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31st August 2011 @ 03:07
RXN 004 - Enantiopure S-PZQamine (MNR2-2) is converted to S-PZQ (MNR1-2).

See
Resolution of praziquanamine with (+)-dibenzoyl-D-tartaric acid to obtain S-(+)-PZQamine (MNR2-2)

MNR1-2.png

MNR1-2%20table.PNG
Hazard and Risk Assessment:

As for MNR1-1

To a cooled solution of S-(-)Praziquanamine (MNR2-2, S-PZQamine, 0.30 g g, 1.48 mmol) in DCM (8 mL) at 0°C was added triethylamine (0.31 mL, 2.22 mmol) and cyclohexanecarbonyl chloride (0.22 mL, 1.63 mmol). The solution was stirred overnight at room temperature.

The solution was quenched with water (5 mL) and stirred for a further 30 minutes. The layers were separated and the organic layer was washed with saturated sodium carbonate solution (10 mL), 0.5 M HCl (10 mL) and brine (10 mL). Dried over magnesium sulfate, filtered and concentrated under reduced pressure. The remaining yellow oil was dried under high vacuum for 4 hours to give a foam which was dissolved in a mixture of acetone/hexane (15 mL, 1:1 mixture) and heated until dissolved. The solution was allowed to stand at room temperature over night and the crystals that were formed did not look clean but were filtered off and rinsed with a cold mixture of acetone/hexane. After washing the crystals very little remained. The washings were concentrated again and ran through a column (50% EtOAc/hexane) to give a clear oil that crystallized after 4 hours under high vacuum.

Clean fractions* 0.153 g, 0.49 mmol, 33%
[α]D20 = +117.1 (c = 1, EtOH) -> ee 86%

1H NMR - very poor resolution but this is standard
mnr1-2.pdf


*product also co-eluted with a higher spot, these fractions kept to one side.

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31st August 2011 @ 03:03

RXN 003 - Resolution of rac-PZQamine with (+)-dibenzoyl-D-tartaric acid (MW10-6) to obtain S-(+)-PZQamine (MNR2-2)

See Synthesis of (+)-Dibenzoyl-D-tartaric acid - alternative route (MW10-6) Hydrolysis of rac-PZQ (MW2-14)

Hazard and Risk Assessment: As for MNR2-1

rac-PZQamine (1.0 g, 4.94 mmol) and (+)-dibenzoyl-D-tartaric acid. 2IPA (2.37 g, 4.94 mmol) was dissolved in a mixture of isopropanol (20 mL) and water (2 mL) by heating. The solution was allowed to cool to room temperature and stand overnight. The solid was then filtered and rinsed with IPA/water (5:1, 50 mL).

Crude salt (1.626 g)

The salt (1.626 g) was dissolved in NaOH solution (2M, 25 mL) and extracted with DCM (25 ml x 3). The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a white solid (0.361 g, 1.78 mmol, 72 %).

MNR2-2 [α]D20 = +284° (c=1, DCM) ee 96 %

1H NMR

1H NMR - MNR2-2.pdf

Product taken on and used is N-Cyclohexanoyl-protection of MNR2-2 to give S-PZQ (MNR1-2)

IR 

1H NMR - MNR2-2.pdf

*Note, tartaric acid should have been recovered but was lost during a clean up.

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29th August 2011 @ 02:00
RXN 002 - Resolution of rac-PZQamine with (-)-di-p-anisoyl-L-tartaric acid (MW46-6) to obtain S-(+)-PZQamine (MNR2-1)

See:
Hydrolysis of rac-PZQ (MW2-14)
Repetition: Synthesis of (+)-Di-p-anisoyl-D-tartaric acid (MW46-6)

MNR2-1%20scheme.png

MNR2-1%20table.PNG
Hazard and Risk Assessment:

HIRAC MNR2.pdf


reaction on 0930
reaction off 1300

rac-PZQamine (1.0 g, 4.94 mmol) and (-)-di-p-anisoyl-L-tartaric acid (2.07 g, 4.94 mmol) was dissolved in a mixture of isopropanol (20 mL) and water (2 mL) by heating. The solution was allowed to cool to room temperature and stand for 3 hours. The solid was then filtered and rinsed with IPA/water (5:1, 50 mL).

Crude salt (2.597 g, 4.18 mmol, 85 %)

The salt (2.597 g, 4.18 mmol) was dissolved in NaOH solution (2M, 75 mL) and extracted with DCM (75 ml x 2). The aqueous layer was pH adjusted to pH2 using 6M HCl - see below. The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a cloudy white thick oil (0.263 g, 1.30 mmol, 26 %). The oil was taken up in refluxing IPA/Water (5:1, 10 mL) and left to stand overnight at room temperature. No crystals formed over night (too dilute?) so mixture was concentrated under reduced pressure and extracted with DCM (15 mL) and brine (15 mL), dried over magnesium sulphate, filtered and concentrated to give the oil as before. Upon drying on the high vac the oil slowly crystallized. Optical rotation of this showed the undesired enantiomer

MNR2-1 [α]D20 = -268° (c=1, DCM)

reaction not taken any further and moved onto MNR2-2

MNR2-1%20-%20resolved%20prodcut%20MNR3-1

1H NMR - resolved product
1H NMR -MNR2-1 - resolved product MNR3-1.pdf


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25th August 2011 @ 06:26
Multigram-scale racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-13)
MW49-13 [α]D20 = +146.2° (c=1, DCM)
100% ee ->[α]D20 = +296° (c=1, DCM)
-> ee = 146.2/296
-> ee = 49%

N-Cyclohexanoyl-protection of the enantiopure R-(-)-PZQamine in a multigram scale (MW48-4)
MW48-4 [α]D20 = -135.0° (c=1, EtOH)
100% ee ->[α]D20 = -139° (c=1, EtOH)

-> ee = -135.0/-139
-> ee = 98%

-> No change since original calculation therefore R-PZQ is stable stored at 5°C for at least 10 months.
24th August 2011 @ 02:02
RXN 001 - Enantiopure S-(+)-Praziquanamine (S-PZQamine) from MW49-13 is converted to S-(-)-Praziquantel (S-PZQ) (MNR1-1) for biological evaluation.

Starting material from Multigram-scale racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-13)

MNR1-1%20scheme.png

MNR1-1%20table.PNG

Hazard and Risk Assessment:

HIRAC MNR1



reaction on 1600
reaction off 0900

To a cooled solution of S-(-)Praziquanamine (MW49-13, S-PZQamine, 2.00 g, 9.89 mmol; M.W. = 202.25 g/mol) in DCM (50 mL) at 0°C was added triethylamine (1.50 g, 2.07 mL, 14.83 mmol, 1.5 eq.; M.W.=101.19 g/mol, density=0.73 g/mL) and cyclohexanecarbonyl chloride (1.59 g, 1.46 mL, 10.88 mmol, 1.1 eq.; M.W.=146.61 g/mol, density=1.10 g/mL). The solution was stirred for 17 h at room temperature.

The solution was quenched with water (10 mL) and stirred for a further 30 min. The layers were separated and the organic layer was washed with saturated sodium carbonate solution (50 mL), 0.5 M HCl (50 mL) and brine (50 mL). Dried over magnesium sulfate, filtered (some product spilt at this stage) and concentrated under reduced pressure. The remaining yellow oil was dried under high vacuum for 4 hours to give a foam which was dissolved in a mixture of acetone/hexane (15 mL, 1:1 mixture) and heated until dissolved. The solution was allowed to stand at room temperature over night and the crystals were filtered off and rinsed with a cold mixture of acetone/hexane.

1st Crop = 0.438 g - very pale yellow crystals

* At this stage it was found the the ee of the starting amine was only 49 % - reaction not taken further.

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