opposite enantioselectivity compared to other lipases, starting from closely related
prochiral diols (15). Unfortunately, in our case, LCA yielded (R)-4 with almost no
enantioselectivity (entry 10). We then turned to another strategy, in which the first
step consisted of the diacetylation of compound 3 by means of LCA as the catalyst
in vinyl acetate to afford the new prochiral compound 6 (entry 11). (S)-2-Benzyl-1-
hydroxypropyl acetate (S)-4 was obtained via an enantioselective hydrolysis using
lipase LPF. A similar synthetic pathway as above allowed the transformation of
(S)-4 into (S)-2.
In conclusion, we describe herein the first convenient access to both enan-
tiomers of 3-acetylthio-2-benzylpropionic acid 2 by an enzymatic process starting
from a single prochiral precursor 3. The low amount of catalyst needed and the
efficiency of most of the synthetic steps allowed the method to be used on a multi-
gram scale.
EXPERIMENTAL
Synthesis of 3
To a THF (200 mL) suspension of LiAlH4 (15 g, 395 mmol) was added at
room temperature a THF (30 mL) solution of dimethylbenzylmalonate (22.5 g,
101 mmol). The mixture was stirred for 3 h at reflux. The reaction was cooled at
5◦C, diluted with THF (140 mL), then quenched by addition of water (15 mL), 15%
NaOH aqueous solution (15 mL), and water (45 mL). After stirring for 30 min,
the reaction mixture was filtered. The solid residue was washed with diethylether
(300 mL). The organic layers were combined, dried over magnesium sulfate, then
evaporated to give 16 g of compound 3 as a white solid. After treatment by cold
petroleum ether (200 mL), the residue was filtered and dried in vacuo to give pure
3 (15 g, 89% yield), m.p.: 68◦C. 1H NMR (CDCl3, 200 MHz): 7.4–7.0 (m, 5H);
3.9–3.5 (m, 4H); 3.1 (s broad, 2H); 2.55 (d, 2H, J = 7 Hz); 2.1–1.9 (m, 1H). 13
C
NMR (CDCl3, 50 MHz): 139.7; 128.9; 128.3; 126.0; 65.0; 43.7; 34.1.
Synthesis of (R)-4
A suspension of 3 (4 g, 24 mmol) in vinylacetate (40 mL) was stirred at
50◦C for 15 min, then cooled to 25◦C. Lipase PS Amano (10 mg) was added at this

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215
temperature. After 48 h of stirring, the mixture was filtered on Celite. The filtrate
was concentrated in vacuo to give (R)-4 (4.3 g, 86% yield, see Table 1, entry 9)
as a colorless oil. Physical and spectral data were in agreement with reported
values (11–13).
1H NMR (CDCl3, 200 MHz): 7.35–7.10 (m, 5H); 4.25–4.0 (m, 2H); 3.65–
3.40 (m, 2H); 2.75–2.50 (m, 2H); 2.20–2.00 (m, 2H); 2.05 (s, 3H). 13C NMR
(CDCl3, 50 MHz): 171.6; 138.1; 128.9; 128.4; 126.2; 63.6; 61.9; 42.5; 34.2; 20.8.
[α]D = +28.5 (20◦C, c = 1.15, CHCl3).
Synthesis of (S)-5
To a solution of compound (R)-4 (4 g, 19.2 mmol) in acetone (80 mL), Jones
reagent was added dropwise at 0◦C (22.8 mL). After stirring for 10 min at 0◦C,
the mixture was quenched by addition of isopropanol (10 mL). After additional
stirring for 1 h, the mixture was filtered, then diluted with water (40 mL) and
acetone was removed by concentration in vacuo. The resulting aqueous layer was
adjusted to pH9 by addition at 5◦C of solid sodium hydrogenocarbonate, washed
with ethylacetate (3 × 15 mL), then acidified with concentrated HCl (pH1). After
extraction with ethylacetate (3 × 15 mL), the organic layer was washed with water
(10 mL), dried over magnesium sulfate, filtrated, and concentrated in vacuo to give
(S)-2-benzyl-3-acetoxypropanoic acid (2.8 g, 65%).
1H NMR (CDCl3, 200 MHz): 10.4 (s broad, 1H); 7.35–7.10 (m, 5H); 4.30–
4.15 (m, 2H); 3.15–2.95 (m, 2H); 2.95–2.75 (m, 1H); 2.05 (s, 3H). 13C NMR
(CDCl3, 50 MHz): 178.5; 170.6; 137.4; 128.7; 128.5; 126.7; 63.4; 46.1; 34.3;
20.8. [α]D = +11.5 (20◦C, c = 1, CHCl3).
(S)-2-benzyl-3-acetoxypropanoic acid (3.52 g, 15.8 mmol) was saponified at
0◦C by lithine (2.64 g, 62.9 mmol) in a mixture of THF and water (75/25, 35 mL).
After1h, thereactionmixturewasacidifiedbya3MaqueousHClsolution(22mL),
then extracted by diethylether (50 mL, then 2×15 mL). The organic layers were
combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The
solid residue was treated with cold petroleum ether, filtrated, and dried in vacuo
to give the β-hydroxy acid (S)-5 (2.45 g, 86%). m.p.: 63◦–65◦C.
1H NMR (CDCl3, 200 MHz): 7.40–7.10 (m, 5H); 5.85 (s broad, 2H); 3.85–
3.60 (m, 2H); 3.15–2.95 (m, 1H); 2.95–2.75 (m, 2H). 13C NMR (CDCl3, 50 MHz):
178.3; 138.2; 128.8; 128.5; 126.5; 61.9; 48.8; 33.9. [α]D = −14.3 (20◦C, c = 1.15,
CHCl3); lit. (R)-5, [α]D = +13.9 (20◦C, c = 0.97, CHCl3),11H and [α]D = +14.9
(20◦C, c = 1.11, CHCl3) (16).
Synthesis of (R)-2
A mixture of (S)-5 (1.45 g, 8.05 mmol) and thioacetic acid (0.92 g,
12.05 mmol) in THF (10 mL) was added dropwise at −10◦C to a stirred suspension

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MONTEIL ET AL.
of the preformed adduct of triphenylphoshine (3.16 g, 12.05 mmol) and DIAD
(2.44 g, 12.05 mmol) in THF (30 mL). The mixture was then stirred at −10◦C
for 1 h, then 2 h at RT. The solution was concentrated and the residue was dis-
solved in ethyl acetate (15 mL), then extracted with an aqueous solution of sodium
hydrogenocarbonate (3×20 mL). After washing with ethyl acetate (10 mL), the
aqueous phase was acidified with concentrated hydrochloric acid (3 mL) and ex-
tracted with ethyl acetate (2×15 mL). The organic layer was dried over magnesium
sulfate, then evaporated to give the (R)-2 acid as a light yellow oil (82%).
1H NMR (CDCl3, 200 MHz): 9.5 (broad s, 1H); 7.4–7.1 (m, 5H); 3.2–2.8
(m, 5H); 2.3 (s, 3H). 13C NMR (CDCl3, 50 MHz): 195.1; 179.3; 137.3; 128.8;
128.4; 126.6; 46.8; 37.3; 30.3; 29.4. [α]D = +33.7 (25◦C, c = 1, MeOH), lit.
[α]D = +35.3 (25◦C, c = 1.3, MeOH) (5). The enantiomeric excess was deter-
mined to be 94% ee by means of HPLC analysis (retention time: 22.14 min;
Chiralpack AD, 250 × 4.6 mm, 5 µm, n-heptane/iPrOH/TFA = 90/10/0.1; detec-
tion: 240 nm; flow rate: 0.5 mL/mn).
Synthesis of (R)-1
To a solution of (R)-2 (2 g, 8.4 mmol) in THF (14 mL) were successively
addedat5◦Casolutionofbenzylglycinatep-toluenesulfonicsalt(2.83g, 8.4mmol)
and triethylamine (0.85 g, 8.4 mmol) in dichloromethane (15 mL), then a solution
of hydroxybenzotriazole (1.28 g, 8.4 mmol) in THF (14 mL), then a solution
of DCC (1.73 g, 8.4 mmol) in dichloromethane (14 mL). The reaction mixture
was stirred overnight at room temperature, filtrated then concentrated in vacuo.
After evaporation, the residue was diluted in ethylacetate (10 mL), filtrated, and
successively washed with water, aqueous sodium hydrogenocarbonate, and brine.
The organic layer was dried, filtrated, and concentrated in vacuo. The residue was
chromatographied over silicagel (EP/diethylether: 60/40) to give pure (R)-1 as a
white solid (2.1 g, 65%). m.p.: 69◦C.
1H NMR (CDCl3, 200 MHz): 7.40–7.10 (m, 10H); 6.15 (broad t, 1H);
5.25 (s, 2H); 4.10–3.50 (m, 2H); 3.10–2.55 (m, 5H); 2.30 (s, 3H). 13C NMR
(CDCl3, 50 MHz): 195.8; 172.9; 169.2; 138.4; 135.0; 128.7; 128.4; 128.2;
126.5; 66.9; 49.1; 41.2; 38.2; 31.0; 30.4. [α]D = +24.5 (20◦C, c = 1, MeOH).
Synthesis of 6
To a suspension of compound 3 (1.89 g, 11.37 mmol) in vinylacetate (10 mL)
was added at 29◦C the enzyme Novozym 435 (100 mg). The mixture was stirred
for 24 h at 29◦C. After filtration and concentration, the diacetate 6 was obtained
as an oil (2.79 g, 98%).

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217
1H NMR (CDCl3, 200 MHz): 7.35–7.10 (m, 5H); 4.15–3.90 (m, 4H);
2.75–2.60 (m, 2H); 2.40–2.25 (m, 1H); 2.05 (s, 6H).
Synthesis of (S)-4
To a solution of 6 (0.25 g, 1 mmol) in a mixture of acetone (9.9 mL) and
phosphate buffer (pH 7, 23.1 mL) was added lipase LPF (0.13 g). The reaction
medium was warmed to 30◦C for 48 h. The solution was then extracted with diethyl
ether (2×20 mL). The combined organic layers were dried over magnesium sulfate,
then evaporated to give (S)-4 (0.08 g, 38% yield, [α]D = −27.7, 20◦C, c = 1.04,
CHCl3; lit. (10–13): [α]D = −28.1, 20◦C, c = 1.01, CHCl3), as a colorless oil. All
spectral data were identical to that of the enantiomer (R)-4.
Compounds (S)-2 and (S)-1 were prepared using same experimental condi-
tions as described above for the enantiomeric series.
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Accepted April 11, 2000

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