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22nd January 2012 @ 10:46
MNR3.png

MNR3-3_table.PNG

Hazard and Risk Assessment:
As for MNR2-1

rac-PZQamine (2.65 g, 13.10 mmol) and dibenzoyl-L-tartaric acid.2IPA (MNR6-1)(6.27 g, 13.10 mmol) was dissolved in a mixture of isopropanol (60 mL) and water (10 mL) by taking to reflux. The solution was allowed to cool to room temperature and stand overnight. The solid was then filtered and rinsed with IPA/water (5:1).

Crude salt (4.634 g) not dried under vacuum

MNR3-salt.png

The salt (4.634 g) was dissolved in a mixture of i-PrOH (50 mL) and water (25 mL) by heating (heat gun). It was then allowed to cool to room temperature and stand overnight. The solid was then filtered and rinsed with IPA/water (5:1).

The salt was then mixed with water (20 mL) and taken to pH 11 with the addition of NaOH solution (2M) and extracted with DCM (25 ml x 4) and the aqueous layer was pH adjusted to pH 2 using 2M HCl. The organic fractions were combined, washed with brine (30 mL) and dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a white solid (0.779 g, 3.85 mmol, 59 %).

The combined washings from the two crystalisations were concentrated and mixed with water (20 mL) and taken to pH 11 with the addition of NaOH solution (2M) and extracted with DCM (25 ml x 4) and the aqueous layer was pH adjusted to pH 2 using 2M HCl. The organic fractions were combined, washed with brine (30 mL) and dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a yellow solid (1.35 g, 6.67 mmol)

Total PZQ-amine recovered (2.129 g, 10.52 mmol, 80 %)

The aqueous layers were combined in an attempt to recover the resolving agent. Nothing precipitated out over night so the volume was reduced under vacuum.
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22nd January 2012 @ 10:43
Mnr: 1-10

Hazard and Risk Assessment: As for MNR2-1

rac-PZQamine (2.65 g, 13.10 mmol) and (+)-dibenzoyl-D-tartaric acid. 2IPA (6.27 g, 13.10 mmol) was dissolved in a mixture of isopropanol (60 mL) and water (10 mL) by taking to reflux. The solution was allowed to cool to room temperature and stand overnight. The solid was then filtered and rinsed with IPA/water (5:1).

The salt was dissolved in a mixture of i-PrOH (80 mL) and water (20 mL) by heating. It was then allowed to cool to room temperature and stand overnight, filtered and washed with IPA/Water.

The salt was then mixed with water (20 mL) and taken to pH 11 with the addition of NaOH solution (2M) and extracted with DCM (25 ml x 4) and the aqueous layer was pH adjusted to pH 2 using 2M HCl. The organic fractions were combined, washed with brine (30 mL) and dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a white solid (0.886 g, 4.38 mmol, 67 %).

The combined washings from the two crystalisations were concentrated and mixed with water (20 mL) and taken to pH 11 with the addition of NaOH solution (2M) and extracted with DCM (25 ml x 4) and the aqueous layer was pH adjusted to pH 2 using 2M HCl. The organic fractions were combined, washed with brine (30 mL) and dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a yellow solid (1.471 g, 7.27 mmol)

Total PZQ-amine recovered (2.357 g, 11.65 mmol, 89 %)

The aqueous layers were combined in an attempt to recover the resolving agent. Nothing precipitated out over night so the volume was reduced under vacuum.

Characterisation

mnr02-1_1H.pdf
mnr1-2.zip

1H NMR (300 MHz, CDCl3): d = 7.31-7.10 (m, 3H), 4.92-4.78 (m, 2H), 3,81-3,48 (m, 3H), 3.09-2.69 (m, 4H), 2.25 (br, NH).

mnr02-1_13C.pdf
mnr1-2.zip

13C NMR (CDCl3, 75 MHz): d= 167.2, 134.9, 134.1, 129.4, 127.1, 126.7, 124.7, 56.8, 49.9, 49.7, 38.8, 28.8.

HRMS 

HRMS - MNR2-4

IR 

5e S IR MNR2-2.jpg

m.p. 117–118°C.

Lit m.p. - 120 °C - Patent number: 3993760

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18th January 2012 @ 05:09
Preparation of starting material for the scaled-up racemic resolution of PZQamine
MNR7-1_scheme.png
MNR7-1%20table.PNG

Hazard and Risk Assessment:
HIRAC MNR7.pdf


Procedure:
rac-PZQ (13.0 g, 41.6 mmol) was dissolved in a mixture of EtOH (80 mL) and 1M HCl (420 mL(85 mL in 1 L)) and heated to reflux for 15 h. The solution was allowed to cool to room temperature then cooled in an ice bath, basified with NaOH pellet (approx 22 g, pellets used to minimise volume of aqueous material) to pH 12-13 and extracted with DCM (4 x 150 mL). The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a clear oil which was placed on the high vac for 4 hours by which time the oil had crystallized into white crystals.

* something went wrong with the reaction during the night. Power had tripped in the fumehood. By the looks of things, I'd say the heating mantle has overheated and the reaction has bumped (quiet violently) out the top of the condenser (which had an additional air condenser on top) and water has tripped the power on coming in contact with the mantle. It's unclear how much material has been lost but there was a sticky residue all over the base of the fumehood. This is unusal as the reaction had been monitored for 5 hours before leaving the lab for the night.

Crude - 6.675 g, 79 %

Recrystallized in toluene:hexane (60:6 mL) and left in the freezer overnight. Crystals filtered off in the morning and washed with hexane.

Off white/pale orange crystals:- 5.372 g, 64 %

1H NMR MNR7-5

The washing were concentrated and allowed to crystallise in the freezer over the weekend.
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