A synthesis of captopril through a Baylis-Hillman reaction

Article abstract of DOI:10.1081/SCC-120017189

A synthesis of the antihipertensive amide 1, named captopril, is described. The strategy is based on a Baylis-Hillman reaction between N-acryloylproline and formaldehyde. Subsequential diaster eoselective hydrogenation step and functional group interconversion provided captopril in good overall yield.

Full text of DOI:10.1081/SCC-120017189

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A Synthesis of Captopril Through a Baylis–Hillman
Reaction
a
a
Melissa P. Feltrin & Wanda P. Almeida
a
Instituto de Ciências da Saúde , Universidade Paulista , Campinas, SP, Brazil
Published online: 21 Aug 2006.
To cite this article: Melissa P. Feltrin & Wanda P. Almeida (2003) A Synthesis of Captopril Through a Baylis–Hillman Reaction,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:7,
1141-1146, DOI: 10.1081/SCC-120017189
To link to this article: http://dx.doi.org/10.1081/SCC-120017189
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 7, pp. 1141–1146, 2003
A Synthesis of Captopril Through
a Baylis–Hillman Reaction
Melissa P. Feltrin and Wanda P. Almeida*
Instituto de Cieˆ ncias da Sau´ de,
Universidade Paulista, Campinas, SP, Brazil
ABSTRACT
A synthesis of the antihipertensive amide 1, named captopril, is
described. The strategy is based on a Baylis–Hillman reaction
between N-acryloylproline and formaldehyde. Subsequential diaster-
eoselective hydrogenation step and functional group interconversion
provided captopril in good overall yield.
Angiotensin-converting enzyme (ACE) inhibitors have been used for
[
1]
the treatment of high blood pressure. Careful and extensive studies
2
þ
based on carboxypeptidase structure as a model for Zn
protease
*
Correspondence: Wanda P. Almeida, Instituto de Cieˆ ncias da Sau´ de,
Universidade Paulista, Av. Comendador Enzo Ferrari 280, Swift, Campinas,
SP, 13055-044–Brazil; E-mail: wciuffo@aol.com.
1
141
DOI: 10.1081/SCC-120017189
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1
142
Feltrin and Almeida
[2]
action led to the synthesis of a small, potent and orally available inhi-
[
bitor of ACE, named captopril (1, Fig. 1).
3]
In this work we report an alternative route (Sch. 1) to prepare
, based on a diastereoselective double bond hydrogenation of amide
, derived from N-acryloylproline 3.
1
2
Captopril 1 contains two stereogenic carbon atoms. In our strategy,
one of these is provided by (S)-proline, a natural aminoacid. The stereo-
selectivity in the hydrogenation step to generate the other chiral center
is one of the synthetic challenges of this route. Our synthesis is illustrated
in Sch. 2.
Amide 2 was readily prepared by a DABCO catalysed Baylis-
[4]
Hillman reaction between N-acryloylproline 3 and formaldehyde.
N-acryloylproline 3 was obtained by treatment of acryloyl chloride
[
5]
with (S)-proline in the presence of potassium hydroxide (Sch. 2).
Compound 3 was then investigated as substrate for the Baylis–Hillman
[
4]
reaction. Acrylamides are reluctant substrates in this reaction. After
considerable experimentation under a variety of reaction conditions
Figure 1. Captopril.
Scheme 1.

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Captopril Through a Baylis-Hillman Reaction
1143
ꢀ
Scheme 2. Reagents and Conditions. a: KOH, H
b: aq. CH O 40%, H O, ultrasound, 47%; c: H , Pd/C, 92% (4:1 diastereomeric
2
O-Acetone, 0 ! r.t., 70%;
2
2
2
2 2
ratio); d: silica gel, 70% of the major isomer; e: SOCl , THF-H O; then
NH SH/H O, 87%.
4
2
Figure 2. Diastereoisomers obtained from the hydrogenation step.
(
reflux, stoichiometry of the catalyst, etc.), ultrasound technique at room
temperature was found to be the most suitable condition.
Hydroxyacrylamide 2 was obtained in 47% yield.
Hydrogenation of 2 was achieved at room temperature and atmo-
spheric pressure, in the presence of Pd/C. Amide 4 was obtained as a
diastereomeric mixture, in a 4:1 ratio (Fig. 2). Despite of the easy separa-
tion of the diastereoisomers (4a/4b), stereochemical assignments of the
major compound could not be determined at this stage.
The major diastereoisomer treated with thionyl chloride followed by
NH SH in H O/THF furnished the mercapto derivative 1, in 87% yield.
4
2
The a value of 1 (À129.5, c1.7, ethanol) is comparable to those reported
D
[
6]
in literature (À131.0, c1.7, ethanol) and therefore, confirmed the con-
figuration of the major diastereoisomer.

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Feltrin and Almeida
In conclusion we have synthesized the target compound 1 in four
steps from (S )-proline in 20% overall yield. We believe that despite
the moderate selectivity in the hydrogenation step, the simple and
efficient synthetic strategy associated with the readily chromatographic
separation of the diastereoisomers provided a valuable entry to capto-
pril. In this work we have also observed that ultrasound technique
could be improved the Baylis–Hillman reaction of N-acryloylproline.
EXPERIMENTAL
General
1
The H NMR spectra were recorded on a Varian GEMINI BB-300 at
3
00 MHz. Purification and separations by column chromatography were
performed on silica gel, using flash chromatography. Acryloyl chloride,
S)-proline and DABCO (1,4-diazabicyclo[2.2.2]octane) were purchased
(
from Aldrich and used without purification. Formaldehyde was
employed as a 40% aqueous solution. Thin Layer Chromatography
visualization was achieved by spraying with 10% ninhydrin/acetone solu-
tion and heating.
N-acryloyl-(S)-proline 3. A stirred solution of (S)-proline (5 g,
3 mmol) in 2 M aqueous KOH (26 mL, 52 mmol) was cooled in an ice-
4
bath and diluted with acetone (26 mL). An acetone solution (26 mL) of
acryloyl chloride (4.34 g, 48 mmol) and 2 M aqueous KOH solution
(
30 mL, 61 mmol) were simultaneously added over 40 min with good stir-
ring to the aqueous proline in an ice-bath. After 3 h at room temperature
the mixture was evaporated in vacuo to remove acetone. The residual
solution was washed with ether and acidified (pH 3) with hydrochloric
acid. The acidic mixture, after saturation with NaCl, was extracted with
ethyl acetate and the combined extracts were washed with brine and
evaporated. The residue was purified by column chromatography
(
yield. IR (neat, ꢀmax): 3465–2621; 1728; 1688; 1641; 1452; 1196; 912;
CH Cl :CH OH:NH OH, 8:1.5:0.5). Amide 3 was obtained in 70%
2 2 3 4
1
7
35. H NMR: ꢁ 11.3 (br, 1H); 6.62–6.47 (br, 1H); 6.18–5.37 (m, 2H);
.71(dd, J ¼ 8.2 and 1.8 Hz; 1H), 3.66 (m, 2H); 2.45 (m, 1H); 2.09–1.89
4
(m, 3H). Anal. calcd. for C H NO : C, 56.80; H, 6.55; N, 8.28. Found:
8 11 3
C, 56.61; H, 6.51; N, 8.18.
b-Hydroxy-a-methylene-N-acryloyl-(S)-proline 2. To
a mixture
of 3 (0.472 g, 1.89 mmol) and 10 mL of THF, 5 mL of a 40% aqueous
formaldehyde were added. The suspension was sonicated for 48 h. The
mixture was partionated with ethyl acetate (60 mL) and extracted. The

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Captopril Through a Baylis-Hillman Reaction
1145
solid was washed with ether (50 mL). The combined organic extracts were
washed with a saturated solution of NaHCO (100 mL), brine (100 mL)
3
and dried over anhydrous sodium sulfate. Concentration under reduced
pressure followed by flash chromatography on silica gel with hexane-
ethyl acetate (9:1) gave compound 3 (0.32 g, 93%) as a yellow tinged
oil. IR (neat, ꢀmax): 3444–2625; 1728; 1716; 1688; 1633; 1456;
À1
1
1
196 cm . H NMR: ꢁ 10.7 (br, 1H); 6.27 (d, J ¼ 1.1 Hz; 1H), 5.86 (d,
J ¼ 1.5 Hz, 1H); 4.75 (m, 1H); 4.34 (d, J ¼ 4.5 Hz, 2H); 3.71 (m, 2H); 2.48
(
m, 1H); 2.13–1.83 (m, 3H). Anal. calcd. for C H NO : C, 54.26; H,
9 13 4
6
.58; N, 7.03. Found: C, 54.14; H, 6.53; N, 6.99.
b-Hydroxy-a-methyl-N-acryloyl-(S)-proline 4. A suspension of 2
0.219 g, 1.21 mmol) and 5% Pd/C (21 mg) in ethyl acetate was hydro-
(
genated at room temperature and atmospheric pressure for 4 h. After this
period, the reaction mixture was filtered through a pad of celite. After
concentration at reduced pressure, the residue was dried over anhydrous
sodium sulfate. Filtration, concentration and flash chromatography
(Hex-EtOAc-MeOH, 7:2:1) gave the major isomer (0.102 g, 70% from
diastereomeric mixture). IR (KBr, ꢀmax): 3418, 3220, 1698, 1490, 1089,
À1
1
8
2
3
5
27 cm . H NMR: ꢁ 11.5 (br, 1H); 4.61 (m, 1H); 4.38 (m, 2H); 3.78 (m,
H); 2.61 (m, 1H); 2.51 (m, 1H), 2.05–1.78 (m, 3H), 1.07 (d, J ¼ 7.7 Hz,
H). Anal. calcd. for C H NO : C, 53.72; H, 7.51; N, 6.96. Found: C,
9
15
4
3.54; H, 7.47; N, 6.98.
b-Mercapto-a-methyl-N-acryloyl-(S)-proline 1 (Captopril). To a solu-
tion of 0.160 mg (ꢁ0.8 mmol) of the major isomer obtained from hydro-
genation step (amide 6) in dry THF (10 mL), thionyl chloride (4.0 mmol) in
2
5
0 mL of dry THF was added. Stirring was kept at room temperature for
ꢀ
h. The reaction mixture was cooled to 0 C and a solution of 204 mg
(
ꢁ4 mmol) of NH SH in 15 mL H O-THF (1:1) was carefully added.
4
2
Stirring was continuated at the same temperature for 30 min, and then
warmed to room temperature. After 3 h, 15 mL of 5% aqueous
NaHCO , were added and the reaction mixture was kept under stirring
3
for 2 h. The mixture was washed with ether (2 ꢂ 20 mL), and the aqueous
layer acidified with HCl (pH ꢁ 4) and extracted with ethyl acetate. The
combined organic extracts were washed with brine (100 mL) and dried
over anhydrous sodium sulfate. Concentration under reduced pressure
gave a white solid which was crystallized from ethyl acetate-hexane.
Captopril was obtained in 87% yield. [a] : À129.5 (c1.7, ethanol).
D
[6b]
ꢀ
[6b]
ꢀ
Lit. : À131.0, (c1.7, ethanol). M.p.: 103–105 C: Lit. : 104–105 C. IR
À1 1
KBr,ꢀ ):3300–2197,2560,1744,1741,1646,1590,1445 cm . H NMR:
max
(
ꢁ
4.79 (m, 1H); 3.74 (m, 2H); 2.63 (m, 1H); 2.51 (m, 1H); 2.1–1.8 (m, 3H);
1
6
.09 (d, J ¼ 7.7 Hz, 3H). Anal. calcd. for C H NO S: C, 49.75; H, 6.96; N,
9
15
3
.45; S, 14.75. Found: C, 49.62; H, 6.27; N, 6.42; S, 14.23.

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146
Feltrin and Almeida
ACKNOWLEDGMENTS
We wish to thank Prof. Dr. Fernando Coelho (IQ/UNICAMP) for
ultrasound apparatus. The authors thank FAPESP for Melissa
P. Feltrin’s fellowship (99/10904-5).
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1
2
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3
4
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Received in the USA May 15, 2002