for both 4 and 5·H2O were 47% and 46%, respectively. Both
processes required no chromatography, and the desired com-
pounds 4 and 5·H2O were isolated in high purity (>99%).
was acidified with a 2 N HCl (500 mL) solution to a pH of 1
(pH meter). The white precipitate that formed was filtered and
washed with distilled water (100 mL). The filter cake was dried
under vacuum to afford 49 g of 4 as a white solid (93%, yield).
Mp 184-186 °C. 1H NMR: δ 3.72 (d, J ) 5.1, 2H), 6.65 (d,
J ) 8.8, 2H), 7.20 (d, J ) 8.8, 2H), 7.39 (s, 1H), 7.65-7.77
(m, 3H), 7.93 (m, 1H), 9.21 (s, 1H), 9.71 (s, 1H), 13.81 (b,
1H). 13C NMR: δ 46.5, 115.8, 121.7, 129.3, 130.4, 130.7, 131.7,
133.2, 133.4, 138.2, 154.2, 166.0, 169.5. Anal. Calcd for
C15H14N2O6S: C, 51.42; H, 4.03; N, 8.00. Found: C, 51.42; H,
4.15; N, 7.86.
SCP-123ss·H2O (5·H2O). The acid 4 (71.5 g, 0.24 mol)
was suspended in ethanol (400 mL) and cooled to 0 °C. A
precooled (0 °C) solution of NaOH (8.2 g, 0.24 mol) in distilled
water (40 mL) was added dropwise to the ethanolic suspension
over 10 min. After the addition of the basic solution was
complete, more ethanol was added to the mixture, if needed,
to dissolve all the solids. The clear reaction mixture was stirred
for an additional 2 h. The reaction volume was reduced by 10%
(∼50 mL) on a rotoevaporator without a water bath. Once a
precipitate started to form, the mixture was removed from the
rotoevaporator and cooled at 0 °C for 1 h. The white precipitate
was filtered and washed with distilled water (100 mL). The
filter cake was dried under vacuum at 60 °C to afford 93 g of
5·H2O as white solid (99% yield). Mp 188-190 °C. 1H NMR:
δ 3.57 (s, 2H), 6.65 (d, J ) 8.8, 2H), 7.24 (d, J ) 8.8, 2H),
7.39 (t, J ) 7.0, 1H), 7.51 (t, J ) 7.5, 1H), 7.63 (d, J ) 6.6,
1H), 7.74 (d, J ) 7.7, 1H), 9.00 (s, 1H), 9.58 (s, 1H), 10.03 (s,
1H). 13C NMR: δ 47.1, 115.7, 121.7, 128.0, 128.1, 130.7, 130.8,
132.9, 136.3, 142.5, 154.3, 166.4, 171.3. Anal. Calcd for
C15H13N2NaO6S·H2O: C, 46.15; H, 3.87; N, 7.18. Found: C,
46.01; H, 3.89; N, 7.14.
Experimental Section
General Methods. NMR spectra were recorded on a Varian-
400 MHz nuclear magnetic resonance spectrometer at ambient
temperature in DMSO-d6. HPLC was used to monitor the purity
of all intermediates using standard HPLC equipment with UV
detection (254 nm) and data system. Separations were per-
formed with a Waters Nova-Pak C18 (3.9 mm × 150 mm)
steel analytical column. The mobile phases for isocratic and
gradient separations were prepared using 0.01% TFA in water
and 0.01% TFA in CH3CN.
N-(4-Hydroxyphenyl)-2-chloroacetamide (8). 4-Aminophe-
nol (6, 150 g, 1.37 mol) was added to a saturated solution of
sodium acetate (500 mL) followed by acetic acid (500 mL).
The suspension was cooled to 0 °C, and the 2-chloroacetyl
chloride (7, 155 g, 109 mL, 1.37 mol) was added portionwise
to the suspension at e5 °C. As the addition of 7 progressed,
the suspension dissipated, and the mixture clarified. Prior to
completion of the addition of 7, a white precipitate began to
form. Upon completion of the addition, the heterogeneous
mixture was brought to 25 °C and stirred at room temperature
for 2 h. The white precipitate was filtered, washed with distilled
water solution (2 × 100 mL) and dried under vacuum to afford
177 g of 8 as a white solid (70% yield). Mp 142-144 °C. 1H
NMR: δ 4.17 (s, 2H), 6.70 (d, J ) 8.8, 2H), 7.35 (d, J ) 8.8,
2H), 9.26 (s, 1H), 10.02 (s, 1H). 13C NMR: δ 44.2, 115.9, 121.9,
130.7, 154.5, 164.6. Anal. Calcd for C8H8ClNO2: C, 51.77; H,
4.34; N, 7.55. Found: C, 51.87; H, 4.31; N, 7.49.
SCP-1 (3). 2-Chloroacetamide (8, 326 g, 1.75 mol) and
saccharin sodium salt hydrate 9 (433 g, 2.10 mol) were mixed
together in the presence of NaI (1.0 g, 0.0067 mol, 0.4 mol %)
in DMF (1 L). The mixture was heated to reflux for 2 h, cooled
to 25 °C, and poured into ice water (500 mL). A white
precipitate formed, and more ice (∼100 g) was added until no
additional precipitate formed. The sticky white precipitate was
collected by vacuum filtration and allowed to dry in air for 30
min. The filter cake was dissolved in 50% ethanol-water (2
L) and recrystallized to furnish 419 g of 3 as white crystals
(72% yield). Mp 204-207 °C. 1H NMR: δ 4.54 (s, 2H), 6.73
(d, J ) 8.8, 2H), 7.36 (d, J ) 8.8, 2H), 8.00 (dt, J ) 6.8, 14.3,
2H), 8.11 (d, J ) 7.5, 1H), 8.30 (d, J ) 7.6, 1H), 9.26 (s, 1H),
10.07 (s, 1H). 13C NMR: δ 41.2, 115.9, 121.8, 122.3, 125.8,
127.2, 130.8, 135.9, 136.5, 137.6, 154.4, 159.4, 163.3. Anal.
Calcd for C15H12N2O5S: C, 54.21; H, 3.64; N, 8.43. Found: C,
54.15; H, 3.58; N, 8.41.
Acknowledgment
We are grateful to the National Institute on Neurological
Disorders and Stroke for the support of this research. The project
described was supported by Grant Number U44NS046891 from
the National Institute of Neurological Disorders And Stroke.
The content is solely the responsibility of the authors and does
not necessarily represent the official views of the National
Institute of Neurological Disorders And Stroke or the National
Institutes of Health.
Supporting Information Available
Proton NMR of compounds 4, 5, and 12, HPLC conditions
and retention times for compounds 3, 4, and 12, and LC-ESI
MS spectrum of 12. This material is available free of charge
SCP-123 (4). A suspension of 3 (50 g, 0.15 mol) and
aqueous 0.5 N NaOH (600 mL, 0.30 mol) was stirred at 25 °C
for 1 h. Ethanol (400 mL) was added until the solution became
clear. Stirring was continued for an additional 1 h. The solution
Received for review May 4, 2009.
OP900113B
822
•
Vol. 13, No. 4, 2009 / Organic Process Research & Development