g, 250 mmol) and KOH (85%, 8.25 g, 125 mmol) in H2O
(250 mL) was stirred and heated at reflux, (S)-1 (20.4 g,
125 mmol) was added dropwise over 20 min. After the
heating was continued at a refluxing temperature for 20 min,
the mixture was allowed to cool to ambient temperature. The
precipitated solids were collected by filtration at ambient
temperature, washed with ice-chilled water, and dried in
vacuo to give crude 9 [43.4 g; 94.0% yield based on (S)-1,
47.0% yield based on the whole amount of (()-2], which
precipitate. After the mixture was warmed to 50 °C, it was
allowed to cool to 40 °C, and warmed again up to 45 °C.
After the mixture was allowed to cool to 10 °C over 1 h,
the stirring was continued at 5-10 °C for 1 h. The
precipitated solids were collected by filtration, washed with
ice-chilled MTBE (1.0 L × 3), and dried in vacuo to give
14 [741 g, 37.7% based on the whole amount of (()-3],
which contained (S)-3 of 99.1% ee as determined by HPLC
[Opti Pak TA (Waters) 3.9 mmφ × 300 mm; n-hexane:IPA:
TFA (92:8:0.3), 1.0 mL/min, ambient temperature; 255 nm;
after 5% HCl aqueous solution (5.0 mL) was added to 14
(50 mg), the mixture was extracted with n-hexane (5.0 mL),
and 10 µL of the n-hexane solution was injected; tR 20.3
min for (S)-3, 14.7 min for (R)-3]; 14: mp 131.0-132.0 °C;
[R]25D +10.2 (c 1.0, EtOH); IR ν (KBr) 2978 (m), 2962 (m),
2929 (m), 1647 (s), 1636 (s), 1552 (s), 1533 (s), 1387 (s),
1319 (m), 1281 (m), 1246 (m), 710 (s) cm-1. Anal. calcd
for C27H31NO3: C, 77.67; H, 7.48; N, 3.35; found: C, 77.5;
H, 7.4; N, 3.3.
contained (S)-2 of 85% ee {[R]25 +50.1 (c 1.0, MeOH)}
D
as determined by HPLC [Chiralcel OJ (Daicel) 4.6 mmφ ×
250 mm; n-hexane:IPA:trifluoroacetic acid (TFA) (100:0.8:
0.1), 1.3 mL/min, 25 °C; 254 nm; after 5% HCl aqueous
solution (5.0 mL) was added to the crude salt 9 (50 mg), the
mixture was extracted with n-hexane (5.0 mL), and 10 µL
of the n-hexane solution was injected; tR 18.5 min for (S)-2,
26.6 min for (R)-2]. The solids thus obtained (40 g) were
recrystallized from MeOH (250 mL) and H2O (40 mL) to
give purified 9 [34.7 g, 86.8% yield; 40.8% overall yield
based on the whole amount of (()-2], and the optical purity
of (S)-2 contained in it was 98.7% ee {[R]25D +59.1 (c 1.0,
MeOH)} as determined by the HPLC method described
2.2. (S)-Ketoprofen 3. The diastereomeric salt 14 thus
obtained (720 g, 1.72 mol) was poured into a stirred 4%
(w/v) HCl aqueous solution (2.28 kg), and the mixture was
made homogeneous by warming up to 50 °C. The stirred
mixture was allowed to cool to 15 °C, during which solids
started to precipitate. After H2O (0.79 L) was added at the
same temperature, the mixture was allowed to cool to 10
°C, and the stirring was continued at 5-10 °C for 2 h. The
precipitated solids were collected by filtration, washed with
H2O (1.0 L × 3), and dried in vacuo to give (S)-3 as a white
powder (431 g, 98.3%), the optical purity of which was
determined to be 99.4% ee by the HPLC method described
above in which 5 µL of a solution of (S)-3 (10 mg) in IPA
(20 mL) was injected: mp 76.8-77.4 °C [lit.:8a mp 73.2-
above; purified 9: mp 170-171 °C; [R]25 -10.1 (c 1.06,
D
EtOH); IR ν (KBr) 2964 (s), 2875 (m), 2665 (w), 2200 (w),
1637 (s),1549 (s), 1454 (s), 1384 (m), 1288 (s), 1217 (m),
1176 (m), 1062 (m), 881 (m), 845 (m), 791 (m), 706 (m),
580 (w) cm-1. Anal. calcd for C24H35NO2: C, 78.00; H, 9.55;
N, 3.79; found: C, 77.9; H, 9.4; N, 3.7.
1.2. (S)-Ibuprofen 2. To the purified 9 (17.5 g, 41.8
mmol) was added 1.0 M NaOH aqueous solution (52 mL).
After the mixture was extracted with diisopropyl ether (IPE;
30 mL × 2) to recover (S)-1, the aqueous layer was acidified
with 3.0 M HCl aqueous solution (30 mL) and extracted with
IPE (30 mL × 3). The combined IPE extracts were dried
(MgSO4) and concentrated in vacuo to give (S)-2 as a
colorless oil (8.41 g, 97.6%), which solidified spontaneously
on standing at ambient temperature; its optical purity was
determined to be 98.7% ee by the HPLC method described
above in which 10 µL of a solution of (S)-2 (10 mg) in
n-hexane (2.0 mL) was injected: mp 52-53 °C [lit.:7a mp
40-48 °C for 99% pure (S)-2]; [R]25D +59.0 (c 1.0, MeOH)
{lit.:7a [R]D +56 for (S)-2 of 99% purity}. IR ν (KBr) 2976
(m), 2638 (w), 1706 (s), 1510(s), 1467 (s), 1417 (s), 1381
(m), 1283 (s), 1228 (m), 1184 (m), 1053 (m), 945 (m), 866
(m), 779 (m), 655 (m), 590 (m), 428 (m) cm-1; 1H NMR δ
(CDCl3) 7.21 (d, J ) 8.0 Hz, 2H), 7.09 (d, J ) 8.0 Hz, 2H),
3.70 (q, J ) 7.2 Hz, 1H), 2.44(d, J ) 6.8 Hz, 2H), 1.95-
1.75 (m, 1H), 1.49 (d, J ) 7.2 Hz, 3H), 0.89(d, J ) 7.2 Hz,
6H); MS m/z 205 {[M - H]-}.
2. Optical Resolution of (()-Ketoprofen 3 by (S)-PBA
1. 2.1. (S)-3-Methyl-2-phenylbutylammonium (S)-2-(3-
Benzoylphenyl)propionate 14. To a stirred solution of (()-3
(1.20 kg, 4.72 mol) in MTBE (4.80 L) was added H2O (600
g), and the mixture was warmed to 50-55 °C, during which
it became homogeneous with increasing temperature. To this
solution was added (S)-1 (388 g, 2.38 mol) dropwise at the
same range of temperature over 30 min. The mixture was
allowed to cool to 35 °C, during which solids started to
74.7 °C for (S)-3 of 97% ee]; [R]25 +46.3 (c 1.0, MeOH)
D
{lit.:8a [R]D +54.3 for (S)-3 of 97% ee}; IR ν (KBr) 3211
(m), 2982 (m), 2941 (m), 2879 (m), 1728 (v s), 1687 (m),
1655 (s), 1284 (m), 1173 (m), 1157 (m), 829 (m), 716 (m),
1
700 (m) cm-1; H NMR δ (CDCl3) 1.56 (3H, d, J ) 7.2
Hz), 3.83 (1H, q, J ) 7.2 Hz), 7.45 (1H, t, J ) 8.0 Hz),
7.47 (2H, t, J ) 8.0 Hz), 7.56 (1H, t, J ) 8.0 Hz), 7.59 (1H,
t, J ) 8.0 Hz), 7.69 (1H, t, J ) 8.0 Hz), 7.78 (1H, s), 7.79
(2H, d, J ) 8.0 Hz), 9.00-12.00 (1H, br s); MS m/z 253
{[M - H]-}.
3. Optical Resolution of (()-Naproxen 4 by (S)-PBA
1. 3.1. (S)-3-Methyl-2-phenylbutylammonium (S)-2-(6-
Methoxy-2-naphthyl)propionate 15. A mixture of (()-
naproxen 4 (10.0 g, 43.4 mmol) and IPA (120 mL) was
stirred and warmed until it became homogeneous, and the
resulting solution was further heated to 70 °C. After (S)-1
(3.63 g, 22.2 mmol) was added dropwise, the mixture was
allowed to cool to 30 °C over 1 h. The precipitated solids
were collected by filtration, washed with IPA (15 mL), and
dried to give crude 15 [7.35 g, 43.0% yield based on the
whole amount of (()-4], which contained (S)-4 of 86.5%
ee as determined by HPLC [Optipak-TA (Waters), 3.9 mmφ
× 300 mm; n-hexane:IPA:TFA (75:25:0.3), 0.8 mL/min,
ambient temperature; 254 nm; 1.0 M HCl aqueous solution
(1.0 mL) was added to the crude 15 (20 mg), and the mixture
294
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Vol. 6, No. 3, 2002 / Organic Process Research & Development