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31st January 2012 @ 23:47
MNR8-3%20scheme.png
MNR8-3%20table.PNG

Hazard and Risk Assessment:

As for MNR8-1

Procedure:

To a stirring suspension of paraformaldehyde (0.63 g, 21.0 mmol), 2,2-dimethoxyethylamine (3.04 mL, 21.0 mmol) and cyclohexanecarboxylic acid (2.60 mL, 21.0 mmol) in methanol (20 mL) at 0 °C was added 2-(3,4-Dimethoxyphenyl)ethyl isocyanide MNR4-2 (4.0 g, 21.0 mmol) dropwise and stirred at room temperature for 22 hours.

The reaction was concentrated and dissolved in EtOAc (50 mL) then washed with water (25 mL) and brine (25 mL) then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude as a pale yellow oil.

Crude :- 8.056 g

Column :- 40-66 % EtOAc/Hex

Frac 9-40
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31st January 2012 @ 23:29
Mnr: 1-10
MNR10-2%20scheme.png

MNR10-2%20table.PNG

Hazard and Risk Assessment:
HIRAC MNR10.pdf


Procedure:

To a stirring suspension of paraformaldehyde (2.73 g, 91.0 mmol), 2,2-dimethoxyethylamine (13.2 mL, 91.0 mmol) and benzoic acid (11.11 g, 91.0 mmol) in methanol (90 mL) at 0 °C was added 2-(3,4-Dimethoxyphenyl)ethyl isocyanide MNR4-2 (17.4 g, 91.0 mmol) dropwise and stirred at room temperature for 40 hours.

The reaction was concentrated and dissolved in EtOAc (150 mL) then washed with water (75 mL) and brine (75 mL) then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude as a yellow oil.

Crude :- 46.856 g

Column :- 50-100 % EtOAc/Hex

Frac 3-8 :- 36.126 g, 78.78 mmol, 87 %

Characterisation

mnr10-2_1H.pdf
mnr10-2_frac3-8.zip


As a 50:50 mixture of rotamers. Peaks not fully resolved at 300 K

1H NMR (500 MHz, CDCl3): d = 7.44-7.99 (m, 5H), 7.25 (br, NH), 6.84-6.66 (m, ,3H), 5.03 (br, 1H), 4.49 (br, 1H), 4.20 (br, 1H), 3.96 (br, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.66-3.15 (m, 8H), 2.85-2.72 (m, 2H), 1.23-1.03 (m, 6H).

mnr10-2_13C.pdf
mnr10-2_frac3-8.zip


13C NMR (125 MHz, CDCl3): d= 173.1, 168.9, 168.7, 149.1, 147.7, 135.4, 131.3, 130.3, 129.8, 128.5, 128.2, 127.0, 126.8, 120.7, 111.9, 111.4, 101.0, 100.5, 64.0, 63.4, 62.0, 55.9, 55.9, 55.4, 55.3, 53.4, 53.3, 51.4, 51.2, 40.7, 35.2, 15.4


______________________________________________________________________

23/08/12
MNR10-3

Procedure:

To a stirring suspension of paraformaldehyde (3.38 g, 112.43 mmol), 2,2-dimethoxyethylamine (16.4 mL, 112.43 mmol) and benzoic acid (13.73 g, 112.43 mmol) in methanol (90 mL) at 0 °C was added 2-(3,4-Dimethoxyphenyl)ethyl isocyanide MNR4-5 (21.5 g, 112.43 mmol) in methanol (20 mL) dropwise and stirred at room temperature for 41 hours.

The reaction was then concentrated and taken up in EtOAc (200 mL) then washed with water (150 mL) and brine (150 ml) then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude as a yellow oil (49.47 g, 96%)

Due to the crude recovered being less than 100% the aqueous fractions were extraced again with EtOAc (200 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give more crude as a yellow oil (1.364 g, 2.87 mmol, 3%)

Total crude recovered - 50.834 g, 110.86, 99%

TLC of crude mixture run in 50% and 100% EtOAc/Hex
SANY0237.JPG


Crude taken on without further purification.
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30th January 2012 @ 23:47
*PS = Pictet-Spengler

Concluded on 06/02/12.

Background
Preparing the enediamide for future acid catalysed reactions to give PZQ. The second and final cyclisatiton step to give PZQ from the enediamide does not require the loss of ethoxy groups, which may reduce side reactions and result in cleaner reactions.

Scheme%20KAB13-1.png
Table%20KAB13-1.jpg

Hazard and Risk Assessment
Hazard and Risk Assessment KAB13-1


Previous Related Experiments
Enediamide intermediate cyclisation to give the dimethoxy N-benzoyl PZQ analogue (KAB12-1)
Copper(II) triflate catalysed preparation of the dimethoxy N-benzoyl PZQ enediamide (KAB11-3)

Following Experiments

Procedure
KAB5-1 (1.80 g, 4.45 mmol) was dissolved in stirred toluene (45 mL) before the solution was cooled in a brine ice bath. Methanesulfonic acid (MSA, 0.63 mL, 4.45 mmol, 1 eq) was added to 0.1 M at 0 °C. The reaction mixture was stirred at rt from 11:45.
Reaction mixture at 5 min
Reaction mixture at 1 hr

TLC taken at 12:00 (+75 min) and indicated complete consumption of the starting material (KAB5-1), formation of the enediamide (KAB13-1) and some completely cyclised product (to give PZQ). The reaction was immediately terminated by quenching with saturated sodium bicarbonate solution (50 mL) following dilution of the reaction mixture with EtOAc (25 mL).
Dilution with EtOAc
Quenched with NaHCO3

The organic layer was set aside and the aqueous fraction further extracted with EtOAc (3 × 30 mL). The organic layers were combined and the bright yellow solution dried over magnesium sulfate. After removal of the drying agent by filtration, the yellow solution was concentrated in vacuo to give crude KAB13-1 as a yellow oil (2.144 g).
First extraction with EtOAc
Left: aqueous fraction; Right: combined organic layers
Organic layers after drying
Crude KAB13-1


Purification
The crude KAB13-1 was purified by silica gel column chromatography, eluting in 60-75% EtOAc in hexane, and monitoring by TLC. The product eluted in fractions 6-16, which were then combined and concentrated under reduced pressure. The yellow oil rapidly crystallised on standing (wet yield 270 mg).
The flask was sealed and put in the freezer to promote crystallisation.
Concentrated combined fractions 6-16

Fractions 1-5 and 17-30 were separately combined and concentrated under reduced pressure.
The KAB13-1 main spot (frac 17-30) was stored in the freezer.


Summary and Conclusion
The use of MSA was inappropriate and resulted in side reactions, decomposition of reaction components and poor yield. Use metal triflates for future preparations of the PZQ enediamide intermediate.

-----------------------------------------------------------------------------
NOTES 31/01/12
- I should have just used silver triflate to do this reaction, and not MSA. It would have been cleaner, with higher yield and I would likely not have required to column the product.
-----------------------------------------------------------------------------
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30th January 2012 @ 04:54
*PS = Pictet-Spengler

TO DO:
- Write conclusion

START: 30/01/12
FINISH: 02/02/12

Background
Further reduction of catalyst loading. See procedure for the preparation of KAB8-7 and KAB8-8.

Scheme%20KAB8-9.png


Hazard and Risk Assessment
As for KAB8-5 (here)

Previous Related Experiments
TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-7 & KAB8-8)
Controls for the AgOTf catalysed PS* to give the dimethoxy N-benzoyl PZQ analogue (KAB8-5 & KAB8-6)
The silver(I) triflate catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-4)

Following Experiments
The TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-11)
The TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-12)
TfOH catalysed PS* reactions to give the dimethoxy PZQ analogues (KAB8-14 & KAB1-5)
AgOTf catalysed PS reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-15)

Procedure
MNR10-1 (123.8 mg, 0.270 mmol) was dissolved in toluene (33 mL) before the addition of TfOH/toluene* (51.9 uL, 0.25 M, 13.5 umol) at rt. The clear, colourless reaction mixture was reflux heated at 90 °C from 15:35.
Reaction mixture at 1 hr

The reaction progress was monitored by TLC of extracted aliquots (20-50 uL) against the MNR10-1 starting material and the expected product (identical to KAB8-1). The TLCs were eluted with EtOAc/hexane, 4:1, v/v and stained with KMnO4.

30/01/12
15:40 - Aliquot 1
16:00 - Aliquot 2
16:15 - Aliquot 3
16:30 - Aliquot 4
16:45 - Aliquot 5
17:15 - Aliquot 6
18:00 - Aliquot 7

31/01/12
08:45 - Aliquot 8
09:00 - Taken off heat

TLC of reaction mixture (1)
TLC of reaction mixture (2)
TLC of reaction mixture (3)
TLC of reaction mixture (4)


31/01/12. TLC of the extracted aliquot 8 suggested no change had occurred overnight and the reaction mixture contained the enediamide intermediate, in lower concentration, and the major component, the completely cyclised product (identical to KAB8-1).
The reaction mixture was quenched after 22 hours, with saturated sodium bicarbonate solution (50 mL). The organic fraction was separated and the aqueous layer extracted with EtOAc (3 × 30 mL). The organic layers were combined, dried over magnesium sulfate, filtered, then concentrated under reduced pressure to give crude KAB8-9 as a pale yellow oil. The product began crystallising on standing and was put in the freezer overnight to promote crystallisation.
Crystals forming


02/01/12
The crystals were filtered and washed with hexane to give KAB8-9 as pale orange crystals (92.4 mg, 93%). 1H-NMR confirmed KAB8-9 as the dimethoxy N-benzoyl PZQ analogue.
H-NMR KAB8-9
Raw H-NMR KAB8-9



Summary and Conclusion


--------------------------------------------------------------
NOTES 30/01/12
- TfOH/toluene solution made up in previous experiment (here).
- First time seeing a decent amount of the enediamide intermediate with the TfOH reaction. The unknown low Rf spot started to disappear just as the high enediamide spot appeared.
- 17:24. The enediamide spot hasn't got less intense over the last 30 minutes. Will leave the reaction overnight. The amount of acid may be low enough that if it the reaction goes to completion overnight, the product won't decompose (too much).

NOTES 31/01/12
- Still no apparent change based on TLC. i.e. reaction contains intermediate and product.
- After work-up: product stored in freezer.
--------------------------------------------------------------
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30th January 2012 @ 00:37
Mnr: 1-10
MNR4-1%20scheme.png
MNR4-1%20table.PNG

Hazard and Risk Assessment:
HIRAC MNR4.pdf


A solution of 3,4-dimethoxyphenethylamine (24.0 mL, 132 mmol) in ethyl formate (130 mL, 1590 mmol) was heated to reflux for 13 h. The remaining ethyl formate and the by-product ethanol were removed under reduced pressure to give yellow liquid.

The crude 2-(3,4-Dimethoxyphenyl)ethylformamide and triethylamine (55.4 mL, 397 mmol) were dissoved in dry DCM (240 mL) and phosphoryl chloride (12.3 mL, 132 mmol) was added dropwise added at 0°C. The mixture was then stirred for 1 h at 0°C and a further 4 h at room temperature.
The mixture was quenched with water and neutralized with NaHCO3 solution. The organic layer was separated and the aqueous solution was extracted DCM (250 mL x4). The organic layers were combined, dried over magnesium sulphate, filtered and evaporated afforded a dark brown oil.

Crude:- 30.519 g

Column:- 25-33% EtOAc/Hex

Frac 3-5 :- 21.751 g as a pale yellow oil (86 %)

Characterisation

mnr04-2_1H.pdf
mnr4-2frac3-5.zip


1H NMR (500 MHz, CDCl3): d = 6.84 (d, J = 8.7 Hz, 1H), 6.81-6.76 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.59 (t, J = 6.9 Hz, 2H), 2.91 (t, J = 6.9 Hz, 2H).

mnr04-2_13C_conc.pdf
mnr4-2_conc.zip



13C NMR (75 MHz, CDCl3): d= 156.4 (t, J = 5.2 Hz), 149.4, 148.3, 129.4, 120.9, 112.0, 111.4, 56.0, 43.4 (t, J = 6.3 Hz), 35.4.

HRMS (ESI (+)) Calcd. for [C33H40N3O6]+ (for [3M+H]+): 574.2912, found: 574.2914.

IR MW37-1


Vmax/cm-1 2939, 2147, 1515.

Preparation of 2-(3,4-Dimethoxyphenyl)ethyl isocyanide (MW37)



Lab book page complete, MNR
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