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Pictet-Spengler route to Praziquantel
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8th February 2012 @ 00:00
PS = Pictet-Spengler

TO DO
- Record C-NMR
- Upload MS
- Record IR


START: 08/02/12
FINISH: 25/02/12 - intermediate still unidentified.

Scheme%20KAB14-1.png

Hazard and Risk Assessment
Hazard and Risk Assessment KAB14-1


Previous Related Experiments
TfOH catalysed PS* reaction to give PZQ (KAB3-12 to KAB3-16)

Following Experiments

Procedure
KAB5-2 (780 mg, 1.928 mmol) was dissolved in toluene (70 mL) before the addition of TfOH (3 drops, ~29 mg, 10 mol%). The pale yellow solution instantly turned a darker yellow following addition of the TfOH. The reaction mixture was left to stir at rt from 11:05.
Reaction mixture (<10 min)
Reaction mixture (4.5 hr)

Monitoring the Reaction Progress by TLC
Eluent: EtOAc/hexane, 1:1, v/v.
Stain: KMnO4
TLC of reaction mixture (1.5 hr)
TLC of reaction mixture (3 hr)

At 15:30 (+4.5 hours) the reaction mixture was concentrated under reduced pressure. The yellow solution was loaded onto a silica gel column, which was then flushed with neat hexane to remove the residual toluene. The column was eluted with 20-100% EtOAc in hexane.
Loaded column

115 Fractions were collected and checked by TLC and stained with KMnO4. The following fractions were combined then concentrated under reduced pressure: 24-27, 28-34, 69-86, 95-105, 106-115.

TLC of the collected fractions (EtOAc/hexane, 1:1, v/v)
Fractions 24-31
Fractions 68-80
Fractions 94-103
Fractions 103-109
Fractions 106-114

Rf values of isolated spots: ~0.42, 0.42, 0.23, 0.13, 0.06.

KAB14-1a (Combined fractions 24-27)
Rf ~0.42 (EtOAc/hexane, 1:1, v/v)
Yield: 28.1 mg
TLC of the product shows some decomposition/further reaction. Major co-spotting is above 0.42, but there is also a baseline spot.

KAB14-1b (Combined fractions 28-34)
Rf 0.42 (EtOAc/hexane, 1:1, v/v)
Yield: 14.1 mg

KAB14-1c (Combined fractions 69-86)
Rf 0.23 (EtOAc/hexane, 1:1, v/v)
Yield: 213 mg
H-NMR KAB14-1c
Raw H-NMR KAB14-1c

The NMR suggested more than one product was present. Re-TLC of the product in CDCl3 showed multiple spots. Possibly due to continuation of the reaction when the combined fractions were concentrated under reduced pressure at 40 °C.
TLC of KAB14-1c


KAB14-1d (Combined fractions 95-105)
Rf 0.13 (EtOAc/hexane, 1:1, v/v)
Yield: 163 mg
KAB14-1d was concentrated to a yellow oil, which after standing at rt for 2 hours, began to show signs of crystallisation. The product was put in the freezer overnight (09/02/12-10/02/12) to promote crystallisation.
TLC of the oil/crystal showed no co-spotting.
KAB14-1d
TLC of KAB14-1d
Raw H-NMR KAB14-1d
H-NMR KAB14-1d


KAB14-1e (Combined fractions 106-115)
Rf 0.13 and 0.06 (EtOAc/hexane, 1:1, v/v)
Yield: 215 mg

22/01/12
In an attempt to purify the isolated product KAB14-1d, the solid was recrystallised from EtOAc/hexane to give small white crystals. The crystals were washed with hexane, then filtered. The 1H-NMR of the crystals was recorded. Spectra identical to that previously recorded.
Mass spec --> m/z 708

02/03/12
The intermediate as white crystals appears to be stable.

--------------------------------------------------------------
NOTES 08/02/12
- TLC of the reaction mixture at 11:05 showed the major component of the reaction mixture was the starting material, suggesting it should follow the same reaction course as KAB3-15 and the intermediates should be discretely formed by 3 hours.
- 14:32. Will let the reaction go for a total of 4.5 hours.
- All spots poorly absorbed UV light and TLC of the fractions required staining.
- Will need to re-column the cospotting fractions (106-115) in a different solvent system.
- Was unable to isolate the spot that appears with Rf between PZQ and KAB5-2.

NOTES 09/02/12
- Next available NMR slot is 12:30 tomorrow.
- Managed to NMR one sample (KAB14-1c). The NMR suggested more than one product was present. Possibly due to concentration under reduced pressure at 40 °C. Re-column?
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Linked Posts
Attached Files
Hazard and Risk Assessment KAB14-1
Scheme KAB14-1
Reaction mixture (<10 min)
TLC of reaction mixture (1.5 hr)
TLC of reaction mixture (3 hr)
Reaction mixture (4.5 hr)
Fractions 24-31
Loaded column
Fractions 68-80
Fractions 94-103
Fractions 103-109
Fractions 106-114
Raw H-NMR KAB14-1c
H-NMR KAB14-1c
TLC of KAB14-1c
KAB14-1d
TLC of KAB14-1d
H-NMR KAB14-1d
Raw H-NMR KAB14-1d
Comments
Re: Isolation of the TfOH catalysed PS to PZQ reaction intermediates (KAB14-1) by Matthew Todd
9th February 2012 @ 10:05
So 1a, 1b and 1d are behaving? Only 1c that's changing? And is the 1c turning into others things you've isolated, and not a separate, new thing?

Remember that you can easily get rotamers in these NMR spectra. You won't see them as separate things on TLC, but they can complicate NMR.

You have good amounts of each thing here, so should be possible to identify each - collate all the data you can. Once we know, our assay will be much more effective.
Re: Isolation of the TfOH catalysed PS to PZQ reaction intermediates (KAB14-1) by Katrina Badiola
9th February 2012 @ 10:18
1a isn't changing. Unsure about 1b or 1d. Will check before NMR slot (12:30) tomorrow.
Based on the TLC, 1c is turning into 1 or 2 of the other isolated spots, plus another spot, which is slightly higher than SM, but I was unable to isolate with the 10% loading - That particular spot was only clear after 6.5 hours with the 60% load (KAB3-12).