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5th July 2011 @ 00:45
Resolution of PZQ with chloride substituted tartaric acid derivative resolving agent.

See related experiments:
Resolution of PZQ with (-)-O,O'-dibenzoyl-(L)-tartaric acid (KB-PZQ-1009)
Multigram-scale racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-13)
Scale-up: Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-12)
Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-5 - MW49-11)
Racemic resolution of praziquanamine with (+)-Dibenzoyl-D-tartaric acid (MW49)
Synthesis of (-)-Dibenzoyl-L-tartaric acid (MW10-1-30) -> S-(+)-PZQamine
Diastereomeric salt resolution of praziquanamine with (-)-di-p-anisoyl-L-tartaric acid obtainig S-(+)-PZQamine (MW47-3)

Procedure
(rac)-praziquanamine (298 mg, 1.47 mmol, 1 eq.) and O'O-di-4-chlorobenzoyl-L-tartaric acid (633 mg, 1.47mmo1 1 eq.) were dissolved in i-PrOH/H2O (13 mL/2.6 mL) with heating and stirring. Mixture was allowed to cool to room temperature before being kept at 3oC for 48 hrs. White precipitate then formed (2.255 g).
1st July 2011 @ 06:52
4-bromo.png


See related experiments:
Resolution of PZQ with (-)-O,O'-dibenzoyl-(L)-tartaric acid (KB-PZQ-1009)
Multigram-scale racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-13)
Scale-up: Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-12)
Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-5 - MW49-11)
Racemic resolution of praziquanamine with (+)-Dibenzoyl-D-tartaric acid (MW49)
Synthesis of (-)-Dibenzoyl-L-tartaric acid (MW10-1-30) -> S-(+)-PZQamine
Diastereomeric salt resolution of praziquanamine with (-)-di-p-anisoyl-L-tartaric acid obtainig S-(+)-PZQamine (MW47-3)

Procedure:

[1] A hot solution of Praziquanamine (206 mg, 1 mmol, 1eq) in isopropanol:water mixture (2:1) (3 mL) was added to a hot solution of (-)-O,O'-di-4-bromobenzoyl-(L)-tartaric acid*EtOH (567 mg, 1 mmol, 1 eq) in isopropanol:water mixture (2:1) (3 mL).

[2] After standing for 2 days the mixture was filtered and washed with isopropanol:water (2:1) to give a pale yellow solid. The solid was recrystallised with isopropanol:water (2:1) to yield the diastereomeric salt as a white solid (616 mg, 85.8%, m.p. 174-176 oC).

[3] The combined filtrate (Note 1) was evaporated under reduced pressure and the resulting solid was basified with 12% aqueous solution of K2CO3. The solution was extracted with DCM (3 X 5 mL) and the combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the oil-like liquid, which was then dried (Note 2) to give (+)-PZQamine as a yellow solid (68.7 mg, 66.7%, m.p. 113-114 oC).

[4] The diastereomeric salt (from [2]) was basified with 12% aqueous solution of K2CO3 and the resulting solution was extracted with DCM (3 X 5 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the oil-like liquid, which was then dried (Note 2) to give (-)-PZQamine as a pale yellow solid (67.9 mg, 65.9%, m.p. 118-120 oC) (Note 3).

Notes:

(1) Colloid-like substance was observed after the first filtrate was stood overnight.

(2) The oil-like liquid would't solidify no matter being in vacuo or under nitrogen gas. Ethyl acetate (ca 1.5 mL) was added and crystallisation started after putting under nitrogen gas.

(3) Judging from the melting point of two PZQamine enantiomers, (-)-PZQamine is better purified than (+)-PZQamine. Most importantly,by comparing to Kaitlin's results that the change of the solvent from isopropanol to isopropanol:water (2:1) mixture while other conditions remain the same, the outcome of the experiment turned to the opposite direction: the resolving agent extracted (-)-PZQamine instead of (+)-PZQamine.
Attached Files
16th June 2011 @ 08:29
See related experiments:
Resolution of PZQ with (-)-O,O'-dibenzoyl-(L)-tartaric acid (KB-PZQ-1009)
Multigram-scale racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-13)
Scale-up: Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-12)
Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-5 - MW49-11)
Racemic resolution of praziquanamine with (+)-Dibenzoyl-D-tartaric acid (MW49)
Synthesis of (-)-Dibenzoyl-L-tartaric acid (MW10-1-30) -> S-(+)-PZQamine
Diastereomeric salt resolution of praziquanamine with (-)-di-p-anisoyl-L-tartaric acid obtainig S-(+)-PZQamine (MW47-3)

scheme MW49-5.png


Procedure:
A hot solution of Praziquanamine (202 mg, 1 mmol, 1eq) in i-PrOH (3 mL) was added to a hot solution of (-)O,O'-di-4-bromobenzoyl-(L)-tartaric acid*EtOH (560 mg, 1 mmol, 1 eq) in i-PrOH (3 mL) (Note 1) A white precipiate was formed imediately. The mixture was cooled to r.t. and filtered to give the diastereomeric salt as a white solid (350 mg, 50%).

Crystallization:
The diasteriomeric salt (304 mg) was recrystallised from a mixture of i-PrOH and water (isopropanol:water = 2:1) to give the salt as white crystals (275 mg, 38%, m.p. 199-200 oC).

Liberation of (+)-prazaqanamine
The diasteremeric salt (273 mg) was treated with a 12% aqueous solution of K2CO3. The resulting solution was extracted with DCM (3 X 5 mL) and the combined organic layers concentrated in vacuo to give (+)-prazaquanamine as a white solid (66 mg, 33%, 73% ee).

Liberation of (-)-prazaquanamine
The combined mother liquers from the resolution and recrystallisation were concentrated in vacuo and treated with a 12% aqueous solution of K2CO3. The resulting solution was extracted with DCM (3 X 5 mL) and the combined organic layers concentrated in vacuo to give (-)-prazaquanamine as a pale yellow solid (75 mg, 37%, 62% ee).

Notes:
(1) An initial attempt to prepare the diastereomeric salt by heating a mixture of PZQamine and the resolving agent in i-PrOH/H2 (5:1) resulted in the formation of a colloid-type substance, which would not dissolve on further heating and was not ammenable to filtration.
14th June 2011 @ 06:57
See related experiments:
Multigram-scale racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-13)
Scale-up: Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-12)
Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-5 - MW49-11)
Racemic resolution of praziquanamine with (+)-Dibenzoyl-D-tartaric acid (MW49)
Synthesis of (-)-Dibenzoyl-L-tartaric acid (MW10-1-30) -> S-(+)-PZQamine
Diastereomeric salt resolution of praziquanamine with (-)-di-p-anisoyl-L-tartaric acid obtainig S-(+)-PZQamine (MW47-3)

scheme MW49-5.png


Procedure:
Praziquanamine (202 mg, 1 mmol, 1eq) and (-)-O,O'-dibenzoyl-(L)-tartaric acid* 2 i-PrOH (478 mg, 1 mmol, 1 eq) were dissolved in a mixture of i-PrOH (5 mL) and water (1 mL) by heating the stirred mixture. The solution was allowed to cool to room temperature and then kept at 3 oC for 48 h. The resulting white precipiate was then filtered off (304 mg, 54%) and the mother liquer saved.

Crystallization:
The diasteriomeric salt (304 mg) was recrystallised from a mixture of i-PrOH and water (isopropanol:water = 2:1) to give the salt as white crystals (231 mg, 41%, m.p. 147-148 oC).

Liberation of (-)-prazaqanamine
The diasteremeric salt (230 mg) was treated with a 12% aqueous solution of K2CO3. The resulting solution was extracted with DCM (3 X 5 mL) and the combined organic layers concentrated in vacuo to give (-)-prazaquanamine as a white solid (73 mg, 36%, 99% ee).

Liberation of (+)-prazaquanamine
The combined mother liquers from the resolution and recrystallisation were concentrated in vacuo and treated with a 12% aqueous solution of K2CO3. The resulting solution was extracted with DCM (3 X 5 mL) and the combined organic layers concentrated in vacuo to give (+)-prazaquanamine as a pale yellow solid (39 mg, 19%, 99% ee).
Attached Files
31st May 2011 @ 07:29
Testing of (+)-di-p-toluoyl-D-tartaric acid as a possible resolving agent for PZQamine via a diastereomic salt.

Scheme:
cs-5-1.png


See Also (Synthesis of resolving agent):
Synthesis of p-toluoyl chloride (CS-1-1)
Synthesis of di-p-toluoyl-D-tartaric acid (CS-2-1)

See also (Resolution experiments):
Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-5 to MW49-11)
Scale-up: Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-12)
Racemic resolution of praziquanamine with (+)-Dibenzoyl-D-tartaric acid (MW49-1 to MW49-4)

Start: 11:30am 13/05/11
Finish:

Procedure: rac-Praziquanamine (101 mg, 500 ┬Ámol) and di-p-toluoyl-D-tartaric acid(192 mg, 0.5 mmol) were dissolved in a various solvents (mixture or isopropanol and water (5mL in a 5:1 ratio) by heating the stirred mixture.

Overnight in fridge (5 degrees C) - white precipitate appeared but not crystalline, rather clumpy-white.

Solvent was removed and solid was washed with isopropanol. The salt was liberated with sodium hydroxide (2N, 8 mL), and extracted with dichloromethane (10 mL), then dried over sodium sulfate. The solvent was evaporated leaving a yellowish solid.

Yield: 27.7 mg