2714
DHARESHWAR AND STELLA
((M þ H)þ, 100). HRMS (M þ H)þ, C20H22N2Na2
O6P: anal. calculated, 463.1011; found, 463.1003,
0.008 amu.
((M þ H)þ, 75). HRMS (M þ H)þ, C22H27N2SO3: anal.
calculated, 399.1742; found, 399.1745, 0.003 amu.
2-((Methylthiomethoxy)Methyl)-2-Phenylin-
Disodium(1,3-Dioxo-2-Phenylinden-2yl)-
Methyl Phosphate (2b). To a stirred solution of 5b
(2.0 g, 7.92 mmol) in anhydrous methylene chloride
(75 mL) maintained under argon atmosphere in ice-
bath was added dropwise pyridine (0.7 mL, 8.7 mmol,
1.1 equiv.). Solution was stirred at reduced tempera-
ture for 0.5 h, followed by dropwise addition of
dene-1,3-Dione (7b). Seventy-seven percent yield,
1
distinct odor. H NMR (acetone-d6, 400 MHz): d 1.61
(s, 3H), 4.30 (d, J ¼ 7.76 Hz, 2H), 4.52 (s, 2H), 7.39–
7.26 (m, 3H), 7.40–7.51 (m, 2H), 7.85–7.94 (m, 2H),
8.03–8.11 (m, 2H). MS (FABþ in TG/G): m/z (relative
intensity) 312.3 (Mþ, 50).
phosphorus oxychloride
(3.6 mL,
23.76 mmol,
3 equiv.). Stir solution at room temperature till
complete loss of starting compound is confirmed
using a TLC plate (n-hexanes/ethyl acetate 70/30, v/v,
for 5b, Rf ¼ 0.14). The workup for 2b is similar to
that described above for 2a. The disodium salt 2b
General Procedure for the Dibenzyl Protected
Phosphate Esters (8a,b)
To a stirred solution of 7a or 7b (15 mmol) in
anhydrous THF (50 mL) was added N-iodosuccini-
mide (2.0 equiv., 30 mmol) and dibenzyl phosphate
(3.0 equiv., 45 mmol). After 12 h, the mixture was
filtered and concentrated in vacuo. To this residue
was added dichloromethane (50 mL) and aqueous
solution of sodium thiosulfate (50 mL) and allowed to
stir at room temperature for 30 min. The organic layer
was separated, washed with brine, filtered, dried over
sodium sulfate, and then concentrated in vacuo. The
viscous reddish residue was chromatographed on
normal phase silica gel (approximately 100 g) with n-
hexanes/ethyl acetate (60/40) for eluent. Fractions
containing 8a (Rf ¼ 0.3) or 8b (Rf ¼ 0.35) were
combined and concentrated in vacuo to afford the
desired products as oil.
is obtained as
a white powder; 75.4% yield.
1H NMR (D2O, 400 MHz): d 4.45 (d, J ¼ 3.06 Hz, 2H,
–CCH2OP–), 7.13–7.22 (m, 2H), 7.27 (m, 3H), 7.93
(dd, J ¼ 5.68, 2.92 Hz, 2H), 8.01 (dd, J ¼ 5.55, 3.05 Hz,
2H). 31P NMR (D2O, 400 MHz): d 3.1 (s, 1P). MS (ESþ):
m/z (relative intensity) 377 ((M þ H)þ, 50). HRMS
(M þ H)þ, C16H11Na2O6P: anal. calculated, 377.0167;
found, 377.0170, 0.0003 amu.
General Procedure for the Methylthiomethoxymethyl
Adduct of Carbon Acids (7a,b)
To a stirred suspension of 5a,b (20 mmol) in acetic
anhydride (10 mL) and acetic acid (2 mL), maintained
under argon atmosphere, was added anhydrous
DMSO (20 mL). The reaction mixture was stirred at
room temperature for 24 h. To this solution is added
an aqueous solution of NaHCO3 dropwise, and
contents let to stir for further 0.5 h. An organic-
aqueous extraction was performed using dichloro-
methane (50 mL). The organic phase was washed
with brine, filtered, dried over sodium sulfate, and
concentrated in vacuo. The yellowish oily residue was
chromatographed on normal phase silica gel (approx.
100 g) with n-hexanes/ethyl acetate (80/20) for eluent.
Fractions containing 7a (Rf ¼ 0.58) or 7b (Rf ¼ 0.36)
were combined and concentrated in vacuo, followed
by recrystallization from n-hexanes to yield the
product as a yellowish powder.
Dibenzyl((4-Butyl-3,5-Dioxo-1,2-Diphenylpyr-
azolidin-4-yl)Methoxy)Methyl Phosphate (8a).
61.1% yield, reddish viscous oil. 1H NMR (acetone-d6,
400 MHz): d 0.87–0.99 (m, 3H), 1.39 (dd, 4H, J ¼ 7.13,
3.44 Hz), 1.83 (dd, J ¼ 9.5, 5.85 Hz, 2H), 4.09–4.16 (m,
2H), 5.12 (d, J ¼ 7.99 Hz, 4H), 7.19–7.33 (m, 2H),
7.35–7.55 (m, 18H). 13C NMR (acetone-d6, 500 MHz):
d 12.898, 22.284, 26.115, 28.398, 68.693, 68.736,
72.433, 92.320, 123.272, 126.729, 127.835, 128.189,
128.359, 128.725, 136.289, 171.626. 31P NMR (acet-
one-d6, 162 MHz): À20.04 (s, 1P). MS (FABþ in NBA):
m/z (relative intensity) 628.7 (Mþ, 60).
4-Butyl-4-((Methylthiomethoxy)Methyl)-1,2-
Dibenzyl((1,3-Dioxo-2-Phenylinden-2-yl)-
Diphenylpyrazolodine-3,5-Dione (7a). 83.7%
yield, distinct odor. H NMR (acetone-d6, 400 MHz):
Methoxy)Methyl Phosphate (8b). 59.7% yield,
reddish viscous oil. H NMR (acetone-d6, 400 MHz):
1
1
d 0.86 (d, 3H, J ¼ 5.39 Hz), 1.33 (d, 5H, J ¼ 2.94 Hz),
1.71–1.84 (m, 2H), 1.92 (d, 2H, J ¼ 5.68 Hz), 3.89 (d,
2H, J ¼ 5.49 Hz), 4.62 (d, 2H, J ¼ 5.60 Hz), 7.22 (t, 2H,
J ¼ 6.57 Hz), 7.32–7.48 (m, 8H). 13C NMR (acetone-d6,
500 MHz): d 12.572, 13.007, 22.403, 26.332, 28.383,
70.253, 74.811, 123.122, 126.76, 128.768, 136.675,
172.258. MS (CI): m/z (relative intensity) 399
d 4.48 (s, 2H), 5.09 (dd, J ¼ 9.98 Hz, 6H), 7.31–7.46 (m,
16H), 8.02–8.12 (m, 4H). 13C NMR (acetone-d6,
500 MHz): d 61.85, 68.689, 72.06, 92.391, 123.366,
126.802, 127.803, 128.193, 128.362, 128.947, 133.434,
135.994, 136.303, 136.359, 136.437, 142.16, 198.61.
31P NMR (acetone-d6, 162 MHz): À17.1 (s, 1P). MS
(CI): m/z (relative intensity) 543 ((M þ H)þ, 25).
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 6, JUNE 2010
DOI 10.1002/jps