ASYMMETRIC SYNTHESIS OF (S)-ESMOLOL
1607
temperature. Then reaction mixture was cooled to 0 ꢂC, and water (0.1 mL,
6.9 mmol) was added over a period of 1 h through a syringe pump. After complete
addition of water, the cooling was removed, and stirring continued at room tempera-
ture (monitored by HPLC [(ODS-column) UV: 225 nm, 60% CH3CN in H2O]). After
completion of the reaction, the reaction mixture was diluted by adding ethylacetate
(30 mL), dried over Na2SO4, and evaporated under reduced pressure. The residue
was chromatographed on silica gel (60–120 mesh) using ethyl acetate and petroleum
ether mixture in a 1:9 ratio. The less polar epoxide 6 was eluted first as a colorless
21
liquid, yield 1.38 g (46%) and 94% enantiomeric excess. ½aꢀD þ 4.42 (c 1, CHCl3).
The chiral epoxide 6 was confirmed by its spectral data. IR (KBr) t 3451, 3000,
2928, 1736, 1612, 1512, 1439, 1362, 1296, 1243, 1176, 1111, 1035, 987, 913, 835,
1
768 cmꢁ1; H NMR (CDCl3): d 2.55 (t, 2H, J ¼ 4.0 Hz), 2.70 (t, 1H, J ¼ 3.0 Hz),
2.80–2.90 (m, 3H), 3.25–3.32 (m, 1H), 3.65 (s, 3H), 3.95 (q, 1H, J ¼ 3.0 Hz), 4.10
(dd, 1H, J ¼ 9.0, 2.0 Hz), 6.80 (d, 2H, J ¼ 6.0 Hz), 7.05 (d, 2H, J ¼ 6.0 Hz). EIMS
m=z (%) 236 (100), 221 (12), 203 (10), 194 (15), 177 (25), 159 (22), 147 (10), 132
(15), 118 (35), 102 (18), 96 (12), 76 (42), 51 (25).
Later, the ethyl acetate and petroleum ether ratio was raised to 3:7 to elute the
R-diol compound 7, which was obtained as a thick syrup, yield 1.44 g (48%) and 98%
21
enantiomeric excess. The optical rotation shows as ½aꢀD ꢁ 4.6 (c 1, CHCl3). IR (KBr)
t 3380, 2928, 1732, 1610, 1513, 1441, 1375, 1280, 1244, 1176, 1109, 1052, 980, 946,
873, 826, 783 cmꢁ1
;
1H NMR (CDCl3): d 2.55 (t, 2H, J ¼ 6.0 Hz), 2.89 (t, 2H,
J ¼ 6.0 Hz), 3.62 (s, 3H), 3.68–3.85 (m, 2H), 3.95–4.15 (m, 3H), 6.80 (d, 2H,
J ¼ 6.0 Hz), 7.08 (d, 2H, J ¼ 6.0 Hz); EIMS m=z (%) 254 (10), 242 (100), 186 (22),
142 (15), 124 (20), 104 (10), 76 (30), 51 (15).
Preparation of 3-[4-[2-Hydroxy-3-
(isopropylamino)propoxy]phenyl]propanoate (1)
A mixture of S-epoxide 6 (1.0 g, 4.2 mmol), isopropyl amine (3.75 mL,
42.3 mmol), and water (0.13 mL) was refluxed for 5 h, and the unreacted isopropyl
amine was removed under reduced pressure. The residue was diluted with water
and extracted with ethyl acetate (2 ꢃ 20 mL). The combined organic layer was dried
over Na2SO4 and concentrated. The crude product was purified by column chroma-
21
tography to afford the final pure product as thick syrup (1.0 gm, 80%). ½aꢀD þ 4.5 (c 1,
CHCl3). IR (KBr) t 3318, 2928, 2854, 1735, 1612, 1513, 1441, 1368, 1297, 1244,
1176, 1109, 1045, 832 cmꢁ1 1H NMR (CDCl3): d 1.15 (s, 6H), 2.55 (t, 2H,
.
J ¼ 5.0 Hz), 2.78 (q, 1H, J ¼ 5.0 Hz), 2.85–2.93 (m, 4H), 3.15 (brs, 1H), 3.65 (s,
3H), 3.85–4.10 (m, 3H), 6.80 (d, 2H, J ¼ 6.0 Hz), 7.05 (d, 2H, J ¼ 6.0 Hz). EIMS
m=z (%) 297 (40), 296 (100), 277 (15), 254 (10), 219 (20), 193 (12), 163 (10), 145
(25), 118 (15), 102 (12), 96 (18), 76 (35), 51 (22). HRMS calculated for
C16H25NO4 296.1861; found 296.1855.
ACKNOWLEDGMENT
J. K. K. is thankful to the University Grants Commission, New Delhi, for
providing a fellowship.