Preparation of (2-{2-[1-Methyl-5-(4-methyl-benzoyl)-1H-
pyrrol-2-yl]acetylamino}-acetylamino)acetic Acid 2-Meth-
oxy-phenyl Ester (12). To a heterogeneous solution of 8
(50 g, 0.159 mol) in dichloromethane (200 mL) at 0 °C
was sequentially added 1-hydroxybenzotriazole (4.3 g,
0.031 mol), triethylamine (3.2 g, 0.031 mol) and 11 (34.63
g, 0.159 mol). After stirring for 15 min, a solution of
dicyclohexylcarbodiimide (39.5 g, 0.191 mol) in dichlo-
romethane (150 mL) was added slowly in 50 min at 30
°C; the reaction mixture was stirred for 3 h. Thereafter,
it was cooled to 0 °C and stirred for 30 min. The unwanted
solid was filtered (DCU) and washed with chilled dichlo-
romethane (100 mL). The filtrate was washed with 2%
Na2CO3 solution (100 mL) followed by water (100 mL).
The organic layer was separated, and distilled off com-
pletely below 40 °C under vacuum, and the residue was
dissolved in isopropyl alcohol (600 mL) at 80 °C and
cooled to 25-30 °C. The solid stirred for 3 h and was
filtered and washed with isopropyl alcohol (150 mL). The
compound was dried at 60 °C under vacuum for 6 h to
provide the title compound 12 (34.2 g, 45% yield). Mass
o-methoxyphenol (24.1 g, 0.194 mol) in dichloromethane
(50 mL). After stirring for 15 min, a solution of dicyclo-
hexylcarbodiimide (39.5 g, 0.191 mol) in dichloromethane
(150 mL) was added slowly dropwise in 50 min at 30 °C.
After stirring for 3 h, it was cooled to 0 °C and stirred
for additionally 30 min. The unwanted solid was filtered
(DCU) and washed with chilled dichloromethane (100
mL). Filtrate was washed with 2% Na2CO3 solution (100
mL) followed by water (100 mL). Organic layer was
separated and distilled off completely below 40 °C under
vacuum and the residue was dissolved in isopropyl alcohol
(600 mL) at 80 °C. It was slowly cooled to 25-30 °C
and stirred for 3 h. Filtered the solid and washed with
isopropyl alcohol (150 mL). Dried the compound at 60
°C under vacuum for 6 h to provide the title compound
14 (49.5 g, 70% yield, and >99.5% HPLC purity). Mass
1
(M + 1): 364; H NMR (CDCl3, 400 MHz): δ 7.73(d, J
) 7.8 Hz, 2H), 7.25 (d, J ) 8.2 Hz, 2H), 7.20 (m, 1H),
7.04 (dd, J ) 1.4 Hz, 7.8 Hz, 1H), 6.95 (m, 2H), 6.70 (d,
J ) 3.9 Hz, 1H), 6.23 (d, J ) 3.9 Hz, 1H), 4.03 (s, 3H),
3.97 (s, 2H), 3.80 (s, 3H), 2.41 (s, 3H).
1
(M + 1): 478; H NMR (CDCl3, 400 MHz): δ 7.71(d, J
Preparation of 1-Methyl-5-p-toluoyl-2-acetamidoacetic
Acid (8). Glycine methyl ester hydrochloride (5.86 kg, 46.7
mol) and dichloromethane (50 L) were charged into a flask.
To this heterogeneous mass, was slowly added a solution of
triethylamine (4.72 kg, 46.7 mol) in dichloromethane (10 L) at
30 °C in 20 min. After stirring for 30 min, 1-methyl-5-p-
toluoylpyrrole-2-acetic acid 2 (tolmetin) (10 kg, 38.91 mol) and
1-hydroxybenzotriazole were charged. Thereafter a solution of
dicyclohexyl carbodiimide (8.8 kg, 42.7 mol) in dichlo-
romethane (40 L) was added slowly during 45-60 min at 30
°C. After stirring for 3 h at 30 °C, it was cooled to 0 °C and
stirred for 30 min at 0-5 °C. The unwanted solid was filtered
(DCU) and washed with dichloromethane (10 L). The filtrate
was washed with 2% Na2CO3 solution (20 L). Organic layer
was distilled off completely below 40 °C under vacuum. To
the obtained residue was added a solution of NaOH (23.4 kg,
58.5 mol) in water (50 L) and stirred for 3 h at 30 °C. Thereafter,
ethylacetate (40 L) was added to the reaction mixture and stirred
for 15 min. The aqueous layer was separated and washed with
ethylacetate (30 L). Water (200 L) was charged to the aqueous
layer, and the pH was slowly adjusted to 1.0-2.0 with 50% of
12 N hydrochloric acid and stirred for an additional 60 min.
The compound was filtered and washed with water (20 L). The
wet compound was again slurried in water (140 L) to reach
the neutral pH of the compound. The compound was dried to
a constant weight at 60-70 °C under vacuum to give 10.76 kg
of 8 (88.2% yield, 99.3% HPLC). Melting point: 200°-202
) 7.8 Hz, 2H), 7.24 (m, 3H), 7.04 (dd, J ) 1.8 Hz, 7.8
Hz, 1H), 6.95 (m, 2H), 6.68 (d, J ) 4.1 Hz, 1H), 6.54
(bs, 1H), 6.37 (bs, 1H), 6.14 (d, J ) 3.7 Hz, 1H),4.34 (d,
J ) 5.5 Hz, 2H), 3.99 (d, J ) 5.1 Hz, 2H) 3.91 (s, 3H),
3.81 (s, 3H), 3.70 (s, 2H), 2.42 (s, 3H).
Preparation of 1-Methyl-5-p-toluoylpyrrole-2-acetami-
doacetic Acid Isopropyl Alcohol Ester (13). To a heteroge-
neous solution of 8 (50 g, 0.159 mol) in dichloromethane
(200 mL) at 0 °C was sequentially added 1-hydroxyben-
zotriazole (4.3 g, 0.031 mol), triethylamine (3.2 g, 0.031
mol), and isopropyl alcohol (20 mL) at 0 °C. After stirring
for 15 min, a solution of dicyclohexylcarbodiimide (39.5
g, 0.191 mol) in (150 mL) was added slowly dropwise in
50 min at 25-35 °C. After stirring for 3 h, the reaction
mixture was cooled to 0 °C and stirred additionally for
30 min. The unwanted solid was filtered (DCU) and
washed with chilled dichloromethane (100 mL). Filtrate
was washed with 2% Na2CO3 solution (100 mL) followed
by water (100 mL). The organic layer was separated and
distilled off completely below 40 °C under vacuum, and
the residue was dissolved in isopropyl alcohol (600 mL)
at 80 °C. The solution was cooled to 25-30 °C and stirred
for 3 h. The solid was filtered and washed with isopropyl
alcohol (150 mL). The compound was dried at 60 °C under
vacuum for 6 h to provide the title compound 13 (34.0 g,
1
60% yield). Mass (M + 1): 357; H NMR (CDCl3, 400
1
MHz): δ 7.72(d, J ) 7.9 Hz, 2H), 7.26 (d, J ) 9.4 Hz,
2H), 6.70 (d, J ) 3.9 Hz, 1H), 6.16 (d, J ) 3.9 Hz, 1H),
6.00 (bs, 1H), 5.04 (m, 1H), 3.99 (d, J ) 5.4 Hz, 2H)
3.94 (s, 3H), 3.70 (s, 2H), 2.42 (s, 3H), 1.25 (s, 3H), 1.24
(s, 3H).
Preparation of 1-Methyl-5-p-toluoylpyrrole-2-acetic Acid
Guacil Ester (14). To a heterogeneous solution of tolmetin
2 (50 g, 0.194 mol) in dichloromethane (200 mL) was
sequentially added 1-hydroxybenzotriazole (5.3 g, 0.039
mol), triethylamine (3.9 g, 0.039 mol), and a solution of
°C. Mass (M + 1): 315; H NMR (DMSO-d6, 400 MHz): δ
7.64 (dd, J ) 6.3 Hz, 1.9 Hz, 2H), 7.28 (d, J ) 7.8 Hz, 2H),
6.65 (d, J ) 3.9 Hz, 1H), 6.17 (d, J ) 3.9 Hz, 1H), 3.92 (s,
3H), 3.73 (s, 2H), 3.30 (t, J ) 1.4 Hz, 2H), 2.41(s, 3H).
Preparation of 1-Methyl-5-p-toluoylpyrrole-2-acetami-
doacetic Acid Guacil Ester (1). To a solution of 8 (10 kg,
31.8 mol) in dichloromethane (40 L) was sequentially added
1-hydroxybenzotriazole (0.86 kg, 6.2 mol), triethylamine (0.64
kg, 6.2 mol), and a solution of o-methoxyphenol (3.95 kg, 31.8
mol) in dichloromethane (10 L). After stirring the reaction
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