Metabolites of the Antidiabetic Agent Pioglitazone
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5059
(27%) of the target (hydroxyethyl)pyridine 14 as a yellow oil:
TLC (Merck; acetone-CH2Cl2, 25:75, UV(+)) Rf ) 0.23; 1H-
NMR (CDCl3) δ 8.46 (d, J ) 2.1 Hz, 1), 7.66 (dd, J ) 8.0, 2.3
Hz, 1), 7.20 (d, J ) 8.0 Hz, 1), 4.79 (q, J ) 6.6 Hz, 1), 4.5b
(ABq, J ) 23.6, 6.8 Hz, 2), 4.02 (t, J ) 5.6 Hz, 2), 3.36 (s, 3),
3.04 (t, J ) 5.6 Hz, 2), 1.49 (d, J ) 6.6 Hz, 3); IR (neat) 3374,
2974, 2948, 2933, 1603, 1571, 1491, 1444, 1374, 1217, 1155,
1136, 1100, 1060, 1037, 998, 919, 850, 837 cm-1; EI/MS (70
eV) 211 (M+, 34.1), 194 (90.7), 181 (39.4), 166 (7.4), 150 (27),
The combined organic extracts were washed with brine, dried
(Na2SO4), filtered, and evaporated in vacuo. The crude product
was dissolved in hot acetone/CH2Cl2 and purified by chroma-
tography on a column of silica gel (230-400 mesh, 300 g, 70
mm o.d., acetone-CH2Cl2, 25:75, 250 mL fractions), using the
flash technique. Fractions 5-9 afforded 1.13 g (61%) of the
target compound 17 as an off-white solid (mp 130-132 °C):
TLC (Merck; acetone-CH2Cl2, 10:90, UV(+)) Rf ) 0.17; 1H-
NMR (CDCl3) δ 8.51 (d, J ) 2.2 Hz, 1), 7.64 (d, J ) 6.0 Hz, 1),
7.28 (d, J ) 8.0 Hz, 1), 7.12 (d, J ) 8.6 Hz, 2), 6.83 (d, J ) 8.6
Hz, 2), 4.79 (q, J ) 6.5 Hz, 1), 4.58 (ABq, J ) 6.8 Hz, 2), 4.46
(dd, J ) 9.3, 3.9 Hz, 1), 4.32 (t, J ) 6.4 Hz, 2), 3.42 (dd, J )
14.1, 3.9 Hz, 1), 3.36 (s, 3), 3.27 (t, J ) 6.4 Hz, 2), 3.09 (dd, J
) 14.1, 9.3 Hz, 1), 1.49 (d, J ) 6.5, 3); IR (Nujol) 1705, 1514,
1252, 1165, 1152, 1058, 1034, 1022 cm-1; EI/MS (70 eV) 416
(M+, 2.3), 355 (8.4), 346 (2.1), 194 (92.1), 181 (base). Anal.
(C21H24N2O5S) C, H, N.
5-(4-(2-(5-(1-Hyd r oxyeth yl)-2-p yr id yl)eth oxy)ben zyl)-
2,4-t h ia zolid in ed ion e (6). To a stirring suspension of 17
(0.50 g, 1.20 mmol) in MeOH (20 mL) was added 2 N aqueous
HCl (1.5 mL), and the resulting solution was heated under
reflux for 2 h. After cooling to room temperature, the reaction
mixture was evaporated in vacuo. The residue was dissolved
in H2O (25 mL), and the solution was neutralized with
saturated aqueous NaHCO3. The resulting white precipitate
was collected by filtration, washed with H2O, and dried. The
crude product was purified by chromatography on a small
column of silica gel (acetone-CH2Cl2-MeOH) to afford 0.43 g
(98%) of 6 as an off-white solid (mp 153-158 °C): TLC (Merck;
MeOH-CH2Cl2, 5:95, UV(+)) Rf ) 0.15; 1H-NMR (CDCl3) δ
8.49 (d, J ) 2.1 Hz, 1), 7.70 (dd, J ) 8.0, 2.3 Hz, 1), 7.33 (d, J
) 8.0 Hz, 1), 7.16 (d, J ) 8.6 Hz, 2), 6.89 (d, J ) 8.6 Hz, 2),
4.86 (dd, J ) 9.0 Hz, 4.3, 1), 4.78 (q, J ) 6.5, 1), 4.33 (t, J )
6.6 Hz, 2), 3.42 (brs, 1), 3.32 (dd, J ) 14.1, 4.3 Hz, 1), 3.17
(dd, J ) 8.1, 6.6 Hz, 2), 3.06 (dd, J ) 14.1, 9.0 Hz, 1), 1.36 (d,
J ) 6.5, 3); IR (Nujol) 1611, 1515, 1473, 1333, 1318, 1253, 1162,
1023 cm-1; EI/MS (70 eV) 372 (M+, 11.8), 193 (7.7), 166 (5.1),
150 (base); HRMS (EI) calcd for C19H20N2O4S (M+) 372.1144,
found 372.1139.
134 (25.7), 120 (74), 45 (base); HRMS (EI) calcd for C11H17
-
NO3 (M+) 211.1208, found 211.1213.
4-(2-(5-(1-(Meth oxym eth oxy)eth yl)-2-p yr id yl)eth oxy)-
ben za ld eh yd e (15). To a stirring solution of the (hydroxy-
ethyl)pyridine 14 (4.06 g, 19.2 mmol), p-hydroxybenzaldehyde
(2.35 g, 19.2 mmol), and triphenylphosphine (5.54 g, 21.1
mmol) in THF (100 mL) at 0 °C was added diethyl azodicar-
boxylate (3.3 mL, 21.1 mmol) over 15 min. After stirring at
room temperature for 18 h, the solvent was evaporated in
vacuo. The resulting yellow oil was chromatographed on a
column of silica gel (230-400 mesh, 300 g, 70 mm o.d., packed
with acetone-CH2Cl2, 25:75, eluted with acetone-CH2Cl2, 35:
65, 250 mL fractions), using the flash technique. Fractions
3-6 afforded an oily solid which consisted of the target
compound 15 as a mixture with dicarbethoxyhydrazine. This
material was treated with Et2O-hexanes, 50:50, and the white
solid (dicarbethoxyhydrazine) was removed by suction filtra-
tion. The mother liquor was evaporated in vacuo, and the
residue was purified by chromatography on a column of silica
gel (230-400 mesh, 500 g, 70 mm o.d., EtOAc-hexanes, 40:
60, 250 mL fractions), using the flash technique. Fractions
13-30 were combined and evaporated in vacuo to give 3.75 g
(62%) of the target compound 15 as a yellow oil: TLC (Merck;
acetone-CH2Cl2, 10:90, UV(+)) Rf ) 0.42; 1H-NMR (CDCl3) δ
9.87 (s, 1), 8.52 (d, J ) 2.1 Hz, 1), 7.80 (m, 2), 7.64 (dd, J )
8.0, 2.3 Hz, 1), 7.28 (s, 1), 7.01 (d, J ) 8.7 Hz, 2), 4.79 (q, J )
6.6 Hz, 1), 4.58 (ABq, J ) 6.8 Hz, 2), 4.46 (t, J ) 6.7 Hz, 2),
3.36 (s, 3), 3.30 (t, J ) 6.6 Hz, 2), 1.49 (d, J ) 6.6 Hz, 3); IR
(Nujol) 2933, 2887, 2838, 2824, 1695, 1601, 1578, 1510, 1259,
1216, 1160, 1100, 1036, 1024 cm-1; EI/MS (70 eV) 315 (M+,
4.7), 284 (2.1), 270 (1.3), 254 (10.6), 224 (10.8), 210 (7.3), 194
(74.7), 181 (base); HRMS (EI) calcd for C18H21NO4 (M+)
315.1470, found 315.1479.
5-(4-(2-(5-(1-(Meth oxym eth oxy)eth yl)-2-pyr idyl)eth oxy)-
ben zylid en e)-2,4-th ia zolid in ed ion e (16). A stirring solu-
tion of aldehyde 15 (3.67 g, 11.6 mmol), 2,4-thiazolidinedione
(1.36 g, 11.6 mmol), and piperidine (0.50 g, 5.82 mmol) in
absolute EtOH (25 mL) was heated under reflux for 18 h. After
cooling to room temperature, the solvent was evaporated in
vacuo. The crude product was purified by chromatography on
a column of silica gel (230-400 mesh, 500 g, 70 mm o.d.,
packed with acetone-CH2Cl2, 10:90, eluted with acetone-CH2-
Cl2, 10:90 (3 L), 20% acetone-CH2Cl2, 20:80 (2 L), and MeOH-
acetone-CH2Cl2, 2.5:25:72.5, 250 mL fractions) using the flash
technique. Fractions 17-23 afforded 2.77 g (58%) of the target
compound 16 as a yellow solid (mp 122-123 °C): TLC (Merck;
acetone-CH2Cl2, 10:90, UV(+)) Rf ) 0.30; 1H-NMR (CDCl3) δ
8.52 (d, J ) 2.1 Hz, 1), 7.72 (dd, J ) 8.0, 2.2 Hz, 1), 7.64 (s, 1),
7.39 (d, J ) 8.8 Hz, 2), 7.32 (d, J ) 8.0 Hz, 1), 6.96 (d, J ) 8.8
Hz, 2), 4.81 (q, J ) 6.5 Hz, 1), 4.59 (ABq, J ) 6.8 Hz, 2), 4.48
(t, J ) 6.2 Hz, 2), 3.37 (s, 3), 3.35 (t, J ) 6.2 Hz, 2), 1.51 (d, J
) 6.5 Hz, 3); IR (Nujol) 1730, 1696, 1597, 1508, 1291, 1272,
1240, 1229, 1184, 1109, 1056, 1046, 1033, 1017 cm-1; EI/MS
(70 eV) 414 (M+, 11.0), 353 (5.9), 221 (47.9), 194 (68.2), 181
(33.9), 178 (34.6), 150 (base). Anal. (C21H22N2O5S) C, H, N.
5-(4-(2-(5-(1-(Meth oxym eth oxy)eth yl)-2-pyr idyl)eth oxy)-
ben zyl)-2,4-th ia zolid in ed ion e (17). To a stirring solution
of CoCl2‚6H2O (10 mg, 0.04 mmol) and 2,2′-dipyridyl (24.7 mg,
0.158 mmol) in H2O (10 mL) was added 1.0 N NaOH (0.13
mL) followed by NaBH4 (568 mg, 15.0 mmol), and the resulting
deep blue mixture was cooled to 0 °C. A solution of the olefin
16 (1.85 g, 4.46 mmol) in DMF (15 mL) was added over 0.5 h.
The reaction mixture stirred for 18 h at room temperature,
and then an additional portion of NaBH4 (250 mg) was added.
After stirring for 24 h, acetic acid was added until the pH of
the mixture was approximately 6. The mixture was diluted
with H2O (25 mL) and extracted with CH2Cl2 (2 × 50 mL).
3-(2-Met h yl-1,3-d ioxola n -2-yl)-6-m et h ylp yr id in e (18).
To a stirring mixture of the methylacetylpyridine 11 (14.4 g,
106 mmol) in toluene (100 mL) were added ethylene glycol (8.9
mL, 160 mmol) and p-toluenesulfonic acid monohydrate (22.3
g, 117 mmol). The mixture was heated under reflux for 8 h,
and H2O was removed from the system through the use of a
Dean-Stark trap. After cooling to room temperature, the
reaction mixture was neutralized with K2CO3. The mixture
was diluted with H2O (100 mL) and extracted with EtOAc (150
mL). The organic extract was washed with H2O and brine (150
mL each), dried (Na2SO4), filtered, and evaporated in vacuo
to give the desired ketal 6 as a light yellow oil. Distillation
afforded 17.4 g (92%) of 18 as a clear, colorless, viscous liquid
(bp 67-68 °C, 0.06 mmHg): TLC (Merck; acetone-CH2Cl2, 10:
1
90, UV(+)) Rf ) 0.29; H-NMR (CDCl3) δ 8.61 (d, J ) 2.1 Hz,
1), 7.66 (dd, J ) 8.0, 2.3 Hz, 1), 7.13 (d, J ) 8.0 Hz, 1), 4.06
(m, 2), 3.78 (m, 2), 2.56 (s, 3), 1.66 (s, 3); IR (Nujol) 3401, 3063,
3040, 1603, 1488, 1376, 1261, 1223, 1200, 1108, 1088, 1041,
1023, 949, 891, 873, 835, 738 cm-1; EI/MS (70 eV) 164 (base),
120 (47.6), 87 (35.5), 42 (34.6). Anal. (C10H13NO2) C, H, N.
2-(5-(2-Meth yl-1,3-dioxolan -2-yl)-2-pyr idyl)eth an ol (19).
A stirring solution of the ketal 18 (40.0 g, 223 mmol) and 37%
aqueous formaldehyde (18.1 g, 223 mmol) was heated at 150
°C in a sealed glass tube for 5 h. After cooling to room
temperature, the solvent was evaporated in vacuo, and re-
sidual H2O was removed by azeotropic distillation with toluene
(2 × 100 mL). The crude product was purified by chromatog-
raphy on a column of silica gel (230-400 mesh, 500 g, 70 mm
o.d., packed and eluted with acetone-CH2Cl2, 25:75 (3 L), then
MeOH-acetone-CH2Cl2, 2.5:25:72.5, 250 mL fractions), using
the flash technique. Fractions 5-9 afforded 24.91 g (62%) of
recovered starting material 18. Fractions 12-30 afforded
11.36 g (24%) of the target (hydroxyethyl)pyridine 19 as a
yellow oil: TLC (Merck; acetone-CH2Cl2, 25:75, UV(+)) Rf )
0.23; 1H-NMR (CDCl3) δ 8.62 (d, J ) 2.2 Hz, 1), 7.74 (dd, J )
8.0, 2.3 Hz, 1), 7.17 (d, J ) 8.0 Hz, 1), 4.05 (m, 4), 3.81 (m, 2),
3.03 (t, J ) 5.5 Hz, 2), 1.66 (s, 3); IR (Nujol) 1600, 1567, 1488,