1H), 6.94 (m, 2H), 7.02 (m, 2H), 7.08 (m, 2H), 7.84 (m,
2H), 8.32 (s, 1H), 9.90 (s, 1H); 13C NMR (100 MHz, CDCl3)
δ 3706, 53.4, 56.1, 62.5, 86.1, 115.1, 122.8, 128.5, 130.8,
146.7, 157.3, 157.9, 164.8, 170.9, 174.9; MS (ESI) m/z (M
+ 1) 380.41; Anal. Calcd for C21H21N3O4: C, 66.48; H, 5.58;
N, 11.08. Found: C, 66.31; H, 5.42; N, 10.95.
Hantzsch ester (1.4 kg, 5.6 mol) and silica gel (6 kg). After
each addition, the reaction mixture was stirred at reflux
temperature for 12 h, at which point HPLC showed the
complete conversion of 10 to 1 in the case where a Dean-
Stark water trap was used (HPLC retention time; starting
material 10: 13.5 min, desired product 1: 12.5 min). The
mixture was hot filtered to remove the silica gel (Note: In
order to ensure safe handling, a good exhausting hood and
sufficient caution are required). The filter cake was washed
with ethyl acetate (2 × 5.0 L), and the filtrate was
concentrated in vacuo.
Preparation of 5-[4-(2-{[6-(4-Methoxyphenoxy)pyri-
midin-4-yl]methylamino}ethoxy)benzylidene]thiazolidine-
2,4-dione (10). To a dry, nitrogen-purged 70-L reactor
(Buchi) with a mechanically stirred solution of 7 (1.8 kg,
4.8 mol) in 30 L of toluene were successively added 2,4-
thiazolidinedione (0.48 kg, 4.8 mol), acetic acid (70 mL, 1.44
mol), and piperidine (0.12 L, 1.4 mol), and then the reaction
mixture was stirred at reflux temperature for 5 h with a
Dean-Stark water trap (the amount of condensed water was
about 86 mL). The disappearance of the starting material 7
was detected by monitoring HPLC (HPLC retention time;
starting 7: 12.5 min, product 10: 13.5 min). Once the
reaction was completed, the mixture was cooled to room
temperature, and the precipitates formed were collected by
filtration and washed twice with fresh anhydrous toluene.
Recrystallization of Crude 10. To a dry, nitrogen-purged
70-L glass-lined reactor were added the crude 10 and ethanol
(10 L). The resulting slurry was then heated at 35-40 °C
for about 5 h (Note: Not all of the solid cakes were dissolVed
after this time). The reaction mixture was then cooled to ca.
25 °C for at least 3 h and stirred for 20 h at the same
temperature. The resulting solid was collected by filtration
and washed with precooled ethanol (5 L, about 5 °C in a
refrigerator) (Note: Through the recrystallization process,
the major impurities (compounds 6, 8, 9, and 11) were
effectiVely remoVed, as confirmed by HPLC analysis). To a
dry 20-L glass reactor was added the obtained yellowish solid
10 followed by trituration with (i-Pr)2O (15 L) for 12 h at
room temperature. The resultant solids were collected by
filtration and washed with (i-Pr)2O (2 × 5 L), and dried in
a vacuum oven to afford 2.06 kg of the purified 10 (90%
yield based on 95% HPLC purity) as a light-yellow solid
(containing 0.85% of the impurity 11), which was used in
the next reaction without further purification. Silica gel TLC
Rf ) 0.32 (detection: Iodine char chamber, ninhydrin
solution, developing solvents: CH2Cl2/MeOH, 20:1); mp
194-195 °C; IR (KBr) ν 3428, 2948, 2748, 1741, 1704,
1591, 1508, 1292, 1257 cm-1; 1H NMR (400 MHz, DMSO-
d6) δ 3.07 (s, 3H), 3.75 (s, 3H), 3.94 (m, 2H), 4.23 (m, 2H),
6.05 (s, 1H), 6.95 (d, J ) 8.84 Hz, 2H), 7.00 (m, 4H), 7.54
(d, J ) 8.86 Hz, 2H), 7.73 (s, 1H), 8.16 (s, 1H); 13C-NMR
(100 MHz, DMSO-d6) δ 37.3, 48.9, 56.2, 66.5, 86.4, 115.4,
116.2, 121.3, 123.3, 126.5, 132.5, 132.9, 146.9, 157.2, 158.1,
160.8, 164.5, 168.4, 168.8, 170.6; MS (ESI) m/z (M + 1)
479.51; Anal. Calcd for C24H22N4O5S: C, 60.24; H, 4.63;
N, 11.71; S, 6.70. Found: C, 60.11; H, 4.49; N, 11.65; S,
6.52.
Recrystallization of Crude 1. To a dry, 70-L glass
reactor was added the oily residue in anhydrous ethyl acetate
(5 L) followed by stirring at 25 °C for about 3.5 h until the
residue was clearly dissolved, and then hexanes (20 L) was
added. The reaction mixture was stirred at 25 °C for 10 h,
allowed to stand for 24 h at room temperature, and then
filtered to afford a yellowish solid. The resulting solid was
completely dissolved in 15 L of mixed solvent (dichlo-
romethane/ethanol ) 12:3) with stirring for about 5 h, and
the reaction solution was concentrated in vacuo to an inner
volume of approximately 3.5-4 L. The condensed organic
mixture was stirred for 1 day at room temperature, and the
yellowish solid formed was collected by filtration. The
obtained solid was triturated with isopropyl ether (15 L) for
1 day at ambient temperature, filtered, and dried in a vacuum
oven at 85 °C for 10 h to afford the desired product 1 as a
light yellow solid. SiO2 TLC Rf ) 0.35 (detection: Iodine
char chamber, ninhydrin solution, developing solvents: CH2-
Cl2/MeOH, 20:1); mp 145-146 °C; IR (KBr) ν 3427, 3112,
2924, 2835, 2752, 1749, 1693, 1590, 1545, 1506, 1444, 1363
1
cm-1; H NMR (400 MHz, CDCl3) δ 3.12 (m, 4H), 3.45
(m, 1H), 3.83 (s, 3H), 4.00 (m, 2H), 4.16 (m, 2H), 4.50 (m,
1H), 5.84 (bs, 1H), 6.83 (m, 2H), 7.06 (m, 2H), 7.15 (m,
2H), 8.31 (s, 1H), 8.89 (bs, NH); 13C NMR (100 MHz,
CDCl3) δ 37.9, 38.1, 49.7, 54.0, 55.9, 66.6, 85.9, 115.0,
122.8, 128.8, 130.7, 146.7, 157.3, 157.9, 158.4, 164.2, 170.8,
171.1, 174.9; MS (ESI) m/z (M + 1) 481.5; Anal. Calcd for
C24H24N4O5S: C, 59.99; H, 5.03; N, 11.66; S, 6.67. Found:
C, 60.11; H, 5.05; N, 11.67; S, 6.50.
Preparation of 5-(4-{2-[6-(4-Methoxyphenoxy)pyrimi-
din-4-yl]methylamino ethoxy}benzyl)thiazolidine-2,4-di-
one sulfate (2). To a dry, nitrogen-purged 20-L glass reactor
was added compound 1 (1.87 kg, 3.89 mol) in 15 L of
anhydrous methanol (obtained by passage through Linde-
type 4 Å molecular sieves) and then stirred at 0 °C until it
was clearly dissolved. While the temperature was maintained
at 0-5 °C, sulfuric acid (96%, 216 mL, 3.89 mol) was added
dropwise for 30 min to the reaction mixture, and then the
resulting mixture was stirred for 1-1.5 h more. The mixture
was condensed to one tenth of its original volume in vacuo
maintaining the water bath temperature less than 10 °C (Note:
with higher bath temperature, a gradual increase, up to
<3%, in the amount of CKD-501-monomethyl sulfate was
obserVed by HPLC analysis).
Preparation of 5-(4-{2-[6-(4-Methoxyphenoxy)pyrimi-
din-4-yl]methylamino ethoxy}benzyl)thiazolidine-2,4-di-
one (1). To a dry, nitrogen-purged 70-L reactor (Buchi) with
a mechanically stirred suspension of compound 10 (2.1 kg,
4.3 mol) in toluene (50 L) were successively added the
Crystallization of Crude Lobeglitazone Sulfate (CKD-
501). The residual pale-yellow syrup was crystallized with
isopropyl ether (20 L) at room temperature for 24 h, and
198
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Vol. 11, No. 2, 2007 / Organic Process Research & Development