9416 Yang et al.
Asian J. Chem.
carbonate was used as an acid scavenger accelerated the
biphasic reaction and improved the yield over 96 % in scale
up preparation.
Scale-up preparation of 2-(2,2-dimethoxyethylamino)-
N-phenethylacetamide (3): To a mixture of 2-chloro-N-
phenethylacetamide (950 g, 4.8 mol) and K2CO3 (731 g, 5.3
mol) in DMF (12 L) was added aminoacetaldehyde dimethyl
acetal (556 g, 5.3 mol) at room temperature. After stirring at
75 ºC for 5 h, DMF was recovered by distillation and the
residual yellow oil was cooled to room temperature and diluted
with water (3 L), then extracted with dichloromethane (1.5 L
× 4). The combined organic solution were washed with brine
and concentrated to afford 36 (1203 g, 94 %) as a yellow oil
and the dichloromethane was recovered.
In step 2, potassium carbonate (1.2 eq) was found to be
the most effective acid scavenger and also to be an attractive
choice in view of (a) mild reactivity, (b) environmentally
friendly by-product (KCl and CO2), (c) low cost, (d) conve-
nience in storage. With DMF as solvent, the 3 was obtained in
94 % yield, which is much higher than 67 % yield in Scheme-I.
In summary, an improved method for large-scale prepa-
ration of intermediates 2 and 3 for synthesis of praziquantel
has been developed. This method will be valuable in manu-
facture of praziquantel by lowering production costs and
reducing environmental pollution.
ACKNOWLEDGEMENTS
The authors are grateful to National High-Tech Program
of China (863 Program, 2012AA020306) for financial support.
All commercially available materials and solvents were
used without any further purification. 1H NMR spectra were
recorded in CDCl3-d3 at 400 MHz. The chemical shift values
are reported on the δ scale with respect to TMS (δ 0.00) and
CDCl3-d3 (δ 7.26) as internal standards, respectively.
Scale-up preparation 2-chloro-N-phenethylacetamide
(2): To a solution of phenethylamine (1212.0 g, 10 mol) and
K2CO3 ( 1520.0 g, 11 mol) in water (8 L) was added dropwise
a solution of chloroacetyl chloride (1135.0 g, 10.05 mol) in
dichloromethane (4 L) at room temperature. The reaction
mixture was stirred with mechanical rabbling for 2 h at room
temperature. The organic layer was separated and washed with
brine. Evaporation of solvent (recovery of CH2Cl2), gave a
resulting solid that was recrystallized from a mixture of CH3OH
(8 L) and water (6 L) to afford 2 (1901 g, 96 %) as a white
needles, m.p. 62-64 ºC (lit.6 m.p. 60-63 ºC).
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