Derivatives of PZQ: 9,10-dimethoxy-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a] isoquinoline

31 Mar
Published by Michael Wolfle
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reaction
 
In a 3-step-sequence 3,4-dimethoxyphenethylamine 8 was converted to the tetrahydroisoquinoline derivative 9. Chloroacetyl chloride was added to 8 in the first step, some starting material was present in the product but could purified by an acidic wash.
In the following step 2.1 equivalents of aminoacetaldehyde dimethyl acetal were used, because the reagent also had the function as a base to trap the forming HCl. The HCl-salt of the amin precipitated when the solution was cooled down to 0° C and was filtered off.
The resulting intermediate was directly cyclisized to the Pictet-Spengler product 9 by treating the amine with concentrated sulfuric acid. In literature, the aminoacetal was first isolated by its HCl-salt before it was converted to the heterocycle 9, which led to a loss of yield.[1]

Procedure:
To a suspension of 3,4-dimethoxyphenethylamine 8 (2.62 g, 14.4 mmol) and NaHCO3 (1.81 g, 21.6 mmol) in DCM (15 mL) chloroacetyl chloride (2.44 g, 21.6 mmol) was added dropwise at 0° C over a period of 90 min. The mixture was warmed to room temperature and stirred for 12 h. After which time, the mixture was quenched with water and the aqueous layer was extracted with DCM. The combined organic layers were washed with 1 N HCl solution and brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was obtained as a yellow solid (3.28 g, 12.7 mmol, 88%).

1H NMR (CDCl3, 200 MHz): δ = 2.79 (t, J = 7 Hz, 2H), 3.54 (td, J = 7 Hz, 3 Hz) 3.86 (s, 3H), 3.87 (s, 3H), 4.02 (s, 2H), 6.72-6.85 (m, 3H, NH). 13C NMR (CDCl3, 50.3 MHz): δ = 35.6, 41.7, 43.2, 56.4, 56.5, 112.1, 112.5, 121.3, 131.5, 148.4, 149.7, 166.4. C12H16ClNO3 (257.7).

The product of the former step (2.00 g, 7.76 mmol) was dissolved in toluene (7 mL), aminoacetaldehyde dimethyl acetal (1.71 g, 16.3 mmol) was added and the solution was heated to reflux for 1 h. After complete conversion the solution was cooled to 0° C and filtered off of the colorless precipitate. The filtrate was concentrated under reduced pressure to give 2.26 g (6.91 mmol, 89%) of a yellow and viscous oil.

1H NMR (CDCl3, 200 MHz): δ = 1.78 (bs, 1H), 2.65 (d, J = 5.3 Hz, 2 H), 2.78 (t, J = 7.0 Hz, 2 H), 3.25 (s, 2H), 3.35 (s, 6 H), 3.53 (td, J = 7.0, 6.3 Hz, 2 H), 3.86 (s, 3H), 3.87(s, 3H), 4.31 (t, J = 5.3 Hz, 1 H), 6.72-6.84 (m, 3H), 7.31 (bs, 1H). 13C NMR (CDCl3, 50.3 MHz): δ = 35.4, 40.2, 51.1, 52.4, 54.0 (2 C), 55.9, 56.0, 103.4, 111.4, 112.0, 120.7, 131.5, 147.4, 149.1, 171.5. C16H26N2O5 (326.4).

To the yellow oil (500 mg, 1.53 mmol) cold concentrated sulfuric acid (1mL) was added at 0° C and stirred for 3 h at room temperature. The viscous solution was quenched with ice, made basic to pH 12 by adding 2 N NaOH solution and extracted with DCM. The organic layer was washed with water and brine and dried over sodium sulfate. Purification of product by column chromatography (silica gel, EtOAc:MeOH:Et3N, 1:1:0.01) obtained 9 (233 mg, 888 µmol, 58%) as a orange viscous oil.

Rf (EtOAc:MeOH:Et3N, 1:1:0.01) = 0.25. 1H NMR (CDCl3, 200 MHz): δ = 2.61-2.91 (m, 4H), 3.58 (ABq, J = 17.z Hz, Δν = 21 Hz, 2H) 3.86 (s, 6H), 4.73-4.01 (m, 2H), 4.30 (bs, 1H), 6.64-6.66 (m, 2 H). 13C NMR (CDCl3, 50.3 MHz): δ = 27.9, 38.3, 49.1, 49.3, 55.4, 55.7, 55.9, 107.6, 111.5, 125.5, 126.7, 147.4, 147.6, 166.7, 174.0. C14H18N2O3 (262.3).

[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.
 

Comments

MatTodd's picture

Great. This is a good process. I guess the yield in the cyclization is a little surprising. Naturally the issue is the need to purify with column chromatography. If this were to become an interesting route from the point of view of an industrial synthesis (e.g. if those methoxy groups helped a catalytic asymmetric version of the Pictet-Spengler) then we would want solids, which can be crystallized, throughout.
For a resolution, though, at this stage, we are interested only in crystallizing the final amine. Is this possible as a simple hydrochloride salt? If this amine is easier to resolve than the PZQ praziquanamine, then that would also increase the profile of this molecule.