M. K. Gurjar et al. / Tetrahedron Letters 44 (2003) 4853–4855
4855
Acknowledgements
USV group profoundly thanks Mr P. K. Tewari, Dr.
K. K. Maheshwari and Mr R. K. Sarma for support
and encouragement. S.R.C. acknowledges CSIR, New
Delhi for financial support in the form of a Senior
Research Fellowship.
References
1. (a) Muller, G.; Wied, S. Diabetes 1993, 42, 1852–1867; (b)
Kramer, W.; Muller, G.; Girbig, F. Biochim. Biophys. Acta
1994, 119, 278–290.
2. (a) Weyer, R.; Hitzel, V.; Geisen, K.; Regitz, G. (Hoechst
AG). EP 031058; (b) Weyer, R.; Hitzel, V. Arzneim-
Forsch-Drug Res. 1988, 38, 1079.
3. Geisen, K. Arzneim-Forsch-Drug. 1988, 38, 1120.
4. Drager, E. Diabetes Res Clin Pract. 1995, 28 (Suppl 1),
139–146.
Scheme 3. Reagents and conditions: (a) K2CO3, CH3COCH3,
reflux, 8 h (80%); (b) BF3:OEt3, CH2Cl2, rt (65%); (c) prepar-
ative HPLC.
5. Drugs of the Future; Prous Science, Barcelona, Spain,
1992, 17, 774–778.
6. All new compounds were characterised by analytical and
spectroscopic data.
Deprotection of the PMB group turned out to be
difficult. We observed that the deprotection of PMB
with DDQ in aqueous acetonitrile produced a number
of compounds which were difficult to separate. The best
result for the deprotection was when compound 12 was
exposed to a catalytic amount of BF3:Et2O in CH2Cl2
7. Zhang, H.; Huang, H.; Zhou, J.; Zhao, S.; Huang, W. J.
China Pharma. Univ. 1999, 30, 163–165.
8. NMR spectroscopic data for hydroxyglimepiride-2a (cis):
1H NMR (500 MHz, CDCl3): l 1.06 (t, 3 H, J=6.4 Hz),
1.5–1.65 (m, 7 H), 1.68–1.77 (m, 2 H), 2.05 (s, 3 H), 2.27
(q, 2 H, J=6.4 Hz), 2.97 (t, 2 H, J=6.3 Hz), 3.51 (d, 2 H,
J=6.3 Hz), 3.62 (dd, 2 H, J=7.8, 14.1 Hz), 3.90 (m, 1 H),
4.19 (s, 2 H), 6.71 (d, 1 H, J=8.5 Hz), 7.41 (d, 2 H, J=8.3
Hz), 7.87 (d, 2 H, J=8.3 Hz), 8.52 (t, 1 H, J=6.9 Hz); 13C
(125 MHz): l 12.7, 13.1, 16.6, 24.0 (2C), 29.3 (2C), 36.1,
38.8, 40.5, 46.2, 52.2, 67.2, 127.3, 129.7, 133.9, 138.0,
at 0°C giving
a mixture of cis/trans hydroxy-
1
glimepirides 2. The H NMR spectrum and elemental
analysis supported the assigned structure. It is pertinent
to mention that to the best of our knowledge deprotec-
tion of a PMB group with BF3:Et2O is being reported
for the first time.
Separation of the cis and trans mixture was accom-
plished by preparative HPLC (mobile phase, 40:60 ace-
tonitrile:pH3 buffer) using an ODS column. Based on
the comparision of their 1H and 13C NMR spectro-
scopic data with that of authentic glimepiride 1, the
structures for the cis-isomer 2a and the trans-isomer 2b
of hydroxyglimepiride were assigned.8
1
145.6, 150.5, 152.6, 172.6. 2b (trans): H NMR (200 MHz,
CDCl3): l 1.04 (t, 3 H, J=6.5 Hz), 1.1 (m, 4 H), 1.5–2.0
(m, 5 H), 2.04 (s, 3 H), 2.28 (q, 2 H, J=6.5 Hz), 2.94 (t,
2 H, J=6.7 Hz), 3.42 (d, 2 H, J=6.7 Hz), 3.58 (m, 3 H),
4.18 (s, 2 H), 6.43 (d, 1 H, J=7.6 Hz), 7.39 (d, 2 H, J=8.3
Hz), 7.83 (d, 2 H, J=8.3 Hz), 8.52 (t, 1 H, J=6.4 Hz); 13C
(125 MHz): 12.8 (2C), 13.1, 16.7 (2C), 28.1, 32.5, 36.2,
39.5, 41.0, 49.7, 52.3, 67.8, 127.4, 129.6, 133.9, 138.1,
145.5, 150.8, 152.7, 172.5. FAB-MS m/z 529 (M++Na), 507
(M++1).
In summary, we have successfully synthesized cis and
trans-hydroxyglimepiride using a very straightforward
method.