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Organic Process Research & Development
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wt% NaOEt in EtOH solution (55.0 kg) was added at 71 ꢀ 72 oC. After reaction completion with >99.5% conversion
by HPLC, the reaction was stirred for additional 30 min, followed by HPLC analysis.18 The reaction was cooled to
35 °C and EtOH (14 kg) was removed by distillation over 2 h,19 prior to quenching with DI water (200.0 kg). The
aqueous layer was extracted with toluene (87.4 kg and 88.2 kg) twice and the combined organic solution was washed
with DI water (75.0 kg), then concentrated to ~130 L in vacuo. The mixture was heated to 70 °C to form a clear
solution before hexanes (63.1 kg) was charged to form a cloudy mixture. Additional hexanes (30.0 kg) was charged
over 20 min. The slurry was gradually cooled to 0 °C over 3 h and the final thick slurry was stirred at 0 °C for 30
min. before the solids were isolated by filtration and washed with 37.0 kg ice cold solution (40% toluene / 60%
hexanes). After drying under vacuum, 40.2 kg of 16 (91% purity from HPLC) were isolated as a yellow solid (59 %
yield from 3ꢀbromo furan 6).
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Formation of 5:
To a mixture of 16 (40.2 kg) in toluene (349.0 kg) was added Cs2CO3 (53.8 kg) and CuI (6.4 kg). After purging with
N2 for 15 min at rt, the slurry was heated to reflux. After 7 h at reflux, >99.0% HPLC conversion was achieved. The
o
mixture was cooled to 30 C and ethylene diamine (26.5 kg) was charged. The mixture was allowed to stir for 50
min. to accomplish >99.0% conversion by HPLC. Subsequently, the reaction was quenched with 15 wt% brine
(162.0 kg). The aqueous layer was extracted with toluene (175.8 kg) and the combined organic layers washed
sequentially with 10 wt% citric acid (aq) solution (80.0 kg) and NaHCO3 (sat.) (81.0 kg). The organic stream was
concentrated to ~120 L of a crude suspension, then diluted with hexanes (162.6 kg) and heated to form a clear
solution. The solution was cooled to 20 °C over 2 h and the resulting slurry continued to be cooled to ꢀ5 °C over 1.5
h. After stirring for an additional 1 h at ꢀ5 °C, the solid was filtered and dried under vacuum to give 5 as a yellow
solid (14.3 kg, with 99.2% purity from HPLC).
ꢀ
AUTHOR INFORMATION
*Eꢀmail: hang.zhao@mpi.com. Telephone: 617ꢀ444ꢀ1579.
Current address: Millennium Pharmaceutical, Inc., 40 Landsdowne St., Cambridge, MA 02139
ꢀ
SUPPORTING INFORMATION AVAILABLE
1H and 13C NMR spectra of 14, 16 and 17. This information is available free of charge via the Internet at
ꢀ
REFERENCES
(1) (a) Heffernan, M. L. R.; Fang, Q. K.; Foglesong, R. J.; Hopkins, S.C.; Ogbu, C. O.; Soukri, M.; Spear, K. L.;
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Prasad, G. S.; Sachs, N.; Sakatis, M.; Sardana, V.; Venkatraman, S.; Young, M. B. Bioorg. Med. Chem. Lett. 2008,
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