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and dichloromethane (240 L) in the reactor at 0−5 °C.
Aqueous ammonia was employed to slowly adjust the pH to
10.0−10.5. The phases were separated, and the aqueous phase
was extracted with dichloromethane (60 L) at 0−5 °C. The
combined organic layers were dried over sodium sulphate.
Removal of the solvent by evaporation below 40 °C under
reduced pressure affords 7.41 kg (98.7% yield) of the product
as a light yellow organic liquid. [α]29.6D −6.86° (c 1.00 MeOH);
1H NMR (CDCl3) δ 1.0 (d, J = 6.7 Hz, 3H), 2.05 (t, J = 11.3
Hz, 1H), 2.36 (s, 3H), 2.31−2.38 (m, 2H), 2.6−2.7 (m, 2H),
3.03−3.08 (m, 2H); 13C NMR (CDCl3) δ 11.8, 40.8, 44.1, 45.3,
56.2, 63.2, 210.4; IR (cm−1) 2969, 2939, 2790, 1718, 1257.
HPLC: 97.8%; Optical purity: 95.2%.
Racemization of the Mixture of Isomers [4a(minor)/
ent-4a(major)] to 1,3-Dimethyl-4-piperidinone (4). The
filtrate from the preparation of 4a was distilled completely at
below 65 °C in a 100 L glass reactor. The distilled product was
cooled to 0−5 °C, and 10% NaOH solution was added (21 L).
Thereafter, the solution was stirred at 25−35 °C for 4 h. The
product was extracted with DCM (1 × 75 L and 1 × 45 L). The
organic phase was dried over sodium sulphate. Subsequently,
the organic phase was completely distilled under reduced
pressure at below 45 °C. The product is distilled below 80 °C
under high vacuum (less than 10 mbar) to afford 5.25 kg (70%
yields) of 4. [α]29.6D 0.0° (c 1.00 MeOH); 1H NMR (CDCl3) δ
1.0 (d, J = 6.7 Hz, 3H), 2.06 (t, J = 11.2 Hz, 1H), 2.36 (s, 3H),
2.31−2.38 (m, 2H), 2.6−2.7 (m, 2H), 3.04−3.09 (m, 2H); 13C
NMR (CDCl3) δ 11.7, 40.7, 44.1, 45.2, 56.2, 63.2, 210.4; IR
(cm−1) 2969, 2939, 2790, 1718, 1257. HPLC: 98.6%; Optical
purity: 50.1%.
Preparation of (3S)-1,3-Dimethyl-4-[3-(1-
methoxyethoxy)phenyl]-4-piperidinyl Ester (7). A 200 L
glass reactor was arranged and charged with 3-bromoisopro-
poxy benzene (3; 8.5 kg, 39.53 mol) and 2-methyl-THF (27 L).
The solution was cooled to −60 to −70 °C. 15% n-BuLi in
hexane (29.75 Lit, 44.62 mol) solution was added slowly at the
same temperature for 1 h. The reaction mixture was stirred for
1 h at −60 to −70 °C. Thereafter, (S)-1,3-dimethyl-4-
piperidinone (4a) (4.5 kg, 35.4 mol) was added at the same
temperature for the span of 2 h and maintained for 1 h. The
reaction mass was slowly quenched with hydrochloric acid (30
L, 6 N) below 0 °C. The hexane layer was separated at 25−35
°C, and the aqueous phase was washed with hexane (2 × 12 L).
Toluene (27.0 L) was charged to the aqueous phase, and the
mass was cooled to 15−20 °C. The pH of the mass was
adjusted to 10.0−10.5 by using 20% NaOH solution. The
phases were separated, and the aqueous phase was extracted
Figure 1. Structure of potential impurities.
synthesized/isolated and well characterized. Impurity ent-1 is an
enantiomer of 1 whereas impurities 12 and 13 were the
desmethyl derivative of 10 and the dehydro derivative of 1,
respectively, which have been formed during chemical
manipulations in the downstream process.
During manufacturing events, water is considered as a less
hazardous effluent, which is due to a matter of fact that we
ensured the contaminated water out of the process stream is
not discharged before sending it to the effluent treatment plant.
In order to account for mass balance, we calculated the molar
quantities of starting material, resolving agent output, and
unaccounted material as shown in Figure 2. We employed 1.55
mol of (−)-DPTTA monohydrate to resolve 0.79 mol of 4.
Considering recycling of ent-4a, we were able to obtain 0.63
mol of 4a whereas 0.16 mol of the mixture 4/4a/ent-4a
accounted for handling loss. In addition to this, we are able to
recover 1.24 mol of (−)-DPTTA monohydrate (as indicated by
KF), and due to its solubility in water, 0.31 mol for the same is
lost along with water stream.
EXPERIMENTAL SECTION
The H NMR spectra were recorded in CDCl3 and DMSO-d6
on a Varian Gemini-2000 FT NMR spectrometer at 400 and
500 MHz; the chemical shifts are reported in ppm relative to
TMS. The solvents and reagents were used without further
purification.
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1
Preparation of (S)-1,3-Dimethyl-4-piperidinone (4a). A
200 L glass reactor was charged with 1,3-dimethyl-4-
piperidinone (15 kg, 118.1 mol) and methanol (105 L) and
(−)-di-p-toluoyl-D-tartaric acid monohydrate [(−)-
DPTTA.H2O] (60 kg, 148.5 mol) and stirred for 45 min at
25−35 °C. Methanol was completely distilled under reduced
pressure below 75 °C. Subsequently, methanol (90 L) was
added and the mixture was cooled to 25−35 °C. The reaction
mixture was stirred at the same temperature for 2 h. Thereafter,
the product was filtered and washed with chilled methanol (15
L). The filtered product was charged along with water (240 L)
Figure 2. Material balance for 4a.
D
dx.doi.org/10.1021/op400144z | Org. Process Res. Dev. XXXX, XXX, XXX−XXX