MHz, CDCl3): δ 3.11 (3H, s), 3.99 (2H, t, J = 5.6 Hz), 4.24 (2H,
t, J = 5.6 Hz), 6.49 (1H, d, J = 8.8 Hz), 6.54 (1H, m), 6.97 (2H,
d, J = 8.8 Hz), 7.43 (1H, m), 7.77 (2H, d, J = 8.8 Hz), 8.13 (1H,
m), 9.83 (1H, s); 13C NMR (100 MHz, CDCl3): δ 190.2, 163.3,
157.5, 147.2, 136.7, 131.3 (2C), 129.2, 114.1 (2C), 111.3, 105.1,
Acknowledgements
We thank GlaxoSmithKline for financial support and a
postdoctoral fellowship (to X. L.).
66.0, 48.6, 37.3. LC–MS: tR = 2.72 min, m/z (ESI) [M ϩ H]ϩ
=
References
257.4; HR-MS (ESI): m/z calc. for C15H17N2O2 257.1290, found
1 (a) K. M. Brummond and J. Lu, J. Org. Chem., 1999, 64, 1723;
(b) B. C. C. Cantello, M. A. Cawthorne, G. P. Cottam, P. T. Duff,
D. Haigh, R. M. Hindley, C. A. Lister, S. A. Smith and
P. L. Thurlby, J. Med. Chem., 1994, 37, 3977; (c) B. C. C. Cantello,
M. A. Cawthorne, D. Haigh, R. M. Hindley, S. S. Smith and
P. L. Thurly, Bioorg. Med. Chem. Lett., 1994, 4, 1181.
257.1295 [M ϩ H]ϩ.
(Z )-5-{4-[2-(Methylpyridin-2-ylamino)ethoxy]benzylidene}-
thiazolidine-2,4-dione (8)
To a solution of the aldehyde 7 (1.46 g, 5.70 mmol) and 2,4-
thiazolidinedinone (3.33 g, 28.5 mmol) in toluene (50 mL), was
added piperazinomethyl polystyrene16 (0.83 mmol gϪ1, 3.00 g,
2.49 mmol). The resulting mixture was heated at 88 ЊC for 24 h
and then allowed to cool to room temperature. The suspension
was filtered and the resin was washed thoroughly with CH2Cl2.
The combined filtrates were evaporated in vacuo, and the
residue was loaded onto 3 × 10 g SCX-2 cartridges. The
cartridges were eluted first with ethyl acetate, and then with a
mixture of dimethylethylamine and methanol (1 : 1) to elute the
benzylidene 8 as a yellow solid (2.02 g, 99%). Mp: 196–198 ЊC
2 R. A. DeFronzo, R. C. Bonnadonna and E. Ferrannini, Diabetes
Care, 1992, 15, 318.
3 J. M. Lehmann, L. B. Moore, T. A. Smith-Oliver, W. O. Wilkison,
T. M. Willson and S. A. Kliewer, J. Biol. Chem., 1995, 270, 12953.
4 T. M. Willson, P. J. Brown, D. D. Sternbach and B. R. Henke,
J. Med. Chem., 2000, 43, 27.
5 (a) V. Shantaram, Clin. Exp. Hypertens., 1999, 21, 69; (b) J. R.
Sowers, M. Epstein and E. D. Frohlich, Hypertension, 2001, 37,
1053.
6 (a) S. V. Ley and I. R. Baxendale, Nat. Rev. Drug Discovery, 2002,
573; (b) J. J. Parlow, W. Naing, M. S. South and D. L. Flynn,
Tetrahedron Lett., 1997, 38, 7959; (c) J. A. Porco, Jr., Comb. Chem.
High Throughput Screening, 2000, 3, 93.
7 (a) J. Yoshida and K. Itami, Chem. Rev., 2002, 102, 3693; (b)
A. Ganesan, Drug Discovery Today, 2002, 7, 47; (c) F. Z. Dörwald,
Organic Synthesis on Solid Phase, Wiley-VCH, Weinheim, 2000; (d )
D. Obrecht and J. M. Villalgordo, Solid-Supported Combinatorial
and Parallel Synthesis of Small-Molecular-Weight Compound
Libraries, Pergamon, Oxford, 1998.
8 (a) S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson,
A. G. Leach, D. A. Longbottom, M. Nesi, J. S. Scott, R. I. Storer
and S. J. Taylor, J. Chem. Soc., Perkin Trans. 1, 2000, 3815; (b)
A. Kirschning, H. Monenschein and R. Wittenberg, Angew. Chem.,
Int. Ed., 2001, 40, 650; (c) D. H. Drewry, D. M. Coe and S. Poon,
Med. Res. Rev., 1999, 19, 97; (d ) L. A. Thompson, Curr. Opin.
Chem. Biol., 2000, 4, 324.
9 For example: (a) I. R. Baxendale, A.-L. Lee and S. V. Ley, J. Chem.
Soc., Perkin Trans. 1, 2002, 1850; (b) I. R. Baxendale, S. V. Ley,
M. Nessi and C. Piutti, Tetrahedron, 2002, 6285; (c) M. Caldarelli,
J. Habermann and S. V. Ley, Bioorg. Med. Chem. Lett., 1999, 9,
2049; (d ) A. Lee and J. A. Ellman, Org. Lett., 2001, 3, 3707; (e)
I. R. Baxendale and S. V. Ley, Bioorg. Med. Chem. Lett., 2000, 10,
1983.
(from MeOH); IR νmax/cmϪ1: 1688 (νC᎐O) cmϪ1; 1H NMR (400
᎐
MHz, d6-DMSO): δ 3.04 (3H, s), 3.90 (2H, t, J = 5.6 Hz), 4.19
(2H, t, J = 5.6 Hz), 6.54 (1H, m), 6.62 (1H, d, J = 8.8 Hz), 7.07
(2H, d, J = 8.8 Hz), 7.47 (1H, m), 7.50 (2H, d, J = 8.8 Hz), 8.05
(1H, m); 13C NMR (100 MHz, d6-DMSO): δ 167.8, 167.4,
160.0, 157.8, 147.3, 137.1, 131.9 (2C), 131.5, 125.4, 120.3, 115.1
(2C), 111.4, 105.6, 65.6, 48.1, 36.8; LC–MS: tR = 3.19 min, m/z
(ESI) [M ϩ H]ϩ = 356.2; HR-MS (ESI): m/z calc. for
C18H18N3O3S 356.1069, found 356.1082 [M ϩ H]ϩ.
5-{4-[2-(Methylpyridin-2-ylamino)ethoxy]benzyl}thiazolidine-
2,4-dione (1)
Palladium hydroxide (20% on charcoal, 300 mg) was suspended
in a solution of the benzylidene 8 (355 mg, 1.00 mmol) in
1,4-dioxane (40 mL). The suspension was heated at 80 ЊC with
stirring under a hydrogen atmosphere (∼1 atm) for 24 h and
then allowed to cool to room temperature. The mixture was
filtered through a Celite pad and the pad was washed
thoroughly with ethanol. The combined organic filtrates were
evaporated in vacuo and the residue obtained was loaded onto
a 5 g SCX-2 cartridge. The cartridge was first washed with
methanol, and then eluted with 2 M methanolic ammonia. The
methanolic ammonia fractions were collected and the solvent
was evaporated in vacuo. The residue obtained was diluted with
water (10 mL), adjusted to pH 7.5–8.0 with 10% hydrochloric
acid, and extracted with CH2Cl2 (3 × 10 mL). The combined
organic extracts were dried (MgSO4) and concentrated in vacuo
to give Rosiglitazone 1 as a white solid (0.30 g, 82%) with
physical properties identical to those previously reported.1 Mp:
153–154 ЊC (from MeOH); Found: C, 60.66; H, 5.42; N, 11.57;
S, 8.68. C18H19N3O3S requires: C, 60.49; H, 5.36; N, 11.76; S,
10 D. L. Flynn, Med. Res. Rev., 1999, 19, 408.
11 An alternative, more advanced, starting material would have been
4-hydroxybenzaldehyde. However, in our hands, this material was
found to undergo a Cannizzaro reaction under strongly basic
conditions to afford a mixture of the corresponding alcohol and
carboxylic acid products.
12 C. P. Miller, M. D. Collini, B. D. Tran, H. A. Harris, Y. P. Kharode,
J. T. Marzolf, R. A. Moran, R. A. Henderson, R. H. W. Bender,
R. J. Unwalla, L. M. Greenberger, J. P. Yardley, M. A.
Abou-Gharbia, C. R. Lyttle and B. S. Komm, J. Med. Chem., 2001,
44, 1654.
13 PS-BEMP
(2-tert-Butylimino-2-diethylamino-1,3-dimethyl-
perhydro-1,3,2-diazaphosporine on polystyrene), 2.3 mmol gϪ1 was
obtained from Fluka Cat. No. 20026.
14 MP-carbonate was obtained from Argonaut Technologies Inc. Cat.
No. 800268.
15 Isolute SCX-2 (alkylsulfonic acid) cartridges were obtained from
8.97%; IR νmax/cmϪ1: 1695 (νC᎐O); 1H NMR (400 MHz,
᎐
Jones Chromatography (e.g. Cat. No. 532-0100-C).
CDCl3): δ 3.08 (1H, dd, J = 9.2 and 14.0 Hz), 3.13 (3H, s), 3.40
(1H, dd, J = 3.6 and 14.0 Hz), 3.94 (2H, m), 4.13 (2H, m), 4.46
(1H, dd, J = 3.6 and 9.2 Hz), 6.50 (1H, d, J = 8.8 Hz), 6.54 (1H,
m), 6.82 (2H, d, J = 8.8 Hz), 7.10 (2H, d, J = 8.8 Hz), 7.44 (1H,
m), 8.12 (1H, m); 1H NMR (400 MHz, d6-DMSO): δ 3.03 (1H,
dd, J = 9.2 and 14.0 Hz), 3.05 (3H, s), 3.26 (1H, dd, J = 4.1 and
14.0 Hz), 3.86 (2H, t, J = 6.0 Hz), 5.68 (2H, t, J = 6.0 Hz), 4.83
(1H, dd, J = 4.1 and 9.2 Hz), 6.54 (1H, dd, J = 4.6 and 7.0 Hz),
6.61 (1H, d, J = 9.0 Hz), 6.85 (2H, d, J = 8.4 Hz), 7.11 (2H, d,
J = 8.4 Hz), 7.47 (1H, m), 8.05 (1H, m); 13C NMR (100 MHz,
CDCl3): δ 174.4, 170.6, 157.6, 157.5, 146.9, 136.8, 129.7 (2C),
127.2, 114.0 (2C), 111.1, 105.3, 65.5, 53.1, 48.9 37.2, 37.1;
LC–MS: tR = 2.89 min, m/z (ESI) [M ϩ H]ϩ = 358.2; HR-MS
(ESI): m/z calc. for C18H20N3O3S 358.1225, found 358.1228
[M ϩ H]ϩ;
16 Chromic acid on Amberlyst A-26 was obtained from Sigma-Aldrich
Cat. No. 35,982-3.
17 Piperazinomethyl polystyrene was obtained from NovaBiochem
Cat. No. 01-64-0310; cf: J. Simpson, D. L. Rathbone and
D. C. Billington, Tetrahedron Lett., 1999, 40, 7031.
18 We found that this 1,4-reduction could also be mediated using
aqueous sodium dithionite, however the procedure proved to be
difficult to reproduce reliably and therefore catalytic hydrogenation
under forcing conditions was preferred.
19 According to the reported procedure in ref. 2b, Rosiglitazone was
obtained in 31% overall yield as compared to 46% overall yield in the
present synthesis.
20 For the present synthesis, we found that 1H NMR spectroscopy was
more indicative of the purity of synthetic intermediates than
LC–MS since many of the compounds are quite polar and tend to
elute close to the origin using conventional RP-HPLC methods and
solvent gradients.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 9 2 – 4 3 9 5
4395