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23rd April 2013 @ 00:09
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).

TLC
Reaction mixture after 2.5 hours ran in 100% EtOAc
2013-04-23 13.15.20.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
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23rd April 2013 @ 00:07
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)





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
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5th October 2012 @ 11:39
Sc: 1-10
Synthesis of SC3-3 and SC3-4 from SC2-1.

HIRAC

Refer to risk/hazard assessment prepared for SC3-1 and SC3-2.

3rd October 2012

Aim: to repeat SC3-1 and SC3-2.

This experiment is a repeat of SC3-1 and SC3-2. These original products were obtained on 3/9/12 as crude yellow oils. Chromatographic separation yielded the cyclised products expected, plus additional products, as was evident in significant co-spotting observed on TLCs of the fractions. Suspected contamination of the laboratory hexane supply used for the column purification warrants repetition of the reactions. The procedure is described below.

SC2-1 (0.0996 g, 0.34 mmol) was reacted with acetyl chloride (0.05 mL, 0.61 mmol) in the presence of 2,6-lutidine (0.05 mL, 0.48 mmol) in acetonitrile (0.03 M, 13 mL), under argon gas and with stirring for 25 hr, to give SC3-3.
SC2-1 (0.0975 g, 0.33 mmol) was again reacted under the same conditions, with the addition of freshly prepared Yb(OTf)3 (0.0115 g/mL, 1.0 mL, 0.018 mmol) to give SC3-4.

Both reactions changed in hue from colourless to a transparent yellow over the first two hours. Unlike the previous experiment, there were small particles visible in the SC3-4 reaction mixture after 25 hr. This is thought to be Yb(OTf)3. Since the same concentration of Yb(OTf)3 was used in SC3-2 and SC3-4, it is possible that the freshness of the Yb(OTf)3 had an effect on how readily it dissolved in the reaction mixture.

TLC analysis confirmed that both reactions had gone to completion, however, residual lutidine was present, as was the case for SC3-1 and SC3-2.

4th October 2012

Products were extracted in ethyl acetate (10mL) and sodium hydrogen carbonate (10mL). The aqueous layer was twice more extracted in ethyl acetate (i.e. 2 x 10mL). Organic fractions were combined and the solvent was removed using rotary evaporation. Crude products were dark yellow/orange oils.
3rd October 2012 @ 06:43
Mnr: 41-50
Attempted Synthesis of MNR46-5




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.
26th September 2012 @ 04:42
Mnr: 41-50
re-synthesis of MNR46 to try and get a clean sample for characterisation and HPLC analysis




Hazard Assessment
HIRAC MNR41_47_48.pdf


Procedure
To a solution of KAB22-1 (0.60 g, 2.36 mmol) in HPLC grade acetonitrile (25 mL) under argon at 0 °C , was added was added acetyl chloride (0.30 mL, 4.25 mmol), lutidine (0.38 mL, 3.30 mmol) and Yb(OTf)3 (0.146 g, 0.24 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 × 25 mL). The organic fractions were combined and washed with citric acid (10%) (30 mL). The organic fraction was then dried over MgSO4, filtered and concentrated under reduced pressure to yield a yellow oil (0.857 g, 122%)

Column using 30-40% EtOAC/Hex.

Product eluted (by TLC) between fractions 15 and 35 but to test purity of the samples early and late fractions were kept separate.

Fracs 15-20 - 0.140 g

Fracs 21-30 - 0.202 g

Fracs 31-35 - 0.018 g

Fractions 15-20 and 31-35 were immediately vac'd down and dried under high vacuum. 1H NMR of 15-20 showed clean product. 1H NMR of 31-35 was messy.

1H NMR

Frac 15-20 - Clean product
mnr46-13_frac15-20_1H.pdf
mnr46-13_frac15-20.zip


Frac 31-35 - messy
mnr46-13_frac31-35_1H.pdf
mnr46-13_frac31-35.zip


The remaining fractions containing product (fracs 21-30) we combined but not concentrated to complete dryness on the day of running the column due to time. Upon drying, 1H NMR showed only hydrolysis products.

Frac 21-30
mnr46-13_frac21-30_1H.pdf
mnr46-13_frac21-30.zip


This is unusual as the hydrolysis products run higher on TLC and came off before fraction 15. Also, it's exclusively mono-Ac amine where as the higher running spot contains di-Ac amine.

Frac 1-11
mnr46-13_frac1-11_friday.pdf
mnr46-13_frac1-11.zip


------------------------------------------------------------------

Monday, 2nd October 2012
TLC of the three batches of fractions spotted against MNR46-4 (still product by NMR) showed none of the 3 batches contained product any more.

SANY0334.JPG


running a new sample of MNR46-13 fracs 15-20 confirmed this

mnr46-13_frac15-20_monday.pdf
mnr46-13_f15-20_monday.zip


Conclusions

Using Yb(OTf)3 under catalytic conditions the reaction goes to completion in 16 hours. However, it has become clear that the product can decompose back to the relevant aldehyde and mono-Ac amine. This appears to take place in solvent but at this stage it's unclear the rate of this reverse reaction.

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