7
.0 using 30% NaOH (w/w) solution. After 24 h, a GC
with minor modifications. The spectral data on this compound
1
13
sample was taken (45–48% conversion), and titrator and
agitation were stopped. Layers were settled for 15–30 min,
and the upper layer separated. Toluene (1.0 L) was then
charged to the aqueous solution, and the resulting mixture
stirred for 10 min. Layers were settled for 15–30 min,
and the upper (organic) layer separated and was combined
with the (R)-1 solution previously separated. The aqueous
layer was then taken forward to the next step without any
further workup or isolation. For spectral characterization,
a tert-butylamine salt of 2 was prepared: 1 L of an aqueous
solution of 2 (∼1 mol) was acidified to pH 3.0 by adding
concentrated HCl, and the free acid was extracted with
(MS, H NMR, C NMR) were in agreement with the previous
3
report.
Preparation of (S)-3-(Aminomethyl)-5-methylhexanoic
Acid from 5. A suitable vessel was charged with 50 g (∼80%
purity) of 5 and a solution of 41 mL of concentrated HCl and
41 mL of water. Then 4 mL of glacial HOAc were charged,
and the resulting slurry was refluxed for ∼36-48 h at 80 °C.
The temperature of the reaction was then increased to 110 °C
and reaction continued for another 6 h. The water and excess
HCl were evaporated to afford an oily residue. The residue was
washed with MTBE (15 mL × 2), and water (54.5 mL) was
then added, and the mixture was stirred until a clear solution
was formed. The pH of the solution was adjusted to 5.2–5.5
with 45% KOH, when a precipitate was formed. The mixture
was heated up to 70 °C and then cooled down to 4 °C. After
0
.5 vol. of MTBE (three times). To the combined MTBE
free acid solution was charged tert-butylamine (1 equiv)
as a solution with 0.1 vol. of isopropanol. The solid was
collected (>95% recovery, >95% pure) and recrystallized
from 1 vol. of isopropanol and dried in a vacuum oven
using house vacuum at 50 °C. Mp 135.4 °C, MS (acid)
10 h, crystalline Pregabalin (19.5 g) was filtered and washed
with cold IPA (20 mL). To collect a second crop of crystals,
the filtrate was concentrated to afford an oily residue, followed
by addition of H
was heated up to 70 °C and then cooled down to 4 °C. After
0 h, a second crop of crystalline Pregabalin (8.0 g) was filtered
2
O (22 mL) and ethanol (22 mL). The mixture
+
1
m/z [M + H] 227, H NMR (for tert-butylamine salt 300
MHz, D O): δ 0.91 (dd, 6H), 1.28 (t, 3H), 1.37 (s, 9H)
.60 (m, 1H), 1.78 (m, 1H), 3.29 (m, 1H), 3.50 (d, 1H),
2
1
1
4
1
5
and washed with IPA (15 mL). The combined crystals were
dried in a vacuum oven at 45 °C for 24 h to afford enantiopure
Pregabalin (in 80% yield and >99.5% ee). The spectral data
1
3
.22 (q, 2H), 4.22 (s, 3H). C NMR (75 ppm, D O) δ
2
3.73, 20.88, 22.61, 26.20, 27.11, 30.20, 38.65, 52.39,
7.25, 62.99, 122.90, 171.02, 172.54.
Preparation of (S)-3-Cyano-5-methylhexanoic Acid Ethyl
1
13
on this compound (MS, H NMR, C NMR) were in agreement
3
with the previous report.
Ester (3). An aqueous solution from the Lipolase reaction (2
L, ∼3 mol) was charged in a suitable reactor and heated to 85
Recycling of rac-2-Carboxyethyl-3-cyano-5-methylhex-
anoic Acid Ethyl Ester (1) from R-1. A suitable vessel was
charged with 1 kg of (R)-cyanodiester 1 from step 1 as a toluene
solution, followed by 1.42 kg of 21 wt % sodium ethoxide
solution in ethanol (1.1 equiv). The mixture was then heated to
°C for 3 h while stirring under a nitrogen atmosphere. The
mixture was then cooled to 50 °C, and layers were settled for
5–30 min. The organic layer containing the neat crude
1
80 °C for 8–16 h. After reaction completion, the mixture was
compound 3 was then transferred into the next step (KOH
1
cooled down to 4 °C and neutralized by adding 0.27 L of glacial
acetic acid. The slurry was filtered, and the filtrate was
evaporated to afford racemic ester 1. The material was then
hydrolysis). The spectral data on this compound (MS, H NMR,
1
3
3
C
N
M
R
)
w
e
r
e
i
n
a
g
r
e
e
m
e
n
t
w
i
t
h
t
h
o
s
e
r
e
p
o
r
t
e
d
p
r
e
v
i
o
u
s
l
y
.
Preparation of 3-Carboxy-4-alkyl-pyrrolidin-2-one (5).
3
distilled following literature procedure to afford rac-1 in >95%
A suitable hydrogenation vessel was charged with an aqueous
solution of 2 (100 mL, ∼0.15 mol), followed by 21.5 mL of
Raney nickel water solution (50%) and the mixture hydroge-
nated at 50 psi for 20 h. After reaction completion, the catalyst
was filtered. The pH of the remaining solution was adjusted to
1
isolated yield. The spectral data on this compound (MS, H
13
3
NMR, C NMR) were in agreement with the previous report.
Acknowledgment
We gratefully acknowledge the following: Xiaobing Xiong,
Xiaoxing Liao, and Mike McLoughlin for providing analytical
support; Padraig Kelly, David Amspacher, Simon Davies, David
Hogan, Tim Evans, and Vivienne Lee for providing technical
assistance; Pfizer PGRD, Pfizer Global Manufacturing Pre-
gabalin team for their input and support during the research
and scale up of this second-generation route; Peter Dunn and
John Wong for providing input on green chemistry, Mike
Williams for correcting the manuscript, and Bob Hamburger
from Novozymes for technical assistance and for supplying
samples of Lipolase.
3
0
.0 using 37% HCl and the solution extracted three times with
.5 vol of EtOAc. The combined organic layers were concen-
trated in Vacuo to afford 26.5 g of compound 5 as an oily
residue, in 40–42% isolated yield. Compound 5 was analyzed
using the chiral HPLC method described above and found to
+
1
be present in >97% ee. MS m/z [M + H] 186.1130, H NMR
300 MHz, CDCl ): δ 0.87 (d, 6H), 1.33 (m, 1H), 1.51 (m,
H) 2.88 (m, 1H), 2.99 (t, 1H), 3.06 (d, 1H), 3.54 (t, 1H), 7.64
(
3
2
13
(
s, 1H), 9.80 (b, 1H); C NMR (75 ppm, CDCl
72.23, 54.09, 47.62, 43.69, 37.22, 26.31, 23.34, 22.54.
Preparation of (S)-3-(Aminomethyl)-5-methylhexanoic
3
) δ 175.67,
1
Received for review October 5, 2007.
OP7002248
Acid (Pregabalin) from 3. The crude oil 3 was converted to
crude Pregabalin following previously published procedures
3
98
•
Vol. 12, No. 3, 2008 / Organic Process Research & Development