Enantioselective Hydrogenation of dehydro-PZQ and derivatives

 

Hazard and Risk Assessment:


Procedure:
A mixture of recovered SM from MNR40-1 (3.29 g, 10.74 mmol) and sulfur (0.69 g, 21.48 mmol) under argon was heated at 190°C in a sand bath for 2 hours.

Hazard and Risk Assessment:


Procedure:
A mixture of MNR14-5 (3.9 g, 12.73 mmol) and sulfur (0.82 g, 25.46 mmol) under argon was heated at 190°C for 15 minutes by use of a heat gun. The mixture was then allowed to cool and diluted with EtOAc (20 mL) at which time a lot of solid crashed out of the mixture. Toluene (20 mL) was added and the mixture was heated to get everything into solution. The mixture was then left to cool and stand at room temperature. After 2 hours crystals had formed and they were filtered and washed with toluene. to give off white crystals 0.76 g - before washing there appeared to be more crystals so it can be assumed that a different solvent should be used to wash the crystals. The filtrate was concentrated to about 20 mL and left to stand overnight, more crystals appeared but they didn't look as clean. They were filtered and washed with toluene:hexane (50:50) to give what looked like a mixture of the above crystals and a yellow/orange solid.

1H NMR of the crystals showed that both drops were clean starting material



TLC (100% EtOAc) showed some reaction had occurred. spots from left to right. SM, Co, Crystals, Co, Filtrate. Product expected to run higher than SM.



1st crop 0.760 g
2nd crop 2.559 g

Total recovered by crystallisation 3.319 g

Hazard and Risk Assessment:


Procedure:
A mixture of rac-PZQ (10.0 g, 32.0 mmol) and sulfur (2.1 g, 64.0 mmol) under argon was heated at 190°C for 15 minutes by use of a heat gun. The mixture was then allowed to cool and diluted with DCM and EtOAc (100 mL) (probelems getting everything into solution, some white solid left behind). Silica was added and the solvent was evaporated and purified by column chromatography (25% EtoAC/Hex)

Frac 1-6
Frac 7-8 - attempted re-cryst with toluene
Frac 9-12

Hazard and Risk Assessment:

Procedure: A mixture of rac-PZQ (1.0 g, 3.2 mmol) and sulfur (0.210 g, 6.4 mmol) under argon was heated at 190°C for 15 minutes by use of a heat gun. The dark brown solid was dissolved in ethyl acetate, evaporated on silica gel and purified by column chromatography (20-40% EtoAC/Hex)

Frac 17-30 - 0.455 g, 1.46 mmol, 46 % as a yellow solid

Frac 40-44 - 0.328 g, 1.05 mmol, 33 % recovered PZQ

1 H NMR 13C NMR

FCC fractions ran in 50% EtOAC/Hexane

 

IR 

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1H NMR data from MW59-7 recently found, uploaded here

Scale-up: Oxidation of N-benzoyl-PZQ by sulfur (MW59-7)

Experiments on the oxidation of N-benzoyl-PZQ to the enamide by molten sulfur. Repetition of Scale-up: Oxidation of N-benzoyl-PZQ by sulfur (MW59-7) to synthesize more N-benzoyl-PZQ enamide



See related experiments on rac-PZQ:
Sulfur melt data smogasbord
Oxidation of N-benzoyl-PZQ by sulfur (MW59-1 to MW59-6)

Hazard and Risk Assessment:


Start time: 4:20 PM 2/05/2011

A mixture of N-benzoyl-PZQ (518 mg, 1.69 mmol, M.W. 306.4 g/mol) and sulfur (108 mg, 3.38 mmol, 2 eq., M.W. 32.1 g/mol) were heated at 190°C for 2 h.
The dark brown solid was dissolved in ethyl acetate, evaporated on silica gel and purified by column chromatography (ethyl acetate: hexane, 1:1)
-TLC showed that there was still starting material left

Yield: 237 mg (780 µmol, 46%) yellow solid [M.W. 304.3 g/mol]
-> sulfur impurities

Further procedure, see: Scale-up: Oxidation of N-benzoyl-PZQ by sulfur (MW59-7)

Results:
The reaction had not gone to completion after 2 h, however an increase in reaction time / temperature would more than likely improve the yield.