Enantiopure PZQ

Background Preparation for the imidobis(sulfuryl chloride) component for use in the synthesis of racemic 1,1'-Binaphthyl-2,2'-bis(sulfuryl)imide.[1] Hazard and Risk Assessment HRA KAB15-1.pdf Following Experiments Procedure References A. Berkessel, P. Christ, N. Leconte, J. M. Neudorfl, M. Schafer, Eur. J. Org. Chem. 2010, 5165. -------------------------------------------------------------- NOTES --------------------------------------------------------------

Safety clearance: Process discussed with Kat 10 a.m. 13/2/12. Discussed procedures to minimize hazards associated with water-sensitive and corrosive reagents, method to purify product with distillation and method for quenching reaction upon completion. Postdoc Murray Robertson to supervise hazardous procedures.

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.

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).

KAB1 The dimethoxy praziquantel analogue via the Pictet-Spengler cyclisation of the peptide acetal precursor. Acid-catalyzed Pictet-Spengler of MNR8-1 using binapthalenedisulfonic acid to give KAB1-1 KAB3 Racemic praziquantel via the Pictet-Spengler cyclisation of the peptide acetal precursor. Stoichiometric acid-mediated Pictet-Spengler of MW29-4 to give racemic PZQ (KAB3-1 and KAB3-2) Stoichiometric acid-mediated Pictet-Spengler cyclisation of the PZQ Ugi-intermediate and the N-benzoyl PZQ, dimethoxy PZQ and dimethoxy N-benzoyl PZQ analogue intermediates (KAB5-1, KAB6-1, MNR8-2 & MNR10-1 to give KAB3-3, KAB7-1, KAB1-2 & KAB8-1, respec Acid-mediated Pictet-Spengler reaction to give PZQ (KAB3-4) and the N-benzoyl PZQ analogue (KAB7-2) Acid-mediated Pictet-Spengler reaction to give PZQ (KAB3-5) Reattempt acid-mediated Pictet-Spengler reaction to give PZQ (KAB3-6) Reducing decomposition in the acid mediated Pictet-Spengler to give PZQ (KAB3-7). The Pictet-Spengler reaction to give PZQ...

PS = Pictet-Spengler START: 08/02/12 FINISH: 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) Monitoring the Reaction Progress by TLC -------------------------------------------------------------- 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. --------------------------------------------------------------

The following compounds have been identified as potential antimalarial drugs by GSK-Tres Cantos. The top compound, known hereafter as 'compound 3', can be found on ChEMBL and ChemSpider: https://www.ebi.ac.uk/chembld... - ChEMBL https://www.chemspider.com/Chemica...... - ChemSpider   As can the bottom compound, known hereafter as 'compound 4': read more

*PS = Pictet-Spengler Parallel PS reaction of KAB5-2 to give PZQ catalysed by 60, 30, 15, 10 and 5 mol% TfOH. Hazard and Risk Assessment Previous Related Experiments Following Experiments Procedure Monitoring the Reaction Progress by TLC References ----------------------------------------------------------------------------- NOTES -----------------------------------------------------------------------------

Hazard and Risk Assessment: Procedure: To a stirring solution of MNR10-2 (15.5 g, 38.8 mmol) in toluene (500 mL) at 0 °C was added a solution of TfOH (1.5 mL, 16.90 mmol) in toluene (35 mL) dropwise via canula. The reaction was then stirred at 0 °C for XX hours

*PS = Pictet-Spengler START: 06/02/12 FINISH: Hazard and Risk Assessment Previous Related Experiments Following Experiments Procedure Monitoring the Reaction Progress by TLC References ----------------------------------------------------------------------------- NOTES ----------------------------------------------------------------------------

PS = Pictet-Spengler Background Reducing catalyst loading in the procedure of KAB8-4. Hazard and Risk Assessment Hazard and Risk Assessment KAB8-10 Previous Related Experiments The silver(I) triflate catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-4) TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-7 & KAB8-8) Following Experiments Procedure A mixture of MNR10-1 (95.5, 0.208 mmol) and AgOTf (13.7 mg, 53 μmol, 27 mol%) in toluene (30 mL) was reflux heated at 90 °C from 09:00. Monitoring the Reaction Progress by TLC ----------------------------------------------------------------------------- NOTES -----------------------------------------------------------------------------

Hazard and Risk Assessment: As for MNR8-1 Procedure: To a stirring suspension of paraformaldehyde (0.63 g, 21.0 mmol), 2,2-dimethoxyethylamine (3.04 mL, 21.0 mmol) and cyclohexanecarboxylic acid (2.60 mL, 21.0 mmol) in methanol (20 mL) at 0 °C was added 2-(3,4-Dimethoxyphenyl)ethyl isocyanide MNR4-2 (4.0 g, 21.0 mmol) dropwise and stirred at room temperature for XX hours.

Hazard and Risk Assessment HRA KAB5-2 & KAB62 Previous Related Experiments Following Experiments Procedure References -------------------------------------------------------------- NOTES 01/02/12 --------------------------------------------------------------

Hazard and Risk Assessment HRA KAB5-2 & KAB62 Previous Related Experiments Preparation of 2-(3,4-Dimethoxyphenyl)ethyl isocyanide (MNR4-2) Preparation of the PZQ analogue Ugi-intermediate (KAB5-1) Preparation of the N-benzoyl PZQ analogue Ugi-intermediate (KAB6-1) Following Experiments Procedure 01/02/12 A mixture of paraformaldehyde (2.29 g, 76.2 mmol), cyclohexanecarboxylic acid (9.77 g, 76.2 mmol), 2,2-diethoxyethylamine (10.15 g, 76.2 mmol) in methanol (76 mL) was cooled in a brine ice bath. KAB4-2 (~10 g, 76 mmol) was added dropwise to the mixture at 0 °C, turning the white solution yellow. The reaction mixture was allowed to warm to room temperature and stirred from 14:00. References [1] H. Cao, H. Liu, A. Doemling, Chemistry-a European Journal 2010, 16, 12296 (DOI: 10.1002/chem.201002046) -------------------------------------------------------------- NOTES 01/02/12 --------------------------------------------------------------

Hazard and Risk Assessment: HIRAC MNR10.pdf Procedure: To a stirring suspension of paraformaldehyde (17.40 g, 91.0 mmol), 2,2-dimethoxyethylamine (13.2 mL, 91.0 mmol) and benzoic acid (11.11 g, 91.0 mmol) in methanol (90 mL) at 0 °C was added 2-(3,4-Dimethoxyphenyl)ethyl isocyanide MNR4-2 (17.4 g, 91.0 mmol) dropwise and stirred at room temperature for XX hours.

*PS = Pictet-Spengler Background Preparing the enediamide for future acid catalysed reactions to give PZQ. The second and final cyclisatiton step to give PZQ from the enediamide does not require the loss of ethoxy groups, which may reduce side reactions and result in cleaner reactions. Hazard and Risk Assessment Hazard and Risk Assessment KAB13-1 Previous Related Experiments Enediamide intermediate cyclisation to give the dimethoxy N-benzoyl PZQ analogue (KAB12-1) Copper(II) triflate catalysed preparation of the dimethoxy N-benzoyl PZQ enediamide (KAB11-3) Following Experiments Procedure KAB5-1 (1.80 g, 4.45 mmol) was dissolved in stirred toluene (45 mL) before the solution was cooled in a brine ice bath. Methanesulfonic acid (MSA, 0.63 mL, 4.45 mmol, 1 eq) was added to 0.1 M at 0 oC. The reaction mixture was stirred at rt from 11:45. Reaction mixture at 5 min Monitoring the Reaction Progress by TLC References

*PS = Pictet-Spengler *****Experiment still in progress with regular updates. Last updated 30/01/12. Background Further reduction of catalyst loading. See procedure for the preparation of KAB8-7 and KAB8-8. Hazard and Risk Assessment As for KAB8-5 (here) Previous Related Experiments Controls for the AgOTf catalysed PS* to give the dimethoxy N-benzoyl PZQ analogue (KAB8-5 & KAB8-6) The silver(I) triflate catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-4) Following Experiments Procedure Conclusion -------------------------------------------------------------- NOTES 30/01/12 --------------------------------------------------------------

*PS = Pictet-Spengler *****Experiment still in progress with regular updates. Last updated 30/01/12. Background Repeat of procedure for the preparation of KAB8-5 with reduced catalyst loading. Hazard and Risk Assessment As for KAB8-5 (here) Previous Related Experiments Following Experiments Procedure A 64 mM solution of TfOH in toluene was prepared by mixing TfOH (5 drops, ~9.66 mg/drop) in toluene (5 mL). Conclusion -------------------------------------------------------------- NOTES 30/01/12 --------------------------------------------------------------

Hazard and Risk Assessment: HIRAC MNR4.pdf A solution of 3,4-dimethoxyphenethylamine (24.0 mL, 132 mmol) in ethyl formate (130 mL, 1590 mmol) was heated to reflux for 13 h. The remaining ethyl formate and the by-product ethanol were removed under reduced pressure to give yellow liquid. The crude 2-(3,4-Dimethoxyphenyl)ethylformamide and triethylamine (55.4 mL, 397 mmol) were dissoved in dry DCM (240 mL) and phosphoryl chloride (12.3 mL, 132 mmol) was added dropwise added at 0°C. The mixture was then stirred for 1 h at 0°C and a further 4 h at room temperature. The mixture was quenched with water and neutralized with NaHCO3 solution. The organic layer was separated and the aqueous solution was extracted DCM (x3). The organic layers were combined, dried over magnesium sulphate, filtered and evaporated afforded a dark brown oil.

*****Experiment in progress with regular updates. Last updated 30/01/12. Scheme Hazard and Risk Assessment Following Experiments Procedure 30/01/12 References Related Experiments -------------------------------------------------------------- NOTES 30/01/12 --------------------------------------------------------------

*PS = Pictet-Spengler Background Hazard and Risk Assessment Hazard and Risk Assessment Previous Related Experiments The silver(I) triflate catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-4) Silver(I) triflate catalysed preparation of the dimethoxy N-benzoyl PZQ enediamide (KAB11-2) Lewis acid catalysed preparation of the dimethoxy N-benzoyl PZQ enediamide (KAB11-1) Following Experiments Procedure Start: 27/01/12 Finish: The MNR10-1 starting material was dissolved in toluene before the addition of either triflic acid (TfOH) or silver trifluoroacetate. KAB8-5. MNR10-1 - 0.1018 g, 0.222 mmol Toluene - 34 mL TfOH - 2 drops, ~20 mg, 60 mol% KAB8-6. MNR10 - 97.8 mg Toluene - 34 mL AgCO2CF3 - 28.1 mg, 60 mol% Both mixtures were heated to 90 oC from 10:10. Monitoring the Reaction Progress by TLC References -------------------------------------------------------------- NOTES 27/01/12 - Estimated TfOH mass by weighing 10 drops then 5 drops: 10 drops = 0.1029 g (10.3 mg/drop); 5...

I've been working with the Todd research group at Sydney University for six weeks now as part of a summer research program. read more

*****Experiment in progress with regular updates. Last updated 25/01/12. Background Scheme Hazard and Risk Assessment Hazard and Risk Assessment KAB12-1 Following Experiments Procedure Start: 25/01/12 Finish: KAB8-2 (57 m, 16 mmol) was dissolved in toluene (2 mL) before MW45-3 (11 mg, 17 mol%) was added. The mixture was stirred and reflux heated at 70 oC from 15:10. Related Experiments -------------------------------------------------------------- NOTES 25/01/12 - Put as much in catalyst as I could get out of the vial but, couldn't quite get out 20 mol%. --------------------------------------------------------------

January 2012, Here’s a quick update on where we are regards the Bronsted Acid catalysed Pictet-Spengler reaction.   read more

*********Experiment still in progress with regular updates. Last updated 23/01/12 Attempt at the AgOTf and Cu(OTf)2 catalysed Pictet-Spengler reactions to give racemic PZQ. This method was previously applied to the synthesis of the electron rich dimethoxy N-benzoyl PZQ analogue (see KAB8-3 and KAB8-4). Scheme NOTE: Scheme should say 110 oC Hazard and Risk Assessment Hazard and Risk Assessment Following Experiments Procedure - KAB3-9 23/01/12 KAB5-1 (0.2153 g, 53.2 mmol) was dissolved in toluene (84 mL) before the addition of AgOTf (79.0 mg, 58 mol%). The mixture was stirred and heated to 110 oC from 09:22. KAB3-9 reaction mixture at 30 min Procedure - KAB3-10 23/01/12 KAB5-1 (0.1953 g) was dissolved in toluene (77 mL) before the addition of Cu(OTf)2 (105.0 mg, 60 mol%). The mixture was stirred and heated to 110 oC from 09:40. KAB3-10 reaction mixture at 15 min References Todd, M. H., Ndubaku, C. & Bartlett, P. A., J. Org. Chem. 2002, 67, 3985-3988 - DOI: 10.1021/jo010990m (Paper)...

We have received encouraging biological results for the analogues we sent for testing before Christmas. Mat has discussed this here on TSL and on G+. Our best hit came from the "near-neighbour" compound and the original GSK hits came out slightly less active than in their original high throughput screen. However, Paul Willis at MMV rates TCMDC-123794 as a better lead than PMY 14-1 (TSL post). read more

It’s been too long since I’ve updated the progress of this project on here but here’s a brief summary of where we are and what’s planned for the near future.  From late November we’ve had a summer student, Kat Badiola, working on the project.  She started with preparing pure, racemic samples of the 3 PZQ analogues shown below (compounds 6-8) via the Pictet-Spengler cyc read more