Pictet-Spengler approach to PZQ: 2-((2,2-dimethoxyethyl)amino)-N-phenethylacetamide

09 Mar
Published by Michael Wolfle

The next step in the PZQ synthesis via the Pictet-Spengler route is an aminoalkylation of the chloroacetamide 2 with aminoacetaldehyde dimethyl acetal 3. The aminoacetal also acted as a base to trap the HCl which was generated during the reaction and therefore 2.1 equivalents were used. The aminoacetal could be easily recovered by basic liberation of its HCl-salt which precipitated from the cold toluene solution. The crude product was obtained as a brown oil and was isolated by forming the HCl-salt 4 in an overall yield of 79%. (lit.[1] 67%)
Compound 2 (10.0 g, 50.6 mmol) and aminoacetaldehyde dimethyl acetal 3 (11.2 g, 106 mmol, 2.1 eq.) were dissolved in toluene (50 mL) and heated to reflux for 2 h. After which time, the mixture was cooled to 0°C then the resulting precipitate was separated by filtration and washed with cold toluene. The colorless solid, aminoacetaldehyde dimethyl acetal hydrochloride, was recycled by treating the aqueous solution of the salt with a 5 N NaOH solution to pH 12, and extracting with diethyl ether.
The filtered toluene solution was washed with water, dried over sodium sulfate and concentrated under reduced pressure to give the crude product as a brown oil (12.7 g, 47.7 mmol, 94%). The oil was dissolved in diethyl ether and dry HCl-gas was passed through the solution to precipitate the HCl-salt of the amine as a pale brown solid. The procedure was repeated to complete the precipitation and 12.2 g (40.1 mmol, 79%) of 4 was obtained.
m.p. 151.5-152.5°C. 1H NMR (D2O, 200 MHz): δ = 2.87 (t, J=6.8 Hz, 2H), 3.08 (d, J=4.9Hz, 2H), 3.49 (s, 6H), 3.57 (t, J=6.8 Hz, 2H), 3.80 (s, 2H), 4.75 (t, J=4.9Hz, 1H), 7.31-7.45 (m, 5H). 13C NMR (D2O, 50.3 MHz): δ = 35.1, 41.2, 48.5, 48.6, 56.2 (2C), 100.7, 127.2, 129.3 (2C), 129.6 (2C), 139.7, 165.8. C14H23ClN2O3 (302.8).

One-pot synthesis of 2-((2,2-dimethoxyethyl)amino)-N-phenethylacetamide


In a shortened one-pot two step procedure 2-phenylethylamine 1 was reacted consecutively with chloroacetyl chloride and aminoacetaldehyde diethylacetal in chloroform. As chloroform has a lower boiling point than toluene, it was necessary to extend the reaction time to 22 h for complete conversion of intermediate 2 to the required compound 4. To separate the side product aminoacetal hydrochloride from the reaction mixture, first the chloroform was removed, then the residue was dissolved in hot toluene and the resulting precipitate was filtered off. From the orange filtrate the amine was separated as its hydrochloric salt. The yield of hydrochloric amine 4 over two steps is nearly the same (69%) as the conversion with an isolation of the intermediate 2, but the synthesis could possibly be improved by selection of a higher boiling solvents (i.e. dichloroethane) or a change of the solvent to toluene after the first step.

To a suspension of 2-phenylethylamine 1 (5.00 g, 47.6 mmol) and NaHCO3 (4.08 g, 48.5 mmol) in CHCl3 (80 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 to room temperature and stirred for an additional 2 h. After complete consumption of the starting material (TLC control) aminoacetaldehyde diethylacetal (10.5 g, 100 mmol, 2.1 eq.) was added and the mixture was heated to reflux for 22 h. The solvent was removed under reduced pressure and the residue was heated to reflux with toluene (20 mL). The ice-cooled solution was separated from the resulting residue by filtration. The filtered liquid was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude amine, obtained as orange oil (10.6 g, 39.8 mmol, 84% over 2 steps) was dissolved in dry diethyl ether and treated with dry HCl-gas to form the hydrochloric salt 4 as light brown solid (9.91 g, 32.7 mmol, 69% over 2 steps).  

[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.