C
Synlett
D. K. Tanwar et al.
Letter
method for similar compounds.11 In the final step, the reac-
tion of intermediates 2 and 3 gave glimepiride in an isolated
yield of 85% (Scheme 2).
(12) Phenyl 3-Ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-
carboxylate (1)
NaH (0.960 g, 40 mmol) was added to anhyd DMF (20 mL) in a
flask kept in an ice bath, and the mixture was stirred for 30 min.
In conclusion, an efficient, cost-effective, and practical
method has been developed for the preparation of glime-
3-Ethyl-4-methyl-1H-pyrrol-2(5H)-one (1.252 g, 10 mmol) in
anhyd DMF (10 mL) was added dropwise to the above mixture,
and the resulting mixture was stirred for 1.5 h. Diphenyl car-
bonate (4.284 g, 20 mmol) in anhyd DMF (10 mL) was added,
and stirring was continued for another 5 h at r.t. When the reac-
tion was complete (TLC), the solvent was removed under
reduced pressure, and the residue was diluted with EtOAc (100
mL), washed with brine (2 × 50 mL), and dried (Na SO ). The
12–15
piride
without the use of hazardous or moisture-sensi-
tive reagents such as phosgene, isocyanates, or chlorofor-
mates. In this process, 4-(2-aminoethyl)benzenesulfon-
amide is used to eliminate the sulfonamide-formation step.
This renders this process free from ortho- substituted sul-
fonamide or sulfonic acid derivatives or para-substituted
sulfonic acid impurities. This efficient procedure yields
glimepiride in good overall yield and with high purity un-
der mild reaction conditions.
2
4
organic layer was filtered and concentrated under reduced pres-
sure, and the crude product was purified by column chromatog-
raphy (silica gel, 12% hexane–EtOAc) to give a viscous liquid;
yield: 1.600 g, (65%).
1
H NMR (400 MHz, DMSO-d ): δ = 7.45 (t, J = 7.9 Hz, 2 H), 7.29
6
(
t, J = 7.4 Hz, 1 H), 7.23 (d, J = 7.5 Hz, 2 H), 4.38 (s, 2 H), 2.22 (q,
13
Acknowledgment
J = 7.5 Hz, 2 H), 2.05 (s, 3 H), 1.01 (t, J = 7.5 Hz, 3 H). C NMR
100 MHz, DMSO-d ): δ = 169.5, 152.5, 150.5, 149.0, 132.6,
(
6
This study was supported by National Institute of Pharmaceutical Ed-
ucation and Research, S.A.S. Nagar, Punjab, India. D.K.T. thanks the
University Grants Commission, New Delhi, India for awarding a schol-
arship for doctoral studies.
1
29.9, 126.4, 122.2, 53.0, 16.5, 13.4, 13.1. HRMS (ESI): m/z [M +
+
Na] calcd for C14H15NNaO : 268.0950; found: 268.0967.
3
(
13) N-{2-[4-(Aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-
oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (2)
3-Ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxyl-
ate (1; 1.349 g, 5.5 mmol) and 4-(2-aminoethyl)benzenesulfon-
amide (1.001 g, 5 mmol) were dissolved in THF (40 mL), and the
mixture was stirred at r.t. over night. After completion of the
reaction (TLC), the solvent was evaporated under reduced pres-
sure, and the crude product was purified by crystallization
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590836.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(EtOAc) to give a white solid yield: 1.495 g, (85%); mp 183–
1
85 °C.
References and Notes
1
H NMR (400 MHz, DMSO-d ): δ = 8.37 (t, J = 5.2 Hz, 1 H), 7.45
6
(
d, J = 7.8 Hz, 2 H), 7.43 (d, J = 7.8 Hz, 2 H), 7.32 (s, 2 H), 4.17 (s, 2
(
(
1) Schneider, J. Horm. Metab. Res. 1996, 28, 413.
2) (a) Skillman, T. G.; Feldman, J. M. Am. J. Med. 1981, 70, 361.
b) Kramer, W.; Müller, G.; Geisen, K. Horm. Metab. Res. 1996,
H), 3.49 (q, J = 6.0 Hz, 2 H), 2.88 (t, J = 6.5 Hz, 2 H), 2.18 (q, J = 7.3
Hz, 2 H), 2.01 (s, 3 H), 0.97 (t, J = 7.4 Hz, 3 H). C NMR (100
MHz, DMSO-d ): δ = 172.3, 152.5, 152.1, 143.8, 142.6, 132.3,
1
13
(
28, 464. (c) Zimmerman, B. R. Endocrinol. Metab. Clin. North Am.
6
29.5, 126.2, 52.3, 40.6, 35.5, 16.4, 13.3, 13.2. HRMS (ESI): m/z
1997, 26, 511.
+
[
M + Na] calcd for C16H N NaO S: 374.1150; found: 374.1140.
(
3) (a) Lebovitz, H. E.; Feinglos, M. N. Diabetes Care 1978, 1, 189.
b) Aquilante, C. L. Expert Rev. Cardiovasc. Ther. 2010, 8, 359.
4) Basit, A.; Riaz, M.; Fawwad, A. Vasc. Health Risk. Manage. 2012,
, 463.
21
3
4
(
14) Phenyl (trans-4-Methylcyclohexyl)carbamate (3)
(
Finely powdered diphenyl carbonate (3.213 g, 15 mmol) was
suspended in a mixture of THF (4 mL) and H O (36 mL), and the
(
8
2
resulting suspension was stirred at r.t. trans-(4-Methylcyclo-
hexyl)amine (1.698 g, 15 mmol) was added, and the reaction
was kept at r.t. for 8 h until the reaction was complete (TLC). The
mixture was extracted with EtOAc (150 mL), and the organic
layer was washed sequentially with cold 10% aq NaOH (3 × 50
mL) and brine (2 × 50 mL). The organic layer was dried (Na SO ),
(
(
5) Davis, S. N. J. Diabetes Complications 2004, 18, 367.
6) (a) Massi-Benedetti, M. Clin. Ther. 2003, 25, 799. (b) Campbell, R.
K. Ann. Pharmacother. 1998, 32, 1044.
(
7) (a) Weyer, R.; Hitzel, V.; Geisen, K.; Regitz, G. US 4379785, 1983.
(b) Radl, S.; Jarrah, K. US 7282517, 2007. (c) Mathur, P. K.;
Mathur, A.; Dalavi, D. S.; Gunjal, S. T.; Sawant, U. A.; Sankla, J.;
Srivastava, B. K.; Singh, P. K.; Soudagar, S. R.; Dhurandhare, V.;
Kumar, A.; Saxena, A. IN 234843, 2009. (d) Tarur, V. R.; Kadam,
S. M.; Naik, S. J.; Gavhane, S. B. IN 235644, 2009.
2
4
filtered, and concentrated under reduced pressure to give a
crude product that was purified by column chromatography
(silica gel, 8% hexane–EtOAc) to give a white solid; yield: 2.945 g
(
84%); mp 175–177 °C.
H NMR (400 MHz, DMSO-d ): δ = 7.68 (d, J = 7.9 Hz, 1 H), 7.36
(8) Lara Ochoa, J. M. F.; De La Torre Garcia, J. A.; Franco Andrade, F.
WO 2001005354, 2001.
1
6
(t, J = 8.1 Hz, 2 H), 7.18 (t, J = 7.3 Hz, 1 H), 7.08 (d, J = 7.6 Hz, 2
(9) Soni, R. R.; Rehani, R. B.; Thennati, R. IN 214216, 2008.
H), 3.34–3.18 (m, 1 H), 1.85 (d, J = 10.1 Hz, 2 H), 1.67 (d, J = 12.2
Hz, 2 H), 1.29–1.22 (m, 3 H), 1.03–0.91 (m, 2 H), 0.86 (d, J = 6.4
(
10) (a) Wicks, Z. W. Jr. Prog. Org. Coat. 1975, 3, 73. (b) Wicks, D. A.;
Wicks, Z. W. Jr. Prog. Org. Coat. 1999, 36, 148. (c) Kreye, O.;
Mutlu, H.; Meier, M. A. R. Green Chem. 2013, 15, 1431. (d) Hron,
R.; Jursic, B. S. Tetrahedron Lett. 2014, 55, 1540.
13
Hz, 3 H). C NMR (100 MHz, DMSO-d ): δ = 153.9, 151.5, 129.6,
6
1
25.2, 122.2, 50.3, 33.9, 32.8, 31.8, 22.6. HRMS (ESI): m/z [M +
+
Na] calcd for C14H NNaO : 256.1313; found: 256.1309.
(
11) Tanwar, D. K.; Ratan, A.; Burman, R. P.; Suresh, S.; Gill, M. S. IN
19
2
(
15) Glimepiride
3386/DEL/2015, 2015.
Carboxamide 2 (1.054 g, 3 mmol) and carbamate 3 (0.770 g, 3.3
mmol) were dissolved in MeCN (40 mL), and DBU (0.685 g, 4 5
mmole) was added. The mixture was then refluxed for 5 h until
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D