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24th October 2012 @ 06:25
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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24th October 2012 @ 03:52
Product obtained in 64% yield.

===

Hydrolysis of PMY 58-2 methyl ester to the acid using aqueous sodium hydroxide.

PMY59-1.png

Reaction Start Time: 12.30 24/10/12
PMY 58-3 (240 mg, 0.76 mmol, 1 equiv.) was dissolved in hot methanol (15 mL). 5M NaOH(aq) (4 mL) was added and the reaction stirred at room temperature. After 2 hours, reaction not complete. 3 pellets of NaOH added and the mixture heated to reflux briefly then cooled. After 30 minutes, reaction complete. The mixture was acidified using 6M HCl and cooled in a salt/ice bath. Pale yellow needle crystals form. Filtered and washed with water then dried (146 mg, 64%).

TLC (5% MeOH/DCM) visualised with UV and vanillin:
TLC


NMR:
1H NMR


See also:
Cyclodehydration of carboxamide PMY 67-1 (PMY 58-3)
Hydrolysis of PMY 58-2 methyl ester (PMY 59-2)

Risk and Hazard Assessment:
As for Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (PMY 8-2)
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24th October 2012 @ 03:14
Reaction Scheme

Repeated as purification of AEW 11-1 was problematic, this time 1:1 aldehyde:amine used to prevent problems of separating excess piperidine

PMY 2-5 (100 mg, 0.46 mmol, 1 equiv.) was dissolved in anhydrous MeOH (4 mL) and AcOH (0.12 mL) was added. Piperidine (45 μL, 0.46 mmol, 1 equiv.) in anhydrous MeOH (1 mL) was added and the reaction mixture stirred at room temperature for 1h. Sodium cyanoborohydride (32 mg, 0.51 mmol, 1.1 equiv.) was added in two portions over two minutes and the reaction mixture stirred at room temperature for 16 hours. TLC indicated product, SM (AEW 2-1) and a spot above the SM. Reaction was stopped to prevent formation of further side products: Methanol removed in vacuo and then the crude orange oil treated with 1M NaOH (5 mL). The mixture was then extracted with DCM (2 x 10 mL). The organic extracts were washed with brine then dried (MgSO4) and concentrated to give an orange oil.

TLC (5% MeOH in DCM) after hours, UV then vanillin:
22nd October 2012 @ 04:42
AEW%2018-1.png

Reaction start time: 3.20pm
Powdered KOH (81 mg, 1.45 mmol, 4 equiv.) was added to DMSO (0.7 mL) and stirred for 5 min. AEW 5-2 (100 mg, 0.36 mmol, 1 equiv.) was added, followed immediately by methyl iodide (23 microlitre, 0.36 mmol, 1 equiv.). After 3.5 h, the reaction mixture was poured into water (7 mL), extracted with DCM (3x 7 mL), washed with brine, dried (MgSO4), filtered and evaporated to give a clear oil. Turned cloudy on addition of CDCl3, indicating presence of DMSO..confirmed by crude NMR

TLC: (10% EtOAc in DCM):
AEW 18-1.jpg


Hazard and Risk Assessment:
AEW 18-1 HIRAC.pdf


Reference:

http://dx.doi.org/10.1016/0040-4020(79)87035-0
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22nd October 2012 @ 01:13
AEW%2017-1.png

AEW 10-1 (200 mg, 0.86 mmol, 1 equiv.) was dissolved in toluene (1.6 mL) and then thionyl chloride (0.12 mL, 1.71, 2 equiv.) was added. The dark brown solution was stirred at room temperature for 4 hours. Volatiles were removed at the toxic buchi and the resulting black oil was dissolved in hexane (10 ml) under argon with sonication, taken up by syringe and filtered through syringe filter into a separate flask. Prior to evaporation I had to go to a PhD seminar and so the acid chloride remained in solution for 1.5 h Hexane was removed in vacuo to give a brown waxy solid (140 mg, ~0.56 mmol, ~64%). The waxy solid was dissolved in DCM (1.6 mL) and hydrazine hydrate (65 microlitres, 0.86 mmo, 1 equiv wrt acid sm) was added via syringe. The mixture effervesced and the yellow solution was left to stir o/n.

TLC plates after 16 h, UV then vanillin:

AEW 17-1 Vanillin.jpg
a


Hazard and Risk Assessment:
AEW 17-1.pdf
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