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.
466
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Vol. 13, No. 3, 2009 / Organic Process Research & Development