Pictet-Spengler route to Praziquantel

 

START: 20/03/12
FINISH:



Hazard and Risk Assessment


Previous Experiments
Synthesis of N-[2-(3,4-Dimethoxyphenyl)ethyl]-1-phenylmethanimine (KAB19-1)
Synthesis of 1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB20-2)
Synthesis of 1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB20-3)

Following Experiments
TFA mediated synthesis of 6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (KAB24-1)

Chemical Information
N-[2-(3,4-Dimethoxyphenyl)ethyl]-1-phenylmethanimine (1, KAB19-1) SMILES: O(c1ccc(cc1OC)CC/N=C/c2ccccc2)C, InChI: InChI=1S/C17H19NO2/c1-19-16-9-8-14(12-17(16)20-2)10-11-18-13-15-6-4-3-5-7-15/h3-9,12-13H,10-11H2,1-2H3/b18-13+, InChIKey: HEYKSOUNCDDROU-QGOAFFKASA-N
6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (2, KAB21-1) - SMILES: O(c1c(OC)cc3c(c1)C(c2ccccc2)NCC3)C, InChI: InChI=1S/C17H19NO2/c1-19-15-10-13-8-9-18-17(12-6-4-3-5-7-12)14(13)11-16(15)20-2/h3-7,10-11,17-18H,8-9H2,1-2H3, InChIKey: GZGZWZVAJDFXJK-UHFFFAOYSA-N

References


Procedure
20/03/12. KAB19-1 (1.9 g, 7.1 mmol) was dissolved in toluene (40 mL) before the addition of trifluoroacetic acid (TFA, 30 mL, 50 eq) at rt. The pale yellowish solution turned a darker yellow after addition of the TFA. The reaction mixture was reflux heated at 110 °C from 12:00.
22/03/12. At 10:00 (+22 hours) the reaction mixture was allowed to cool before it was poured over ice and basified with NaOH solution (6 M), which resulted in the precipitation of a white solid. Attempted filtration. Solid was too fine and passed through the sintered funnel. The reaction mixture was transferred to a separating funnel and the organic fraction isolated. The basic aqueous fraction was extracted with EtOAc (4 × 50 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, then concentrated under reduced pressure to give a crude KAB21-2 as a brown foam (2.1 g, 111%).
¹H-NMR of the crude product confirmed the presence of the tetrahydroisoquinoline scaffold.


27/03/12. Attempted purification of the crude product by silica gel column chromatography, eluting with EtOAC/hexane, 2:5, v/v.
Fraction 2 - fastest eluting spot. Fraction was oncentrated under reduced pressure to give a sweet smelling orange oil (26 mg). H-NMR suggested the collected fraction was a byproduct. Presence of aldehyde proton ~10 ppm.
[see notes below]
The column was flushed with MeOH and all the collected eluent after fraction 2 was combined and concentrated under reduce pressure. Recovery: 2.6 g. Increased mass balance may be due to the presence of silica.

Summary and Conclusion

-----------------------------------------------------------------------------
NOTES 21/03/12
- Forgot to weigh flask before adding the product to it.
- Need to purify product.

NOTES 27/03/12
- Recovery flask weight: 60.617 g
- Stuffed up column. Flushed with MeOH. Removed 26 mg worth of impurity.
-----------------------------------------------------------------------------