All Notebooks | Help | Support | About
21st September 2011 @ 04:30
RXN 013 - Enantiopure R-PZQamine (MNR3-2) is converted to R-PZQ (MNR1-3).

MNR9-1%20scheme.png

MNR9-1%20table.PNG
Hazard and Risk Assessment:

As for MNR1-1

To a cooled solution of R-Praziquanamine (MNR3-2, 3.88 g, 18.99 mmol) in DCM (95 mL) at 0°C was added triethylamine (3.97 mL, 28.48 mol) and cyclohexanecarbonyl chloride (2.79 mL, 20.89 mmol). The solution was stirred overnight at room temperature.

The solution was quenched with water (25 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 and concentrated under reduced pressure.

Crude as a yellow oil; 4.61 g.

The crude oil was purified by FCC (30-100% EtOAc/hexane) to give a pale yellow oil that turned into a foam under high vacuum. The foam was recrystallized in 50% acetone/hexane and crystals were filtered off and rinsed with hexane after standing in the freezer overnight.

1H NMR MNR9-1 in CDCl3
1H NMR MNR9-1 in MeOD
VT NMR of MNR9-1 in CDCl3 Improved resolution in areas but loss in other areas with temperature.


**ee determined by chiral HPLC, 99.9 %

HPLC trace for MNR9-1

mnr9-1 CDCl3.pdf


HPLC trace for rac-PZQ

mnr_rac-PZQ.pdf


HPLC trace for MNR1-3 :- N-Cyclohexanoyl-protection of MNR2-3 to give S-PZQ (MNR1-3)

mnr1-3_S-PZQ.pdf


-------------------------------------------------------------------

Checking the purity of the samples after sitting in the fridge for over 1 year.

HPLC conditions - Chiralcel OD-H column, IPA:Hex:TEA (40:60:0.1), flow rate 0.6 ml/min

Note - the conditions have changed slightly from above as the HPLC has had a new pump fitted as the previous one was giving unreliable flow rates.

rac-PZQ - the peak at 12.8 mins is some contaminant in the system as it was showing up on blank runs and was much larger on early runs. multiple blanks runs reduced the peak to what is seen here.

rac-PZQ_110213_04.pdf


MNR9-1 - ee 99%

mn9-1_110213.pdf
Linked Posts
Attached Files
21st September 2011 @ 04:21
Mnr: MNR1-10
RXN 012 - Enantiopure S-PZQamine (MNR2-3) is converted to S-PZQ (MNR1-3).

MNR1-2%20scheme.png

MNR1-3%20table.PNG
Hazard and Risk Assessment:

As for MNR1-1

To a cooled solution of S-(-)Praziquanamine (MNR2-3, 2.99 g g, 14.78 mmol) in DCM (75 mL) at 0°C was added triethylamine (3.09 mL, 22.18 mol) and cyclohexanecarbonyl chloride (2.18 mL, 16.26 mmol). The solution was stirred overnight at room temperature.

The solution was quenched with water (25 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 and concentrated under reduced pressure. The crude oil was purified by FCC (30-100% EtOAc/hexane) to give a pale yellow oil that turned into a foam under high vacuum. The foam was recrystallized in 50% acetone/hexane and crystals were filtered off and rinsed with hexane after standing in the freezer overnight to give the product as white crystals.

Crop 1:- 2.275 g, 7.28 mmol, 49%

The mother liquor was concentrated and recrystallized as before.

HPLC-PZQ.pdf


1H NMR MNR1-3 S-PZQ

-------------------------------------------------------------------

Checking the purity of the samples after sitting in the fridge for over 1 year.

HPLC conditions - Chiralcel OD-H column, IPA:Hex:TEA (40:60:0.1), flow rate 0.6 ml/min

Note - the conditions have changed slightly from above as the HPLC has had a new pump fitted as the previous one was giving unreliable flow rates.

rac-PZQ - the peak at 12.8 mins is some contaminant in the system as it was showing up on blank runs and was much larger on early runs. multiple blanks runs reduced the peak to what is seen here.

rac-PZQ_110213_04.pdf


MNR1-3 - ee 99%

mn1-3_110213_02.pdf
Linked Posts
Attached Files
17th September 2011 @ 05:43
RXN 011 - Resolution of rac-PZQamine (MNR7-1) with (+)-dibenzoyl-D-tartaric acid (MNR5-1) to obtain S-PZQamine (MNR2-3)

MNR2-3.png

MNR2-3%20table.PNG

Hazard and Risk Assessment:
As for MNR2-1

rac-PZQamine (13.92 g, 68.83 mmol) and (+)-dibenzoyl-D-tartaric acid. 2IPA (32.93 g, 68.83 mmol) was dissolved in a mixture of isopropanol (280 mL) and water (60 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 (18.22 g, 32.61 mmol, 95%)

MNR2-salt.png

Mother liquor
Solvent was evaporated and solid residue was dried under high vac.
diastereomeric salt

The salt (18.22 g, 32.61 mmol) was dissolved in a mixture of i-PrOH (200 mL) and water (100 mL) by heating. It was then allowed to cool to room temperature and stand overnight (in an attempt to see if better crystallization could be achieved - it was)

The salt (13.78 g) was mixed with water (80 mL) and taken to pH 11 with the addition of NaOH solution (2M) and extracted with DCM (100 ml x 3). The aqueous layer was pH adjusted to pH2 using 2M HCl - see below. The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give an off white solid (3.38 g, 16.7 mmol, 49 %).

Again, why such a low yield?



MNR2-3 [α]D20 = +280° (c=1, DCM) (level 5 polorimiter was broken, used the old one on level 4)

1H NMR MNR2-3

Product used in
N-Cyclohexanoyl-protection of MNR2-3 to give S-PZQ (MNR1-3)

Lab book page complete, MNR
Linked Posts
Attached Files
16th September 2011 @ 08:10
RXN 010 - Resolution of rac-PZQamine (MNR7-1) with (-)-dibenzoyl-L-tartaric acid (MNR6-1) to obtain R-(-)-PZQamine (MNR3-2)

MNR3-2%20scheme.png

MNR3-2%20table.PNG

Hazard and Risk Assessment:
As for MNR2-1

rac-PZQamine (MNR7-1) (13.8 g, 68.23 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA (32.65 g, 68.23 mmol) was dissolved in a mixture of isopropanol (280 mL) and water (60 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 (19.74 g, 35.15 mmol, 103%)

MNR3-salt.png

Mother liquor
Solvent was evaporated to give a sticky pale yellow solid - see below.

The salt (19.74 g, 35.15 mmol) was dissolved in a mixture of IPA (200 mL) and water (100 mL) by heating, allowed to cool then placed in an ice bath for two hours. The salt didn't give as nice crystals as before but were filtered off and washed with hexane. The sticky white solid recovered was dried in a vacuum desiccator. (is this recrystallization needed?)

Recrystallized salt:- 15.88 g, 28.33 mmol, 82%

The salt (15.88 g) was mixed with water (80 mL) and taken to pH 11 with the addition of NaOH solution (2M) and extracted with DCM (100 ml x 3). The aqueous layer was pH adjusted to pH2 using 2M HCl - see below. The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give an off white solid (4.09 g, 20.22 mmol, 59 %).

Unsure why this yield is so low?

The combined mother liquor layers were also mixed with water (80 mL) and taken to pH 11 with the addition of NaOH solution (2M)and extracted with DCM (150 ml x 3). The aqueous layer was pH adjusted to pH2 using 2M HCl - see below. The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a white solid (15.28 g, 75.55 mmol, >100 %).

The combined aqueous layers were left to stand overnight nothing crystallized out therefore it was extracted with EtOAc (150 mL x 3). The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a yellow oil (26.21 g, 54.78 mmol, 80 %). - requires recrystallization, also looks like some tartaric acid is still in the enriched product?

Total mass recovered - 45.58 g, 98 %

MNR3-2 [α]D20 = -291.7° (c=1, DCM)

1H NMR NMR3-2

Product used in
N-Cyclohexanoyl-protection of MNR3-2 to give R-PZQ (MNR9-1)

Lab book page complete, MNR
Linked Posts
Attached Files
13th September 2011 @ 06:43
Mnr: 1-10
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) and heated to reflux for 14 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

Reaction repeated a total of 4 times to bring through enough material.

Batch 1+2 combined:- 18.96 g, 113%

Recrystallized in toluene:hexane (9:1) and left in the freezer overnight. Crystals filtered off in the morning and washed with hexane.

Off white/pale orange crystals:- 14.28 g, 85%

Batch 3+4 (as above)

White crystals:- 13.92 g, 83%

Characterisation

mnr07-5_1H.pdf
mnr7-5.zip


1H NMR (CDCl3, 300 MHz): d = 7.29-7.10 (m, 4H), 4.94-4.75 (m, 2H), 3.80-3.47 (m, 3H), 3.07-2.60 (m, 4H), 1.85 (s, 1H).

mnr07-5_13C.pdf
mnr7-5.zip


13C NMR (CDCl3, 75 MHz): d= 167.4, 135.1, 134.4, 129.5, 127.2, 126.8, 124.8, 57.0, 50.2, 50.0, 38.9, 29.0.

m.p. 117–118 °C

lit m.p. 116-118 Laurent, S. A. L., J. Boissier, et al. (2008). "Synthesis of “Trioxaquantel”® Derivatives as Potential New Antischistosomal Drugs." European Journal of Organic Chemistry 2008(5): 895-913.


Product used in

Resolution of rac-PZQamine with (-)-dibenzoyl-L-tartaric acid to obtain R-(-)-PZQamine (MNR3-2)
Resolution of rac-PZQamine with (+)-dibenzoyl-D-tartaric acid to obtain S-PZQamine (MNR2-3)

Lab book page complete, MNR
Linked Posts
This post is linked by:
Attached Files