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16th March 2012 @ 04:02

Resolution of MNR26-1 with (+)-dibenzoyl-D-tartaric acid (MNR5-1)

Hazard and Risk Assessment: As for MNR2-1

MNR26-1 (016 g, 0.61 mmol) and MNR5-1 (0.29 g, 0.61 mmol) was dissolved in a mixture of isopropanol (3 mL) and water (3 mL) and heated till the reagents went into solution. After standing at room temperature overnight no crystals appeared. The reaction mixture was concentrated and taken up in IPA (25 mL) and hexane (15 mL) with heating, allowed to cool to room temperature and left in the freezer overnight. No crystals formed but a small trace of brown solid did. It was filtered off and the solvent was concentrated. The resulting crude was then taken up in IPA (20 mL) and heated to 60 C in a water bath. Hexane (20 mL) was added and the flask was left to stand open at room temperature. After approximately 1 week sitting open in the back of the fume hood crystals started to form, after being left for 3 mores days the crystals were filtered and washed with hexane and EtOAc. More more solid crashed out of this wash and the filtrated was reduced in volume and filtered again, washing with EtOAc.

First crop - fine white solid/crystals 0.055 g Second crop - off white solid 0.055 g

Both crops were kept separate and mixed with water (2 mL) and taken to pH 11 with the addition of NaOH solution (2M) and extracted with DCM (4 ml x 3). The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give...

 

IR 

5f S IR MNR30-1.jpg
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15th March 2012 @ 05:04
mnr31%20scheme.png

mnr31-1%20table.PNG

Hazard and Risk Assessment:

To a cooled solution of MNR27-1 ( mmol) in DCM (5 mL) at 0°C was added triethylamine (0.21 mL, mol) and benzoyl chloride(0.13 mL, 1.09 mmol). The solution was stirred overnight at room temperature.

The solution was quenched with water (5 mL) and stirred for a further 30 min. The layers were separated and the organic layer was washed with saturated sodium carbonate solution (5 mL), 0.5 M HCl (5 mL) and brine (5 mL). Dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude as an orange oil (0.240 g).

Column:- 50-100 EtOAc/PetEther

Fracs 15-24 0.121 g, 0.33 mmol, 67% yield

Melting point 94-95 °C
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15th March 2012 @ 04:53
Mnr: 21-30

Hazard and Risk Assessment:

As for MNR1-1

MNR28-3

To a cooled solution of MNR27-1 (0.1 g, 0.38 mmol) in DCM (2 mL) at 0°C was added triethylamine (0.0.8 mL, 0.57 mmol) and cyclohexanecarbonyl chloride (0.06 mL, 0.42 mmol). The solution was stirred overnight at room temperature.

The solution was quenched with water (2 mL) and stirred for a further 30 min. The layers were separated and the organic layer was washed with saturated sodium carbonate solution (5 mL), 0.5 M HCl (5 mL) and brine (5 mL). Dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude as an orange oil (0.176 g)

Column:- 50-100 EtOAc/PetEther

Fracs 17-26 - 0.063 g, 0.169 mmol, 44% yield (fraction 21 spilt, one of the major fractions)

Characterisation

mnr28-3_1H.pdf
mnr28-3_col.zip

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

1H NMR (300 MHz, CDCl3): d = 6.73 (s, 1H), 6.65 (s, 1H), 5.17-5.005 (m, 1H), 4.91-4.79 (m, 1H), 4.78-4.67 (m, 1H), 4.50 (s, 0.5H), 4.44 (s, 0.5H), 4.17-4.02 (m, 1H), 3.87 (s, 6H), 3.00-2.63 (m, 4H) 2.48 (t, J = 11.1 Hz, 1H), 1.93-1.20 (m, 10H).

mnr28-3_13C.pdf
mnr28-3_col.zip

13C NMR (75 MHz, CDCl3): d =174.8, 164.3, 148.3, 148.1, 126.9, 124.4, 111.7, 108.1, 56.1, 55.9, 54.8, 49.0, 45.3, 40.7, 39.1, 29.2, 29.0, 28.2, 25.7.

Chiral HPLC

KAB1-2.pdf

 

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8th March 2012 @ 06:10
mnr29-1.png

Hazard and Risk Assessment:
HIRAC MNR29.pdf


Procedure

CS-3-1 (7.5 g, XX mmol) in toluene (60 mL) was heated to reflux overnight
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7th March 2012 @ 23:13
Mnr: 21-30
Based on the potential success of mnr27-23, a small scale up is required to attempt a second crystallisation and also a longer crystallisation period should be looked at to improve the yield of the crystals recovered.

Screening conditions for optimum resolution of MNR26-1 with various tartaric acids previously synthesised in the lab

MNR27-26%20scheme.png

mnr27-26%20table.PNG

Hazard and Risk Assessment:
As for MNR2-1

MNR27-26

MNR26-1 (0.220 g, 0.84 mmol) and CS-3-1 (0.36 g, 0.84 mmol) was dissolved in isopropanol (8 mL) and water (8 mL) in a conical flask and heated with the heat gun to dissolve the reagents. After reaching room temperature, the conical flask was left to sit overnight. In the morning, no crystals had formed to the flask was covered with parafilm and moved to the fridge. After 24 hours in the fridge the solution had turned into a gel therefore the flask was removed from the fridge and left to stand on the bench over the weekend

MNR27-27

*This may not work as well but the material was recovered so it was just used as a test.

MNR26-1 (recovered from 27-2 - 27-11)(0.48 g, 1.83 mmol) and MNR6-1 (0.92 g, 1.83 mmol) was dissolved in isopropanol (18 mL) and water (18 mL) in a conical flask and heated with the heat gun to dissolve the reagents. After reaching room temperature, the conical flask was left to sit overnight. In the morning, no crystals had formed to the flask was covered with parafilm and moved to the fridge. No crystals after 24 hours in the fridge, left over the weekend.


MNR27-28 - concentrated version of 27-23

MNR26-1 (0.120 g, 0.46 mmol) and CS-3-1 (0.20 g, 0.46 mmol) was dissolved in isopropanol (2.5 mL) and water (2.5 mL) in a conical flask and heated with the heat gun to dissolve the reagents. After reaching room temperature, the conical flask was sealed with parafilm and moved to the fridge. After 2 hours in the fridge the solution had turned into a gel therefore the flask was removed from the fridge and left to stand on the bench overnight. Some crystals had formed and the solution was filtered to give a light brown solid (0.279 g).

A portion (0.095 g) of the solid was was mixed with water (2 mL) and taken to pH 11 with the addition of NaOH solution (2M) and extracted with DCM (4 ml x 3). The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give XXX

The remainder of the solid was taken up in IPA (2 mL) and water (2 mL) in an attempt to recrystallise the salt.

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MNR27-29

21/08/12
What looked like MNR26 was found on the bench so an attempt at a resolution was attempted although the purity and quality of the SM is not clear as it had been sitting around on the bench for a while.

SM (1.7 g, 6.48 mmol) and MNR6-1 (3.1 g, 6.48 mmol) was dissolved in IPA (30 mL) and water (3 mL) was added. The dark brown solution was left to stand for 5 hours at room temperature in which time nothing happend so was transferred to the the freezer overnight. In the morning the solution was frozen so it was allowed to warm at room temperature and still nothing crystallised. Hexane (10 mL) was added dropwise forming a white precipitate which went back into solution upon swirling of the flask. The mixture was allowed to stand for 4 hour at which point something had crystalised out. The solid was filtered and washed with IPA:Hex (50:50) and dried to give
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