Efficient synthesis of (2S,3S)-2-ethyl-3-methylvaleramide using (1S,2S)-pseudoephedrine as a chiral auxiliary

Article abstract of DOI:10.1021/op800260j

An efficient and scaleable synthesis of (2S,3S)-2-ethyl-3-methylvaleramide (1) has been developed starting from inexpensive and readily available L-isoleucine. The key step in this process is an asymmetric alkylation using (1S,2S)-pseudoephedrine as a chiral auxiliary. A practical procedure was developed to remove the sterically hindered pseudoephedrine auxiliary from the amide. The process consists of eight chemical steps and five isolations without any chromatographic purification. It has been successfully implemented to prepare several multikilogram batches of the target compound 1 in 41% overall yield.

Full text of DOI:10.1021/op800260j

Organic Process Research & Development 2009, 13, 463–467
Efficient Synthesis of (2S,3S)-2-Ethyl-3-methylvaleramide Using
(1S,2S)-Pseudoephedrine as a Chiral Auxiliary
Bin-Feng Li,* Robert M. Hughes, Jackie Le, Kevin McGee, Donald J. Gallagher, Raymond S. Gross, David Provencal,
Jayachandra P. Reddy, Peng Wang, Lev Zegelman, Yuxin Zhao, and Scott E. Zook
Neurocrine Biosciences, Inc., 12780 El Camino Real, San Diego, California 92130, U.S.A.
Abstract:
chromatography. This approach was only suitable to fulfill a
short-term need for a few grams of material.
An efficient and scaleable synthesis of (2S,3S)-2-ethyl-3-methylval-
eramide (1) has been developed starting from inexpensive and
readily available L-isoleucine. The key step in this process is an
asymmetric alkylation using (1S,2S)-pseudoephedrine as a chiral
auxiliary. A practical procedure was developed to remove the
sterically hindered pseudoephedrine auxiliary from the amide. The
process consists of eight chemical steps and five isolations without
any chromatographic purification. It has been successfully imple-
mented to prepare several multikilogram batches of the target
compound 1 in 41% overall yield.
In order to further elucidate the pharmacokinetic profile and
toxicological effects of 1, several kilograms of material were
required. Thus, a practical, efficient, and scaleable synthesis
method was needed. Our approach was centered on the
replacement of the oxazolidinone auxiliary with a suitable
substitute that obviated the need for cryogenic temperatures and
chromatographic purification. In this contribution we report our
success in optimizing and scaling up the asymmetric alkylation
using pseudoephedrine as the chiral auxiliary.
Introduction
Valnoctamide (2-ethyl-3-methylvaleramide, Nirvanil, VCD)
is used clinically as a mild tranquilizer in several European
countries.1 Valnoctamide contains two stereogenic carbon atoms
and is produced commercially as a mixture of four stereoiso-
mers. Bialer and co-workers have demonstrated that the
diastereomers and enantiomers of VCD exhibit different phar-
macokinetic profiles in healthy subjects and epileptic patients.2
Our preclinical testing showed that the (2S,3S)-2-ethyl-3-
methylvaleramide isomer (1) is more potent and selective in
various pain and seizure models. Neurocrine’s development
efforts have been focused on 1 in accordance with the
preferences of regulatory agencies for single enantiomer drugs.3
Although 1 has a relatively simple constitution, the presence
of two contiguous alkyl asymmetric centers ensures a significant
synthetic challenge. Bialer and co-workers did report a stereo-
selective synthetic method of both stereoisomers using chiral
oxazolidinone auxiliaries.4 This synthesis required the use of
the highly reactive and expensive alkylating agent ethyl triflate
due to the low nucleophilicity of the enolate. During the
alkylation step, the ratio of desired C-alkylated product 3 to
O-alkylated byproduct 4 was ∼1:1. Upon aqueous workup, 4
was converted back to the starting material 2, which was very
difficult to separate from the desired product even by flash
Results and Discussion
Inexpensive and readily available L-isoleucine was used as
the starting material for our synthesis. The key intermediate
(3S)-methylvaleric acid 6 was synthesized as shown below,
utilizing a literature procedure.4 L-Isoleucine underwent diazo-
tization in HBr followed by the reduction of the resultant bromo-
acid 5 with zinc and H2SO4 to provide 6.5 The throughput of
the zinc reduction was improved by using higher concentration
H2SO4 with no significant effect on product yield or purity. Acid
6 was isolated by vacuum distillation in 78% yield overall yield.
Acid 6 was reacted with pivaloyl chloride in CH2Cl2 in the
presence of Et3N to form the corresponding mixed anhydride,
which reacted in situ with (1S,2S)-pseudoephedrine to give
amide 7. (1S,2S)-Pseudoephedrine was added as a solid in order
to minimize the reaction volume. This conversion proceeded
smoothly with <1% of N,O-diacylated byproduct detected by
* To whom correspondence should be addressed. E-mail: bli@neurocrine.com.
Telephone: +1-858-617-7827. Fax: +1-858-617-7717.
(1) Reynolds, J. E. F. In Martindale: The Extra Pharmacopoeia, 31st ed.;
Pharmaceutical Press: London, 1996; p 742.
(2) Barel, S.; Yagen, B.; Schurig, V.; Soback, S.; Pisani, F.; Perucca, E.;
Bialer, M. Clin. Pharmacol. Ther. 1997, 61, 442–449.
(3) Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. J. Chem. ReV.
2006, 106, 2734–2793.
(4) (a) Roeder, M.; Spiegelstein, O.; Schurig, V.; Bialer, M.; Yagen, B.
Tetrahedron: Asymmetry 1999, 10, 841. (b) Bialer, M.; Yagen, B.;
Spiegelstein, O.; Roeder, M.; Schurig, V. PCT Int. Appl. 9830536,
1998.
(5) It should be noted that careful handling of compound 6 is required
due to the stench associated with it. (3S)-Methylvaleric acid 6 is also
commercially available from AstaTech Inc. and other companies.
10.1021/op800260j CCC: $40.75  2009 American Chemical Society
Published on Web 01/30/2009
Vol. 13, No. 3, 2009 / Organic Process Research & Development
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Table 1. Asymmetric alkylation using (1S,2S)-pseudoephedrine as the chiral auxiliarya
entry
LiCl (equiv)
THF volume (L/mol)
temperature (°C)
conversion (%)
purity (%)
dr (2S:2R)
1
2
3
4
5
6
7
8
9
6
6
6
4
4
2
1
2
2
6.0
6.0
6.0
6.0
3.5
1.5
1.0
1.5
1.5
-78,23,0
-20,23,0
-20,23,0
-20,23,0
-20,23,0
-20,23,0
-20,23,0
-15 (5
-15 (5
>99
>99
98.6
90
>99
>99
>99
>99
>99
97.5
97.6
97.3
83.4
97.6
97.3
97.5
>99
>99
97.6:2.4
97.5:2.5
96.8:3.2
93.6:3.4
97.2:2.8
97.1:2.9
97.0:3.0
96.5:3.5
96.1:3.9
a All reactions were at 10 mmol scale under inert atmosphere, except entry 3 (10 mol) and entry 9 (20 mol). The chemical purity was determined by LC-MS with two
major impurities (amide 7 and bis-alkylation). Diastereomeric ratio (dr) was determined by chiral GC analysis.
HPLC. Amide 7 was used as a THF solution in the next step
without any purification after simple workup.
a reaction was piloted starting at -20 °C, then followed with
the same warm-up and cool-down procedure, and an identical
result was obtained (Table 1, entry 2). This reaction was scaled
up to 10 mol scale. Over 99% conversion was achieved with
an acceptable diastereoselectivity (96.8:3.2 dr) (Table 1, entry
3). During this run, we had some problems during the workup.
A large amount of an inorganic salt crashed out during the
concentration of the final organic solution in spite of two
aqueous washes. This was thought to be LiCl, which is
reasonably soluble in THF and was extracted into the organic
layer.
During our optimization experiments, we sought to reduce
the equivalents of LiCl used. When 4 equiv instead of 6 equiv
were used under otherwise identical conditions, the reaction
stalled at ∼90% conversion and produced 6% of the bis-
alkylation byproduct (Table 1, entry 4), similar to the original
report.6 We noticed that solid LiCl was visible when the solution
warmed up to 23 °C with 6 equiv of LiCl, but not with 4 equiv.
This led us to evaluate whether the absolute LiCl stoichiometry
or concentration was important. When the THF amount was
reduced proportionally (maintaining LiCl saturation even at 23
°C), we were pleased to discover that the reaction went to
completion and cleanly gave the product with similar diaste-
reoselectivity (Table 1, entry 5). The amount of LiCl could be
further reduced to 1 equiv (Table 1, entry 7). For operational
convenience, 2 equiv was used in subsequent campaigns. At
the same time, the amount of THF was reduced from 6.0 L/mol
to 1.50 L/mol.
The alkylation reaction was first attempted on 10 mmol
scale following the original protocol reported by Myers
and co-workers.6 The enolate dianion was formed by
treatment with LDA (2.3 equiv) in THF in the presence
of 6 equiv of LiCl using a temperature cycle (-78 °C for
1 h, 0 °C for 15 min, 23 °C for 5 min, 0 °C for alkylation)
followed by the addition of 1.5 equiv of EtI. HPLC
analysis indicated <0.5% of starting material (amide 7),
97.5% of product (amide 8), and about 2% of a single
byproduct (M + 28, postulated to be the O-alkylation of
the secondary hydroxyl group of the pseudoephedrine
auxiliary). Chiral GC analysis indicated that the diaster-
eomeric ratio (dr) was 97.6:2.4 (Table 1, entry 1). This
acceptable but relatively low diastereoselectivity is ap-
parently the result of mismatched asymmetric induction
between the chiral center at the 3-position of the acid
moiety and the (1S,2S)-pseudoephedrine stereochemistry.
When (1R,2R)-pseudoephedrine was used, the diastereo-
selectivity of this alkylation reaction was greater than 99%
de to give the (2R,3S)-diastereomer of amide 8.
Scheme 1. Synthesis of (2S,3S)-2-ethyl-3-methyl-valeric acid
(9)
Another less than ideal processing issue was the use of
multiple temperature ramps. Temperature ramping for a small
laboratory reaction is relatively quick and easy but can take
several hours per ramp for a large-scale reaction. Upon further
optimization, the reaction could be run at -15 ( 5 °C with no
effect on conversion or diastereoselectivity (Table 1, entry 8).
The bis-alkylation byproduct was also reduced to <0.5% using
these conditions.
The reduction of LiCl and THF amount significantly
increased the reaction throughput from about 11 L/mol to 4.5
L/mol. These changes also avoided salt precipitation during the
workup or concentration, making the process operationally
easier. This optimized procedure gave excellent conversion and
diastereoselectivity at 20 mol scale (Table 1, entry 9) in a 100
L reactor. Amide 8 was then used as a 1,4-dioxane solution
(50 w/w %) in the next step without further purification.
With this promising result in hand, we desired to optimize
the reaction for scale-up. One obvious challenge in scale-up of
this procedure was the low temperature (-78 °C). Although
cryogenic reactions are feasible on scale, use of these processes
is more expensive and complex and limits the number of
potential manufacturing sites. Furthermore, our kilo-laboratory
jacketed reactors have a practical operating lower limit of -30
°C, and we desired to perform this initial work in-house due to
timing and cost reasons. Considering these thermal constraints,
(6) (a) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,
D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496. (b) Myers,
A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994,
116, 9361.
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We first attempted the amide hydrolysis using literature
conditions with 4 M H2SO4 in refluxing dioxane.6 Surpris-
ingly, the hydrolysis of amide 8 would not go to
completion even after a week. When 9 M H2SO4 was used,
it was complete overnight. However, the isolated yield
of acid 9 was <30%, and a large amount of black
precipitate formed, which coated the reactor walls and
complicated the workup. The hydrolysis of amide 8 with
NaOH in a 2:1:1 mixture of H2O, MeOH, and tert-butyl
alcohol6 was also very slow and afforded acid 9 in
significantly lower diastereomeric purity (∼75:25).
These results are consistent with literature reports in which
the hydrolysis of R,ꢀ-disubstituted pseudoephedrine amides
under acidic conditions was found to be strongly dependent on
the steric demands of R-alkyl substituents.7 In our case, amide
7 can be hydrolyzed to the corresponding acid 6 in 92% yield
by heating in 4 M H2SO4 for 5 h, whereas hydrolysis of
R-substituted 8 to 9 is problematic.
Another illustration of the effect of R-substitution is provided
by comparison of mixed anhydride-based reactions of acids 6
and 9. Preparation of the mixed anhydride of 6 and reaction
with (1S,2S)-pseudoephedrine provided the expected amide with
only traces of amide 10 derived from addition to the pivaloyl
carbonyl group. However, preparation of the mixed anhydride
of 9 and reaction with (1S,2S)-pseudoephedrine produced a 20:
80 mixture of the desired amide 8 and amide 10.
The following procedure was developed to complete the
hydrolysis in a shorter time and obtain an improved yield:
Amide 8 was first refluxed (∼90 °C) in 3 M H2SO4 until over
90% of amide 8 had converted to the ammonium ester 8a.
Performing the 8 to 8a conversion using less concentrated acid
minimized the amount of 8b formation and subsequent polym-
erization. Concentrated H2SO4 was then added to adjust the
H2SO4 concentration in the reactor to 9 M (reflux temperature
∼125 °C) to speed up the hydrolysis of 8a to acid 9. Using
this modified protocol, the hydrolysis of 8 to 9 was complete
in 24 h. Acid 9 was obtained in 76% overall yield from acid 6
after acid/base extracts. The diastereomeric purity of 9 was
slightly lower (95.0:5.0) than the starting amide 8 (96.1:3.9),
indicating a small amount of epimerization had occurred.9
Scheme 2. Synthesis of (2S,3S)-2-ethyl-3-methylvaleramide
(1)
The original literature procedure used oxalyl chloride/DMF
and NH4OH to convert acid 9 to valeramide 1.4 Although the
reaction was fast and clean, several processing issues were
noticed at large scale, as well as concern about dimethylcar-
bamoyl chloride formation resulting from the presence of
DMF.10 Concentration in vacuo was required to remove the
excess oxalyl chloride, causing loss of the volatile acyl chloride
intermediate. Excess oxalyl chloride would react with am-
monium hydroxide to form a white solid, presumably the
corresponding oxamide, which was nearly insoluble in aqueous
or organic solvents and complicated the workup.
There were several other challenges in developing a scaleable
process to convert 9 to 1. Valeramide 1 is poorly soluble in
organic solvents so extractions would have required a large
volume of any organic solvent. The physical properties of 1
are such that, once nucleation occurs during concentration,
instantaneous crystallization ensues, trapping solvents. The
complete removal of solvents at this point by concentration in
vacuo was impractical for scale-up. A number of options were
investigated, and finally an acceptable alternative process was
developed in which 9 was added to neat thionyl chloride. The
acyl chloride formation reaction was complete after 3 h at
ambient temperature. The reaction solution was added to a
The mechanism of pseudoephedrine amide hydrolysis
is well-documented in the literature.6,7 Under acidic
conditions, a fast N to O acyl-transfer process occurs
followed by rate-determining hydrolysis of the intermedi-
ate ester. Careful monitoring of the hydrolysis reaction
of amide 8 showed that the normally fast intramolecular
N to O acyl transfer reaction was slow, presumably due
to the strong steric hindrance at that carbonyl position.
Using 4 M H2SO4, it took more than 4 h to complete this
intramolecular acyl transformation, whereas use of 9 M
H2SO4 provided reaction completion in <1 h. However,
there was a substantial impurity formed with m/z 273 (M
- 18) under these concentrated conditions. This impurity
is believed to be dehydrated amide 8b. Ammonium ester
8a is converted to acid 9 upon further heating while we
believe 8b is converted to the black, polymerized solid.
Trace amounts of amide 1 were also detected that
presumably arise via hydrolysis of enamine 8b.8
(7) Reyes, E.; Vicario, J. L.; Carrillo, L.; Badia, D.; Uria, U.; Iza, A. J.
Org. Chem. 2006, 71, 7763.
(9) A small-scale experiment showed that the pseudoephedrine auxiliary
can be recovered from the hydrolysis mixture in ∼75% yield by NaOH
basification and CH2Cl2 extractive workup.
(10) Levin, D. Org. Process Res. DeV. 1997, 1, 182.
(8) Efforts to efficiently form and convert 8b directly to 1 were
unsuccessful.
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cooled NH4OH aqueous solution. The resultant slurry was
heated to 65 °C, and acetone was added until a clear solution
was formed. The solution was cooled slowly to ambient
temperature, and seeding was performed at 50 °C, after which
the product crystallized. There was no detectable epimerization
during this operation. This initial crystallization provided product
that was slightly below our specification of 98% enantiomeric
purity, and there remained a small amount of NH4Cl in the
product. An additional crystallization and polish filtration
provided product with consistent chemical and optical purity.
The solid was dissolved into hot EtOAc and washed with water
to remove NH4Cl. The organic solution was passed through a
cartridge filter to remove fines and was concentrated to ∼2
volumes. The API was crystallized by the addition of n-heptane
followed by cooling ramp, while seeding at 60 °C. The isolated
off-white crystalline product 1 was consistently >99.0% chemi-
cal purity and >98.5% enantiomeric purity over several
multikilogram batches.
(S)-3-Methylpentanoic Acid, ((1′S,2′S)-2′-Hydroxy-1′-
methyl-2′-phenylethyl)methyl-amide (7). To a solution of 6
(2.32 kg, 20.00 mol) in CH2Cl2 (14 L) at -5 °C was added
Et3N (2.93 L, 2.12 kg, 21.00 mol, 1.05 equiv), followed by
pivaloyl chloride (2.46 L, 2.41 kg, 20.00 mol, 1.00 equiv), while
maintaining the internal temperature <0 °C. The resultant slurry
was stirred for 1 h, and then Et3N (2.93 L, 2.12 kg, 21.00 mol,
1.05 equiv) was added. (1S,2S)-(+)-Pseudoephedrine (3.30 kg,
20.00 mol, 1.00 equiv) was added as a solid in portions,
maintaining the internal temperature <5 °C. The resultant slurry
was stirred for 1 h, and water (14 L) was added. The organic
layer was isolated, washed with 1 M HCl (14 L), 1 M NaOH
(14 L), and water (14 L) and concentrated in vacuo to constant
residue weight. The residue was dissolved in THF (10 L) and
concentrated in vacuo to constant residue weight again. The
residue (amide 7) was dissolved in THF (10 L) and used in the
next step without any further purification or treatment. LC-MS
indicated >99% purity with m/z: 264 (M + 1), 246 (M - 17).
Chiral HPLC indicated >99.5% chiral purity. A sample was
purified by flash chromatography (5% MeOH in CH2Cl2) for
analytical characterization. [R]20D ) +97.4 (c ) 1.0 in MeOH).
1H NMR (300 MHz, CDCl3): δ 7.36-7.26 (m, 5H), 4.62-4.55
(m, 1H), 4.50-4.40 (m, 1H, with minor rotamer at 4.10-3.95
ppm), 2.81 (s, 3H, with minor rotamer at 2.91 ppm, 3.4:1),
2.29-2.10 (m, 2H), 2.00-1.80 (m, 1H), 1.37-1.32 (m, 2H),
1.22-1.11 (m, 3H), 1.00-0.86 (m, 6H). IR (film, cm-1): 3377,
2961, 1620. Anal. Calcd for C16H25NO2: C, 72.96; H, 9.57; N,
5.32. Found: C, 72.69; H, 9.86; N, 5.12.
(2R,3S)-2-Ethyl-3-methylpentanoic Acid, ((1′S,2′S)-2′-
Hydroxy-1′-methyl-2′-phenylethyl)methyl-amide (8). To a
solution of anhydrous LiCl (1.70 g, 40.00 mol, 2.00 equiv) in
THF (20 L) and diisopropylamine (6.45 L, 4.65 kg, 46.00 mol,
2.30 equiv) at -20 °C was added n-BuLi (18.40 L, 2.50 M in
cyclohexane, 46.00 mol, 2.30 equiv) slowly while maintaining
the internal temperature <-10 °C. After 30 min, a solution of
amide 7 (20.00 mol) in THF (10 L) from the previous step
was slowly added while maintaining the internal temperature
<-10 °C. After 30 min, EtI (3.20 L, 6.24 kg, 40.00 mol, 2.00
equiv) was slowly added while maintaining the internal tem-
perature <-10 °C. After 2 h, the reaction mixture was warmed
to 20 °C and stirred overnight. Saturated NH4Cl (20 L) was
added to quench the reaction. The organic layer was separated
and washed with water (20 L). The combined aqueous layers
were extracted with MTBE (20 L), the layers were separated,
and the MTBE layer was washed with water (20 L). The MTBE
layer was combined with the original organic layer and
concentrated to constant residue weight. The residue was
dissolved in 1,4-dioxane (10 L) and concentrated to constant
residue weight. The residue (amide 8) was dissolved in 1,4-
dioxane (10 L) and used in the next step without any further
purification or treatment. LC-MS indicated >99% purity with
m/z: 292 (M + 1), 274 (M - 17). Chiral GC indicated 96.1:
3.9 diastereomeric purity. A sample was purified by flash
chromatography (5% MeOH in CH2Cl2) for analytical charac-
terization. [R]20D ) +58.9 (c ) 1.0 in MeOH). 1H NMR (300
MHz, CDCl3): δ 7.39-7.22 (m, 5H), 4.65-4.60 (m, 1H),
4.50-4.40 (m, 1H, with minor rotamer at 4.20-4.10 ppm), 2.87
(s, 3H, with minor rotamer at 2.91 ppm, 8.7:1), 2.40-2.17 (m,
In summary, a concise stereoselective total synthesis of 1
was achieved by using (1S,2S)-pseudoephedrine as the chiral
auxiliary. The overall yield of this eight-step synthesis was 41%
with >99.0% chemical purity and >98.5% optical purity.
Experimental Section
All the reactions were performed under a positive pressure
of nitrogen. Solvents and reagents were obtained from com-
mercial sources and used without further purification. NMR
spectra were recorded on a Varian Mercury 300 MHz.
(3S)-Methylvaleric Acid (6). To a suspension of L-isoleu-
cine (5.00 kg, 38.12 mol) in water (12.25 L) at -5 °C was
added 48% HBr (25.90 L) over 1 h to give a clear solution.
The internal temperature rose to ∼10 °C and was cooled to
-5 °C before the slow addition of a sodium nitrite (5.26 kg,
76.24 mol, 2 equiv) solution in water (10.0 L) over 2 h,
maintaining the reaction temperature at 0 ( 5 °C. The heavy,
brown gas released from the reaction was scrubbed by 20%
NaOH solution (40 L). The resultant mixture was warmed to
ambient temperature and stirred for 4 h. This dark-red solution
was extracted with MTBE (15 L × 3). The combined red
organic extracts were washed with 3.0 M sodium bisulfite (15
L × 2), water (15 L), and brine (15 L) and concentrated in
vacuo to afford bromo acid 5.
The bromo acid 5 was dissolved in H2SO4 (2 M, 40 L) and
cooled to 0 °C. Zinc powder (2.74 kg, 41.92 mol, 1.10 equiv)
was added in portions, maintaining the reaction temperature <20
°C. The reaction mixture was warmed to room temperature and
stirred for 1 h. The reaction mixture was filtered and extracted
with MTBE (25 L × 2). The combined organic extracts were
washed with water (25 L) and brine (25 L) and concentrated
in vacuo. The crude yellowish oil was purified by vacuum
distillation (75-78 °C at 5 mmHg) to afford acid 6 as a colorless
oil, 3.50 kg, 79% yield. GC-MS analysis indicated >99%
purity with m/z: 87 (M - 29), 60 (M - 29 - 27). [R]20
)
D
+5.5 (c ) 1.0 in MeOH). 1H NMR (300 MHz, CDCl3): δ 2.35
(dd, J1) 15.0 Hz, J2 ) 6.0 Hz, 1H); 2.14 (dd, J1 ) 15.0 Hz, J2
) 8.1 Hz, 1H); 1.92-1.85 (m, 1H); 1.45-1.35 (m, 1H);
1.34-1.20 (m, 1H); 0.97 (d, J ) 3.9 Hz, 3H); 0.92 (t, J ) 7.5
Hz, 3H). IR (film, cm-1): 2964, 1708. Anal. Calcd for C6H12O2:
C, 62.04; H, 10.41. Found: C, 62.24; H, 10.38.
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1H), 1.68-1.52 (m, 5H), 1.19-1.09 (m, 3H), 1.08-0.82 (m,
6H), 0.74 (t, J ) 7.5 Hz, 3 H). IR (film, cm-1): 3383, 2965,
1616. Anal. Calcd for C18H29NO2: C, 74.18; H, 10.03; N, 4.81.
Found: C, 74.53; H, 10.38; N, 4.62.
resultant clear solution was cooled to 50 °C, and seed crystals
(2 g) were added. The resultant slurry was cooled to 0 °C over
12 h. The solid was collected by filtration and washed with
H2O (4.38 L × 2) and n-heptane (4.38 L × 2). The product
wet cake was dissolved in EtOAc (15 L) at 50 °C, washed with
water (5 L), and filtered through a 0.3 µm filter. Approximately
12 L of EtOAc was removed by distillation at atmospheric
pressure. n-Heptane (15 L) was slowly added to this hot EtOAc
solution while maintaining the internal temperature >75 °C.
The resultant clear solution was cooled to 60 °C, seed crystals
(2 g) were added, and the slurry was cooled to 0 °C over 12 h.
The solid was isolated by filtration, washed with n-heptane (3
L × 2), and dried at 50 °C under vacuum overnight to give
(2S,3S)-2-ethyl-3-methylvaleramide 1 as a white crystalline
solid, 1.42 kg, 68% yield. GC-MS analysis indicated greater
than 99% purity with m/z: 114 (M - 29), 87 (M - 29 - 27).
Chiral GC indicated 99.36% (2S,3S), 0.38% (2R,3S) and 0.26%
(2S,3S)-2-Ethyl-3-methylvaleric Acid (9). To the amide 8
(20.00 mol) solution in 1,4-dioxane (10 L) from the last step
was added 3 M H2SO4 (10 L, 30.00 mol, 1.50 equiv). The
resultant mixture was refluxed (∼90 °C) for 6 h and then cooled
to 80 °C. Concentrated H2SO4 (6.67 L, 18 M, 120 mol, 6.00
equiv) was added, and the mixture was refluxed (∼125 °C) for
16 h followed by cooling to 20 °C. The black mixture was
extracted with n-heptane (20 L × 2). The combined organic
layers were washed with water (10 L), cooled to 0 °C, and then
extracted with 4 M NaOH (7.50 L × 2). The combined basic
extracts were washed with n-heptane (10 L) and cooled to 0
°C. Concentrated HCl (8 L) was carefully added to provide an
acidic solution (pH < 2) that was extracted with n-heptane (20
L × 2). The combined organic layers were washed with water
(10 L), filtered, and concentrated in vacuo to constant residue
weight to afford (2S,3S)-2-ethyl-3-methylvaleric acid 9 as a pale-
yellow oil, 2.19 kg, 76% yield from (3S)-methylvaleric acid 6.
Acid 9 was used in the next step without any further purification
or treatment. GC-MS indicated >99% purity with m/z: 115
(M - 29), 88 (M - 29 - 27). Chiral GC indicated 95.0:5.0
(2S,3R) isomers. Mp (DSC): 131.5 °C. [R]20 ) -12.1 (c )
D
1
1.0 in MeOH). H NMR (300 MHz, CDCl3): δ 5.53 (s, 1H);
5.39 (s, 1H); 1.89-1.84 (m, 1H); 1.64-1.47 (m, 4H); 1.25-1.10
(m, 1H); 1.00-0.86 (m, 9H). IR (KBr, cm-1): 3381, 3198, 2968,
1652. Anal. Calcd for C8H17NO: C, 67.09; H, 11.96; N, 9.78.
Found: C, 67.35; H, 12.06; N, 9.82.
diastereomeric purity. [R]20 ) +2.0 (c ) 1.0 in MeOH). 1H
Acknowledgment
D
NMR (300 MHz, CDCl3): δ 2.24-2.17 (m, 1H); 1.70-1.46
(m, 4H); 1.25-1.15 (m, 1H); 0.95-87 (m, 9H). IR (film, cm-1):
2965, 2879, 1704. Anal. Calcd for C8H16O2: C, 66.63; H, 11.18.
Found: C, 66.35; H, 11.45.
We are grateful to Dianna Cregg, and Raymond Dagnino
for assistance with raw material sourcing. Louise Bernier, Elina
Kolosovsky-Simberg, Laura Kuhn, Nate Martinez, Kevin
Schaab, and Arthur Shurtleff are thanked for timely analytical
method development and product analyses.
(2S,3S)-2-Ethyl-3-methylvaleramide (1). Acid 9 (2.10 kg,
14.56 mol) was slowly added to SOCl2 (1.17 L, 1.91 kg, 16.05
mol, 1.10 equiv) at 20 °C (off-gassing occurs during this
operation, which was scrubbed using a 20% NaOH solution).
After stirring for 3 h, the resultant solution was slowly added
to 28% NH4OH (7.87 L, 7.09 kg, 116.61 mol, 8 equiv) at -20
°C while maintaining the internal temperature <0 °C. The
resultant slurry was warmed to 20 °C and stirred for 1 h. The
slurry was heated to 65 °C, and acetone (5.85 L) was added to
give a clear solution. Water (8.75 L) was added over 30 min
while maintaining the internal temperature >60 °C. The
Supporting Information Available
Detailed analytical methods (HPLC-MS, chiral HPLC,
GC-MS and GC-FID) and spectral data for compounds 1, 6,
7, 8, 9. This material is available free of charge via the Internet
at http://pubs.acs.org.
Received for review October 9, 2008.
OP800260J
Vol. 13, No. 3, 2009 / Organic Process Research & Development
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