EDC Coupling of MNR55 with Ammonium Hydroxide to give MNR56-1
reaction on at 1120am 5/11/12
EDCI (0.056, 0.29 mmol) and HOBt (0.003 g, 0.02 mmol) were added to a solution of MNR55-1 (0.07 g, 0.24 mmol) in DCM (3 mL) and the mixture was stirred for 20 minutes. Ammonium hydroxide(28%, 0.1 mL) was added and the reaction mixture stirred at room temperature. After stirring for 4 hours the TLC still showed signs of starting material but it was decided to work the reaction up. It was quenched with sodium bicarbonate (10 mL) and extracted with DCM (3 x 10 mL), dried over MgSO4, filtered and concentrated to give a white solid (0.084 g)
TLC in 100% EtOAc
Column - 100% EtOAc
Frac 5-17 as a white solid - needs further drying before final NMRs
product poorly soluble in CHCl3 and MeOH
Quick NMR's before going on holiday -
Overnight NMR in MeOD - still very poorly soluble
After further drying - 0.040 g, 0.14 mmol, 57%
Hydrolysis of MJT6-1 to give MNR55-1
See - Synthesis on MJT6-1
NaOH (0.2 g, 4.98 mmol) was added to a solution of MJT6-1 (0.15 g, 0.50 mmol) in EtOH (2 mL) and water (1 mL) and then heated to reflux for 3 hours. The reaction was allowed to cool to room temperature and was then cooled in an ice bath and then acidified to pH 1 using conc. HCl. The mixture was then left to stand overnight at room temperature (time constraints). The white precipitate was then filtered and rinsed with water to give a crude off white solid (0.094 g). 1H NMR of this showed clean, product 0.094 g, 0.327 mmol, 66%.
The washings were concentrated to remove any EtOH in the solution but no further precipitate crashed out.
Reaction Start time 1040 25/10/2012
MJT6-1 (442 mg, 1.37 mmol, 1 equiv.) was stirred in 1,2-dichloroethane (20 mL) giving a colourless solution. XtalFluor-E (640 mg, 2.8 mmol, 2 equiv.) was added and the mixture heated to reflux at 90°C under a nitrogen atmosphere.
After 40 minutes TLC showed consumption of SM and formation of a new product of higher Rf than SM. The reaction is now a dark brown solution, it was allowed to cool to room temperature before adding a solution of Na2CO3 (1:1 saturated soln/water, approx 30 mL). The reaction was stirred for 10 minutes and then separated.
The aqueous layer was washed with DCM (3 x 20 mL) and the combined organic extracts washed with brine (approx 20 mL) before drying over anhydrous MgSO4 and concentration to give the intermediate ( 0.4655g, 1.53 mmol, 112% of theory yield) as a viscous dark brown oil.
TLC of worked up product again showed only one spot. NMR analysis is consistent with expected product but with solvent peak at 3.731 ppm (1,2-DCE) and at 7.26 ppm (DCM). ca 50 mg of intermediate is retained for characterisation.
Intermediate (0.4013 g, 1.32 mmol, 1 equiv.) is dissolved in DCM (15 mL) to give a brown solution. Bromotrichloromethane (0.39 mL, 3.96 mmol, 3 equiv.) and DBU (0.59 mL, 3.96 mmol, 3 equiv.) are added and the reaction stirred under a nitrogen atmosphere. After 45 minutes, TLC showed consumption of starting materials and formation of a product with a higher Rf value than SM as well as another product of much lower Rf. The reaction is left in the freezer overnight.
The reaction mixture is concentrated to a viscous dark brown oil (ca. 1.5 g, 375 % theory yield - excess caused by residual BrCCl3 and DBU). Column chromatography (acetone / hexane, 5%; 10%) is used to isolate MJT6-1 as a white solid (ca. 0.4 g, '101%'), NMR consistent with expected structure but with some contaminant signals. This columned product is left in the freezer over the weekend.
Both product and intermediate are novel compounds
TLC (10% MeOH / DCM) with UV visualisation followed by UV staining
Hazard assessment form
M. Pouliot, L. Angers, J. Hamel & J. Paquin, Synthesis of 2-oxazolines and related N-containing heterocycles using [Et2NSF2]BF4 as a cyclodehydration agent. Tetrahedron letters. 53 (2012), 4121-4123.
Cyclodehydration of carboxamide PMY 67-1 (PMY 58-3)
EDC Couplng of pyrazole carboxylic acid MJT 3-2 with serine methyl ester (MJT 5-1)
Hydrolisis of MNR49-1 to give MNR50-1
See - Synthesis on MNR49-1
reaction on at 11am 22/10/12
NaOH (10.6 g, 265 mmol) was added to a solution of MNR49-1 (6.6 g, XX mmol) in EtOH (90 mL) and water (45 mL) and then heated to reflux for 90 minutes. The reaction was allowed to cool to room temperature and was then cooled in an ice bath and then acidified to pH 1 using conc. HCl. The white precipitate was then filtered and rinsed with water to give a crude (wet) off white solid (9.9 g). The crude was then recrystallised in Et2O (250 ml) and left to stand overnight. The fine white crystals were filtered and washed with Et2O and dried under vacuum. The filtrate was also concentrated and dried under vacuum.
1st crop - 3.285 g 14.91 mmol, 56%
filtrate - 2.012 g, 9.14 mmol, 34% - almost as clean as the crystals
upon standing overnight, more precipitate had formed in the acidified aqueous layer. This was filtered, washed with water and dried under vacuum.
2nd filter - 0.711 g, 3.23 mmol, 12% - nmr was as clean as the recrystallised product.
Total mass recovered - 6.008 g, >26.6 mmol, 102%
No more purification was carried out at this time but the 3 samples were kept separate.
Reaction start time: 1510 22-10-2012
MJT 3-2 (1.257 g, 5.7 mmol, 1 equiv.) was stirred in DCM (40 mL), cloudy solution, kept under nitrogen atmosphere. EDCI (1.20 g, 6.3 mmol, 1.1 equiv.) and HOBt (0.085 g, 0.63 mmol, 0.11 equiv.) were added. DIPEA (2.2 mL, 12.6 mmol, 2.2 equiv.) was added, insoluble at first. Solution stirred for ten minutes and DIPEA dissolved. Serine methyl ester hydrochloride (0.977 g, 6.3 mmol, 1.1 equiv.) to give a colourless solution. Mixture stirred overnight at room temperature.
After 19 hours mixture is a colourless solution with some white solid stuck to sides of vessel. TLC shows some starting material (pyrazole carboxylic acid) remains and formation of a product slightly more polar than this starting material as well as multiple more polar products.
NH4Cl (20 mL) is added to the reaction mixture and then HCl (1M) is added until solution is pH 1. The organic layer was then extracted and washed with water (3 x 20 mL), Na2CO3 (20 mL), water (3 x 20 mL) and finally brine (20 mL) before being dried over MgSO4 and concentrated to a white foam (0.5492 g). TLC analysis shows no SM remains and that three products are present, least polar of highest intensity under UV. NMR analysis consistent with expected product but with minor impurities.
Crude product is purified by column chromatography (5%; 10% MeOH / DCM) to give MJT 5-1 as a white foam (0.44 g, 1.44 mmol, 25%). NMR analysis consistent with expected product.
ca. 50 mg is retained for characterisation.
This is a novel compound
TLC (10 % MeOH / DCM) visuallised with UV then vanillin stain
Hazard and risk assessment
EDC Coupling of Pyrrole Carboxylic acid with Hydrazine Hydrate (AEW 14-2)
Hydrolysis of Ethyl 1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylate (MJT 3-2)