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21st February 2012 @ 07:03
Screening conditions for optimum resolution of MNR26-1 with various tartaric acids previously synthesised in the lab

MNR27-12%20scheme.png

mnr27-12%20table.PNG

Hazard and Risk Assessment:
As for MNR2-1

MNR27-12

MNR26-1 (0.08 g, 0.3 mmol) and CS-2-1 (0.12 g, 0.3 mmol) was dissolved in isopropanol (3 mL) and water (1 mL) in a vial and heated with the heat gun to dissolve the reagents. After reaching room temperature, hexane (1 mL) was added and the vial was allowed to stand overnight. In the morning a solid had crashed out but not crystalline.

The vial was then capped and left sitting, after 5 days the solution had gone solid and started to show signs of crystals forming. IPA (3 mL) was added, heated with the heat gun (not everything went back into solution), capped and left overnight.

In the morning, the vial contained a what looked like a messy solid, thought best not to take forward.

MNR27-13

MNR26-1 (0.08 g, 0.3 mmol) and CS-3-1 (0.13 g, 0.3 mmol) was dissolved in isopropanol (2 mL) and water (1 mL) in a vial and heated with the heat gun to dissolve the reagents. After reaching room temperature, hexane (1 mL) was added and the vial was allowed to stand overnight. In the morning nothing had crashed or crystallised out.

Water (1 mL) and hexane (1 mL) was added to the vail and heated to get the cloudy mixture back to a transparent solution and was then allowed to cool and then sit at room temperature for another 24 hours by which time the mixture had gone completely solid.

The vial was then capped and left sitting, after 5 days the solid started to show signs of crystals forming. IPA (3 mL) was added, heated with the heat gun, capped and left overnight.

After standing overnight, what looked like crystals had formed so the reaction mixture filtered with IPA/hexane (1:1) to give a white solid not very crystalline.

The salt (0.013 g) was mixed with water (4 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 an pale brown solid (0.002 g, 0.007 mmol, 2 %).


MNR27-14

MNR26-1 (0.08 g, 0.3 mmol) and KB-PZQ-1003 (0.15 g, 0.3 mmol) was dissolved in isopropanol (1 mL) and water (1 mL) in a vial and heated with the heat gun to dissolve the reagents. After reaching room temperature, hexane (1 mL) was added and the vial was allowed to stand overnight. In the morning crystals had formed but the vial had gone dry. IPA (2 mL), water (2 mL) and hexane (2 mL) were added and the mixture heated to redissolve the crystals (not everything went back into solution as I couldn't heat the vial to reflux) and the vial was left to stand at room temperature for another 24 hours by which time the mixture was very thick but crystals were present. Filtered and washed with IPA/Hexane to give light brown fluffy crystals

The salt (0.133g, 0.193 mmol, 56 %) was mixed with water (4 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 an pale brown solid (0.032 g, 0.122 mmol, 40 %).

Taken onto MNR28-1

MNR27-15

MNR26-1 (0.08 g, 0.3 mmol) and MW46-6 (0.13 g, 0.3 mmol) was dissolved in isopropanol (6 mL) and water (2 mL) in a vial and heated with the heat gun to dissolve the reagents. After reaching room temperature, hexane (1 mL) was added and the vial was allowed to stand overnight. In the morning nothing had crashed or crystallised out.

Water (4 mL) and hexane (3 mL) was added to the vail and heated to get the cloudy mixture back to a transparent solution and was then allowed to cool and then sit at room temperature for another 24 hours by which time the mixture had gone crusty on top.

After 6 days the reaction mixture was filtered with IPA/hexane (1:1) to give a brown solid not very crystalline.

The salt (0.123 g) was mixed with water (4 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 an pale brown solid (0.0XX g, 0.00X mmol, XX %).


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MNR27-16

MNR26-1 (0.08 g, 0.3 mmol) and MNR6-1 (0.15 g, 0.3 mmol) was dissolved in isopropanol (1 mL), hexane (1 mL) and water (1 mL) in a vial and heated with the heat gun to dissolve the reagents. The mixture was allowed to reach room temperature and allowed to stand overnight by which time the mixture had gone completely solid.

The vial was then capped and left sitting, after 5 days the solid started to show signs of crystals forming. IPA (3 mL) was added, heated with the heat gun, capped and left overnight.

In the morning everything was still in solution so it was just left to stand longer.

MNR27-17

MNR26-1 (0.08 g, 0.3 mmol) and MNR6-1 (0.15 g, 0.3 mmol) was dissolved in isopropanol (2 mL)and water (2 mL) in a vial and heated with the heat gun to dissolve the reagents. The mixture was allowed to reach room temperature and allowed to stand overnight by which time the mixture was still a solution.

The vial was then capped and left sitting, after 5 days the solution had gone solid and started to show signs of crystals forming. IPA (3 mL) was added, heated with the heat gun, capped and left overnight.

In the morning everything was still in solution so it was just left to stand longer.

MNR27-18

MNR26-1 (0.08 g, 0.3 mmol) and MNR6-1 (0.15 g, 0.3 mmol) was dissolved in isopropanol (2 mL), hexane (2 mL) and water (2 mL) in a vial and heated with the heat gun to dissolve the reagents. The mixture was allowed to reach room temperature and allowed to stand overnight by which time the mixture was still a solution.

The vial was then capped and left sitting, after 5 days the solid started to show signs of crystals forming. IPA (3 mL) was added, heated with the heat gun, capped and left overnight.

**It looks like MNR6-1 is a lot more soluble than the acids used above and therefore reducing the chances of the salt crystallising out of the solution.

In the morning everything was still in solution so it was just left to stand longer.

MNR27-19

MNR26-1 (0.08 g, 0.3 mmol) and CS-2-1 (0.12 g, 0.3 mmol) was dissolved in isopropanol (1.5 mL), hexane (1.5 mL) and water (1.5 mL) in a vial and heated with the heat gun to dissolve the reagents. After reaching room temperature the mixture was allowed to stand overnight by which time the mixture had gone completely solid.

The vial was then capped and left sitting, after 5 days the solid started to show signs of crystals forming. IPA (3 mL) was added, heated with the heat gun, capped and left overnight.

After standing overnight, what looked like crystals had formed so the reaction mixture was filtered with IPA/hexane (1:1) to give a white solid not very crystalline.

The salt (0.031 g) was mixed with water (4 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 an pale brown solid (0.002 g, 0.007 mmol, 2 %).


MNR27-20

MNR26-1 (0.08 g, 0.3 mmol) and CS-3-1 (0.13 g, 0.3 mmol) was dissolved in isopropanol (1.5 mL), hexane (1.5 mL) and water (1.5 mL) in a vial and heated with the heat gun to dissolve the reagents. After reaching room temperature,the vial was allowed to stand overnight by which time the mixture had crystallised and was filtered with IPA/hexane to give a light brown solid - not as crystalline as mnr27-14.

The salt (0.168 g, 0.216 mmol, 70 %) was mixed with water (4 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 an pale brown solid (0.036 g, 0.137 mmol, 45 %).

Taken onto MNR28-2

MNR27-21

MNR26-1 (0.08 g, 0.3 mmol) and MW46-6 (0.13 g, 0.3 mmol) was dissolved in isopropanol (1.5 mL), hexane (1.5 mL) and water (1.5 mL) in a vial and heated with the heat gun to dissolve the reagents. After reaching room temperature the vial was allowed to stand overnight by which time the mixture had gone completely solid.

The vial was then capped and left sitting, after 5 days the solid started to show signs of crystals forming. IPA (3 mL) was added, heated with the heat gun, capped and left overnight.

In the morning everything was still in solution so it was just left to stand longer. After 3-4 days crystals/solid started to appear. The vial was left standing over the weekend (another 3 days)

The crystals were filtered and rinsed with IPA/Hex/water and dried to give an off white solid (0.105 g). The solid was mixed with water (4 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 an white solid xxxxx

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MNR27-22

MNR26-1 (0.08 g, 0.3 mmol) and CS-2-1 (0.12 g, 0.3 mmol) was dissolved in isopropanol (1.5 mL), water (4.5 mL) and hexane (3 mL) (*hexane was added by mistake) in a vial and heated with the heat gun. The reagents did not want to disolve in this mixture and the reaction was not taken any further.


MNR27-23

MNR26-1 (0.08 g, 0.3 mmol) and CS-3-1 (0.12 g, 0.3 mmol) was dissolved in isopropanol (3 mL) and water (3 mL) in a vial and heated with the heat gun to dissolve the reagents. After reaching room temperature, the vial was capped and left to stand overnight.

After standing overnight, what looked like crystals had formed so the reaction mixture filtered with IPA/hexane (1:1) to give a white solid not very crystalline.

The salt (0.052 g, 0.075 mmol, 25 %) was mixed with water (4 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 an white solid (0.012 g, 0.039 mmol, 13 %).


MNR27-24

MNR26-1 (0.08 g, 0.3 mmol) and CS-2-1 (0.12 g, 0.3 mmol) was dissolved in isopropanol (4.5 mL) and water (1.5 mL) in a vial and heated with the heat gun to dissolve the reagents. After reaching room temperature, the vial was capped and left to stand overnight.

After standing overnight, what looked like crystals had formed so the reaction mixture was filtered with IPA/hexane (1:1) to give a white solid not very crystalline.

The salt (0.023 g) was mixed with water (4 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 an pale brown solid (0.0XX g, 0.00X mmol, XX %).



MNR27-25

MNR26-1 (0.08 g, 0.3 mmol) and CS-2-1 (0.12 g, 0.3 mmol) was dissolved in isopropanol (1.5 mL) and water (4.5 mL) in a vial and heated with the heat gun to dissolve the reagents. After reaching room temperature, the vial was capped and left to stand overnight.

In the morning everything was still in solution (although it looked cloudy) so it was just left to stand longer.

_________________________________________________________________________
HPLC

Using a solvent system of 15% EtOH/Hex + TEA 0.1% it was found that you can observe partial separation of the racemic amine.

mnr26-1 15EtOH 05mL.pdf


MNR27-13
too dilute to HPLC
MNR27-15
mnr26-1 15EtOH 05mL.pdf

MNR27-19
mnr27-19 15MeOH 05ml.pdf

MNR27-23
mnr27-23 15MeOH 05ml.pdf

what looks like a good ee, this should be improved with a second recrystallisation step but will need to scale up first.
MNR27-24
Attached Files
21st February 2012 @ 07:02
Screening conditions for optimum resolution of MNR26-1 with (-)-dibenzoyl-L-tartaric acid (MNR6-1) to obtain R-di-methoxy-PZQamine (MNR27-x)

* As a result of mnr27-1 not working.

MNR27-1%20scheme.png

mnr27-1%20table.PNG

Hazard and Risk Assessment:
As for MNR2-1

MNR27-2

MNR26-1 (0.08 g, 0.3 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA (0.15 g, 0.3 mmol) was dissolved in isopropanol (4 mL) in a vial and heated with the heat gun to dissolve the reagents.

Everything went into solution and the vial was left to stand at room temperature overnight.

Some material crashed out and was filtered with hexane to give brown crystals/solid. 12 mg


MNR27-3

MNR26-1 (0.08 g, 0.3 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA (0.15 g, 0.3 mmol) was dissolved in hexane (4 mL) in a vial and heated with the heat gun to dissolve the reagents.

very little went into solution and the vial was left to stand at room temperature overnight.

As little went into solution this was not taken any further

MNR27-4

MNR26-1 (0.08 g, 0.3 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA (0.15 g, 0.3 mmol) was dissolved in IPA (1 mL) ans hexane(3 mL) in a vial and heated with the heat gun to dissolve the reagents.

very little went into solution and the vial was left to stand at room temperature overnight.

As little went into solution this was not taken any further

MNR27-5

MNR26-1 (0.08 g, 0.3 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA (0.15 g, 0.3 mmol) was dissolved in IPA (2 mL) ans hexane(2 mL) in a vial and heated with the heat gun to dissolve the reagents.

some went into solution but not completely, the vial was left to stand at room temperature overnight.

The sample looked very meesy in the morning and was not taken any further

MNR27-6

MNR26-1 (0.08 g, 0.3 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA (0.15 g, 0.3 mmol) was dissolved in IPA (3 mL) ans hexane(1 mL) in a vial and heated with the heat gun to dissolve the reagents.

everything went into solution and the vial was left to stand at room temperature overnight.

Some material crashed out and was filtered with hexane to give brown crystals/solid. 20 mg

MNR27-7

MNR26-1 (0.08 g, 0.3 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA (0.15 g, 0.3 mmol) was dissolved in IPA (3.8 mL) ans water(0.2 mL) in a vial and heated with the heat gun to dissolve the reagents.

everything went into solution and the vial was left to stand at room temperature overnight.

Some material crashed out and was filtered with hexane to give brown crystals/solid. 85 mg

MNR27-8

MNR26-1 (0.08 g, 0.3 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA (0.15 g, 0.3 mmol) was dissolved in IPA (4 mL) ans hexane (4 mL) in a vial and heated with the heat gun to dissolve the reagents.

some went into solution but not completely, the vial was left to stand at room temperature overnight.

The sample looked very messy and was not taken any further

MNR27-9

MNR26-1 (0.08 g, 0.3 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA (0.15 g, 0.3 mmol) was dissolved in DCM (2 mL) ans hexane (2 mL) in a vial and heated with the heat gun to dissolve the reagents.

some went into solution but not completely, the vial was left to stand at room temperature overnight.

The sample completely congealed overnight and was not taken any further

MNR27-10

MNR26-1 (0.08 g, 0.3 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA (0.15 g, 0.3 mmol) was dissolved in DCM (2 mL) ans IPA(2 mL) in a vial and heated with the heat gun to dissolve the reagents.

everything went into solution but not completely, the vial was left to stand at room temperature overnight.

Hexane was added and material crashed out and was filtered with hexane to give light brown crystals/solid. 121 mg

MNR27-11

MNR26-1 (0.08 g, 0.3 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA (0.15 g, 0.3 mmol) was dissolved in DCM (1 mL) ans IPA(3 mL) in a vial and heated with the heat gun to dissolve the reagents.

everything went into solution but not completely, the vial was left to stand at room temperature overnight.

Hexane was added and material crashed out and was filtered with hexane to give brown crystals/solid. 118 mg
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21st February 2012 @ 06:59
Screening conditions for optimum resolution of MNR26-1 with (-)-dibenzoyl-L-tartaric acid (MNR6-1) to obtain R-di-methoxy-PZQamine (MNR27-x)

* As a result of mnr27-1 not working.

MNR27-1%20scheme.png

mnr27-1%20table.PNG

Hazard and Risk Assessment:
As for MNR2-1

MNR27-2

MNR26-1 (0.08 g, 0.3 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA (0.15 g, 0.3 mmol) was dissolved in isopropanol (4 mL) in a vial and heated with the heat gun to dissolve the reagents.

Everything went into solution and the vial was left to stand at room temperature overnight.


MNR27-3

MNR26-1 (0.08 g, 0.3 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA (0.15 g, 0.3 mmol) was dissolved in hexane (4 mL) in a vial and heated with the heat gun to dissolve the reagents.

very little went into solution and the vial was left to stand at room temperature overnight.

MNR27-4

MNR26-1 (0.08 g, 0.3 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA (0.15 g, 0.3 mmol) was dissolved in IPA (1 mL) ans hexane(3 mL) in a vial and heated with the heat gun to dissolve the reagents.

very little went into solution and the vial was left to stand at room temperature overnight.


Linked Posts
This post is linked by:
21st February 2012 @ 06:58
Mnr: 21-30
Screening conditions for optimum resolution of MNR26-1 with (-)-dibenzoyl-L-tartaric acid (MNR6-1) to obtain R-di-methoxy-PZQamine (MNR27-x)

* As a result of mnr27-1 not working.

MNR27-1%20scheme.png

mnr27-1%20table.PNG

Hazard and Risk Assessment:
As for MNR2-1

MNR27-2

MNR26-1 (0.08 g, 0.3 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA (0.15 g, 0.3 mmol) was dissolved in isopropanol (4 mL) in a vial and heated with the heat gun to dissolve the reagents.

Everything went into solution and the vial was left to stand at room temperature overnight.


MNR27-3

MNR26-1 (0.08 g, 0.3 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA (0.15 g, 0.3 mmol) was dissolved in hexane (4 mL) in a vial and heated with the heat gun to dissolve the reagents.

very little went into solution and the vial was left to stand at room temperature overnight.

MNR27-4

MNR26-1 (0.08 g, 0.3 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA (0.15 g, 0.3 mmol) was dissolved in IPA (1 mL) ans hexane(3 mL) in a vial and heated with the heat gun to dissolve the reagents.

very little went into solution and the vial was left to stand at room temperature overnight.
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This post is linked by:
15th February 2012 @ 03:17
KAB8-1

In IPA:Hex:TEA
40:60:0.1


KAB8-1_IPA40 flow rate 1 mL per minute

retention time 15 minutes, no separation

KAB8-1_IPA40 flow rate 0.5 mL per minute

retention time 27.6 and 29 minutes, some separation

KAB8-1_IPA40flow rate 0.35 mL per minute

retention time 52and 55 minutes, some separation but broad peaks

In IPA:Hex:TEA
80:20:0.1


KAB8-1_IPA80flow rate 0.35 mL per minute

retention time 34 and 39 minutes, some separation but not all the way to baseline

In IPA:Hex:TEA
90:10:0.1


KAB8-1_IPA90flow rate 0.35 mL per minute

retention time 37and 41 minutes, not as good as 80%

Conclusion, need to change polar solvent as IPA is too viscous and reduced flow rates lead to broadening of peaks.

In EtOH:Hex:TEA
50:50:0.1


KAB8-1_EtOH50 flow rate 1 mL per minute

retention time 11.7 and 12.8 minutes, some separation but too quick

KAB8-1_EtOH50 flow rate 0.5 mL per minute

retention time 24.1 and 26.2 minutes, some separation but not at baseline

In EtOH:Hex:TEA
25:75:0.1


KAB8-1_EtOH25 flow rate 1 mL per minute

retention time 21.9 and 24.5 minutes, some separation but just short of the baseline

KAB8-1_EtOH25 flow rate 0.5 mL per minute

retention time 45.9 and 51.4 minutes, baseline separation.
Attached Files