1-2 (addition time of sulfuric acid was 30 min while
maintaining the internal temperature at <25 °C). Heptane
(13.5 L) was added, and the mixture was stirred for 30 min.
The organic layer was separated and washed with water
(3.0 L). The organic layer was concentrated under a vacuum
(20 mbar; jacket temperature 45-55 °C) to collect ∼14.9 L
of solvent to obtain 2-butylpropanedioic acid monoethyl
ester12 (6, 2.55 kg; 95% crude yield; purity 99% by HPLC)
as a clear liquid; MS (ESI) 187.15 (M-1); 1H NMR (CDCl3,
δ) 0.8-1.0 (m, 3H), 1.2-1.45 (m, 7H), 1.8-2.0 (m, 2H),
3.38 (t, 1H, J ) 7.4 Hz), 4.23 (q, 2H, J ) 7.1 Hz), 11.37
(br, 1H); 13C NMR (CDCl3, δ) 13.79, 14.06, 22.33, 28.56,
29.42, 51.82, 61.70, 169.44, 175.66.
Preparation of (()-2-Butyl-3-hydroxypropionic Acid
(7). A 12-L, four-necked, round-bottomed flask, equipped
with a mechanical stirrer, digital thermometer, and nitrogen
inlet-outlet was charged with 2-butylpropanedioic acid
monoethyl ester (6, 450.0 g, 2.39 mol) and 2-propanol
(4.5 L). The solution was cooled to an internal temperature
at 15-18 °C, and a 2 M solution of lithium borohydride
(2.4 L, 4.8 mol) in tetrahydrofuran was added over a period
of 1.5 h while maintaining the internal temperature at 15-
25 °C. The stirring was continued for an additional 3 h. The
reaction mixture was cooled to an internal temperature of
10-13 °C and quenched by the addition of 2 N HCl (2.4 L)
over a period of 1 h while maintaining the internal temper-
ature at 10-25 °C. The reaction mixture was concentrated
at 35-40 °C (20 mbar) to collect ∼7.5 L of the solvent to
obtain a suspension (∼1.9 kg). This suspension was diluted
with water (2.0 L) and ethyl acetate (2.5 L), and the biphasic
mixture was stirred for 1 h. The organic layer was separated,
and the aqueous layer was extracted with ethyl acetate
(2.0 L). The combined organic layers were washed with 20%
aqueous solution of sodium chloride (1.0 L) and concentrated
under a vacuum (20 mbar) until no further solvent distilled
to afford crude (()-2-butyl-3-hydroxypropionic acid8 (7,
349.4 g, 100%) as a colorless liquid, which was used as such
in the next step.
Resolution of (()-2-Butyl-3-hydroxypropionic Acid (7).
A 5-L, four-necked, round-bottomed flask, equipped with a
mechanical stirrer, digital thermometer, reflux condenser,
addition funnel with nitrogen inlet-outlet, and heating man-
tle, was charged with (R)-R-methylbenzylamine (280.7 g,
2.316 mol), 2-propanol (1.9 L), and ethyl acetate (1.63 L).
The solution was stirred and heated to an internal temperature
at 60-65 °C, and a solution of (()-2-butyl-3-hydroxypro-
pionic acid (7, 322.5 g, 2.206 mol) in ethyl acetate (0.2 L)
was added over a period of 15 min while maintaining the
internal temperature at 60-70 °C. The addition funnel was
washed with ethyl acetate (0.2 L) and added to the mixture.
The solution was cooled to 20-25 °C over a period of 2 h,
and the resulting suspension was stirred at the same tem-
perature for an additional 5 h. The solids were collected by
filtration, washed with a mixture of ethyl acetate-2-propanol
(2:1 v/v) in two equal portions of 0.5 L each, and dried at
50-53 °C (13-49 mbar) to afford crude (R)-2-butyl-
3-hydroxypropionic acid (R)-R-methylbenzylammonium salt
(8, 246.3 g; 41.7%); (R)/(S) ) 94.1:5.9.
Crude (R)-2-butyl-3-hydroxypropionic acid (R)-R-meth-
ylbenzylammonium salt (8, 246.3 g) was transferred to a 5-L,
four-necked, round-bottomed flask, equipped with a me-
chanical stirrer, digital thermometer, reflux condenser, ad-
dition funnel with nitrogen inlet-outlet, and a heating mantle.
Ethyl acetate (1.225 L) and 2-propanol (1.225 L) were
added. The suspension was stirred and heated to an internal
temperature of 70-80 °C over a period of 1 h to obtain a
solution. The solution was cooled to 20-25 °C over a period
of 2 h, and the resulting suspension was stirred at the same
temperature for an additional 5 h. The solids were collected
by filtration, washed with a mixture of ethyl acetate-2-
propanol (2:1 v/v) in two equal portions of 0.4 L each, and
dried at 50-53 °C (13-49 mbar) to afford pure (R)-2-butyl-
3-hydroxypropionic acid (R)-R-methylbenzylammonium salt
(8, 215.6 g; 36.5%; 73.0% of theory); mp 145-147 °C; [R]D
1
+8.8 (c ) 1.0, CH3OH); (R)/(S) ) 99.3:0.7; H NMR
(CDCl3, δ) 0.88 (t, 3H), 1.2-1.4 (m, 4H), 1.4-1.6 (m, 2H),
1.61 (d, 3H, J ) 6.9 Hz), 2.3-2.4 (m,1H), 3.5-3.6 (m, 1H),
3.6-3.7 (m, 1H), 4.42 (q, 1H, J ) 6.9 Hz), 5.13 (s, 4H),
7.3-7.5 (m, 5H); 13C NMR (CDCl3, δ) 14.88, 21.64, 24.42,
30.84, 31.54, 52.58, 52.69, 65.59, 128.08, 130.27, 130.58,
140.96, 183.6. Anal. Calcd for C15H25NO3: C, 67.38; H,
9.42; N, 5.24. Found: C, 67.46; H, 9.45; N, 5.23.
(R)-2-Butyl-3-hydroxypropionic Acid (1). (R)-2-Butyl-
3-hydroxypropionic acid (R)-R-methylbenzylammonium salt
(8, 10.0 g) was dissolved in 2 N HCl (40.0 mL), and
isopropyl acetate (50.0 mL) was added to the mixture. After
mixing for 5 min, the organic layer was separated, and the
aqueous layer was extracted with isopropyl acetate (3 × 50.0
mL). The combined organic layers were washed with water
(20.0 mL) and concentrated under a vacuum (20 mbar) until
no further solvent distilled to afford (R)-2-butyl-3-hydrox-
ypropionic acid (1, 5.4 g, 98%); oil; [R]D +6.5 (c ) 1.0,
1
CH3OH); (R)/(S) ) 99.3:0.7; H NMR (CDCl3, δ) 0.9 (t,
3H), 1.25-1.44 (m, 4H), 1.44-1.59 (m, 1H), 1.59-1.75 (m,
1H), 2.5-2.7 (m, 1H), 3.7-3.9 (m, 2H), 7.04 (br, 2H); 13
C
NMR (CDCl3, δ) 14.21, 22.96, 28.36, 29.67, 47.92, 63.35,
180.80. Anal. Calcd for C7H14O3: C, 57.51%; H, 9.65%.
Found: C, 57.31%; H, 9.90%.
(S)-2-Butyl-3-hydroxypropionic Acid. (S)-2-Butyl-3-
hydroxypropionic acid was prepared by the resolution of (()-
2-butyl-3-hydroxypropionic acid (7) with (S)-R-methylben-
zylamine in a similar manner as that described above for
the (R)-enantiomer. (S)-2-Butyl-3-hydroxypropionic acid (S)-
R-methylbenzylammonium salt, yield 33.2% (66.4% of
theory); mp 145-147 °C; [R]D -8.9 (c ) 1.0, CH3OH); (R)/
(S) ) 0.4:99.6.
(S)-2-Butyl-3-hydroxypropionic acid: yield 98%; oil; [R]D
-6.6 (c ) 1.0, CH3OH); (R)/(S) ) 0.4:99.6.
Received for review September 27, 2006.
OP060199L
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