pressure, at a jacket temperature of 45 °C. The thick slurry
was again diluted with H2O (210 mL) and cooled to 10-13
°C. HCl (10 M, 215 mL, 2.15 mol) was charged to the thick
gel, over 50 min at 12-14 °C, initially causing foaming.
The slurry was stirred for 2 h prior to filtration. The filter
cake was washed with H2O (4 × 340 mL), dried in vacuo at
55 °C to give 65.9 g of the title compound (80% yield,
corrected for 96.8% purity by LC) as small, brownish
granules.
An analytical sample of the solution was evaporated to
dryness and crystallised from toluene (2 volumes) giving the
pure acid 5 (99.5%, LC). Light-yellow crystals: mp 113-
115 °C; 1H NMR (CDCl3) δ 7.79 (d, J ) 8.9 Hz, 2 H), 7.14
(s, 1 H), 6.92 (d, J ) 8.9 Hz, 2 H), 4.02 (q, J ) 7.1 Hz, 2
H), 3.85 (s, 3 H), 1.39 (t, J ) 7.1 Hz, 3 H); 13C NMR
(CDCl3) δ 169.8, 160.5, 141.8, 132.1, 126.6, 126.0, 114.0,
67.7, 55.3, 15.5; MS (ESI- 30 V) m/z 221 (M - 1)-. Anal.
Calcd for C12H14O4: C, 64.8; H, 6.4. Found: C, 64.5; H,
6.2.
with 7a at 80 °C resulted in crystallisation within 5 min.
The slurry was stirred at -1 °C for 2 h before filtration on
glass filter (P3). The filter cake was rinsed with chilled
iPrOAc (60 mL). Drying under vacuum (40 °C) afforded 35.2
g of 7a (38% yield from 5, 76% of the S-enatiomer 7b by
chiral HPLC) as white needles: mp 144-145 °C; 1H NMR
(CDCl3) δ 8.01 (d, J ) 8.4 Hz, 1 H), 7.87 (d, J ) 8.8 Hz,
1 H), 7.81-7.77 (m, 2 H), 7.58-7.45 (m, 3 H), 6.89 (d, J )
8.6 Hz, 2 H), 6.64 (d, J ) 8.6 Hz, 2 H), 5.80 (br, 3 H), 5.16
(q, J ) 6.6 Hz, 1 H), 3.68 (s, 3 H), 3.65 (dd, J ) 3.6 and
8.9 Hz, 1 H), 3.40 and 3.38 (2 q, J ) 7.0 Hz, 1 H), 3.05 and
3.03 (2 q, J ) 7.0, 1 H), 2.77 (dd, J ) 3.6 and 14.1 Hz, 1
H), 2.57 (dd, J ) 8.9 and 14.1 Hz, 1 H), 1.69 (d, J ) 6.7
Hz, 3 H), 0.97 (t, J ) 7.0 Hz, 3 H); 13C NMR (CDCl3) δ
178.9, 157.8, 137.2, 133.8, 130.9, 130.2, 130.1, 129.1, 128.5,
126.7, 125.9, 125.7, 122.5, 122.2, 113.2, 82.1, 65.6, 55.1,
46.6, 38.5, 22.4, 15.1; Anal. Calcd for C24H29NO4: C, 72.9;
H, 7.4; N, 3.5. Found: C, 72.3; H, 7.4; N, 3.6. Chiral HPLC
showed 97% ee of the S-enantiomer 7b.
2-Ethoxy-3-(4-methoxyphenyl)propanoic Acid (6). Iso-
propyl acetate (540 mL, 10 vol) and 5 (54.2 g, 244 mmol)
were mixed in a 1-L flask and stirred until a clear solution
was obtained (some heating was required). A 1-L Buchi steel
autoclave was flushed with N2 and Pd/C (13.6 g, 5% w/w
to C, containing 60% H2O, Johnson-Matthey Type 87 L)
was added followed by the solution of 5. The acid was
hydrogenated at 22-25 °C, 4 bar and 1000 rpm for 3 h.
Analysis by HPLC showed complete conversion of 5 to 6.
The catalyst was filtered off (Supra 1000) and the solution
was concentrated under vacuum. To ensure taking dry
material into the next step additional iPrOAc (300 mL) was
added, and the solution was azeo-dried, adjusting the total
(2S)-Ethoxy-3-(4-hydroxyphenyl)propanoic Acid (8).
The salt 7a (35.0 g, 88 mmol) was suspended in toluene (98
mL), and the mixture was then treated with NaOH (3.89 g,
97 mmol) in H2O (98 mL). The upper layer containing the
chiral amine was separated off. The aqueous layer was
washed with toluene (2 × 98 mL) and was acidified to pH
1 with HCl (10.5 mL, 32%, 106 mmol). The acid 7b was
extracted with EtOAc (2 × 98 mL). The combined EtOAc
layer was washed with H2O (98 mL). The solvent was
evaporated, and NMP (35 mL) was added to the residue.
Remaining EtOAc was coevaporated with NMP (35 mL) at
90 °C. After distilling off ∼22 mL of the solvent, additional
NMP (200 mL) was added to the crude acid. NaOH (16 g,
400 mmol) and 1-octanethiol (54 mL, 310 mmol) were
charged, and the reaction mixture was heated to 125 °C for
19 h with vigorous stirring. Analysis by HPLC showed 95%
conversion of 7b to 8. The reaction mixture was cooled to
50 °C and H2O (130 mL) was added to the slurry. By the
addition of HCl (51 mL, 32%, 515 mmol) pH was adjusted
to ∼2 and the temperature rose to 60 °C. Two layers were
formed, the upper layer containing mainly 1-octanethiol and
the corresponding methyl ether. The layers were separated,
and the aqueous NMP layer was concentrated to 3-4
volumes under vacuum at 90 °C. The residue was partitioned
between H2O (140 mL) and EtOAc (105 mL). The aqueous
layer was extracted with EtOAc (105 mL), and the combined
organic layer was washed with a NaCl solution (3 × 90 mL,
15%, containing 44 mM HCl). Lacking an assay for 8 the
EtOAc solution was concentrated under vacuum at 90 °C to
give 19.0 g of brownish oil. HPLC analysis showed 95% of
8, 4% of the starting material 7b, and 1% of NMP while 1H
NMR showed 88% w/w of 8 and 9% w/w of NMP. On a
large scale the EtOAc solution was used in the following
step without eVaporating to dryness.
i
volume to 590 mL (10 vol PrOAc to 6). The solution of 6
was used directly in the next step. An analytical sample of
the solution was evaporated to dryness and recrystallised
from toluene/isooctane (2 + 8 volumes) giving white
1
crystals: mp 54-55 °C; H NMR (CDCl3) δ 7.17 (d, J )
8.6 Hz, 2 H), 6.84 (d, J ) 8.6 Hz, 2 H), 4.05 (dd, J ) 4.3
and 7.7 Hz, 1 H), 3.79 (s, 3 H), 3.62 and 3.59 (2 q, J ) 7.0
Hz, 1 H), 3.46 and 3.44 (2 q, J ) 7.0, 1 H), 3.08 (dd, J )
4.2 and 14.2 Hz, 1 H), 2.96 (dd, J ) 7.7 and 14.2 Hz, 1 H),
1.18 (t, J ) 7.0 Hz, 3 H); 13C NMR (CDCl3) δ 175.0, 158.5,
130.5, 128.5, 113.8, 79.8, 66.9, 55.2, 37.7, 15.1; MS (ESI-
30 V)- m/z 223 (M-1)-. Anal. Calcd for C12H16O4: C, 64.3;
H, 7.2. Found: C, 64.4; H, 7.2.
(2S)-Ethoxy-3-(4-methoxyphenyl)propanoic Acid (S)-
1-(1-Naphthyl)ethylamine Salt (7a). A solution of 5 (54 g,
240 mmol) in iPrOAc (540 mL, 10 vol) was heated to 45 °C
and (S)-1-(1-naphthyl)ethylamine (23 mL, 142 mmol) was
added at 45-47 °C over 10 min. The solution was seeded
with 7a (0.3 g) and cool-ramped (20 °C/h) to -15 °C. The
crystallisation started within 2 min after seeding. The slurry
was stirred at -15 °C for 13 h and filtered on a glass filter
(P3). The filter cake was rinsed with chilled iPrOAc (60 mL).
Drying under vacuum (40 °C) gave 41.0 g of crystalline
material. Isopropyl acetate (820 mL, 20 vol) and the salt
(41.0 g) were charged to a 1-L reactor and heated to 84 °C.
The solution was cool-ramped (20 °C/h) to -1 °C. Seeding
An analytical sample of the oil was crystallised from
1
toluene to yield white crystals: mp 107-108 °C; H NMR
(DMSO-d6) δ 12.57 (s, 1 H), 9.17 (s, 1 H), 6.99 (d, J ) 8.5
Hz, 2 H), 6.63 (d, J ) 8.4 Hz, 2 H), 3.88 (2 q, J ) 5.3 and
7.7 Hz, 1 H), 3.50 and 3.47 (2 q, J ) 7.0 Hz, 1 H), 3.29 and
844
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Vol. 8, No. 6, 2004 / Organic Process Research & Development