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2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
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.