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Pictet-Spengler route to Praziquantel
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21st May 2010 @ 10:36
Preparing starting material for the Pictet-Spengler cyclisation, Repeated experiment, see here:(www.thesynapticleap.org/node/301)


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

Reaction.png


Ordered starting materials arrived:
  • Aminoacetaldehyde dimethyl acetal (Alfa Aesar, 99%)
  • 3,4-Dimethoxyphenetylamine (Alfa Aesar, 99%)


Table1.jpg



Procedure:
MW9-3-77 (2.39 g, 9.29 mmol) and aminoacetaldehyde dimethyl acetal (2.00 g, 19.0 mmol) were dissolved in toluene (10 mL) and heated to reflux. After 30 min the starting material was completely consumed, as monitored by TLC (hexane/EA = 1:1).
The solution was cooled to 0°C, the resulting precipitate was filtered off and washed with cold toluene. The filtrate was quenched with 2 N NaOH solution and the aqueous layer was extracted five times with ethyl acetate. The combined organic layers were washed brine, dried over sodium sulfate and concentrated under reduced pressure.
  • Purification by column chromatography (silica gel, EA/MeOH/TEA = 20:1:0.1)

    - TLC (EA:MeOH:TEA, 10:1:0.1; stain: Ceric ammonium molybdate):
DSC09862.JPG




Results:
Product MW14-3-79: 2.25 g (6.89 mmol, 74%) yellow oil (small impurities of aminoacetaldehyde dimethyl acetal).


Analytical data:
Rf (EA:MeOH:TEA, 10:1:0.1) = 0.41.
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). [Data: 1H NMR]
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. [Data: 13C MW14-3]
IR (neat): nu = 3325 cm-1, 2935, 2834, 1660, 1652, 1514, 1260, 1234, 1127, 1056, 1025. [Data: IR]
MS (ESI (+)) m/z (%): 653 (100, [M2H]+), 548 (29), 327 (56, [MH]+), 295 (35).
HRMS (ESI (+)) Calcd. for [C16H26N2O5H]+: 327.1914, found: 327.1910.
C16H26N2O5 (326.4).

-> starting material for MW28 (Pictet-Spengler cyclisation) and MW32 (N-cyclohexanoly protection)


References:
[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.
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Attached Files
Reaction.png
Table1.jpg
DSC09862.JPG
IR
1H NMR
1H NMR JCAMP-DX
13C MW14-3
13C MW14-3 JCAMP-DX
Comments
Re: (MeO)2-derivative of PZQ: preparation of starting material (MW14-3-79) by Matthew Todd
22nd May 2010 @ 16:22
The table above of the reagents and equivalents - it would probably save you time if you put that into the main post, rather than making a picture file of it? Just make it a separate section at the start?

Obviously the nicest thing would be to be able to have the picture of the reaction scheme not as a picture but as something that was editable/copyable/pastable. I think that's not possible with the current version of the lab blog, however.

Spectra - I think the best thing would be to post raw NMR data plus a processed spectrum.

We're also going to need links to TSL pages where appropriate. Lots of effort, but at least you don't have to write a paper copy of it too...
Re: (MeO)2-derivative of PZQ: preparation of starting material (MW14-3-79) by Matthew Todd
22nd May 2010 @ 18:07
Just a note for later - it would be nice if the posts contained InChIs for the molecules under discussion. Ideally the structure editor/renderer would automatically generate these. Or they could be generated in some other way. It seems like a shame to involve a human being in their generation!
Re: (MeO)2-derivative of PZQ: preparation of starting material (MW14-3-79) by Michael Wolfle
24th May 2010 @ 04:46
The table is an artefact of my Word template - I included Excel tables which enables a fast calculation of the stoichiometry of the starting materials without using an external calculator. Converting the table into a image file is a short procedure. However, for a better overview a separate itemization would be better...

It would be nice to have a wider variety in data formats and a more convenient upload procedure (copy/paste). With the current version it’s not possible to attach raw data (only .jpg and .png files).
Re: (MeO)2-derivative of PZQ: preparation of starting material (MW14-3-79) by Matthew Todd
24th May 2010 @ 06:59
The link between the blog and the spectral data needs to be automatic - we need the NMR computer to send the data to the relevant blog entry. That's what we're going to be working on behind the scenes! For the moment what you've done is perfect, though it takes too long. The weak link is always going to be TLC. I don't know of a shortcut for that - a photo is very useful, but again too time-consuming for you to do over and over.