Total synthesis of cis and trans-hydroxyglimepiride: Active metabolite of glimepiride

Article abstract of DOI:10.1016/S0040-4039(03)01145-6

Syntheses of trans-hydroxyglimepiride 2b, a human metabolite of the blood glucose lowering agent glimepiride 1 and its corresponding cis-stereoisomer 2a, are described.

Full text of DOI:10.1016/S0040-4039(03)01145-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4853–4855
Total synthesis of cis and trans-hydroxyglimepiride:
active metabolite of glimepiride
Mukund K. Gurjar,a,* Ramesh A. Joshi,a Siddhartha R. Chaudhuri,a Shreerang V. Joshi,b,*
Anup R. Barde,b Lalji K. Gediya,b Prasad V. Ranade,b Suresh M. Kadamb and Sanjay J. Naikb
aNational Chemical Laboratory, Pune 411008, India
bChemical Process Research Laboratory, USV Ltd, Govandi, Mumbai 400 088, India
Received 26 February 2003; revised 23 April 2003; accepted 2 May 2003
Abstract—Syntheses of trans-hydroxyglimepiride 2b, a human metabolite of the blood glucose lowering agent glimepiride 1 and
its corresponding cis-stereoisomer 2a, are described. © 2003 Elsevier Science Ltd. All rights reserved.
Among the sulfonylurea1 class of anti-diabetic drugs,
glimepiride2 1 has many distinctive advantages and is
by far the most superior blood glucose lowering agent.3
Its biological activity initiates with binding to the 65
KD protein of the putative receptor. In addition,
glimepiride shows a three-fold faster rate of association
sive insulin release thereby decreasing the risk of
hypoglycemia.
Studies on the metabolism of therapeutically active
compounds are increasingly being carried out because
metabolites provide superior safety and efficacy profi-
les, but more importantly offer opportunities to study
the metabolic pathways. The metabolism of glimepiride
has been observed in animals and humans via oxidative
and
a nine-fold faster rate of dissociation than
glibenclamide,1 which permitted its use as a once daily
administration drug.4 Glimepiride prevents post exces-
* Corresponding authors.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01145-6

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M. K. Gurjar et al. / Tetrahedron Letters 44 (2003) 4853–4855
Scheme 1. Reagents and conditions: (a) CH2ꢀPPh3, THF, −20°C–rt, 1.5 h (80%); (b) H3B:SMe2, THF, NaOAc, H2O2 (75%); (c)
p-methoxybenzyl bromide, NaH, DMF, 0°C–rt (82%); (d) 0.8% H2SO4, MeOH, rt, 30 min (88%); (e) NH2OH·HCl, EtOH, reflux,
2 h (80%); (f) LAH, THF, reflux, 2 h (70%); (g) COCl2, C6H5CH3, reflux, 7 h (93%).
pathways giving rise to two active metabolites, trans-
hydroxyglimepiride 2b and carboxyglimepiride 3.5 In
spite of their significance in metabolic studies, their
syntheses are yet to be accomplished. However, we were
confronted with the need to produce synthetically both
cis-2a and trans-hydroxyglimepiride 2b, for bio-equiva-
lence studies and this communication describes the total
synthesis.
Our next concern was to convert 8 into the correspond-
ing isocyanate 10. For this endeavour 8 was first treated
with NH2OH·HCl in refluxing ethanol to produce the
oxime whose structure was supported by spectroscopic
data. Reduction of the oxime occurred smoothly in the
presence of LAH in THF to provide a cis and trans
mixture of cyclohexylamine derivatives 9. An attempt
to separate this cis and trans mixture at this juncture
was not successful. Therefore, we decided to continue
our synthetic strategy with the mixture and envisaged
separation at a later stage of the synthetic sequence.
Conversion of the amine 9 into the corresponding
isocyanate derivative 10 was a straightforward exercise
using phosgene in toluene at reflux (Scheme 1).
The synthesis of hydroxyglimepiride was initiated from
commercially available 1,4-cyclohexanedione mono-eth-
ylene ketal 4.6 Subsequent Wittig reaction with
PPh3ꢀCH2 in THF at room temperature gave the exo-
1
methylene product 5. In the H NMR spectrum of 5,
the characteristic signals due to olefinic protons were
located at 4.66 ppm. Compound 5 was subjected to a
hydroboration–oxidation reaction in the presence of
2M H3B:SMe2 solution in THF followed by treatment
with H2O2–NaOAc. The product 6 showed a doublet
(J=6.0 Hz) at 3.45 ppm in its 1H NMR spectrum
attributed to the hydroxymethyl protons. The rest of
the spectrum was in conformity with the assigned struc-
ture. The free hydroxy group present in 6 was protected
using PMB-bromide/NaH followed by acidic cleavage
of ethylene ketal group to yield the ketone 8.
The synthesis7 of sulfonamide intermediate 11 was com-
pleted by adopting the procedure shown in Scheme 2.
Finally the condensation reaction between 10 and 11
was performed in the presence of potassium carbonate
in acetone at reflux to give the coupled product 12. The
1H NMR spectrum of 12 clearly indicated that the
coupling had indeed taken place because characteristic
signals of both the coupling partners were distinctly
visible (Scheme 3).
Scheme 2. Reagents and conditions: (a) HNMe2, Et2SO4, 10–15°C (70%); (b) NaCN, DMF, 0–5°C (80%); (c) H2, Ra–Ni, Ac2O,
40°C, 5 Kg/cm2 (15%); (d) Na2CO3, H2O, reflux (90%); (e) PhCH2CH2NCO, C6H5CH3, reflux (65%); (f) i. ClSO3H, 10°C; ii. NH3,
H2O, 60°C, 4 h (80%, 2 steps).

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.