14.0, 12.8, 12.6; Anal. Calcd for [C48H60O10]: 796.4186,
FAB MS m/z 796.4184 [C48H60O10]+; HPLC 89.6% AUC,
tR ) 7.80 min.
concentrated again to azeotrope any residual water from the
washes. The material was dried under high vacuum to afford
8.49 g of a red solid (106% of theoretical). 1H NMR (CDCl3)
δ 6.68-6.19 (14 H, m), 5.54 (2 H, dd, J ) 13.4, 6.1), 2.82-
2.68 (8 H, m), 2.07-1.99 (16 H, m), 1.89 (6 H, s), 1.35 (6
H, s), 1.24 (6 H, s); 13C NMR (CDCl3) δ 193.9, 177.2, 171.6,
160.8, 142.3, 139.7, 136.7, 135.1, 134.5, 133.8, 130.7, 128.3,
124.6, 123.1, 71.5, 67.6, 42.5, 37.1, 30.4, 28.9, 28.4, 26.3,
21.8, 21.4, 14.0, 12.8, 12.6; Anal. Calcd for [C48H60O10]:
796.4186, FAB MS m/z 796.4180 [C48H60O10]+; HPLC
92.2% AUC, tR ) 7.80 min.
(3S,3′S)-(Sodium succinate mono-(4-{18-[4-(3-carboxy-
propionyloxy)-2,6,6-trimethyl-3-oxo-cyclohex-1-enyl]-
3,7,12,16-tetramethyl-octadeca-1,3,5,7,9,11,13,15,17-nona-
enyl}-3,5,5-trimethyl-2-oxo-cyclohex-3-enyl) ester). A 1 L
three-neck round-bottom flask wrapped with aluminum foil
was equipped with an overhead stirrer and a digital thermo-
couple under nitrogen at room temperature. Disuccinic acid
ester of 3S,3′S-astaxanthin (11.6 g, 14.6 mmol) was charged
to the flask followed by anhydrous 2-propanol (384 mL) and
triethylorthoformate (7.3 mL, 43.8 mmol) and the reaction
was stirred for 30 min. A pre-made solution of sodium
isopropoxide using sodium (1.00 g, 43.8 mmol) in anhydrous
2-propanol (87 mL) was added over 30 min. After 3 h, the
reaction mixture was filtered, then rinsed with 25 mL of
anhydrous 2-propanol, and dried under high vacuum over-
night (78.4% AUC by HPLC). The solid was reslurried in
110 mL of methylene chloride for 1 h, the mixture was
filtered, rinsed with 50 mL of methylene chloride, and then
dried under high vacuum (86.4% AUC by HPLC). The solid
was reslurried a second time in 60 mL of methylene chloride,
the mixture filtered, rinsed with 30 mL of methylene chloride,
and dried under high vacuum (93.4% AUC by HPLC). The
solid was reslurried a third time in 60 mL of methylene
chloride, the mixture was filtered, rinsed with 30 mL of
methylene chloride, and again dried under high vacuum to
afford 4.8 g of a red solid (95.8% AUC by HPLC). A final
reslurry was performed with anhydrous 2-propanol (50 mL)
for 15 min, the mixture was filtered, washed with 2-propanol
(25 mL), and then dried to afford 4.60 g of an amorphous
red solid (37% yield). 1H NMR (Methanol-d4) δ 6.75-6.29
(14 H, m), 5.53 (2 H, dd, J ) 13.2, 6.2), 2.70-2.44 (8 H,
m), 2.08-1.92 (16 H, m), 1.89 (6 H, s), 1.37 (6 H, s), 1.24
(6 H, s); 13C NMR (CDCl3) δ 196.3, 180.7, 180.2, 174.5,
163.3, 143.8, 140.9, 137.9, 136.5, 135.7, 135.1, 131.9, 129.0,
125.8, 124.3, 72.3, 64.7, 43.7, 38.2, 34.3, 33.4, 31.8, 30.8,
26.5, 25.3, 14.2, 12.8, 12.5; DSC one exothermic event at
135.6 °C; Anal. Calcd for [C48H60O10 + Na]: 819.4084, ESI
MS m/z 819.4072 [C48H60O10 + Na]+; HPLC 95.6% AUC,
tR ) 7.80 min.
meso-(Succinic acid mono-(4-{18-[4-(3-carboxy-pro-
pionyloxy)-2,6,6-trimethyl-3-oxo-cyclohex-1-enyl]-3,7,12,16-
tetramethyl-octadeca-1,3,5,7,9,11,13,15,17-nonaenyl}-3,5,5-
trimethyl-2-oxo-cyclohex-3-enyl) ester). A 250 mL three-
neck round-bottom flask wrapped with aluminum foil
was equipped with an overhead stirrer and a digital thermo-
couple under nitrogen at room temperature. meso-(3R,3′S)-
Astaxanthin 6.00 g, 10.1 mmol) was charged to the flask
followed by methylene chloride (60 mL), succinic anhydride
(3.02 g, 30.2 mmol), and DMAP (3.07 g, 25.1 mol). After
14 h, the reaction was complete by HPLC. A citric acid
solution (5% aq, 60 mL) was added to the reaction and stirred
for 30 min. The layers were separated and the organic layer
was extracted two more times with the citric acid solution
(5% aq, 60 mL) and concentrated. The residue was taken
up in IPAC (30 mL) and the resulting solution was
meso-(Sodium succinate mono-(4-{18-[4-(3-carboxy-
propionyloxy)-2,6,6-trimethyl-3-oxo-cyclohex-1-enyl]-
3,7,12,16-tetramethyl-octadeca-1,3,5,7,9,11,13,15,17-nona-
enyl}-3,5,5-trimethyl-2-oxo-cyclohex-3-enyl) ester). A 1 L
three-neck round-bottom flask wrapped with aluminum foil
was equipped with an overhead stirrer and a digital thermo-
couple under nitrogen at room temperature. Disuccinic acid
ester of meso-astaxanthin (8.39 g, 9.74 mmol) was charged
to the flask followed by anhydrous 2-propanol (277 mL) and
triethylorthoformate (3.4 mL, 31.6 mmol) and the reaction
was stirred for 30 min. A pre-made solution of sodium
isopropoxide (0.5 M, 63.2 mL, 31.6 mmol) was added over
30 min under nitrogen. After 3 h, the reaction mixture was
filtered, rinsed with 30 mL of methylene chloride, and dried
under high vacuum overnight to afford 4.11 g of a red solid
(83.7% AUC by HPLC). The solid was reslurried in 40 mL
of methylene chloride for 2 h, the mixture was filtered, rinsed
with 20 mL of methylene chloride, and then dried under high
vacuum (96.0% AUC by HPLC). The solid was reslurried a
second time in 40 mL of methylene chloride for 2 h, the
mixture was filtered, rinsed with 20 mL of methylene
chloride, and then dried under high vacuum (98.4% AUC
by HPLC). A final reslurry was performed with anhydrous
2-propanol (40 mL) for 30 min, the mixture was filtered,
rinsed with 2-propanol (20 mL), and again dried under high
vacuum to afford 3.95 g of an amorphous red solid (45%
yield). 1H NMR (Methanol-d4) δ 6.76-6.30 (14 H, m), 5.53
(2 H, dd, J ) 13.2, 6.2), 2.70-2.48 (8 H, m), 2.10-1.99
(16 H, m), 1.90 (6 H, s), 1.37 (6 H, s), 1.24 (6 H, s); 13C
NMR (CDCl3) δ 196.3, 181.1, 180.3, 180.2, 174.9, 174.6,
163.3, 143.8, 141.0, 137.9, 136.5, 135.7, 135.0, 131.9, 129.0,
125.8, 124.3, 72.3, 68.9, 433.7, 38.2, 34.6, 33.4, 33.4, 32.3,
31.8, 30.8, 28.5, 26.5, 25.3, 22.0, 14.3, 12.8, 12.5; DSC one
exothermic event at 135.4 °C; Anal. Calcd for [C48H60O10
+ Na]: 819.4084, ESI MS m/z 819.4045 [C48H60O10 + Na]+;
HPLC 99.0% AUC, tR ) 7.80 min.
(3R,3′R)-(Succinic acid mono-(4-{18-[4-(3-carboxy-
propionyloxy)-2,6,6-trimethyl-3-oxo-cyclohex-1-enyl]-
3,7,12,16-tetramethyl-octadeca-1,3,5,7,9,11,13,15,17-nona-
enyl}-3,5,5-trimethyl-2-oxo-cyclohex-3-enyl) ester). A 250
mL three-neck round-bottom flask wrapped with aluminum
foil was equipped with an overhead stirrer and a digital
thermocouple under nitrogen at room temperature. 3R,3′R-
astaxanthin (6.00 g, 10.1 mmol) was charged to the flask
followed by methylene chloride (60 mL), succinic anhydride
(3.02 g, 30.2 mmol), and DMAP (3.07 g, 25.1 mol). After
16 h, the reaction was complete by HPLC. A citric acid
800
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Vol. 8, No. 5, 2004 / Organic Process Research & Development