Pictet-Spengler approach to PZQ: 2-chloro-N-phenethylacetamide

19 Feb
Published by Michael Wolfle

 
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Here we started another synthetic approach to PZQ. The Pictet-Spengler route, used for the industrial synthesis of (rac)-PZQ, offers a straightforward way to this anthelmetic drug in 5 steps.[1]
Starting from inexpensive 2-phenylethylamine and chloroacetyl chloride the amide 2 can be obtained in a short reaction time with high yield. 
 
Procedure:
To a suspension of 2-phenylethylamine (15.1 g, 15.7 mL, 125 mmol) and NaHCO3 (11.6 g, 138 mmol) in DCM (200 mL) chloroacetyl chloride (150 mmol, 16.9 g, 11.7 mL) was added dropwise at 0°C over a period of 90 min. The reaction mixture was stirred for 1 h at 10°C, warmed up to room temperature and stirred for additional 2 h. After quenching with water (60 mL), the organic layers was separated, washed with 10% HCl and brine. The concentrated residue was recrystallized from mixture methanol (35 mL) and water (25 mL) and 2 (20.5 g, 104 mmol, 83%) was obtained as spicular crystals. The mother liquid was concentrated again and recrystallized a second time affording light yellow crystals of 2 (2.00 g, 10.1 mmol, 8%). Overall yield: 22.5 g, 114 mmol, 91% (lit.[1] 92% / 81%, yield and resulting weight are inconsistent).
m.p. 64.3-64.6°C. (lit.[1] 60-63°). 1H NMR (CDCl3, 200 MHz): δ = 2.85 (“t”, J = 7.0 Hz, 1H), 3.54 (d, J = 7.0 Hz, 1H), 3.60 (d, J = 7.0 Hz, 1H), 4.01 (s, 2H), 6.65 (bs, 1H), 7.19-7.38 (m, 4H). 13C NMR (CDCl3, 50.3 MHz): δ = 35.6, 41.0, 42.7, 126.8, 128.8 (4 C), 138.4, 165.9. C12H14N2O (197.7).

[1]     “Formation of Pyrazinoisoquinoline Ring System by the Tandem Amidoalkylation and N-Acyliminium Ion Cyclization: An Efficient Synthesis of Praziquantel”, J. H. Kim, Y. S. Lee, H. Park and C. S. Kim, Tetrahedron, 1998, 54, 7395-7400.