10.1002/ejoc.201700998
European Journal of Organic Chemistry
COMMUNICATION
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Conclusions
In summary, we have completed the synthesis of (±)-Pregabalin
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by using
a
three-step sequential-flow system with
heterogeneous catalysts. Knoevenagel reaction of commercial
isovaleraldehyde with methyl malonate, 1,4-addition of
nitromethane, and reduction of
smoothly under the sequential-flow conditions. Heterogeneous
catalysts worked well in each step. We are currently
investigating an asymmetric synthesis of (S)-Pregabalin.
a nitro group proceeded
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Experimental Section
Experimental procedure of 3-step flow reaction for the synthesis of
γ-lactam (7): For the Knoevenagel reaction, Chromatorex NH and MS4A
(2/3, w/w, 14 g) were mixed and packed in a SUS column (10 x 300 mm)
with column ends equipped with a filter. Toluene was flowed into the
column by a plunger pump (for HPLC, 0.50 mL/min) to prepare the
catalyst slurry. The solution of dimethyl malonate (3, 80 mmol),
isovaleraldehyde (a, 100 mmol), 1,3,5-trimethylbenzene (40 mmol,
internal standard) and toluene (400 mL) was mixed in a volumetric flask
and then flowed into the column which was heated at 70 °C. For the 1.4-
addition reaction, an anion exchanged resin catalyst (IRA900 OH) was
washed with a 1M NaOH aqueous solution and then methanol. After that,
by using methanol, an anion exchanged resin catalyst (10 g, MeOH wet.)
was packed in a glass column (10 x 200 mm) with column ends equipped
with a filter. Toluene and n-propanol (1/1, v/v) were flowed into the
column by a plunger pump (for HPLC, 0.50 mL/min) to prepare the
catalyst slurry. After stabilization of the Knoevenagel flow, the solution of
nitromethane (75 mmol) in toluene and n-propanol (1/1, v/v, 300 mL) was
mixed with the Knoevenagel product solution via a connector. The
mixture was then flowed into the 1,4-addition column. For the reduction,
PDMSi-Pd/BC (Pd: 0.30 mmol/g (dry)) and Celite (5/1, w/w, 6 g) were
mixed and packed in a SUS column (10 x 100 mm), and MS 5A and
silica gel (CARiACT Q-6) (1/1, w/w, 5 g) were mixed and packed in a
glass column (10 x 100 mm) as the pre-column. n-Propnaol was flowed
into the column by a intelligent pump (0.50 mL/min) to prepare the
catalyst slurry. After stabilization of the 2-step flow, the stream was
flowed into the pre-column. The stream after the pre-column was mixed
with n-propanol (flow rate: 0.05 mL/min), and the resulting diluted
solution was flowed into the reduction column reactor with hydrogen gas
generated from water using a hydrogen generator (RHG-200, Round
science) at 10 mL/min of flow rate. A reduction column oven was set at
60 °C. At the end of the stream, a reaction solution was collected and
directly analyzed by GC in appropriate time.
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Acknowledgements
This work was partially supported by a Grant-in-Aid for Science
Research from the Japan Society for the Promotion of Science
(JSPS), Global COE Program, The University of Tokyo, MEXT,
Japan, the Japan Science and Technology Agency (JST), and
Japan Agency for Medical Research and Development (AMED).
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The reaction under batch conditions was conducted at 70 °C for 14 h
using dimethyl malonate (1.0 mmol), aldehyde (1.25 mmol), catalyst
(100 mg) and MS 4A (150 mg).
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Keywords: Continuous-flow reaction • Heterogeneous catalysis
• Pregabalin • Knoevenagel • 1,4-Addition • Hydrogenation
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