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23rd April 2013 @ 01:09
Mnr: 21-30

As for Hydrolysis of MNR11-16 to MNR26-4 Hydrolysis of MNR11-17 to MNR26-5 Starting material from Synthesis of MNR11-18

Hazard and Risk Assessment:

HIRAC MNR7.pdf

Procedure:MNR11-8 (3.96 g, 10.63 mmol) was dissolved in EtOH (21 mL) and HCl (1M) (110 mL) and heated to reflux for 2.5 hours. The solution was allowed to cool to room temperature then cooled in an ice bath, basified with NaOH pellets (approx 8 g, pellets used to minimise volume of aqueous material) to pH 12-13 and extracted with DCM (4 x 100 mL). The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give an orange crispy solid (1.008 g).

TLCReaction mixture after 2.5 hours ran in 100% EtOAc

2013-04-23 13.15.20.jpg

IR 

5f rac IR MNR26-7.jpg

Strings Starting material InChI=1S/C21H28N2O4/c1-26-18-10-15-8-9-23-17(16(15)11-19(18)27-2)12-22(13-20(23)24)21(25)14-6-4-3-5-7-14/h10-11,14,17H,3-9,12-13H2,1-2H3 Product InChI=1S/C14H18N2O3/c1-18-12-5-9-3-4-16-11(7-15-8-14(16)17)10(9)6-13(12)19-2/h5-6,11,15H,3-4,7-8H2,1-2H3

Linked Entries
Attached Files
23rd April 2013 @ 01:07
Mnr: 11-20
As for
Synthesis of MNR11-17
and
Synthesis of MNR11-16

Starting material from
Preparation of the dimethoxy Ugi-intermediate (MNR8-5)

MNR11-18%20scheme.png

MNR11-18%20table.PNG

Hazard and Risk Assessment:
HIRAC MNR11.pdf


Procedure:
To a solution of MNR8-5 (4.88 g, 10.5 mmol) in toluene (35 mL) at room temperature was added methanesulfonic acid (1.47 mL, 22.58 mmol) and the mixture was refluxed for 1 hour. The reaction was allowed to cool to room temperature and was quenched with saturated sodium carbonate and extracted with EtOAc (50 mL x 3). The organic fractions were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude as a thick orange oil.

Crude - 3.965 g, 101 %

TLC
100% EtOAc. Starting material, co=spot, reaction mixture after work up
2013-04-22 16.41.25.jpg


NMR
mnr11-18_crude_vs_mnr11-17.pdf
mnr11-18_crude_1H.pdf
mnr11-18_crude.zip


Conclusion
Crude product taken on to the next step without further purification.

Hydrolysis of MNR11-18 to give MNR26-7

Strings
Starting material
InChI=1S/C25H40N2O6/c1-5-32-24(33-6-2)18-27(25(29)20-10-8-7-9-11-20)17-23(28)26-15-14-19-12-13-21(30-3)22(16-19)31-4/h12-13,16,20,24H,5-11,14-15,17-18H2,1-4H3,(H,26,28)
Product
InChI=1S/C21H28N2O4/c1-26-18-10-15-8-9-23-17(16(15)11-19(18)27-2)12-22(13-20(23)24)21(25)14-6-4-3-5-7-14/h10-11,14,17H,3-9,12-13H2,1-2H3
Linked Entries
Attached Files
3rd October 2012 @ 07:43
Mnr: 41-50
Attempted Synthesis of MNR46-5

MNR45-1%20scheme.png
mnr45-5%20table.PNG

Hazard Assessment
HIRAC MNR41_47_48.pdf


Procedure
To a solution of KAB18-2 (0.29 g, 1.39 mmol) in HPLC grade acetonitrile (14 mL) under argon at 0 °C , was added was added acetyl chloride (0.177 mL, 2.49 mmol), lutidine (0.23 mL, 1.94 mmol) and Yb(OTf)3 (0.086 g, 0.14 mmol). The reaction was then stirred at room temperature for 16 hours and then the mixture was washed saturated sodium bicarbonate solution (20 mL) and the aqueous layer was extracted with ethyl acetate (3 × 30 mL). The organic fraction was then dried over MgSO4, filtered and concentrated under reduced pressure to yield a yellow oil (0.334 g, 96%)

TLC did not look promising as it looked like mainly starting material and lutidine.

SANY0335.JPG


Crude NMR confirmed this.

mnr45-5_crude.pdf
mnr45-5_crude.zip


Reaction not taken any further.
Attached Files
25th September 2012 @ 04:31
Mnr: 41-50
Now that it looks like the formation of MNR46 is catalytic (Following the Cyclisation of KAB22-1 to MNR46 by LCMS - MNR46-8, MNR46-9, MNR46-10) it is worth while developing a reliable HPLC method to assay these experiments and calculate yields without the need of purification.

Using HPLC1 early runs showed that there was a significant error in varying the injection volume therefore it was necessary to maintain a constant injection volume. It was also shown that, although the peaks did not "top out" on these runs, peak area at higher concentrations was inaccurate thus requiring us to keep the injection mass below 2 ug.

PZQ calibration

Using the standard 0-100 over 30 mins method and 5 uL injections, PZQ solutions in MeCN showed a linear response with the R2 value of the calculated trend line being closer to one with data points below 2 ug of sample per injection.

pzq_plot.PNG

MNR46 calibration

Using the same method as above and 5 uL injections, MNR46 solutions in MeCN showed a linear response with the R2 value of the calculated trend line being closer to one with data points below 2 ug of sample per injection.

mnr46_plot.PNG

It's unsure if the point at 14 ug is an error or due to the detector maxing out but it has not been followed up as it has been shown else where that the most accurate readings come with injections containing less than 2 ug of material.

Test samples of MNR46 and PZQ

Using the above method samples or varrying concentrations of MNR46 were ran with a constant concentration of PZQ present in all the samples.

mnr46_with%20_PZQ_plot.PNG

The PZQ was expected to be horizontal but showed a linear response with increasing concentration of MNR46.

The gradient of the trend line is also 2,000,000 units out. Due to limited data, it is unsure at this point if this is within reasonable error or if this is another problem with the product/PZQ mixture

As this stands, this method has no value in following the formation of MNR46.
Attached Files
31st August 2012 @ 07:26
Mnr: 41-50
Attempts To Cyclise KAB22-1 using AcCl

MNR46-1%20scheme.png
mnr46-2%20table.PNG

Hazard Assessment
HIRAC MNR41_47_48.pdf


Procedure
To a solution of KAB22-1 (1eq) in HPLC grade acetonitrile (0.03 M) under argon at ambient temperature, was added was added acetyl chloride (1.8 eqs), base (1.4 eqs) and catalyst (0.4 eqs). The reaction was then stirred at room temperature (19 °C) over the weekend.

Monday morning

46-2 was a clear yellow solution
46-3 was a cloudy yellow mixture
46-4 was a cloudy yellow mixture

46 2 hours
46 Monday



Work Up


The mixture was washed saturated sodium bicarbonate solution (10 mL) and the aqueous layer was extracted with ethyl acetate (3 × 15 mL). The organic fractions were combined, dried over MgSO4, filtered and concentrated under reduced pressure to yield a yellow oil.

Post work up TLC showed faint new spot in both Yb reactions, 46-4 selected for column as the spot looked more intense. This spot did appear to be in all 3 reactions pre-work up.

MNR46-4

Column using 40% EtOAC/Hex. new spot collected in fractions 11-20. Lutidine spot ran lower and slightly co-spotted but this can be vac'd away.

NMR shows what looks like product as a mixture of rotamers. NMR also contains traces of EtOAc and an extra Ac peak.

Frac 11-20 0.040 g as a yellow oil.

46-4_column

mnr46-4_frac11-20_1H.pdf

mnr46-4_frac11-20_13C.pdf


Frac 1-9 - 0.020 g as a pale yellow solid (thought to be starting material, turned out to be a mixture of hydrolysis products, no starting material found)

mnr46-4_frac1-9_1H.pdf

mnr46-4_frac1-9_13C.pdf


Conclusion

This cyclisation appears to have worked and was not expected. Has increased catalyst loading aided the reaction or is it increased reaction time? Now need to go back and column the control and the other Yb reaction to test for more cyclisation product.

Crude NMRs of MNR46-2 and MNR46-3

Crude 1H NMR of MNR46-2 showed only hydrolysis products (Ac, mono or di-protected)

mnr46-2_1H_crude.pdf


Crude 1H NMR of MNR46-3 was messy but looked like like mainly hydrolysis products (Ac, mono or di-protected) with the possibility of traces of product but it was decided not to waste time running it through a column,

mnr46-3_1H_crude.pdf


Overlay

mnr46-2to4_overlay.pdf


LCMS

Expected products

mnr46_LCMS.png

Hydrolysis products are too small to be detected by LCMS as the cut off is 250.

LCMS - Starting Material

kab22-1.pdf


Peak with RT of 15 mins with very little m/s activity but SM+H (=255) detected.

LCMS - MNR46-4 frac 11-20


mnr46-4_frac11-20.pdf


Peak with a RT of 22 minsshows m/s peak of Prod+H (=297)

Overall Conclusions

The cyclisation looks to have worked using Yb(OTf)3. Is it catalytic? Based on scale it's hard to tell therefore this needs repeated. Reaction also needs repeated at lower Yb(OTf)3 loadings to understand the reaction more also following the reaction over time will be useful.


SciFinder searching -
Ph ring open - 1466 Reactions

With only a Ph ring - 89 Reactions

With H's on the Et chain - 21 reactions from 6 refs

With Ac group - 6 reactions from 2 refs (only one looks useful - A new method for synthesizing 2-acyl-1-aryl-1,2,3,4-tetrahydroisoquinolines, Mollov, N. and Venkov, A. Synthesis, 62-3; 1978

mnr46_lit.PNG
Attached Files