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30th October 2012 @ 21:28
Mnr: MNR51-60
Friedels-Craft Acylation of AEW1-1 to give MNR51-2. Repeating the conditions of MNR51-1 but with a longer reaction time.

See - Synthesis of AEW1-1
- Synthesis of MNR51-1

MNR51_scheme.png
mnr51-2_table.PNG

Hazard Assessment
HIRAC MNR51.pdf


Procedure

reaction on at 7pm 30/10/12
off at 5pm 1/11/12

AlCl3 (2.26 g, 16.9 mmol) was added to a solution of succinic anhydride (0.931 g, 9.30 mmol) and AEW1-1 (1.60 g, 8.46 mmol) in DCM (40 mL). The reaction mixture was stirred at room temperature for 46 hours by which time it had become very thick with possible precipitate. The mixture was concentrated then water (10 mL) was added and the mixture cooled to 0°C and acidified with HCl (37%, 5 mL). The mixture was allowed to warm to room temperature and stirred for 30 min. Again, no solid crashed out, only a red insoluble oil formed. EtOAc (25 ml) was added and the organic laer extracted. The aq layer was then extract with EtOAc (3 x 25 mL), the organics were then combined, dried of magnesium sulphate, filtered and concentrated to give the crude as a red solid.

Crude TLC vs MNR51-1 50% EtOAc/Hex
SANY0015.JPG


Column 40-50% EtOAc/hex

frac 7-24 original nmr still had DCM and MeOH - left on hi-vac overnight

after overnight on the hivac - 1.156 g

mnr51-2_frac7-24_1H.pdf


Unknown singlet at 3.71 and quartet at 2.67?
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29th October 2012 @ 04:51
Mnr: MNR51-60
Friedels-Craft Acylation of AEW1-1 to give MNR51-1

See - Synthesis on AEW1-1

MNR51_scheme.png
mnr51-1_table.PNG

Hazard Assessment
HIRAC MNR51.pdf


Procedure

reaction on at 3pm 29/10/12

AlCl3 (1.06 g, 7.93 mmol) was added to a solution of succinic anhydride (0.436 g, 4.36 mmol) and AEW1-1 (0.750 g, 3.96 mmol) in DCM (20 mL). The reaction mixture was stirred at room temperature for 18 h at which time there were still traces of SM in the TLC but it was thought best to work up. The reaction mixture was concentrated at reduced pressure then water (6 mL) was added and the mixture cooled to 0°C and acidified with
HCl (37%, 3 mL). The mixture was allowed to warm to room
temperature and stirred for 30 min. No solid crashed out, only a red insoluble oil formed. EtOAc (15 ml) was added and the organic laer extracted. The aq layer was then extract with EtOAc (3 x 15 mL), the organics were then combined, dried of magnesium sulphate, filtered and concentrated to give the crude as a red solid (1.5 g)

Column 40-60% EtOAc/Hex

frac 1-5 - 0.338 g, 1.79 mmol, 45% - recovered starting material - dark red/brown crystals
frac 11-19 - 0.340 g, 1.17 mmol, 30% - product (54% based on SM recovered) - off white/pale red solid

Fractions 20 onwards had white precipitate but did not show up on UV. Still need to collect. Product is poorly soluble in CDCl3 but good enough for a quick NMR.

NMR

Starting material - AEW1-1 1H
mnr_aew1-1_1H.pdf


Column - Fracs 1-5 - Recovered starting material
mnr51-1_frac1-5_sm_1H.pdf
mnr51-1_frac1-5.zip


Column - fracs 11-19 - Product
mnr51-1_frac11-19_1H.pdf
mnr51-1_frac11-19_13C.pdf
mnr51-1_frac11-19_19F.pdf
mnr51-1_frac11-19.zip


Conclusion

Friedels-Craft Acylation of AEW1-1 works to some extent. A longer reaction time or elevated reaction temperature may help drive the reaction to completion. It should also be noted that the AlCl3 used was from a rather old bottle and it was not perfectly white.

Reaction closed - 31/10/12
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29th October 2012 @ 03:31
Reaction Scheme

PMY 2-5 (200 mg, 0.92 mmol, 1 equiv.) was dissolved in anhydrous MeOH (10 mL) and AcOH (0.24 mL) was added. 4-(Aminomethyl)piperidine (111 μL, 0.92 mmol, 1 equiv.) was added and the reaction mixture stirred at room temperature for 2 h. Sodium cyanoborohydride (64 mg, 1.01 mmol, 1.1 equiv.) was added in two portions over two minutes and the reaction mixture stirred at room temperature for x hours.

TLC (5% MeOH in DCM) after x hours, UV then vanillin:
29th October 2012 @ 03:29
Reaction Scheme

PMY 2-5 (200 mg, 0.92 mmol, 1 equiv.) was dissolved in anhydrous MeOH (10 mL) and AcOH (0.24 mL) was added. 4-Aminopiperidine (97 μL, 0.92 mmol, 1 equiv.) was added and the reaction mixture stirred at room temperature for 2 h. Sodium cyanoborohydride (64 mg, 1.01 mmol, 1.1 equiv.) was added in two portions over two minutes and the reaction mixture stirred at room temperature for 40 hours, (N.B should be complete after 16 h or less, left for longer due to unforseen circumstances) TLC indicated two products (presumably products from reductive amination at both nitrogen atoms Methanol removed in vacuo and then the crude orange oil treated with 1M NaOH (10 mL). The mixture was then extracted with DCM (2 x 20 mL). The organic extracts were washed with brine then dried (MgSO4) and concentrated to give an orange oil.

TLC (5% MeOH in DCM) after 40 hours, UV then vanillin:
AEW 19-1 reaction mixture is second spot from the left
AEW 19 and 2_1, vanillin.png
AEW 19and20_1 UV.jpg


1H NMR Data:
AEW 19-1 col.zip
AEW 19-1 Col.pdf
aew19-1 crude.zip
AEW 19-1 crude.pdf
Attached Files
24th October 2012 @ 05:25
Conversion of carboxylic acid PMY 59-3 to the primary amide using EDC and ammonium hydroxide as for PMY 60-3.

PMY60-3.png

Reaction Start Time: 17.05 24/10/12
PMY 59-3 (102 mg, 0.34 mmol, 1 equiv.) was stirred in DCM (7 mL, 0.05M). Partial solution. EDC.HCl (85 mg, 0.44 mmol, 1.3 equiv.) and HOBt (approx 4 mg) was added. EDC.HCl dissolves quickly. After 10 mins, clear solution with some needles. After 20 minutes, 28% NH4OH (1 mL) was added and the reaction left to stir. After overnight stirring, saturated NH4Cl(aq) was added. The layers were separated and the aqueous layer extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated to a pale yellow solid (113 mg). 1H NMR shows multiple products, peaks close to SM and PMY 60-3; inconclusive. Purified by chromatography on silica (5% MeOH, 1% NH4OH/DCM) gave slightly yellow solid (84 mg). 1H NMR mainly consistent with PMY 60-3 and impurities. Further chromatography on silica (2-5% MeOH/DCM) gave an early running fraction and 2 other fractions, -A and -B, white solids.

TLC visualised with UV and vanillin
TLC crude MeOH/DCM
TLC column 2

10% MeOH/DCM

TLC crude MeOH/NH4OH/DCM

10% MeOH/1% NH4OH/DCM

NMR:
1H NMR crude
1H NMR column 1


See Also:
Hydrolysis of PMY 58-3 methyl ester (PMY 59-3)
Conversion of oxazole carboxylic acid to primary amide (PMY 60-3)
EDC Coupling of Pyrrole Carboxylic acid with Hydrazine Hydrate (AEW 14-2)
Conversion of PMY 59-2-B oxazole carboxylic acid to primary amide (PMY 60-2)
Synthesis of N-p-trifluoromethyl-phenyl analogue of TCMDC-123812 (PMY 25-1)

Risk and Hazard Assessment:
As for: Synthesis of N-Phenyl analogue of TCMDC-123812 (PMY 23-1)
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