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24th October 2012 @ 05:07
Cyclodehydration of serine methyl ester coupled pyrazole core MJT5-1 using XtalFluor-E in 1,2-DCE and subsequent oxidation to oxazole using bromotrichloromethane and DBU.

3579.png

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.

1555 25-10-2012
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.

1400 26-10-2012
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

TLC cyclisation step
TLC oxidation step


Hazard assessment form
updated hirac


References

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)
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22nd October 2012 @ 01:45
Mnr: MNR49-50
Hydrolisis of MNR49-1 to give MNR50-1

See - Synthesis on MNR49-1

MNR50_scheme.png
MNR50-1_table.PNG

Hazard Assessment
HIRAC MNR50.pdf


Procedure

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.

NMR

1st crop
mnr50-1_recryst1_1H.pdf
mnr50-1_recryst1_13C.pdf
mnr50-1_recryst1.zip


Filtrate
mnr50-1_crude_1H.pdf
mnr50-1_crude.zip


2nd filter
mnr50-1_filt2_1H.pdf
mnr50-1_filt2.zip
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21st October 2012 @ 08:18
Coupling of the recrystallised pyrazole carboxylic acid MJT 3-2 with serine methyl ester using N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and hydroxybenzotriazole.

3589.png

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.

1030AM 23-10-12.
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.

12PM 24-10-12
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
before workup
TLC after workup


NMR
nmr data crude
crude material NMR pdf


Hazard and risk assessment
HIRAC MJT5-1.pdf


References

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)
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17th October 2012 @ 04:57
Mnr: MNR49-50
Synthesis of ethyl 1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylate (MNR49-1)

See also
MJT2-1 - (0.955 g, 3.85 mmol, 73%)
MJT2-2 - (2.27 g, 9.2 mmol, 58%}
Refs
US20060211603 - Example 109 - page 80

MNR49_scheme.png
MNR49-1_table.PNG

Hazard Assessment
HIRAC MNR49.pdf


Procedure

reaction on t 10am 18/10/12

Dimethylformamide dimethyl acetal (4.17 mL, 31.4 mmol) was added to ethyl acetoacetate (3.97 mL, 31.4 mmol) and the mixture was heated to reflux (110 °C). After 30 mins TLC showed complete consumption of ethyl acetoacetate. Due to NMR timming and breaking the salt the reaction was allowed to cool to room temperature and sat for a further 2 hours.

TLC after 30 mins, 25% EtOAc/Hex
mnr49-1-int_25%EtOAc_1hour.JPG


Breaking the HCl salt
While the above was refluxing, NaOH (20 mL, 2M) was added to 4-fluorophenylhydrazine hydrochloride (5.1 g, 31.4 mmol) and the mixture was heated to give a transparent orange solution. This was extracted with ethyl acetate (3 x 25 mL), the organics were combined and washed with brine (30 mL). The organic fraction was then dried over MgSO4, filtered and concentrated to give 4-fluorophenylhydrazine (3.84 g, 30.46 mmol) as an orange oil.

on at 1230 18/10/12

4-fluorophenylhydrazine (3.84 g, 30.46 mmol) was dissolved in ethanol (60 mL) and added dropwise to the enamine ketone, the reaction was then heated to reflux at 80 °C. After 4 hours TLC showed complete consumption of 4-fluorophenylhydrazine (reaction was completed sooner but I was out of the lab). The reaction was allowed to cool to room temperature then was concentrated under reduced pressure and stored in the fridge overnight.

TLC after 1 hour 25% EtOAc/Hex
mnr49-1_10%EtOAc_4hours.JPG

TLC after 4 hours 10% EtOAc/Hex
mnr49-1_10%EtOAc_4hours_nin.JPG


Crude NMR did not show product nor did TLC co-spotting with MJT2-1. The crude was then taken up in EtOAC (30 mL) and washed with saturated NaHCO3 (25 mL), the organic layer was separated and the aqueous layer was extracted with EtOAc (5 x 30 mL). TLC of this now showed product. The layers were combined, dried, filtered and concentrated to give the crude as a red oil (7.62 g)

Column - 10-30% EtOAc/Hex

Fracs 10-29 - 4.02 g
Fracs 20 only - 2.895 g

Total product recovered 6.915 g, 27.9 mmol, 89%

NMR

Starting materials
mnr49-1 ethyl acetoacetate 1H.pdf
ethyl_acetoacetate.zip
mnr49-1 Dimethylformamide dimethyl acetal.pdf
Dimethylformamide_dimethyl_acetal.zip

4-fluorophenylhydrazine
mnr49-1 4-flurophenl hydrazine 1H.pdf
4_fluorophenylhydrazine.zip


MNR49-1-Int
mnr49-1-Int 1H.pdf
mrr49-1_int_overlay_1H.pdf
mnr49-1_int.zip


MNR49-1
mnr49-1-frac20_conc_1H.pdf
mnr49-1-frac20_conc_13C.pdf
mnr49-1_frac20_conc.zip

mnr49-1_frac10-39_1H.pdf
mnr49-1_frac10-39.zip
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16th October 2012 @ 01:27
Synthesis des-methyl pyrazole analogue of TCMDC-123812. Repeat of PMY 66-1 but with 2-bromoacetamide as the limiting reagent.

PMY66-1.png

Reaction Start Time: 13.10 16/10/12
PMY 65-1 (99 mg, 0.48 mmol, 1.2 equiv.) was dissolved in DMF (1 mL) at room temperature. Potassium carbonate (133 mg, 0.96 mmol, 2.4 equiv.) was added followed by 2-Bromoacetamide (55 mg, 0.40 mmol, 1 equiv.).

See also:
Synthesis des-methyl pyrazole analogue of TCMDC-123812 (PMY 66-1)
Ester synthesis (AEW 5-3)
Hydrolysis of PMY 64-1 ethyl ester (PMY 65-1)

Risk and Hazard Assessment:
As for: Synthesis des-methyl pyrazole analogue of TCMDC-123812 (PMY 66-1)
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