20 min a solution of 43.93 g (1.10 mol) of sodium hydroxide
in 395.4 g of purified water was added, resulting in a slightly
yellowish solution. Within 2-3 h a solution of 143.82 g
(0.659 mol) of di-tert-butyl dicarbonate in 124.2 g of THF
was added. During this addition, the internal temperature did
not exceed 30 °C. The pH of the solution decreased during
addition of the di-tert-butyl dicarbonate solution. The solution
was stirred overnight (about 17 h) at 15-25 °C, during which
time the pH increased to pH ∼7, and the reaction became
heterogeneous. Over 1-2 h a solution of about 167.9 g (1.22
mol) of sodium hydrogen sulphate monohydrate in 160 g of
water was added, resulting in a pH of 3.8-3.9. Some solids
precipitated, and strong evolution of gas was observed. The
suspension was cooled to 5-10 °C, filtered and washed with
50 g of THF. The unified filtrates were reduced by distillation
to one-third of their original volume. Thereafter, 102.9 g of
EtOAc was added, and an equivalent volume of solvent was
distilled off. This solvent replacement procedure was repeated
once more using 99.4 g of EtOAc (coevaporation with EtOAc
completely removed the THF from the process stream). To
the resulting aqueous emulsion was added 64.6 g of sodium
chloride and 100.5 g of EtOAc. The phases were separated,
and the aqueous phase was washed with EtOAc (3 × 20 g).
The unified organic phases were dried over 20 g of anhydrous
sodium sulphate, the drying agent was filtered off, and the
filter cake was washed with 5 g of EtOAc. The resulting
EtOAc solution (about 250 g) containing 15 was used
immediately for precipitation of the (1R,2S)-(-)-ephedrine
salt 16.
166 (MH+). HRMS results: Calcd for C13H18N2O4 (â-amino
acid portion of 16 only), 267.1345; Found: 267.1341. This
material was used immediately as is without further purifica-
tion.
By using the process described in this procedure, a total
of 115.8 kg of an EtOAc solution of 15 was processed to
20.7 kg of 16 (26.6% over two steps from 14).
(S)-3-[(tert-Butoxy)carbonyl]amino-3-(3′-pyridyl)pro-
pionic Acid (17). A beaker was charged with 25.11 g (0.058
mol) of 16 and 50.0 g of water at 15-25 °C, resulting in a
clear solution. Within 10-20 min a solution of 2.63 g (0.066
mol) of NaOH in 23.3 g of water was added. To the resulting
clear solution was added 17.4 g of toluene, and the resulting
emulsion was heated to 70-80 °C with good stirring. After
the stirring was stopped, the phases separated rapidly, and
the clear upper organic phase was separated from the
slightly turbid lower aqueous phase. The aqueous phase
(70-80 °C) was extracted four additional times with 17.4 g
of toluene per extraction. The aqueous phase was cooled to
15-25 °C and filtered, and the filtered solids were washed
with 2.5 g of water. To the unified filtrates a solution of
9.50 g (0.069 mol) of sodium hydrogen sulphate monohy-
drate in 12.1 g of water was added. A pH of 3.6-3.9
(preferably 3.8) resulted, and 17 crystallized from solu-
tion. The slurry was cooled to 0-5 °C and stirred for 1 h,
and the solids were collected by filtration and washed with
5 g of water in two portions. Further drying in vacuo at
40-50 °C gave 11.08 g (72%) 17 as a crystalline solid: mp
87-88 °C (softened), 144-146 °C (d). 1H NMR (d6-DMSO/
TMS) δ 1.35 (s, 9H), 2.64 (dd, 1H), 2.73 (dd, 1H), 4.67
(m, 1H, sharpened after D2O exchange), 7.36 (m, 1H), 7.56
(d, 1H, exchanged with D2O), 7.71 (m, 1H), 8.44 (m, 1H),
8.50 (s, 1H), 12.30 (br s, 1H, exchanged with D2O). MS
(ESI) m/z 267 (MH+), m/z 289 (MNa+). HRMS results:
Calcd for C13H18N2O4, 267.1345; Found: 267.1341. By
HPLC analysis, the chemical purity of this material was
>99%.
By using the process described in this procedure, a total
of 30 kg of 14 was processed to 115.8 kg of an EtOAc
solution of 15, which was used immediately for precipitation
of the (1R,2S)-(-)-ephedrine salt 16.
(S)-3-[(tert-Butoxy)carbonyl]amino-3-(3′-pyridyl)pro-
pionic Acid, (1R,2S)-(-)-Ephedrine Salt (16). A solution
of 15 in EtOAc (250 g, containing about 71.5 g (0.269 mmol)
of 15 and 178.5 g of EtOAc) was heated to 60-70 °C.
Within 10 min a solution of 48.80 g (0.295 mol) of (1R,2S)-
(-)-ephedrine in 90.0 g of EtOAc was added. The clear
solution was slowly cooled to 20-30 °C while the product
crystallized as a voluminuous, white solid. After the crystal-
lization of 16 began, 270 g of EtOAc was added to maintain
efficient stirring. The suspension was cooled to 15-25 °C,
stirred for 3-5 h, and the solids were collected by filtration.
The filter cake was washed with 90 g of EtOAc in two
portions and dried in vacuo at 70-80 °C to yield 52.72 g
16 as a white solid (28% over two steps from 14). In addition
to 16, the NMR spectrum showed residual EtOAc which
could not be removed by further drying in vacuo. 1H NMR
(D2O) δ 1.01 (d, 3H), 1.24 (s, 9H), 2.47 (dd, 1H), 2.57 (dd,
1H), 2.64 (s, 3H), 3.43 (m, 1H), 4.78 (t, 1H), 5.00 (d, 1H),
7.30 (m, 6H), 7.70 (m, 1H), 8.30 (m, 1H), 8.36 (s, 1H). By
HPLC analysis,23 this material was >98% S-enantiomer and
<2% R-enantiomer (â-amino acid portion of 16 only). MS
(ESI, â-amino acid portion only) m/z 266 (MH+), m/z 289
(MNa+). MS (ESI, (1R,2S)-(-)-ephedrine portion only) m/z
By using the process described in this procedure, a
total of 58.4 kg of 16 was processed to 33.2 kg of 17
(92.1%).
Methyl (S)-3-Amino-3-(3′-pyridyl)propionate, Dihy-
drochloride Salt (1). A total of 9.93 g (0.037 mol) of 17
was dissolved in 45.8 g of MeOH, and the resulting milky
white solution was cooled to 0-5 °C. Over 2-3 h, 34.2 g
(0.938 mol) of hydrogen chloride was bubbled into the
solution while maintaining a reaction temperature of <15
°C. During introduction of the HCl, the milky white solution
became clear, then became heterogeneous (solid precipitated).
After the addition of HCl was complete, the slurry was stirred
2h at 20-25 °C, cooled to 0-5 °C and stirred for 30 min at
0-5 °C. Solids were collected by filtration, washed with
14.2 g of cold MeOH (0-5 °C) in two portions, and dried
in vacuo at 20-30 °C to afford 7.86 g (83%) 1 as a white,
crystalline solid: mp 187.5-189 °C. 1H NMR (D2O) δ 3.19
(dd, 1H), 3.28 (dd, 1H), 3.62 (s, 3H), 5.05 (t, 1H), 8.08 (m,
1H), 8.66 (m, 1H), 8.80 (m, 1H), 8.91 (s, 1H). MS (ESI)
m/z 181 (MH+, free base), m/z 203 (MNa+, free base). Calcd
26
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Vol. 5, No. 1, 2001 / Organic Process Research & Development