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12th November 2012 @ 02:46
Mnr: mnr51-60

EDC Coupling of MNR55 with Ammonium Hydroxide to give MNR56-1

See - Synthesis of MNR55-1 - Synthesis of MNR54-1

Hazard Assessment

HIRAC MNR54.pdf

Procedure

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

SANY0019.JPG

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 -

mnr56-1_frac5-17_1H_MeOD.pdf
mnr56-1_frac5-17_19F_MeOD.pdf
mnr56-1_frac5-17.zip

Overnight NMR in MeOD - still very poorly soluble

mnr56-1_frac5-17_13C.pdf
mnr56-1_overnight.zip

 

After further drying - 0.040 g, 0.14 mmol, 57%

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5th November 2012 @ 04:50
Mnr: MNR51-60
Hydrolysis of MJT6-1 to give MNR55-1

See - Synthesis on MJT6-1

MNR55_scheme.png
MNR55-1_table.PNG

Hazard Assessment
MNR55-1.pdf

Procedure

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.

NMR
mnr55-1_filter1_1H.pdf
mnr55-1_filter1.zip


mnr55-1_filter1_19F.pdf
mnr55-1_conc_MeOH.zip


mnr55-1_DMSO_1H.pdf
mnr55-1_DMSO_13C.pdf
mnr55-1_dmso.zip
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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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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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