Scheme 6. Dynamic resolution of racemic UK-350,926 with (S)-(-)-1-phenylethylamine
Scheme 7. Conversion of UK-350,926 to UK-349,862
(approximately 180 L) and diluted with acetonitrile (740 L),
and the distillation continued at constant volume until the
refractive index of the distillate was below 1.345. The
mixture was allowed to cool to 10 °C, and the precipitated
product was granulated for 16 h, collected by filtration,
washed with acetonitrile (2 × 41.1 kg, 52.5 L), and dried at
45 °C under vacuum to give 17 (47.1 kg, 79%) as a white
1
crystalline solid. Mp: 184-185 °C. H NMR δ: 2.40 (s,
3H), 3.44 (s, 3H), 3.74 (s, 3H), 3.94 (s, 3H), 5.04 (s, 1H),
5.90 (d, 2H), 6.57 (s, 1H), 6.57-6.73 (m, 3H), 6.87 (d, 1H),
7.04 (s, 1H), 7.22 (d, 1H), 7.64 (dd, 1H), 7.92 (d, 1H), 8.02
(s, 1H), 8.80 (brs, 1H). 13C NMR (DMSO-d6) δ: 31.5, 42.7,
57.8, 61.9, 65.8, 111.1, 118.1, 118.7, 121.9, 123.1, 128.5,
129.7, 130.7, 131.7, 132.7, 133.4, 140.1, 141.1, 142.1, 145.9,
156.5, 156.8, 157.4, 166.6, 177.3, 180.4.
2-(6-Methoxycarbonyl-1-methyl-1H-indol-3-yl)-2-(3,4-
methylenedioxyphenyl)acetic Acid (16). To a stirred sus-
pension of methyl 1-methyl-1H-indole-6-carboxylate 15 (24
kg, 126.8 mol) and 2-hydroxy-2-(3,4-methylenedioxyphe-
nyl)acetic acid 9 (24.9 kg, 126.8 mol) in acetonitrile (240
L) was added trifluoroacetic acid (28.9 kg, 253.6 mol). The
suspension was heated to reflux for 24 h, allowed to cool to
room temperature, and granulated for 16 h. The precipitated
product was filtered, washed with acetonitrile (2 × 24 L),
and vacuum dried (45 °C) to give 16 (40.2 kg, 86%) as an
3-(1-{[(2-Methoxy-4-methylphenyl)sulfonyl]carbamoyl}-
1-(3,4-methylenedioxyphenyl)methyl)-1-methyl-1H-indole-
6-carboxylic Acid (18). Aqueous sodium hydroxide (41.5
kg, 415 L of a 40% aqueous solution, 415 mol) was added
to a stirred suspension of methyl 3-(1-{[(2-methoxy-4-
methylphenyl)sulfonyl]carbamoyl}-1-(3,4-methylenediox-
yphenyl)methyl)-1-methyl-1H-indole-6-carboxylate 17 (31.9
kg, 57.9 mol) in methanol (160 L) and demineralised water
(140 L). The suspension was warmed to 45 °C for 1.5 h,
cooled to room temperature, and diluted with dichlo-
romethane (180 L). The pH of the aqueous phase was
adjusted to 3 with the addition of concentrated hydrochloric
acid (42.5 kg, 36 L of a 35% aqueous solution), and the
phases were separated. The organic phase was concentrated
to approximately 100 L by distillation at atmospheric pressure
and cooled to 20 °C, and the precipitated product was
granulated for 1 h. The product was filtered, washed with
dichloromethane (40 kg, 30 L), and dried at 50 °C under
vacuum to give 18 (28.4 kg, 90%) as a white crystalline solid.
Mp: 199 °C. 1H NMR δ: 2.41 (s,3H), 3.40 (s, 3H), 3.75 (s,
3H), 5.07 (s, 1H), 5.92 (d, 2H), 6.51 (s, 1H), 6.68-6.73 (m,
3H), 6.89 (d, 1H), 7.11 (s, 1H), 7.23 (d, 1H), 7.66 (dd, 1H),
7.93 (d, 1H), 8.06 (s, 1H), 9.06 (brs, 1H). 13C NMR (DMSO-
d6) δ: 31.5, 42.7, 57.9, 65.9, 111.2, 118,2, 118.7, 121.8,
122.1, 123.3, 128.3, 130.0, 130.8, 131.7, 133.3, 133.8, 139.9,
141.1, 141.7, 142.1, 146.0, 156.5, 156.9, 157.4, 166.6, 178.4,
180.5.
1
off-white crystalline solid. Mp: 194-198 °C. H NMR δ:
3.83 (s, 3H), 3.94 (s, 3H), 5.19 (s, 1H), 5.93 (s, 2H), 6.76
(d, 1H), 6.87-6.90 (m, 2H), 7.26 (s, 1H), 7.44 (d, 1H), 7.76
(d, 1H), 8.07 (s, 1H). 13C NMR (DMSO-d6) δ: 42.7, 57.8,
62.0, 111.1, 118.1, 118.9, 122.0, 123.0, 128.9, 129.6, 131.7,
132.6, 140.3, 141.9, 143.4, 146.0, 156.3, 157.4, 177.3, 183.9.
Anal. Calcd for C20H17NO6: C, 65.39; H, 4.66; N, 3.81%.
Found: C, 65.34; H, 4.61; N, 3.81.
Methyl 3-(1-{[(2-Methoxy-4-methylphenyl)sulfonyl]-
carbamoyl}-1-(3,4-methylenedioxyphenyl)methyl)-1-methyl-
1H-indole-6-carboxylate (17). 1,1′-Carbonyldiimidazole-
(22.7 kg, 119 mol) was added to a stirred solution of
2-(6-methoxycarbonyl-1-methyl-1H-indol-3-yl)-2-(3,4-methylene-
dioxyphenyl)acetic acid 16 (39.8 kg, 108 mol) in dry tetra-
hydrofuran (398 L) at room temperature. The suspension was
heated to reflux for 1.5 h, allowed to cool to room
temperature, and treated sequentially with 2-methoxy-4-
methylbenzenesulfonamide 5 (24 kg, 119 mol) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU, 18.1 kg, 119 mol).
The mixture was heated to reflux for 4.5 h, cooled to room
temperature, and diluted with dichloromethane (318 L) and
demineralised water (270 L), and 2 M hydrochloric acid
(46.5kg, 54.9 L) was added. The phases were separated, and
the organic phase was washed with dilute hydrochloric acid
(2 M, 46.5 kg, 54.9 L) in water (270 L). The phases were
separated, the organic phase was concentrated to low volume
(S)-(+)-3-(1-{[(2-Methoxy-4-methylphenyl)sulfonyl]-
carbamoyl}-1-(3,4-methylenedioxyphenyl)methyl)-1-methyl-
1H-indole-6-carboxylic Acid UK-350,926 (1). (S)-(-)-1-
Phenethylamine (2.94 kg, 24.3 mol) was added over a period
668
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Vol. 9, No. 5, 2005 / Organic Process Research & Development