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28th September 2011 @ 01:44

Hazard and Risk Assessment:

HIRAC MNR11.pdf

Procedure:MNR8-1 (80 mg, 0.22 mmol) was stirred with methanesulfonic acid (1.4 mL, 22 mmol) at 60°C and after 3 hours (first TLC) all the starting material had been consumed. The reaction was quenched with saturated sodium carbonate and extracted with EtOAc (20 mL x2). The organic fractions were dried over magnesium sulfate, filtered and concentrated under reduced pressure.

Crude proton NMR showed what looked like product and the loss of key starting material peaks.

mnr11-1_crude.pdf

FCC EtOAc/Hexane (50-80%).

Frac 27-28:- 0.037 g, 0.1 mmol, 58 % as a white gummy oil.

mnr11-1_frac27-38.pdf
mnr11-1.zip

 

IR 

1b rac IR MNR11-1.jpg

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27th September 2011 @ 02:16
MNR10-1%20scheme.png

MNR10-1%20table.PNG

Hazard and Risk Assessment:
HIRAC MNR10.pdf


Procedure:

To a mixture of formaldehyde solution (1.94 ml, 21.96 mmol), 2,2-dimethoxyethylamine (3.19 mL, 21.96 mmol) and benzoic acid (2.68 g, 21.96 mmol) in methanol (15 mL) was added slowly 2-(3,4-Dimethoxyphenyl)ethyl isocyanide MNR4-1 (4.20 g, 21.96 mmol) and stirred at room temperature for 24 h. EtOAc (20 mL) was then added to the reaction and was washed with 1 M HCl (20 mL), sat. NaCO3 solution (20mL) and brine (20 mL), dried over MgSO4, filtered and concentrated.

Crude:- 9.48 g as a yellow/orange oil

Column:- 20-100% EtOAc/Hex

6.796 g as a thick clear oil

LCMS

LCMS MNR11-6
Ret. Time
18.8___481.3 [M+H]
_______413.3 [Hemiaminal+H]
_______497.2 Unknown
25.3___Impurities found in the MeoH used to make up samples.

Hemiaminal cyclisation happening in the mass spec?

1H NMR MNR10-1

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27th September 2011 @ 02:03
MNR8-2%20scheme.png
MNR8-2%20table.PNG

Hazard and Risk Assessment:

As for MNR8-1

Procedure
To a mixture of formaldehyde solution (1.11 ml, 12.55 mmol), 2,2-dimethoxyethylamine (1.82 mL, 12.55 mmol) and cyclohexanecarboxylic acid (1.56 mL, 12.55 mmol) in methanol (10 mL) was added slowly 2-(3,4-Dimethoxyphenyl)ethyl isocyanide MNR4-1 (2.4 g, 12.55 mmol) and stirred at room temperature for 24 h. EtOAc (20 mL) was then added to the reaction and was washed with 1 M HCl (20 mL), sat. NaCO3 solution (20mL) and brine (20 mL), dried over MgSO4, filtered and concentrated.

Crude:- 4.994 g as a dark orange oil

FCC 2.882 g, 6.20 mmol, 49 % as a clear oil - why such a low yiels and low recovery from the column??

1H NMR MNR8-2 similar to MNR8-1

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13th September 2011 @ 08:31

Hazard and Risk Assessment:

HIRAC MNR8.pdf

ProcedureTo a mixture of formaldehyde solution (0.21 ml, 2.33 mmol), 2,2-dimethoxyethylamine (0.34 mL, 2.33 mmol) and cyclohexanecarboxylic acid (300 mg, 2.33 mmol) in methanol (1.5 mL) was added slowly 2-(3,4-Dimethoxyphenyl)ethyl isocyanide MNR4-1 (0.56 mL, 2.33 mmol) and stirred at room temperature for 24 h. EtOAc (5 mL) was then added to the reaction and was washed with 1 M HCl (5 mL), sat. NaCO3 solution (5mL) and brine (5 mL), dried over MgSO4, filtered and concentrated.

A highly viscous orange-brown oil was obtained which was purified by column chromatography (silica gel, EtOAc/Hexane 75-100%) to give the product as clear oil 0.941 g, 2.0 mmol, 63%

* formaldehyde solution was used rather than paraformaldehyde. The exact concentration of the solution was unclear. Also the wrong density was used for MNR4-1 was used as has not been determined. Therefore, two areas where stoichiometry errors have more than likely occurred.

Column frac 5-14 clear oil

LCMS

LCMS_mnr8-1.pdf
observed peaks rt 19.917-20.333 419 hemiaminal+H 487 M+H

rt 20.683-21.317 415 unknown C22H28N2O5+H

similar to LCMS of MW40 where hemiaminal+H (405) and M+Na (459)

LCMS MW40-1 starting material for MW56-3.pdf

1H NMR MNR8-1contains the same impurities as MW40

LRMS 

7d LRMS MNR8-1 dont include.jpg

HRMS 

7d HRMS MNR8-1.jpg

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5th September 2011 @ 05:56
Preparation of starting material for the Ugi reaction via the MW37-2 method.

MNR4-1%20scheme.png
MNR4-1%20table.PNG

Hazard and Risk Assessment:
HIRAC MNR4.pdf


A solution of 3,4-dimethoxyphenethylamine (8.4 mL, 50.6 mmol) in ethyl formate (48 mL, 607 mmol, bp 52-54°C) was heated to reflux for 18 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 (21.2 mL, 152 mmol) were dissoved in dry DCM (90 mL) and phosphoryl chloride (4.7 mL, 50.6 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 (x3). The organic layers were combined, dried over magnesium sulphate, filtered and evaporated afforded a dark brown oil.

column (25% EtOAc/hexane), fractions 5-21 - 7.99 g, 83%

1H NMR MNR4-1
1H NMR showed traces of EtOAc, sample put back on the high vac for 2 hours.

Yield, 7.421, 38.8 mmol, 77 % - dark yellow oil


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